Datasets:

turingmachine

/

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

like 0

ACCEPTED

Self-flushing electrostatic seperator

The invention relates to an electrostatic separator (1) for separating particles containing oil out of a gas stream, having an emission electrode (2) and a deposition electrode (3), wherein the emission electrode (2) has a front corona region (4) extending into the gas stream and a rear deposition region (5). An outlet opening (9) for separated oil running along the deposition electrode (3) is provided at the level of, or behind, the deposition region (5) of the emission electrode (2).

1. Electrostatic separator for separating particles containing oil out of a gas stream, having an emission electrode and a deposition electrode, wherein the emission electrode has a front corona region extending into the gas stream and a rear deposition region, characterized by an outlet opening (9) for separated oil running along the deposition electrode (3), wherein this outlet opening (9) is provided at the level of, or behind, the deposition region (5) of the emission electrode (2). 2. Electrostatic separator according to claim 1, characterized by an arrangement of the emission electrode (2) with an upward-pointing corona region (4), wherein provided above the emission electrode (2) is a chamber (7) for redirecting the gas stream, whose chamber walls adjoin the deposition electrode (3) such that oil located on the chamber walls flows downward along the deposition electrode (3) to the outlet opening (9). 3. Electrostatic separator according to claim 2, characterized in that a cyclone is provided above the emission electrode (2). 4. Electrostatic separator according to claim 1, characterized by an arrangement of the emission electrode (2) with a downward-pointing corona region (4), wherein a chamber (7) for redirecting the gas stream is provided above the emission electrode (2), and wherein the outlet opening (9) is arranged between the deposition electrode (3) and the chamber (7). 5. Electrostatic separator according to claim 4, characterized in that the chamber (7) contains a baffle (10).

The invention relates to an electrostatic separator according to the preamble of claim 1. Such electrostatic separators are known from the automotive field for separating oil from the gas stream of a crankcase ventilator in internal combustion engines. During operation of the electrostatic separator, deposits can occur on the deposition electrode, which impermissibly reduce the spacing between the deposition electrode and the emission electrode. Proposals are known for cleaning deposits on electrostatic separators by means of moving parts. The object of the invention is to improve an electrostatic separator of the generic type to the effect that it prevents the formation of deposits on the deposition electrode with the most economical and operationally reliable means possible. This object is attained by an electrostatic separator with the features of claim 1. In other words, the invention proposes to continuously flush the deposition electrode, specifically with the oil that has been separated from the gas stream or is yet to be removed from the electrostatic separator. The emission electrode is oriented with its corona region opposing the flow direction of the gas stream. Designated within the framework of the present proposal as the corona region and, respectively, the deposition region, are one region each of the electrostatic separator in the flow direction of the gas stream. Located in the corona region is the portion of the emission electrode forming the corona, which charges or ionizes the particles, and where only a small fraction of the particles are already accumulated on the deposition electrode. The majority of the charged particles are accumulated on the deposition electrode in the adjacent deposition region. Provided on the deposition electrode in this deposition region, or even further downstream in the direction of the gas stream, is an outlet opening through which the oil deposited on the deposition electrode can be drained. Due to the proposed embodiment of the electrostatic separator, moving parts, which under certain circumstances may be prone to vibration, can be dispensed with. In a first version, an inventive electrostatic separator can be provided with an upward-pointing corona region, hence be arranged within a downwardly-directed gas stream. In this case, the outlet opening for the oil is located correspondingly far down. The drainage of the oil at the deposition electrode is supported on the one hand by gravity and on the other hand by the gas stream. A reversal of direction of the air stream above the emission electrode effects a centrifugal-force-induced preliminary separation from the gas stream of the larger particles, in particular, which in this way arrive at the wall of the flow redirection chamber, whence they can flow down to the deposition electrode. Especially advantageously, such a chamber can be embodied as a cyclone so that this chamber can serve as a true coarse separator or preseparator, and further separate coarse separators can be dispensed with. As a result, the installation of the electrostatic separator alone can be sufficient to allow an adequate cleaning of the gas stream, so that the use of an electrostatic separator embodied in such a manner makes possible considerable savings both with regard to the assembly as well as with regard to the installation space required, and finally also with regard to the quantity of material required, as compared to the use of an electrostatic separator which serves solely as a fine separator and works together with a separate coarse separator additionally connected upstream. In a second version, with upward-flowing gas stream, the corona region of the emission electrode points downward in orientation. The gas stream must have a sufficiently high flow velocity for as large a quantity as possible of the oil deposited on the deposition electrode to be transported upward, where it can reach the outlet opening in order to return to the rest of the oil circulation through a separate outlet line. Here, too, a chamber for flow redirection of the gas stream is provided above the emission electrode, wherein the outlet opening for the separated oil is arranged between this chamber and the deposition electrode. In this chamber, a baffle can advantageously be provided, which causes the redirection of the gas stream, thus improving the degree of separation. Two exemplary embodiments of the invention are explained in detail below on the basis of the two purely diagrammatic drawings. In FIG. 1, an electrostatic separator as a whole is diagrammatically labeled 1, which separator has an emission electrode 2 and a deposition electrode 3. The emission electrode 2 has a corona region 4 embodied to be needle-like, and also has a deposition region 5 with a diameter that is much larger in comparison thereto. The gas stream is guided through the electrostatic separator 1 in that it first enters a chamber 7 through a gas inlet opening 6, wherein the gas inlet opening 6 is aligned such and the chamber 7 is designed such that a cyclone effect results and the coarser oil particles, in particular, are separated already in this chamber 7 onto the chamber walls thereof. From the chamber 7, the wall transitions into the deposition electrode 3, so that the oil which was separated within the chamber runs along the deposition electrode 3, wets it, and in this way prevents the formation of deposits on the deposition electrode 3. As the gas stream continues, it reaches the corona region 4, where the particles remaining in the gas stream are charged. In this way, the particles move to the deposition electrode 3, with this deposition collecting on the deposition electrode 3 especially in the section of the electrostatic separator 1 where the deposition region 5 of the emission electrode is located. The entire volume of separated oil arrives at a collecting trough 8 at the bottom of the deposition electrode 3, from which trough an outlet opening 9 feeds the oil back into the oil circulation. In FIG. 2, a second exemplary embodiment of the invention is shown in which essentially like components are labeled with the same reference numbers as in FIG. 1. In this second exemplary embodiment, however, the discharge electrode 2 is oriented downward, thus has a downward-pointing corona region 4, with the flow through this electrostatic separator 1 accordingly taking place from bottom to top. The oil particles located at the deposition electrode 3 are transported upward by the gas stream, yet without being entrained and entering the gas stream since they coagulate on the deposition electrode 3 and form correspondingly large particles or, respectively, an oil film on the deposition electrode 3. Arranged in the chamber 7 for redirection of the gas stream, which is provided above the emission electrode 2 in this exemplary embodiment as well, is a baffle 10, which effects the change in direction and is flow-optimized, despite being called a baffle, since the gas stream is not directed against the baffle 10 for the separation of oil particles, but rather the baffle 10 is intended to divert the gas stream and direct it against the walls of the chamber 7 so that an additional after purification of the gas stream takes place here if needed. The oil ascending along and being separated on the deposition electrode 3 arrives at a collecting trough 8, which is provided between the chamber 7 and the deposition electrode 3, wherein the oil is conveyed by this collecting trough 8 out of the electrostatic separator 1 through an outlet opening 9 and, for example, returned to the remaining oil circulation.

20060414

20090106

20070315

66064.0

B03C300

CHIESA, RICHARD L

SELF-FLUSHING ELECTROSTATIC SEPERATOR

UNDISCOUNTED

ACCEPTED

B03C

ACCEPTED

Antenna coil and antenna device

An antenna coil includes: a core (3) formed by shaping a magnetic material into a bar-like configuration; a bobbin (1) having a through-hole (12) into which the core (3) is to be inserted; a connection section (15) fixed to the bobbin (1) so as to extend in a length direction of the core (3) from the bobbin (1), with the core (3) inserted into the through-hole (12); a winding (14) which is wound around the bobbin (1) and whose ends are connected to the connection section (15); and a connector terminal (25) which is provided at a certain position in the length direction of the core (3), which fixes the connection section (15) in position, and which determines the position of the winding (14) in the length direction of the core (3).

1. An antenna coil comprising: a core formed by shaping a magnetic material into a bar-like configuration; a bobbin having a through-hole into which the core is to be inserted; a connection section fixed to the bobbin so as to extend in a length direction of core from the bobbin, with the core inserted into the through-hole; a winding which is wound around the bobbin and whose ends are connected to the connection section; and a connector terminal which is provided at a certain position in the length direction of the core, which fixes the connection section in position, and which determines a position of the winding in the length direction of the core. 2. An antenna coil according to claim 1, wherein: the connector terminal is provided on a connector main body having another through-hole into which the core is to be inserted. 3. An antenna coil according to claim 2, wherein: the connection section is formed of a rigid material; a second through-hole, is formed in the connector main body so as to extend along the other through-hole the connection section being inserted into the second through-hole. 4. An antenna coil according to claim 2, wherein: a capacitor is provided on the connector main body; and wherein the connector terminal is connected to the capacitor. 5. An antenna coil according to, claim 1, wherein: the connection section has two conductive rigid members; one end of the winding is connected to one rigid member of the connection section; another end of the winding is connected to another rigid member of the connection section; the connector terminal has two conductive joint portions; one joint portion of the connector terminal fixes in position the rigid member of the connection section to which the one end of the winding is connected; and another joint portion of the connector terminal fixes in position the rigid member of the connection section to which the another end of the winding is connected. 6. An antenna device comprising: an antenna coil according to claim 1; a holder having an accommodating portion formed by a holder main body and a side surface portion provided upright on the holder main body, with the accommodating portion accommodating the antenna coil; and a cover for hermetically sealing the accommodating portion. 7. An antenna device according to claim 6, wherein: the connector terminal of the antenna coil is provided on a connector main body having another through-hole into which the core is to be inserted; and the side surface portion and the connector main body of the antenna coil respectively have engagement portions engaged with each other and determining a position of the connector main body in a length direction of the core. 8. An antenna device according to claim 7, further comprising two cushion members having through-holes into which the core of the antenna coil is inserted and higher than a depth of the accommodating portion, wherein an engagement member provided on the cover is inserted into a through-hole formed in the holder main body, whereby the cover hermetically seals the accommodating portion.

TECHNICAL FIELD The present invention relates to an antenna coil and an antenna device to be used, for example, to transmit and receive a radio wave. BACKGROUND ART Japanese Utility Model Examined Publication No. Sho44-18178 (hereinafter referred to as Patent Document 1) discloses a ferrite antenna. This ferrite antenna has abar-shaped ferrite core, a coil bobbin into which the ferrite core is inserted, a main coil wound around the coil bobbin, and a small coil provided on each side of the main coil. In this ferrite antenna, the main coil is moved in a length direction of the ferrite core to cause a change in inductance, making it possible to perform tracking adjustment. However, in the conventional ferrite antenna, the electrical connection between the small coils and the main coil is effected by using windings forming these coils as they are. Thus, in a case in which the main coil is moved with a view to setting the reactance value of the ferrite antenna to a desired value, when the main coil is released, the main coil is pulled by the windings connecting the small coils and the main coil, resulting in positional deviation of the main coil. If the main coil is fixed in position by resin, a tape or the like while retaining it by hand, etc., the main coil is likely to be shifted during curing of the resin, or the adhesive force of the tape is likely to be reduced, resulting in positional deviation of the main coil. As a result, the completed product is likely to involve variation in reactance value. Further, in the case in which an attempt is made to fix the main coil at a desired position with resin, the next operation cannot be performed until the resin has been dried and cured, resulting in a rather long assembly time. To suppress such positional deviation of the main coil, it might be possible to increase the length of the windings connecting the small coils and the main coil, attaining a length providing some room with respect to the adjustment range of the main coil. However, when the length of the windings connecting the small coils and the main coil is increased, the wiring may be shaken due to vibration or the like applied to the ferrite antenna, and a fatal problem, such as a breaking of wire, is likely to occur. Further, due to the shaking of the windings connecting the small coils and the main coil, it is rather difficult to stabilize the reactance value. The present inventor has conducted careful study to solve the above problems before completing the present invention. An object of the present invention is to obtain an antenna coil and an antenna device which allow easy positional adjustment of the winding sand which is relatively free from positional deviation of the windings after the adjustment. DISCLOSURE OF THE INVENTION An antenna coil according to the present invention includes: a core formed by shaping a magnetic material into a bar-like configuration; a bobbin having a through-hole into which the core is to be inserted; a connection section fixed to the bobbin so as to extend in a length direction of the core from the bobbin, with the core inserted into the through-hole; a winding which is wound around the bobbin and whose ends are connected to the connection section; and a connector terminal which is provided at a certain position in the length direction of the core, which fixes the connection section in position, and which determines a position of the winding in the length direction of the core. With this construction, the winding is electrically connected to the connector terminal through the intermediation of the connection section. Therefore, it is possible to set the reactance value at a desired value by moving the winding together with the bobbin in the length direction of the core. In particular, even if the coil is released after being moved with the bobbin in the core length direction to be positioned at a desired position, the coil remains at that position together with the bobbin. Further, even when the coil is moved together with the bobbin in the core length direction, no force due to expansion and contraction of the winding, etc. is generated between the coil, which is moved with the bobbin, and the connector terminal. As a result, it is easy to adjust the position of the coil together with the bobbin such that a desired reactance value is obtained. Further, solely by fixing the connection section and the connector terminal to each other by soldering or the like after adjustment, it is possible to settle the winding at a position providing a desired reactance value. As a result, there is no fear of the winding position being deviated after adjustment, and it is possible to suppress variation in reactance value in the completed product. Further, since it is possible to fix a position of the winding by fixing the connection section in position by the connector terminal, it is possible, in contrast to the case in which the coil is sealed with an insulating resin or the like together with the bobbin, to begin the next operation without having to wait until the resin is dried (until the adhesive is cured). As a result, it is possible to shorten the assembly time. In addition to a construction of the invention as described above, in an antenna coil according to the present invention, the connector terminal is provided on a connector main body having another through-hole into which the core is to be inserted. By adopting this construction, it is also possible to move the connector main body in the core length direction. Therefore, the position of the connector terminal in the antenna coil can be easily changed without changing the basic structure of the antenna coil. As a result, even in a case where antenna coils of a plurality of specifications, for example, antenna coils having the same requisite reactance value and different connector terminal positions, are required, it is possible to provide antenna coils of such specifications by using a single kind of antenna coil. In addition to the constructions of the inventions as described above, in an antenna coil according to the present invention, the connection section is formed of a rigid material; a second through-hole is formed in the connector main body so as to extend along the other through-hole; and the connection section is inserted into the second through-hole. By adopting this construction, the connection section is formed of a rigid material, and both ends thereof are retained by the bobbin, the core, and the connector main body. Therefore, as compared with the case in which the bobbin and the connector are connected by a winding, vibration is less likely to occur even if vibration is applied to the antenna coil, so a fatal problem, such as an electrical breaking of wire, is not easily caused. Further, there is no fear of the connection section slacking between the bobbin and the connector. Therefore, in contrast to the conventional construction in which the wiring slacks between the winding and the connector, there is no fear of the reactance value fluctuating due to shaking of the slack wiring caused by vibration, etc. In addition to the constructions of the inventions as described above, in an antenna coil according to the present invention, a capacitor is provided on the connector main body; and the connector terminal is connected to the capacitor. By adopting this construction, a resonance circuit is formed by the coil and the capacitor in the antenna coil. In particular, the coil and the capacitor are integrated, so it is easy to adjust a characteristic, such as the resonance frequency of this resonance circuit, to a predetermined characteristic. Further, in contrast to the case in which the coil and the capacitor are provided separately, the resonance circuit is relatively free from the influence of the length of the wiring between the coil and the capacitor, so it is possible to suppress variation in characteristics of the resonance circuit. In addition to the constructions of the inventions as described above, in an antenna coil according to the present invention, the connection section has two conductive rigid members; one end of the winding is connected to one rigid member of the connection section; another end of the winding is connected to another rigid member of the connection section; the connector terminal has two conductive joint portions; one joint portion of the connector terminal fixes in position the rigid member of the connection section to which the one end of the winding is connected; and another joint portion of the connector terminal fixes in position the rigid member of the connection section to which the another end of the winding is connected. By adopting this construction, the winding can be connected to a radio circuit through the connector terminal, and there is no need to provide a lead or the like which leads from the winding and the bobbin to the exterior of the antenna coil and which is subject to a breaking of wire, and there is little possibility of a breaking of wire. An antenna device according to the present invention includes: an antenna coil according to the inventions described above; a holder having an accommodating portion formed by a holder main body and a side surface portion provided upright on the holder main body, with the accommodating portion accommodating the antenna coil; and a cover for hermetically sealing the accommodating portion. By adopting this construction, it is possible to cover the entire antenna coil with the holder and the cover. As a result, it is possible to maintain a stable electrical characteristic for a long period of time. In addition to the constructions of the inventions as described above, in an antenna device according to the present invention, the connector terminal of the antenna coil is provided on a connector main body having another through-hole into which the core is to be inserted; and the side surface portion and the connector main body of the antenna coil respectively have engagement portions engaged with each other and determining a position of the connector main body in a length direction of the core. By adopting this construction, the connector main body of the antenna coil is engaged with the side surface portion of the holder by these engagement portions. Therefore, it is possible to fix the connector main body of the antenna coil and the bobbin connected thereto through the connection section (and, by extension, the winding) at desired positions inside the accommodating portion. In addition to the constructions of the inventions as described above, an antenna device according to the present invention, further includes two cushion members having through-holes into which the core of the antenna coil is inserted and higher than a depth of the accommodating portion. In the antenna device, an engagement member provided on the cover is inserted into a through-hole formed in the holder main body, whereby the cover hermetically seals the accommodating portion. By adopting this construction, in the state in which the accommodating portion is hermetically sealed by the cover, the two cushion members are compressed between the cover and the holder main body. The core is held by the pressurizing force of the cushion members, so the core is fixed in position inside the accommodating portion. Therefore, it is possible to fix the connector main body, the bobbin, the winding, and the core in position inside the accommodating portion without having to use fixing members, such as screws, adhesive, or the like. As a result, it is possible to attain, through adjustment, a desired positional relationship between the core and the bobbin, and maintain the same. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an exploded perspective view of an antenna device according to an embodiment of the present invention. FIG. 2 is a perspective view for illustrating a first step of assembling the antenna device shown in FIG. 1. FIG. 3 is a perspective view for illustrating a second step of assembling the antenna device shown in FIG. 1. FIG. 4 is a side view for illustrating a third step of assembling the antenna device shown in FIG. 1. FIG. 5 is a diagram showing an example of a way the antenna device shown in FIG. 1 is used. BEST MODE FOR CARRYING OUT THE INVENTION In the following, an antenna coil and an antenna device according to an embodiment of the present invention will be described with reference to the drawings. In the following description, the antenna coil is regarded as constituting a part of the antenna device. Embodiment FIG. 1 is an exploded perspective view of an antenna device 10 according to an embodiment of the present invention. The antenna device 10 has a bobbin 1, a connector 2, a core 3, two cushion members 4 and 5, a holder 6, and a cover 7. The bobbin 1 has a bobbin main body 11. The bobbin main body 11 is formed of an insulating material such as plastic, and has a substantially rectangular parallelepiped-shaped outer configuration. Flanges are formed at the ends of a pair of opposing surfaces of the bobbin main body 11, and a winding is wound around the remaining four surfaces of the bobbin main body 11. Regarding the outer configuration of the bobbin main body 11, it may also be formed as a cube whose six surfaces are of the same size, or as a cylinder. In the following, in the attitude as shown in FIG. 1, the surface on the upper side as seen in the figure will be referred to as the upper surface 11a of the bobbin main body 11, the side surfaces with a larger lateral width as seen in the figure will be referred to as the longer side surfaces 11b of the bobbin main body 11, the side surfaces with a smaller lateral width as seen in the figure will be referred to as the shorter side surfaces 11c of, the bobbin main body 11, and the surface opposed to the upper surface 11a of the bobbin main body 11 will be referred to as the lower surface lid of the bobbin main body 11. The bobbin main body 11 has a through-hole 12 extending in the longitudinal direction of its rectangular parallelepiped configuration. As a result, openings are formed in the two shorter side surfaces 11c of the bobbin main body 11. The through-hole 12 has a rectangular sectional configuration. The sectional configuration of the through-hole 12 may also be square or circular. The sectional configuration of the through-hole 12 is preferably similar to the outer configuration of the bobbin main body 11. In this case, the bobbin main body 11 is formed in a substantially uniform, thin wall thickness. Further, the bobbin main body 11 has a recess 13 formed by the side surfaces and the flanges. The recess 13 is formed over the entire periphery formed by the upper surface 11a, the two longer side surfaces 11b , and the lower surface 11d of the bobbin main body 11. A winding 14 formed of a conductive material such as copper wire, is wound around the recess 13. As a result, a coil is formed. The bobbin main body 11 has flanges at both longitudinal ends thereof, so there is no fear in that the winding 14 may slip off the bobbin main body 11. Further, the bobbin main body 11 has flanges at both longitudinal ends thereof, so the winding of the winding 14 can be started from one of the those two ends, thus the operation of winding the winding 14 around the bobbin main body 11 can be made easier. Two long terminals 15 as connection sections are fixed to one longitudinal end of the bobbin main body 11. The long terminals 15 are formed as rigid members formed of a metal such as steel or aluminum, which is harder than the winding 14, and each of the long terminals 15 has a long terminal main body 15a and two protrusions 15b, 15c. The long terminal main body 15a is formed in a bar-like configuration. The two protrusions 15b, 15 care provided at positions nearer to one end of the long terminal main body 15a, and protrude in a direction perpendicular to the length direction of the long terminal main body 15a. One end of the long terminal main body 15a of each long terminal 15 is fixed to a portion on one of the surfaces 11c of the bobbin main body 11 near the surface 11a. The fixation of each long terminal 15 is effected by inserting one end of the long terminal main body 15a into a fit-engagement hole formed in the bobbin main body 11. The two long terminals 15 are fixed to the bobbin main body 11 such that their long terminal main bodies 15a are substantially parallel to each other and extend in the longitudinal direction of the through-hole 12 of the bobbin main body 11. Each end of the winding 14 is connected to the protrusions 15b of the two long terminals 15 nearer to the other ends (distal ends) by soldering or the like. The protrusion 15c nearer to one end (fixed end) of each long terminal 15 is bent, and each end of the winding 14 is held by the bent protrusions 15c. As a result, even if, due to vibration or the like, there is exerted to the winding 14 such a force as would move the winding 14 in the longitudinal direction of the bobbin main body 11, that force is not easily allowed to act on the connecting portions. The connector 2 has a connector main body 21. The connector main body 21 is formed of an insulating material such as an insulating plastic, and is formed in a substantially rectangular parallelepiped-shaped configuration. The outer configuration of the connector main body 21 may also be substantially cylindrical. In the following, in the attitude as shown in FIG. 1, the surface on the upper side as seen in the figure will be referred to as the upper surface 21a of the connector main body 21, a pair of opposing side surfaces as seen in the figure will be referred to as the first side surfaces 21b of the connector main body 21, another pair of opposing side surfaces will be referred to as the second side surfaces 21c of the connector main body 21, and the surface opposed to the upper surface 21a of the connector main body 21 will be referred to as the lower surface 21d of the connector main body 21. The connector main body 21 has a through-hole 22 formed therein as another through-hole. As a result, openings are formed in the two second side surfaces 21c of the connector main body 21. The through-hole 22 has a rectangular sectional configuration. The sectional configuration of the through-hole 22 may also be square or circular. It is desirable, however, for the through-hole 22 of the connector main body 21 to be of the same sectional configuration as the through-hole 12 of the bobbin main body 11. Each of the two first side surfaces 21b of the connector main body 21 has rib portions 23 as engagement portions. The rib portions 23 are formed at positions on the first side surfaces 21b near the lower surface 21d so as to be perpendicular to the lower surface 21d. That is, the portions of the first side surfaces 21b near the lower surface 21d are cut away, leaving the rib portions 23. The connector main body 21 has a second through-hole 24 parallel to the through-hole 22. As a result, the two second side surfaces 21c of the connector main body 21 has openings at positions nearer to the upper surface 21a than the through-hole 22. The connector 2 has two connector terminals 25. The connector terminals 25 are formed of a conductive material, and a part thereof protrudes from between the second through-hole 24 of one of the two second side surfaces 21c and the upper surface 2la. At the forward ends of the protrusions 25aof the connector terminals 25, there are formed bent portions 25b protruding in a direction perpendicular to the protruding direction. The bent portions 25b are further bent toward the lower side of the protrusions 25a. Gaps are formed between the bent portions 25b, which are bent, and the protrusions 25a. A capacitor 26 is arranged on the upper surface 21a of the connector main body 21. The capacitor 26 is soldered to one of the two connector terminals 25. A resonance circuit is formed by the capacitor 26 and the winding 14. The two surfaces 21b has grooves 27 formed to be perpendicular to the surfaces 21a, and terminals 28 are provided at the surface 21a side ends of the grooves 27. The terminals 28 are electrically connected to the resonance circuit formed by the capacitor 26 and the winding 14. Connected to the terminals 28 are an external radio circuit, wiring, etc. The core 3 is formed of a magnetic material such as nickel zinc ferrite or manganese zinc ferrite, and has a bar-like configuration. The core 3 has a rectangular section substantially of the same size as the through-hole 12 of the bobbin 1 and the through-hole 22 of the connector 2 or slightly smaller than the through-holes 12, 22. That is, the sectional configuration of the core 3 is such that the through-holes 12, 22 are slidable when the core 3 is inserted into the through-holes 12, 22. The sectional configuration of the core 3 may be square or circular. The holder 6 has a holder main body 31. The holder main body 31 is formed of an insulating material such as insulating plastic, and is formed as a flat plate longer than the core 3. A through-hole 32 is formed at either end of the holder main body 31. Provided upright on the holder main body 31 are two longer side surface portions 33 as side surface portions, and two shorter side surface portions 34 as side surface portions. The two longer side surface portions 33 and the two shorter side surface portions 34 form an oblong box with no lid together with the holder main body 31. In the following, this oblong box will be referred to as an accommodating portion 35. The inside of the accommodating portion 35 is longer than the core 3, and is formed in a width which is the same as or somewhat longer than the width of the shorter side surfaces 11c of the bobbin main body 11 and the second side surfaces 21c of the connector main body 21. In each of the two longer side surface portions 33, there is formed a cutout portion 36 as an engagement portion. Further, the two longer side surface portions 33 are provided upright at positions somewhat on the inner side of the outer peripheral edge of the holder main body 31. Between each of the longer side surface portion 33 and the outer peripheral edge of the holder main body 31, there are formed three through-holes 37. Further, cut out portions 38 are formed in the longer side surface portions 33, and the holder main body 31 has through-holes 39 (see FIG. 4) formed therein extending from the cutout portions 38 of the longer side surface portions 33. The cover 7 has a cover main body 41. The cover main body 41 is formed of an insulating material such as insulating plastic, and is formed as an elongated flat plate. The longer sides of the cover main body 41 have the same length as the longer side surface portions 33 of the holder 6, and the shorter sides of the cover main body 41 have the same length as the shorter side surface portions 34 of the holder 6. Further, the cover main body 41 has six engagement members 42 provided upright. The six engagement members 42 are arranged along the longer sides of the cover main body 41, three on each side. The cushion members 4, 5 have cushion main bodies 51. The cushion main bodies 51 are formed of a flexible rubber material, and are formed as vertically elongated cubes. The height of the cushion main bodies 51 is somewhat larger than the depth of the accommodating portion 35. Further, the cushion main bodies 51 have through-holes 52. The through-holes 52 of the cushion are formed to be of the same size as or slightly smaller than the contour of the core 3. Next, the assembly of the antenna device 10, constructed as described above, and the adjustment of the resonance frequency of the antenna device 10 will be described. FIG. 2 is a perspective view for illustrating a first assembly step for the antenna device 10 shown in FIG. 1. First, the core 3 is inserted into the through-hole 12 of the bobbin 1, to which the two long terminals 15 are fixed, and into the through-hole 22 of the connector 2. Further, the two long terminals 15 of the bobbin 1 are inserted into the gaps between the protrusions 25a and the bent portions 25b of the connector terminals 25, and into the second through-hole 24 of the connector 2. FIG. 3 is a perspective view for illustrating a second assembly step for the antenna device 10 shown in FIG. 1. After that, the end portions of the core 3, inserted into the bobbin and the connector 2, are respectively inserted into the through-holes 52 of the cushion members 4, 5. FIG. 4 is a side view for illustrating a third assembly step for the antenna device 10 shown in FIG. 1. The core 3, to which the bobbin 1, the connector 2, and the two cushion members 4, 5 are mounted, is inserted into the accommodating portion 35 of the holder 6. At this time, the two cushion members 4, 5 are arranged adjacent to the two shorter side surface portions 34. The two rib portions 23 of the connector 2 are respectively inserted into the cutout portions 36 of the holder 6. The grooves 27 of the connector 2 are arranged so as to be continuous with the cutout portions 38. As a result, the connector 2 is fixed in position inside the accommodating portion 35, and there is no fear in that the connector 2 may move even if the holder 6 is moved within the accommodating portion 35. In the assembly state of FIG. 4, the resonance frequency of the antenna device 1 is adjusted by moving the bobbin 1 in the length direction of the core 3. At this point in time, the bobbin 1 is not fixed in position but is slidable in the length direction of the core 3. To be more specific, an AC voltage of a predetermined resonance frequency is applied to the portion between the capacitor 26 and the other connector terminal 25 through the terminal 28, and the impedance is measured while varying the position of the bobbin 1, that is, the position of the winding 14, in the length direction of the core 3, then the bobbin 1, that is, the winding 14 is arranged at a position where the impedance is at an extreme value. As a result, the reactance value due to the winding 14 and the core 3 attains a desired value. After the positional adjustment of the bobbin 1 in the length direction of the core 3 has been completed, the long terminals 15 and the connector terminals 25 are fixed to each other in that state. In this process, for example, a force is applied to the two connector terminals 25 of the connector 2 from above (that is, from the side opposite to the core 3), and the bent portions 25b are brought into contact with the core 3 to press bond the long terminals 15 and the connector terminal 25 to each other. After that, the two long terminals 15 and the two connector terminals 25a are soldered to each other. As a result, synergistically with the fact that the bent portions 25b are engaged in the lower surfaces of the long terminals 15, the electrical connection between the long terminals 15 and the connector terminals 25 is made firm. It is also possible to apply an insulating adhesive to the periphery of the bobbin 1 and the connector 2 to make it hard for them to move. Finally, the cover 7 is put on the accommodating portion 35 of the holder 6. At this time, the six engagement members 42 of the cover 7 are respectively inserted into the thorough-holes 37 of the holder 6. The cover 7 is pushed in until the distal ends of the engagement members 42 hook into the holder 6, thereby sealing the interior of the accommodating portion 35 by the cover main body 41. In the state in which the accommodating portion 35 is sealed, the two cushion members 4, 5 are compressed to some degree by the cover main body 41, and the end portions of the core 3 are held by the pressurizing force of the cushion members 4, 5. As a result, it becomes hard for the core 3 to move within the accommodating portion 35, making it possible to maintain the previously adjusted positional relationship between the core 3 and the bobbin 1. FIG. 5 is a diagram showing an example of the way the antenna device 10 shown in FIG. 1 is used. As shown in FIG. 5, the antenna device 10 shown in FIG. 1 is fixed, for example, to the inner side of an automotive door 61 by means of rivets or screws passed through the two through-holes 32 of the holder 6. Apart from this, the antenna device 10 may also be arranged inside a bumper, a console, etc. of an automobile. The two terminals 28 of the connector 2 are connected to a keyless entry control device 63 or the like through wiring 62 called an automotive harness. When, for example, an AC signal is input from the keyless entry control device 63 to transmit power, a signal, etc., a radio wave based on that signal is transmitted from the antenna device 10. Further, when, for example, a radio wave from a keyless entry key (not shown) is received, the antenna device 10 outputs a signal based on that radio wave to the keyless entry control device 63. The keyless entry control device 63 has a radio circuit, and performs locking or unlocking based on the signal obtained through a radio wave. As described above, in this embodiment, the winding 14 is electrically connected to the connector terminals 25 through the long terminals 15. Thus, it is possible to set the reactance value at a desired value by moving the bobbin 1 and, by extension, the winding 14, in the length direction of the core 3. In particular, even if the bobbin 1 (and, by extension, the winding 14) is released after being moved by hand in the length direction of the core 3 and situated at a desired position, the bobbin 1 (and, by extension, the winding 14) remains at that position. Further, even if the bobbin 1 (and, by extension, the winding 14) is moved in the length direction of the core 3, no force due to expansion and contraction of the winding 14, etc. is generated between the bobbin 1 (and, by extension, the winding 14) and the connector terminals 25. As a result, the position of the bobbin 1 (and, by extension, the winding 14) can be easily adjusted so as to attain a desired reactance value. Further, solely by fixing the long terminals 15 and the connector terminals 25 to each other after the adjustment, it is possible to situate the winding 14 at a position where the desired reactance value can be obtained. As a result, the winding 14 undergoes no positional deviation after adjustment, making it possible to suppress variation in reactance value in the completed product. Further, it is only necessary to fix the long terminals 15 formed of metal and the connector terminals 25 to each other, so, in contrast to the case in which the winding 14 is sealed with an insulating resin or the like, it is possible to start the next operation without having to wait until the resin is dried (until the adhesive is cured). As a result, it is possible to shorten the assembly time. In this embodiment, the connector terminals 25 are arranged on the connector main body 21 having the through-hole 22 into which the core 3 is inserted, so the connector main body 21 can also be moved in the length direction of the core 3. Thus, the positions of the connector terminals 25 in the antenna device 10 can be easily changed without changing the basic construction of the antenna device 10. As a result, even in a case in which there is a need for antenna devices 10 of a plurality of specifications in which, for example, the requisite reactance value is the same and in which the positions of the connector terminals 25 vary, it is possible to meet the need with a single kind of antenna devices 10. In this embodiment, the long terminals 15 are rigid members, and second through-holes are formed in the connector main body 21 to extend along the through-hole 22, with the long terminals 15 being inserted into the second through-holes. Thus, the long terminals 15 are formed as elongated terminals using a material of a higher strength than the winding 14 for the coil, and their ends are retained by the bobbin 1, the core 3, and the connector main body 21. Thus, as compared with the case in which the connection between the bobbin 1 and the connector 2 is effected by the winding 14, the antenna 10 is less likely to vibrate even if vibration is applied thereto, so a fatal problem such as an electrical breaking of wire, is not easily caused. Further, the long terminals 15 do not slack between the bobbin 1 and the connector 2. Thus, in contrast to the conventional construction in which the wiring is slack between the winding 14 and the connector 2, there is no fear in that the reactance value may fluctuate due to shaking of the slack wiring caused by vibration or the like. In this embodiment, the capacitor 26 is arranged on the connector main body 21, and the connector terminals 25 are connected to the capacitor 26. That is, in the antenna device 10, a resonance circuit is formed by the winding 14 as the coil and the capacitor 26. In particular, the winding 14 as the coil and the capacitor 26 are integrated, so the characteristics of the resonance circuit such as the resonance frequency can be easily adjusted to predetermined characteristics. Further, the resonance circuit is not easily influenced by the length, etc. of the wiring between the winding 14 as the coil and the capacitor 26 as in the case in which the winding 14 as the coil and the capacitor 26 are provided separately, so it is possible to suppress variation in characteristics of the resonance circuit. In this embodiment, both ends of the winding 14 are connected to the two long terminals 15 formed of a rigid material, and the connector terminals 25 have two conductive joint portions, with one joint portion of the connector terminals 25 securing in position the long terminal 15 to which one end of the winding 14 is connected, and the other joint portion of the connector terminals 25 securing in position the long terminal 15 to which the other end of the winding 14 is connected. Thus, the winding 14 can be connected to a radio circuit through the connector terminals 25, and there is no need to provide a conductor or the like, which is subject to a breaking of wire, leading from the winding 14 and the bobbin 1 to the exterior of the antenna coil, and there is little possibility of a breaking of wire. In this embodiment, the antenna coil, which is formed by the core 3, the bobbin 1, and the connector 2, is entirely covered with the holder 6 and the cover 7. As a result, it is possible to maintain a stable electrical characteristic for a long period of time. In this embodiment, the cutout portions 36 are formed in the longer side surface portions 33, and the rib portions 23 are formed in the connector main body 21, with the rib portions 23 being engaged with the cutout portions 36, so it is possible to fix the connector main body 21 and the bobbin 1 connected thereto (and, by extension, the winding 14) at desired positions within the accommodating portion 35. In this embodiment, there are provided cushion members 4, 5 which have the through-holes 52 allowing insertion of the core 3 and which are higher than the depth of the accommodating portion 35, and the engagement members 42 provided on the cover 7 are inserted into the through-holes 37 formed in the holder main body 31, thereby sealing the accommodating portion 35. In the state in which the accommodating portion 35 is sealed by the cover 7, the two cushion members 4, 5 are compressed between the cover 7 and the holder main body 31. The core 3 is held by the pressurizing force of the cushion members 4, 5, so the core 3 is secured in position inside the accommodating portion 35. Thus, the connector main body 21, the bobbin 1, the winding 14, and the core 3 can be secured in position inside the accommodating portion 35 without using fastening members such as screws, or adhesive or the like. As a result, it is possible to adjust the core 3 and the bobbin 1 to a desired positional relationship and maintain the same. The preferred embodiment of the present invention described above should not be construed restrictively but allows various modifications and changes. In the above-described embodiment, the winding 14 wound around the bobbin 1 and the connector terminals 25 are connected together by the long terminals 15. It is also possible, for example, to form a protrusion on the bobbin 1, and form on this protrusion a wiring serving as a substitute for the long terminals 15. Apart from this, it is also possible to extend the forward end portion of the winding 14 and to embed the extended portion in the above-mentioned protrusion. Further, while in the above embodiment the capacitor 26 is provided on the connector 2, the capacitor 26 may be provided, if possible, on the circuit side of the keyless entry control device 63 or the like instead of being provided on the connector 2. Further, while in the above embodiment the connector 2 and the holder 6 are separate members, it is also possible to form them as an integral unit. INDUSTRIAL APPLICABILITY The antenna coil and the antenna device according to the present invention can be utilized, for example, as an antenna for transmission and/or reception in a keyless entry system of an automobile, or as an antenna for transmission and/or reception of some other type of radio wave.

<SOH> BACKGROUND ART <EOH>Japanese Utility Model Examined Publication No. Sho44-18178 (hereinafter referred to as Patent Document 1 ) discloses a ferrite antenna. This ferrite antenna has abar-shaped ferrite core, a coil bobbin into which the ferrite core is inserted, a main coil wound around the coil bobbin, and a small coil provided on each side of the main coil. In this ferrite antenna, the main coil is moved in a length direction of the ferrite core to cause a change in inductance, making it possible to perform tracking adjustment. However, in the conventional ferrite antenna, the electrical connection between the small coils and the main coil is effected by using windings forming these coils as they are. Thus, in a case in which the main coil is moved with a view to setting the reactance value of the ferrite antenna to a desired value, when the main coil is released, the main coil is pulled by the windings connecting the small coils and the main coil, resulting in positional deviation of the main coil. If the main coil is fixed in position by resin, a tape or the like while retaining it by hand, etc., the main coil is likely to be shifted during curing of the resin, or the adhesive force of the tape is likely to be reduced, resulting in positional deviation of the main coil. As a result, the completed product is likely to involve variation in reactance value. Further, in the case in which an attempt is made to fix the main coil at a desired position with resin, the next operation cannot be performed until the resin has been dried and cured, resulting in a rather long assembly time. To suppress such positional deviation of the main coil, it might be possible to increase the length of the windings connecting the small coils and the main coil, attaining a length providing some room with respect to the adjustment range of the main coil. However, when the length of the windings connecting the small coils and the main coil is increased, the wiring may be shaken due to vibration or the like applied to the ferrite antenna, and a fatal problem, such as a breaking of wire, is likely to occur. Further, due to the shaking of the windings connecting the small coils and the main coil, it is rather difficult to stabilize the reactance value. The present inventor has conducted careful study to solve the above problems before completing the present invention. An object of the present invention is to obtain an antenna coil and an antenna device which allow easy positional adjustment of the winding sand which is relatively free from positional deviation of the windings after the adjustment.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is an exploded perspective view of an antenna device according to an embodiment of the present invention. FIG. 2 is a perspective view for illustrating a first step of assembling the antenna device shown in FIG. 1 . FIG. 3 is a perspective view for illustrating a second step of assembling the antenna device shown in FIG. 1 . FIG. 4 is a side view for illustrating a third step of assembling the antenna device shown in FIG. 1 . FIG. 5 is a diagram showing an example of a way the antenna device shown in FIG. 1 is used. detailed-description description="Detailed Description" end="lead"?

20060515

20080923

20070405

99492.0

H01Q136

LE, HOANGANH T

ANTENNA COIL AND ANTENNA DEVICE

UNDISCOUNTED

ACCEPTED

H01Q

ACCEPTED

Method of forming luster coating film

The present invention provides: luster coating film forming method I comprising (1) applying an aqueous luster thermosetting base coating composition (A) to a substrate in two to five stages, in such a manner that the thickness of the base coating composition (A) applied in each of the second and subsequent stages becomes 0.3 to 5 μm when cured; (2) applying a thermosetting clear coating (B) over the uncured or heat-cured coating layer of the base coating composition (A); (3) applying an aqueous luster thermosetting base coating composition (C) over the uncured or heat-cured coating layer of the clear coating composition (B) in two to five stages; (4) applying a thermosetting clear coating composition (D) over the coating layer of uncured or heat-cured coating layer of the base coating composition (C); and (5) heating the four-layer coating comprising the base coating composition (A), clear coating composition (B), base coating composition (C) and clear coating composition (D) to obtain a cured four-layer coating film; and luster coating film forming method II comprising the above steps (1) to (5) and further including the step of applying and curing a thermosetting clear coating composition (E).

1. A method of forming a luster coating film, comprising the steps of: (1) applying an aqueous luster thermosetting base coating composition (A) to a substrate in two to five stages, in such a manner that the thickness of the base coating composition (A) applied in each of the second and subsequent stages becomes 0.3 to 5 μm when cured; (2) applying a thermosetting clear coating composition (B) over the uncured or heat-cured coating layer of the base coating composition (A); (3) applying an aqueous luster thermosetting base coating composition (C) to the uncured or heat-cured coating layer of the clear coating composition (B) in two to five stages; (4) applying a thermosetting clear coating composition (D) over the uncured or heat-cured coating layer of the base coating composition (C); and (5) heating the four-layer coating comprising the base coating composition (A), clear coating composition (B), base coating composition (C) and clear coating composition (D) to obtain a cured four-layer coating film. 2. The method according to claim 1, wherein the aqueous luster thermosetting base coating composition (A) comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. 3. The method according to claim 1, wherein, in step (1), the thickness of the aqueous luster thermosetting base coating composition (A) applied in the first stage is 0.3 to 9 μm when cured. 4. The method according to claim 1, wherein, in step (1), the solids content of the aqueous luster thermosetting base coating composition (A) one minute after the application in each stage is at least 40 wt. %. 5. The method according to claim 1, wherein the aqueous luster thermosetting base coating composition (C) comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. 6. The method according to claim 1, wherein, in step (3), the thickness of the aqueous luster thermosetting base coating composition (C) applied in each stage is 0.3 to 5 μm when cured. 7. The method according to claim 1, wherein, in step (3), the solids content of the aqueous luster thermosetting base coating composition (C) one minute after the application in each stage is at least 40 wt. %. 8. The method according to claim 1, wherein the substrate is an automotive body or a part thereof. 9. An automotive body or a part thereof having a luster coating film formed by the method according to claim 8. 10. A method of forming a luster coating film, comprising the steps of: (1) applying an aqueous luster thermosetting base coating composition (A) to a substrate in two to five stages, in such a manner that the thickness of the base coating composition (A) applied in each of the second and subsequent stages becomes 0.3 to 5 μm when cured; (2) applying a thermosetting clear coating (B) over the uncured or heat-cured coating layer of the base coating composition (A); (3) applying an aqueous luster thermosetting base coating composition (C) over the uncured or heat-cured coating layer of the clear coating composition (B) in two to five stages; (4) applying a thermosetting clear coating composition (D) over the uncured or heat-cured coating layer of the base coating composition (C); (5) applying a thermosetting clear coating composition (E) over the uncured or heat-cured coating layer of the clear coating composition (D); and (6) heating the five-layer coating comprising the base coating composition (A), clear coating composition (B), base coating composition (C), clear coating composition (D) and clear coating composition (E) to obtain a cured five-layer coating film. 11. The method according to claim 10, wherein the aqueous luster thermosetting base coating composition (A) comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. 12. The method according to claim 10, wherein, in step (1), the thickness of the aqueous luster thermosetting base coating composition (A) applied in the first stage is 0.3 to 9 μm when cured. 13. The method according to claim 10, wherein, in step (1), the solids content of the aqueous luster thermosetting base coating composition (A) one minute after the application in each stage is at least 40 wt. %. 14. The method according to claim 10, wherein the aqueous luster thermosetting base coating composition (C) comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. 15. The method according to claim 10, wherein, in step (3), the thickness of the aqueous luster thermosetting base coating composition (C) applied in each stage is 0.3 to 5 μm when cured. 16. The method according to claim 10, wherein, in step (3), the solids content of the aqueous luster thermosetting base coating composition (C) one minute after the application in each stage is at least 40 wt. %. 17. The method according to claim 10, wherein the substrate is an automotive body or a part thereof. 18. An automotive body or a part thereof having a luster coating film formed by the method according to claim 17.

FIELD OF THE INVENTION The present invention relates to a method of forming a luster coating film on a substrate. BACKGROUND OF THE INVENTION Luster coating films usually contain flaky luster pigments, such as aluminum flakes, mica flakes, etc., and have various color tones. Such luster coating films shine brilliantly as the luster pigments reflect incident light from outside the coating films, and exhibit a unique and variable aesthetic appearance achieved by the combination of the reflected light and the color tones of the coating films. In recent years, luster coating films, in particular those formed on automotive bodies or the like, are being required to exhibit high-quality appearance characteristics, such as a highly dense texture, high flip-flop property, etc. As used herein, dense texture means uniform, continuous luster created by a luster pigment in a coating film. A highly dense texture can be achieved when a coating film has little graininess caused by the luster pigment contained therein. Flip-flop property is produced by the orientation of the flaky luster pigment in a coating film, parallel to the coating film surface. A coating film with that property reflects light well and has high brightness in the highlight (i.e., when viewed from the front), but has low brightness in the shade (i.e., when viewed at an angle). That is, flip-flop property is a property that produces a difference in brightness depending on the angle of vision. Japanese Unexamined Patent Publication No. 2002-273333 discloses a method of forming a luster coating film, in which a luster base coating is formed on a substrate in two stages, followed by forming a clear coating, the thickness ratio of the base coating composition applied in the first stage to that applied in the second stage being 2/1 to 4/1. This method can prevent unevenness in the luster of luster coating films. However, especially when an aqueous luster base coating composition is used, the above method is likely to result in insufficient orientation of the flaky luster pigment used, and is not capable of forming a luster coating film with a highly dense texture and high flip-flop property. DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention An object of the present invention is to provide a method capable of forming on a substrate a luster multilayer coating film with a highly dense texture and high flip-flop property, using an aqueous luster base coating composition. Means for Solving the Problems The present inventors conducted extensive research to achieve the above object, and found that the object can be achieved by performing two cycles of the steps of applying an aqueous luster thermosetting base coating composition to a substrate in two to five stages and applying a thermosetting clear coating composition. The present invention was accomplished based on this new finding. The present invention provides the following luster coating film forming methods. 1. A method of forming a luster coating film, comprising the steps of: (1) applying an aqueous luster thermosetting base coating composition (A) to a substrate in two to five stages, in such a manner that the thickness of the base coating composition (A) applied in each of the second and subsequent stages becomes 0.3 to 5 μm when cured; (2) applying a thermosetting clear coating composition (B) over the uncured or heat-cured coating layer of the base coating composition (A); (3) applying an aqueous luster thermosetting base coating composition (C) to the uncured or heat-cured coating layer of the clear coating composition (B) in two to five stages; (4) applying a thermosetting clear coating composition (D) over the uncured or heat-cured coating layer of the base coating composition (C); and (5) heating the four-layer coating comprising the base coating composition (A), clear coating composition (B), base coating composition (C) and clear coating composition (D) to obtain a cured four-layer coating film. 2. The method according to item 1, wherein the aqueous luster thermosetting base coating composition (A) comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. 3. The method according to item 1, wherein, in step (1), the thickness of the aqueous luster thermosetting base coating composition (A) applied in the first stage is 0.3 to 9 μm when cured. 4. The method according to item 1, wherein, in step (1), the solids content of the aqueous luster thermosetting base coating composition (A) one minute after the application in each stage is at least 40 wt. %. 5. The method according to item 1, wherein the aqueous luster thermosetting base coating composition (C) comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. 6. The method according to item 1, wherein, in step (3), the thickness of the aqueous luster thermosetting base coating composition (C) applied in each stage is 0.3 to 5 μm when cured. 7. The method according to item 1, wherein, in step (3), the solids content of the aqueous luster thermosetting base coating composition (C) one minute after the application in each stage is at least 40 wt. %. 8. The method according to item 1, wherein the substrate is an automotive body or a part thereof. 9. An automotive body or part thereof having a luster coating film formed by the method according to item 8. 10. A method of forming a luster coating film, comprising the steps of: (1) applying an aqueous luster thermosetting base coating composition (A) to a substrate in two to five stages, in such a manner that the thickness of the base coating composition (A) applied in each of the second and subsequent stages becomes 0.3 to 5 μm when cured; (2) applying a thermosetting clear coating (B) over the uncured or heat-cured coating layer of the base coating composition (A); (3) applying an aqueous luster thermosetting base coating composition (C) over the uncured or heat-cured coating layer of the clear coating composition (B) in two to five stages; (4) applying a thermosetting clear coating composition (D) over the uncured or heat-cured coating layer of the base coating composition (C); (5) applying a thermosetting clear coating composition (E) over the uncured or heat-cured coating layer of the clear coating composition (D); and (6) heating the five-layer coating comprising the base coating composition (A), clear coating composition (B), base coating composition (C), clear coating composition (D) and clear coating composition (E) to obtain a cured five-layer coating film. 11. The method according to item 10, wherein the aqueous luster thermosetting base coating composition (A) comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. 12. The method according to item 10, wherein, in step (1), the thickness of the aqueous luster thermosetting base coating composition (A) applied in the first stage is 0.3 to 9 μm when cured. 13. The method according to item 10, wherein, in step (1), the solids content of the aqueous luster thermosetting base coating composition (A) one minute after the application in each stage is at least 40 wt. %. 14. The method according to item 10, wherein the aqueous luster thermosetting base coating composition (C) comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. 15. The method according to item 10, wherein, in step (3), the thickness of the aqueous luster thermosetting base coating composition (C) applied in each stage is 0.3 to 5 μm when cured. 16. The method according to item 10, wherein, in step (3), the solids content of the aqueous luster thermosetting base coating composition (C) one minute after the application in each stage is at least 40 wt. %. 17. The method according to item 10, wherein the substrate is an automotive body or a part thereof. 18. An automotive body or a part thereof having a luster coating film formed by the method according to item 17. The method of forming a luster coating film according to the present invention is described below in detail. Substrate Usable substrates include bodies of automobiles and motorcycles, parts thereof, etc. Usable substrates further include metal materials that form such bodies and the like, such as cold rolled steel sheets, galvanized steel sheets, zinc alloy-plated steel sheets, stainless steel sheets, tinned steel sheets and other steel sheets, aluminum sheets, aluminum alloy sheets, magnesium sheets, magnesium alloy sheets, etc.; plastic substrates; and the like. Also usable are such bodies, parts and metal materials whose metal surface has been subjected to a chemical conversion treatment, such as phosphate treatment, chromate treatment or the like. Further, such bodies, metal materials, etc., for use as substrates may be coated with an undercoat such as a cationic electrodeposition coating, or with such an undercoat and an intermediate coat, or with such an undercoat, an intermediate coat, and a colored base coat applied over the intermediate coat. Aqueous Luster Thermosetting Base Coating Compositions (A) and (C) In the method of the present invention, an aqueous luster thermosetting base coating composition (A) is applied to a substrate to form a first coating layer, and an aqueous luster thermosetting base coating composition (C) is applied over an uncured or cured coating layer of a clear coating composition (B) to form a third coating layer. The aqueous luster thermosetting base coating composition (A) preferably comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. The base coating composition (C) also preferably comprises a water-soluble or water-dispersible, crosslinkable functional group-containing resin, a crosslinking agent and a flaky luster pigment. The base coating composition (A) and/or base coating composition (B) may also be a coating compositions comprising a self-crosslinking resin, such as a blocked isocyanate-containing polyester resin, and a flaky luster pigment. The base coating compositions (A) and (C) may be the same or different. However, although the base coating (A) may have high or low ability of hiding the underlying surface, the base coating composition (C) needs to be sufficiently transparent to allow the underlying coating layer of the base coating composition (A) to be seen therethrough. Examples of water-soluble or water-dispersible, crosslinkable functional group-containing resins include acrylic resins, polyester resins and polyurethane resins, all having crosslinkable functional group(s) such as hydroxy group(s), carboxyl group(s), etc.; grafts of such resins; and the like. Among these, hydroxy-containing acrylic resins, hydroxy-containing polyester resins and the like are especially preferable. Such hydroxy-containing resins preferably have a hydroxy value of about 1 to about 200 mgKOH/g. Examples of water-soluble or water-dispersible, hydroxy-containing acrylic resins include hydroxy- and carboxy-containing acrylic copolymers obtained by copolymerizing a monomer mixture comprising a carboxyl-containing unsaturated monomer or like hydrophilic group-containing unsaturated monomer, a hydroxy-containing unsaturated monomer, and other unsaturated monomers. Such an acrylic copolymer preferably has a number average molecular weight of about 3,000 to about 100,000, and more preferably about 5,000 to about 50,000. The number average molecular weight as used herein is determined by converting the molecular weight measured by gel permeation chromatography, based on the molecular weight of polystyrene. Examples of carboxy-containing unsaturated monomers include (meth)acrylic acid, crotonic acid and other monocarboxylic acids; maleic acid, fumaric acid, itaconic acid and other dicarboxylic acids; half monoalkyl esters of dicarboxylic acids; etc. These may be used singly or in combination. Examples of hydroxy-containing unsaturated monomers include 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate and other hydroxyalkyl esters of acrylic acid and methacrylic acid, and the like. These may be used singly or in combination. Examples of other unsaturated monomers include methyl (meth)acrylate, ethyl (meth)acrylate, n-propyl (meth)acrylate, i-propyl (meth)acrylate, n-butyl (meth)acrylate, i-butyl (meth)acrylate, t-butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, cyclohexyl (meth)acrylate, lauryl (meth)acrylate, isobornyl (meth)acrylate and other C1-24 alkyl esters and cycloalkyl esters of acrylic acid and methacrylic acid; and glycidyl (meth)acrylate, acrylonitrile, acrylamide, dimethylaminoethyl methacrylate, styrene, vinyltoluene, vinyl acetate, vinyl chloride, 1,6-hexanediol diacrylate, etc. These may be used singly or in combination. Mixtures of such monomers can be copolymerized by known methods, such as emulsion polymerization, solution polymerization, etc. When the acrylic copolymer is an acrylic emulsion obtained by emulsion polymerization, the acrylic emulsion may be an emulsion of multilayer particles, obtained by multistage emulsion polymerization of a monomer mixture in the presence of water and an emulsifier. If necessary, the carboxy groups in the acrylic copolymer may be neutralized with a basic substance. Preferable examples of the basic substance are those soluble in water, such as ammonia, methylamine, ethylamine, propylamine, butylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, morpholine, methylethanolamine, dimethylethanolamine, diethanolamine, triethanolamine, diisopropanolamine, 2-amino-2-methylpropanol, etc. These may be used singly or in combination. Water-soluble or water-dispersible, hydroxy-containing polyester resins can be obtained by neutralizing the carboxy groups of an oil-free or oil-modified, hydroxy- and carboxy-containing polyester resin prepared by an esterification reaction using a polyhydric alcohol and polybasic acid, optionally together with a monobasic acid, oil component (or fatty acid), etc. Such a polyester resin preferably has a number average molecular weight of about 500 to about 50,000, and more preferably about 3,000 to about 30,000. Examples of polyhydric alcohols include ethylene glycol, diethylene glycol, propylene glycol, butanediol, pentanediol, hexanediol, 2,2-dimethylpropanediol, ethylene oxide adducts of bisphenol compounds, propylene oxide adducts of bisphenol compounds and other diols; glycerin, trimethylolpropane, pentaerythritol and other triols and higher polyols; and the like. These may be used singly or in combination. Examples of polybasic acids include phthalic acid, isophthalic acid, tetrahydrophthalic acid, hexahydrophthalic acid, maleic acid, succinic acid, adipic acid, sebacic acid and other dibasic acids, and anhydrides thereof; trimellitic acid, pyromellitic acid and other tribasic and higher polybasic acids, and anhydrides thereof; and the like. These may be used singly or in combination. Examples of monobasic acids include benzoic acid, t-butylbenzoic acid, etc. These may be used singly or in combination. Examples of oil components include castor oil, dehydrated castor oil, safflower oil, soybean oil, linseed oil, tall oil, coconut oil, fatty acids of such oils, etc. These may be used singly or in combination. Carboxy groups can be introduced into polyester resins by, for example, combined use of a dibasic acid and a tribasic or higher polybasic acid as a polybasic acid; addition of a dicarboxylic acid to hydroxy groups of a polyester resin by half esterification; or like methods. Hydroxy groups can be introduced into polyester resins by, for example, combined use of a diol and a triol or higher polyol as a polyhydric alcohol; or like methods. Carboxy groups of such a polyester resin can be neutralized with the above-mentioned basic substances. It is usually preferable to perform neutralization before adding the crosslinking agent and pigment. In order to improve the chipping resistance of the coating film to be obtained, the aqueous luster thermosetting base coating compositions may contain a water-soluble or water-dispersible polyurethane resin. The polyurethane resin can be prepared, for example, as follows. First, a urethane prepolymer is synthesized by polymerizing diisocyanate, polyether diol and/or polyester diol, a low-molecular-weight polyhydroxy compound and a dimethylolalkanoic acid, in such a proportion that the NCO/OH equivalent ratio is 1.1 to 1.9, by a single- or multi-stage process in the presence or absence of a hydrophilic organic solvent containing no active hydrogen groups in its molecule. The urethane prepolymer, after or while being neutralized with a tertiary amine, is mixed with water so as to effect emulsification dispersion in water simultaneously with chain extension. Then, if necessary, the organic solvent is distilled off to thereby obtain an aqueous dispersion of a polyurethane resin. Examples of hydrophilic organic solvents containing no active hydrogen groups in their molecule include acetone, methyl ethyl ketone, ethylene glycol monobutyl ether, etc. These may be used singly or in combination. Examples of usable isocyanates include aliphatic diisocyanates and alicyclic diisocyanates. Specific examples include hexamethylene diisocyanate, 2,2,4-trimethylhexane diisocyanate, lysine diisocyanate and other aliphatic diisocyanates; 1,4-cyclohexane diisocyanate, 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethylcyclohexane (isophorone diisocyanate), 4,4′-dicyclohexylmethane diisocyanate, isopropylidene dicyclohexyl-4,4′-diisocyanate and other alicyclic diisocyanates; modified products of such diisocyanates; etc. Examples of modified products of diisocyanates include carbodiimide-modified diisocyanates, uretdione-modified diisocyanates, uretimine-modified diisocyanates, etc. These may be used singly or in combination. It is preferable to use a polyether diol and/or polyester diol with a number average molecular weight of about 500 to about 5,000, and more preferably about 1,000 to about 3,000. Examples of such polyether diols and polyester diols include polyethylene glycol, polypropylene glycol, polyethylene-propylene block glycol, polyethylene-propylene random glycol, polytetramethylene ether glycol, polyhexamethylene ether glycol, polyhexamethylene ether glycol, polyoctamethylene ether glycol and other glycols; polyethylene adipate, polybutylene adipate, polyhexamethylene adipate, polyneopentyl adipate, poly-3-methylpentyl adipate, polyethylene/butylene adipate, polyneopentyl/hexyl adipate and other adipates; polycaprolactone diol, poly-3-methylvalerolactone diol, polycarbonate diol and other ester diols; etc. These may be used singly or in combination. The low-molecular-weight polyhydroxy compound preferably has a number average molecular weight less than 500. Specific examples include glycols and other dihydric alcohols, and low-mole alkylene oxide adducts thereof; glycerol, trimethylolethane, trimethylolpropane and other trihydric alcohols, and low-mole alkylene oxide adducts thereof; etc. These may be used singly or in combination. The proportion of the low-molecular-weight polyhydroxy compound to the polyether diol and/or polyester diol is preferably about 0.1 to about 20 wt. %, and more preferably about 0.5 to about 10 wt. %. Examples of dimethylolalkanoic acids include dimethylolacetic acid, dimethylolpropionic acid, dimethylolbutyric acid, etc. These may be used singly or in combination. The proportion of the dimethylolalkanoic acid to the polyether diol and/or polyester diol is preferably about 0.5 to about 5 wt. %, and more preferably about 1 to about 3 wt. %. Examples of tertiary amines usable for neutralization of the urethane prepolymer include trimethylamine, triethylamine, triisopropyl amine, tri-n-propylamine, tri-n-butylamine and other tertiary amines; N-methyl morpholine, N-ethyl morpholine and other morpholine amines; N-dimethylethanolamine, N-diethylethanolamine and other alkanolamines; etc. These may be used singly or in combination. Crosslinking agents that can be preferably used in the aqueous luster thermosetting base coating compositions include, for example, blocked polyisocyanates, amino resins, phenol-formaldehyde resins, etc. Such crosslinking agents may be water-soluble or hydrophobic. Melamine resins can be preferably used as amino resins. Preferable melamine resins include, for example, those obtained by etherifying methylol groups of methylolated melamines with C1-8 monohydric alcohols. When preparing such etherified melamine resins, all of the methylol groups of methylolated melamines may be etherified, or part thereof may be etherified, with methylol group(s) and/or imino group(s) remaining. Such melamine resins may be hydrophilic or hydrophobic. When using a hydrophobic melamine resin, it is preferable to mix the resin with an aqueous dispersant resin before use. Specific examples of etherified melamine resins include methyl etherified melamines, ethyl etherified melamines, butyl etherified melamines and other alkyl etherified melamines. Such etherified melamine resins can be used singly or in combination. The proportions of the water-soluble or water-dispersible, crosslinkable functional group-containing resin and the crosslinking agent are, based on solids, preferably about 50 to about 90 wt. % of the former and about 50 to about 10 wt. % of the latter, and more preferably about 60 to about 80 wt. % of the former and about 40 to about 20 wt. % of the latter, relative to the total weight of the resin and agent. Examples of flaky luster pigments usable in the aqueous luster thermosetting base coating compositions include aluminum flakes, metal oxide-covered alumina flakes, metal oxide-covered silica flakes, graphite pigments, metal oxide-covered mica, titanium flakes, stainless steel flakes, plate-like iron oxide pigments, metal-plated glass flakes, metal oxide-covered glass flakes, holographic pigments, etc. Such pigments can be used singly or in combination. The flaky luster pigment to be used preferably has a mean particle diameter of about 5 to about 50 μm, and more preferably about 5 to about 30 μm. The mean thickness of the flaky luster pigment is preferably about 0.01 to about 2 μm, and more preferably about 0.05 to about 1.5 μm. The ratio of the mean particle diameter to the mean thickness is preferably about 5 to about 500, and more preferably about 20 to about 300. The amount of the flaky luster pigment to be added is preferably about 1 to about 50 parts by weight, and more preferably about 5 to about 30 parts by weight, per 100 parts by weight of the total solids of the crosslinkable functional group-containing resin and crosslinking agent. The aqueous luster thermosetting base coating compositions may further contain, if necessary, a coloring pigment and/or dye. Examples of coloring pigments include titanium dioxide, carbon black, zinc white, molybdenum red, Prussian blue, cobalt blue, phthalocyanine pigments, azo pigments, quinacridone pigments, isoindoline pigments, threne pigments, perylene pigments, etc. These may be used singly or in combination. Examples of dyes include azo dyes, anthraquinone dyes, indigoid dyes, carbonium dyes, quinoneimine dyes, phthalocyanine dyes, etc. These may be used singly or in combination. When using a coloring pigment and/or dye, the amount thereof is preferably about 0.1 to about 50 parts by weight, and more preferably about 1 to about 30 parts by weight, per 100 parts by weight of the total solids of the crosslinkable functional group-containing resin and crosslinking agent. The aqueous luster thermosetting base coating compositions may further contain, if necessary, paint additives, such as organic solvents, curing catalysts, coating surface conditioners, pigment dispersants, rheology control agents, ultraviolet absorbers, light stabilizers, antioxidants, antifoaming agents, etc. The aqueous luster thermosetting base coating compositions can be prepared by mixing the components described. above. Pigments may be mixed with a dispersant resin or the like to form a paste before use. Water or a mixed solvent of water and an organic solvent is used as the medium. Known organic solvents can be used in the base coating compositions, including, for example, ester solvents, ketone solvents, ether solvents, alcohol solvents, etc. These may be used singly or in combination. It is especially preferable to use a hydrophilic organic solvent such that at least 50 parts by weight of the solvent is dissolved in 100 parts by weight of water at 20° C. The solids contents of the base coating compositions are not limited, and are preferably about 5 to about 40 wt. % at the time of application of the coating compositions, to achieve excellent film-forming properties. Thermosetting Clear Coating Compositions (B), (D) and (E) In the method of the present invention, a thermosetting clear coating composition (B) is applied over an uncured or cured coating layer of the base coating composition (A), a thermosetting clear coating composition (D) is applied over an uncured or cured coating layer of the base coating composition (C), and a thermosetting clear coating composition (E) is applied over an uncured or cured coating layer of the clear coating composition (D). The thermosetting clear coating compositions (B), (D) and (E) may be any of the known organic solvent-based or aqueous coating compositions, as long as they can form coating layers that are sufficiently transparent to allow the underlying luster coating layer of the coating compositions (A) and/or (C) to be seen therethrough. The clear coating compositions (B), (D) and (E) may be the same or different. Usable thermosetting clear coating compositions include those comprising a base resin, a crosslinking agent therefor, and an organic solvent and/or water as a medium, and further containing, if necessary, a coloring pigment, luster pigment, dye, ultraviolet absorber, light stabilizer, etc. Examples of base resins include acrylic resins, polyester resins, alkyd resins, fluorine resins, urethane resins, silicon-containing resins, etc., all containing crosslinkable functional group(s), among which crosslinkable functional group-containing acrylic resins are especially preferable. Such resins contain at least one crosslinkable functional group, such as a hydroxy group, carboxy group, silanol group, epoxy group and/or the like. Usable crosslinking agents are those capable of reacting with crosslinkable functional group(s) in the base resin. Specific examples include melamine resins, urea resins, polyisocyanate compounds, blocked polyisocyanate compounds, epoxy compounds, carboxy-containing compounds, acid anhydrides, alkoxysilane-containing compounds, etc. The proportions of the base resin and crosslinking agent are, based on solids, preferably about 50 to about 90 wt. % of the former and about 50 to about 10 wt. % of the latter, and more preferably about 65 to 80 wt. % of the former and about 45 to about 20 wt. % of the latter, relative to the total weight of the resin and agent. The thermosetting clear coating compositions may further contain, if necessary, paint additives such as curing catalysts, coating surface conditioners, rheology control agents, antioxidants, defoaming agents, waxes, etc. Steps for Forming Coating Film The coating film-forming method of the present invention encompasses two embodiments: method I in which the aqueous luster thermosetting base coating composition (A), thermosetting clear coating composition (B), aqueous luster thermosetting base coating composition (C) and thermosetting clear coating composition (D) are applied in this order to a substrate, the base coating compositions (A) and (C) being applied in two to five stages; and method II in which the thermosetting clear coating composition (E) is applied in addition to the above coating compositions (A) to (D). Specifically, method I comprises the steps of: (1) applying the aqueous luster thermosetting base coating composition (A) to a substrate in two to five stages, in such a manner that the thickness of the coating composition applied in each of the second and subsequent stages becomes 0.3 to 5 μm (when cured). (2) optionally heat-curing the base coating composition (A) and applying the thermosetting clear coating composition (B) over the uncured or heat-cured coating layer of the base coating composition (A); (3) optionally heat-curing the base coating composition (B) and applying the aqueous luster thermosetting base coating composition (C) over the uncured or heat-cured coating layer of the clear coating composition (B) in two to five stages; (4) optionally heat-curing the base coating composition (C) and applying the thermosetting clear coating composition (D) over the uncured or heat-cured coating layer of the base coating composition (C); and (5) heating the four-layer coating comprising the base coating composition (A), clear coating composition (B), base coating composition (C) and clear coating composition (D) to obtain a cured four-layer coating film. In step (1), the aqueous luster thermosetting base coating composition (A) is applied to a substrate in two to five stages. The base coating composition (A) is applied in two to five stages using a coater, such as a rotary electrostatic coater, air spray coater, airless spray coater or the like. After each coating stage, the applied composition may be allowed to stand for about 0.5 to about 3 minutes, or may be preheated at about 50 to about 80° C. for about 1 to about 10 minutes in order to promote evaporation of moisture. It is preferable to adjust, for application in each stage, the solids content of the base coating composition (A) to about 5 to about 40 wt. %, and more preferably about 5 to about 15 wt. %. In the final stage, it is especially preferable to adjust the solids content of the composition to about 5 to about 15 wt. %. The solids content of the base coating composition (A) one minute after the application in each stage is preferably at least about 40 wt. %, and more preferably about 50 to about 80 wt. %, so that the flaky luster pigment is easily orientated parallel to the coating surface. The solids content of the composition one minute after the application can be determined, for example, as follows. First, the base coating composition (A) is applied over a predetermined area of aluminum foil under the same conditions as above, recovered after 1 minute, immediately folded in the aluminum foil so that the moisture does not further evaporate, and immediately weighed. The aluminum foil is then opened, and the coating composition is cured under the same conditions as the heat-curing conditions for the multilayer coating, and weighed. The solids content of the applied composition is calculated from these weights and the weight of the aluminum foil measured beforehand. It is essential that the thickness of the base coating composition (A) applied in each of the second and subsequent stages be about 0.3 to about 5 μm (when cured), and preferably about 1 to about 4 μm (when cured). When the thickness is less than 0.3 μm, it may be difficult to form a continuous coating film, whereas when the thickness is more than 5 μm, the moisture may not sufficiently evaporate, making it difficult for the flaky luster pigment to be orientated parallel to the coating surface. To sufficiently hide the underlying surface, the base coating composition (A) is applied in the first stage to a thickness of preferably about 0.3 to about 9 μm (when cured), and more preferably about 1 to about 8 μm (when cured). The total thickness of the base coating composition (A) applied in all of the stages in step (1) is preferably about 4 to about 20 μm (when cured), and more preferably about 5 to about 15 μm (when cured). In step (2), without curing or after heat-curing the coating layer of the base coating composition (A) formed in step (1), the thermosetting clear coating composition (B) is applied over the coating layer of the base coating composition (A). When the coating layer of the coating composition (A) is heat-cured before applying the clear coating composition (B), it is usually suitable to heat the coating layer at about 60 to about 210° C., and preferably about 100 to about 180° C., for about 10 to about 60 minutes. The clear coating composition (B) is applied using a coater, such as a rotary electrostatic coater, air spray coater, airless spray coater or the like. The thickness of the coating layer of the clear coating composition (B) is preferably about 15 to about 55 μm (when cured), and more preferably about 25 to about 40 μm (when cured). In step (3), without curing or after heat-curing the coating layer of the clear coating composition (B) formed in step (2), the aqueous luster thermosetting base coating composition (C) is applied in two to five stages over the coating layer of the clear coating composition (B). When the coating layer of the coating composition (B) is heat-cured before applying the clear coating composition (C), it is usually suitable to heat the coating layer at about 60 to about 210° C., and preferably about 100 to about 180° C., for about 10 to about 60 minutes. Under such heating conditions, the coating layer of the coating composition (A), when uncured, is cured simultaneously with the coating layer of the coating composition (B). The base coating composition (C) is applied in two to five stages using a coater, such as a rotary electrostatic coater, air spray coater, airless spray coater or the like. After each coating stage, the applied composition may be allowed to stand for about 0.5 to about 3 minutes, or may be preheated at about 50 to about 80° C. for about 1 to about 10 minutes in order to promote evaporation of moisture. It is preferable to adjust, for application in each stage, the solids content of the base coating composition (C) to about 5 to about 40 wt. %, and more preferably about 5 to about 15 wt. %. In the final stage, it is especially preferable to adjust the solids content of the composition to about 5 to about 15 wt. %. The solids content of the base coating composition (C) one minute after the application in each stage is preferably at least about 40 wt. %, and more preferably about 50 to about 80 wt. %, so that the flaky luster pigment is easily orientated parallel to the coating surface. The solids content of the applied composition can be measured as described above. The thickness of the base coating composition (C) applied in each stage is preferably about 0.3 to about 5 μm (when cured), and more preferably about 1 to about 4 μm (when cured). When the thickness is less than 0.3 μm, it may be difficult to form a continuous coating film, whereas when the thickness is more than 5 μm, the moisture may not sufficiently evaporate, making it difficult for the flaky luster pigment to be orientated parallel to the coating surface. The total thickness of the base coating composition (C) applied in all of the stages in step (3) is preferably about 3 to about 15 μm (when cured), and more preferably about 5 to about 12 μm (when cured). In step (4), without curing or after heat-curing the coating layer of the base coating composition (C) formed in step (3), the thermosetting clear coating composition (D) is applied over the coating layer of the base coating composition (C). When the coating layer of the coating composition (C) is heat-cured before applying the clear coating composition (D), it is usually suitable to heat the coating layer at about 60 to about 210° C., and preferably about 100 to about 180° C., for about 10 to about 60 minutes. Under such heating conditions, the coating layers of the coating compositions (A) and (B), when uncured, are cured simultaneously with the coating layer of the coating composition (C). The clear coating composition (D) is applied using a coater, such as a rotary electrostatic coater, air spray coater, airless spray coater or the like. The thickness of the coating layer of the clear coating composition (D) is preferably about 15 to about 50 μm (when cured), and more preferably about 25 to about 40 μm. In step (5), the four-layer coating comprising the base coating composition (A), clear coating composition (B), base coating composition (C) and clear coating composition (D) is heated to obtain a cured four-layer coating film. It is usually suitable to perform heat curing at about 60 to about 210° C., and preferably about 100 to about 180° C., for about 10 to about 60 minutes. Under such heating conditions, the coating layer of the coating composition (C), the two coating layers of the coating compositions (C) and (B), or the three coating layers of the coating compositions (C), (B) and (A), when uncured, are cured simultaneously with the coating layer of the coating composition (D). Preferably, in method I, the clear coating composition (B) is applied over an uncured coating layer of the base coating composition (A); the coating layers of the base coating composition (A) and clear coating composition (B) are simultaneously heat-cured; the base coating composition (C) is applied over the cured coating layer of the clear coating composition (B); the clear coating composition (D) is applied over the uncured coating layer of the base coating composition (C); and the uncured coating layers of the base coating composition (C) and clear coating composition (D) are simultaneously heat-cured. In this case, method I is a four-coat two-bake method. Method II for forming a luster coating film specifically comprises: (1) applying the aqueous luster thermosetting base coating composition (A) to a substrate in two to five stages, in such a manner that the thickness of the base coating composition (A) applied in each of the second and subsequent stages becomes 0.3 to 5 μm (when cured); (2) optionally heat-curing the base coating composition (A) and applying the thermosetting clear coating composition (B) over the uncured or heat-cured coating layer of the base coating composition (A); (3) optionally heat-curing the clear coating composition (B) and applying an aqueous luster thermosetting base coating composition (C) over the uncured or heat-cured coating layer of the clear coating composition (B) in two to five stages; (4) optionally heat-curing the base coating composition (C) and applying a thermosetting clear coating composition (D) over the uncured or heat-cured coating layer of the base coating composition (C); (5) optionally heat-curing the clear coating composition (D) and applying a thermosetting clear coating composition (E) over the uncured or heat-cured coating layer of the clear coating composition (D); and (6) heating the five-layer coating comprising the base coating composition (A), clear coating composition (B), base coating composition (C), clear coating composition (D) and clear coating composition (E) to obtain a cured five-layer coating film. Steps (1) to (4) are the same as those of method I. In step (5), without curing or after heat-curing the coating layer of the clear coating composition (D) formed in step (4), the thermosetting clear coating composition (E) is applied over the coating layer of the clear coating composition (D). When the uncured coating layer of the coating composition (D) is heat-cured before applying the clear coating composition (E), it is usually suitable to heat the coating layer at about 60 to about 210° C., and preferably about 100 to about 180° C., for about 10 to about 60 minutes. Under such heating conditions, the coating layer of the coating composition (C), the two coating layers of the coating compositions (C) and (B), or the three coating layers of the coating compositions (C), (B) and (A), when uncured, are cured simultaneously with the coating layer of the coating composition (D). The clear coating composition (E) is applied using a coater, such as a rotary electrostatic coater, air spray coater, airless spray coater or the like. The thickness of the coating layer of the clear coating composition (E) is preferably about 15 to about 55 μm (when cured), and more preferably about 25 to about 40 μm. In step (6), the five-layer coating comprising the base coating composition (A), clear coating composition (B), base coating composition (C), clear coating composition (D) and clear coating composition (E) is heated to obtain a cured five-layer coating film. It is usually suitable to perform heat curing at about 60 to about 210° C., and preferably about 100 to about 180° C., for about 10 to about 60 minutes. Under such heating conditions, the coating layer of the coating composition (D), the two layers. of the coating compositions (D) and (C), the three coating layers of the coating compositions (D), (C) and (B), or the four coating layers of the coating compositions (D), (C), (B) and (A), when uncured, are cured simultaneously with the coating layer of the coating composition (E). Preferably, in method II, the clear coating composition (B) is applied over an uncured coating layer of the base coating composition (A); the coating layers of the base coating composition (A) and clear coating composition (B) are simultaneously heat-cured; the base coating composition (C) is applied over the cured coating layer of the clear coating composition (B); the clear coating composition (D) is applied over the uncured coating layer of the base coating composition (C); the clear coating composition (E) is applied over the uncured coating layer of the clear coating composition (D); and the uncured coating layers of the base coating composition (C), clear coating composition (D) and clear coating composition (E) are simultaneously heat-cured. In this case, method II is a five-coat two-bake method. Also preferably, in method II, the clear coating composition (B) is applied over an uncured coating layer of the base coating composition (A); the uncured coating layers of the base coating composition (A) and clear coating composition (B) are simultaneously heat-cured; the base coating composition (C) is applied over the cured coating layer of the clear coating composition (B); the clear coating composition (D) is applied over the uncured coating layer of the base coating composition (C); the uncured coating layers of the base coating composition (C) and clear coating composition (D) are simultaneously heat-cured; the clear coating composition (E) is applied over the cured coating layer of the clear coating composition (D); and heat-curing the uncured coating layer of the clear coating composition (E). In this case, method II is a five-coat three-bake method. A desired luster multilayer coating film is thus formed on a substrate. Effects of the Invention The method of the present invention has a remarkable effect of making it possible to form a luster multilayer coating film with a highly dense texture and high flip-flop property on a substrate such as an automotive body or the like, using an aqueous luster base coating composition. Such an effect is achieved presumably because four to ten uncured thin coats, in which a flaky luster pigment is uniformly orientated parallel to the surfaces of the coats, are superimposed by applying the aqueous luster thermosetting base coating composition (A) in two to five stages to form thin coats, and after applying the clear coating composition (B), further applying the luster thermosetting base coating composition (C) in two to five stages to form thin coats. BEST MODE OF CARRYING OUT THE INVENTION The following Production Examples, Examples and Comparative Examples are provided to illustrate the present invention in further detail. In these examples, parts and percentages are by weight. PRODUCTION OF ACRYLIC RESIN EMULSION Production Example 1 One hundred and forty parts of deionized water, 2.5 parts of a 30% aqueous solution of a surfactant (tradename “Newcol 707SF”, product of Nippon Nyukazai Co., Ltd.) and 1 part of the monomer mixture (1) shown below were placed in a reactor and mixed by stirring under a nitrogen stream, followed by the addition of 3 parts of 3% ammonium persulfate at 60° C. The resulting mixture was then heated to 80° C., and a monomer emulsion consisting of 79 parts of monomer mixture (1), 2.5 parts of a 30% aqueous solution of a surfactant (tradename “Newcol 707SF”, product of Nippon Nyukazai Co., Ltd.), 4 parts of 3% ammonium persulfate and 42 parts of deionized water was added to the reactor over 4 hours using a metering pump. After addition, the resulting mixture was aged for 1 hour. Further, 20.5 parts of the monomer mixture (2) shown below and 4 parts of a 3% aqueous solution of ammonium persulfate were added concurrently and dropwise to the reactor over 1.5 hours. After addition, the resulting mixture was aged for 1 hour, diluted with 30 parts of deionized water and filtered through 200-mesh nylon cloth at 30° C. Deionized water was further added to the filtrate, and the pH was adjusted to 7.5 with dimethylaminoethanolamine to thereby obtain an acrylic resin emulsion with a mean particle size of 0.1 μm and a solids content of 20%. The acrylic resin had a hydroxy value of 15 mgKOH/g. Monomer mixture (1): a mixture of 55 parts of methyl methacrylate, 8 parts of styrene, 9 parts of n-butyl acrylate, 5 parts of 2-hydroxyethyl acrylate, 2 parts of 1,6-hexanediol diacrylate and 1 part of methacrylic acid. Monomer mixture (2): a mixture of 5 parts of methyl methacrylate, 7 parts of n-butyl acrylate, 5 parts of 2-ethylhexyl acrylate, 3 parts of methacrylic acid and 0.5 parts of a 30% aqueous solution of a surfactant (tradename “Newcol 707SF”, product of Nippon Nyukazai Co., Ltd.). PRODUCTION OF POLYURETHANE RESIN EMULSION Production Example 2 In a polymerization reactor, 115.5 parts of polybutylene adipate with a number average molecular weight of 2,000, 115.5 parts of polycaprolactone diol with a number average molecular weight of 2,000, 23.2 parts of dimethylolpropionic acid, 6.5 parts of 1,4-butanediol and 120.1 parts of 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethylcyclohexane were placed and reacted while stirring in a nitrogen gas atmosphere at 85° C. for 7 hours to obtain an NCO-terminated prepolymer with an NCO content of 4.0%. The prepolymer was then cooled to 50° C., and 165 parts of acetone was added to form a homogeneous solution. While stirring, 15.7 parts of triethylamine was added, and 600 parts of ion exchange water was added while maintaining the temperature of 50° C. or lower. After maintaining the temperature at 50° C. for 2 hours to complete the water extension reaction, the acetone was distilled off under reduced pressure at 70° C. to obtain a polyurethane resin emulsion with a solids content of 42%. PREPARATION OF CROSSLINKING AGENT Production Example 3 (1) Sixty parts of ethylene glycol monobutyl ether and 15 parts of isobutyl alcohol were placed in a reactor, and heated to 115° C. under a nitrogen stream. When the mixture had been heated to 115° C., a mixture of 26 parts of n-butyl acrylate, 47 parts of methyl methacrylate, 10 parts of styrene, 10 parts of 2-hydroxyethyl methacrylate, 6 parts of acrylic acid and 1 part of azoisobutyronitrile was added over 3 hours. After completion of addition, aging was performed at 115° C. for 30 minutes, and a mixture of 1 part of 2,2′-azobisisobutyronitril and 115 parts of ethylene glycol monobutyl ether was added over 1 hour. After aging for 30 minutes, the resulting mixture was filtered through 200-mesh nylon cloth at 50° C. The obtained reaction product had an acid value of 48 mgKOH/g, a viscosity of Z4 (Gardner bubble viscometer) and a nonvolatile content of 55%. The reaction product was neutralized with an equivalent amount of dimethylaminoethanol, followed by the addition of deionized water, to obtain a 50% aqueous solution of an acrylic resin. (2) In a stirring container, 41.7 parts of butyl etherified melamine resin (tradename “U-Van 28SE”, product of Mitsui Chemicals, Inc., nonvolatile content: 60%) was placed as a hydrophobic melamine resin, and 20 parts of the aqueous acrylic resin solution obtained in (1) above was added. Eighty parts of deionized water was gradually added while stirring with an agitating blade mixer at an rpm of 1,000 to 1,500. Stirring was continued for another 30 minutes to thereby obtain an aqueous dispersion of a crosslinking agent with a solids content of about 20% and a mean particle diameter of 0.11 μm. PRODUCTION OF AQUEOUS LUSTER THERMOSETTING BASE COATING COMPOSITION (A) Production Example 4 Three hundred and twenty five parts of the acrylic resin emulsion with a solids content of 20% obtained in Production Example 1, 35.7 parts of the polyurethane resin emulsion with a solids content of 42% obtained in Production Example 2, and 100 parts of the crosslinking agent dispersion with a solids content of 20% obtained in Production Example 3 were mixed. Twenty-six parts of paste-form aluminum flake pigment (tradename “Alpaste MH-6601”; product of Asahi Chemical Industry Co., Ltd.; a paste with a pigment content of 65%, comprising aluminum flakes with a mean particle diameter of 14.5 μm, a mean thickness of 0.21 μm and a mean particle diameter/mean thickness ratio of 70, the aluminum flakes being dispersed in a petroleum solvent) was further added, followed by mixing. The resulting mixture was adjusted to a solids content of 15% with deionized water to obtain aqueous luster base coating composition (A-1). PRODUCTION OF THERMOSETTING CLEAR COATING COMPOSITION (B) Production Example 5 (1) A monomer mixture of 20 parts of acrylic acid, 20 parts of styrene, 40 parts of n-butyl acrylate and 20 parts of 4-hydroxy n-butyl acrylate was copolymerized in a standard manner to obtain a carboxy- and hydroxy-containing acrylic resin with a number average molecular weight of 3,500, acid value of 86 mgKOH/g and hydroxy value of 78 mgKOH/g. (2) A monomer mixture of 30 parts of glycidyl methacrylate, 20 parts of 4-hydroxy n-butyl acrylate, 40 parts of n-butyl acrylate and 20 parts of styrene was copolymerized in a standard manner to obtain an epoxy- and hydroxy-containing acrylic resin with a number average molecular weight of 3,000, epoxy content of 2.1 mmol/g and hydroxyl value of 78 mgKOH/g. (3) A mixture of 50 parts of the carboxy- and hydroxy-containing acrylic resin obtained (1) above, 50 parts of the epoxy- and hydroxy-containing acrylic resin obtained in (2) above, 1 part of an ultraviolet absorber (tradename “Tinuvin 900”, product of Ciba-Geigy), 1 part of tetrabutylammonium bromide and 0.1 part of a surface conditioner (tradename “BYK-300”, product of BYK-Chemie) was diluted with an aromatic hydrocarbon solvent (tradename “Swasol #1000”, product of Cosmo Oil Co., Ltd.) to adjust the viscosity to 20 seconds (Ford cup #4, 20° C.) and thereby obtain thermosetting clear coating composition (B-1). PRODUCTION OF SUBSTRATE Production Example 6 A cationic electrodeposition coating composition (tradename “Elecron 9400HB”, product of Kansai Paint Co., Ltd.) was applied by electrodeposition to a degreased and zinc phosphate-treated steel sheet to a thickness of 25 μm (when cured), and heat-cured at 170° C. for 20 minutes. A polyester resin-based intermediate coating composition (tradename “Amilac Intermediate Coat, Gray”, product of Kansai Paint Co., Ltd.) was applied by air spraying to the cured electrodeposition coating to a thickness of 35 μm (when cured), heat-cured at 140° C. for 20 minutes to obtain a substrate having an electrodeposition coating and intermediate coating. EXAMPLE 1 Aqueous luster base coating composition (A-1) obtained in Production Example 4 was applied in two stages to the substrate obtained in Production Example 6, using a Metabell rotary electrostatic coater at 30,000 rpm, shaping pressure of 1.7 kg/cm2, gun distance of 30 cm, booth temperature of 20° C. and booth humidity of 75%, in such a manner that the thickness of the coating composition applied in each stage became about 3.5 μm (when cured) and the total thickness of the coating composition applied in the two stages became 7 μm (when cured). The applied coating composition was allowed to stand for 1 minute between the stages. The solids content of the applied composition one minute after the application in each stage was 50%. After the two stages of application, the applied composition was allowed to stand for 3 minutes and preheated at 80° C. for 10 minutes. Clear coating composition (B-1) was applied over the uncured coating layer of base coating composition (A-1) to a thickness of 30 μm (when cured), using a Minibell rotary electrostatic coater at 30,000 rpm, shaping pressure of 1.5 kg/cm2, gun distance of 30 cm, booth temperature of 20° C. and booth humidity of 75%, allowed to stand for 7 minutes, and heated at 140° C. for 30 minutes to simultaneously cure the two uncured coating layers of base coating composition (A-1) and clear coating composition (B-1). Aqueous luster base coating composition (A-1) was applied in two stages over the cured coating layer of clear coating composition (B-1) using a Metabell rotary electrostatic coater at 30,000 rpm, shaping pressure of 1.7 kg/cm2, gun distance of 30 cm, booth temperature of 20° C. and booth humidity of 75° C., in such a manner that the thickness of the coating composition applied in each stage became about 3.5 μm (when cured) and the total thickness of the coating composition applied in the two stages became 7 μm (when cured). The applied coating composition was allowed to stand for 1 minute between the stages. The solids content of the applied composition one minute after the application in each stage was 50%. After the two stages of application, the applied composition was allowed to stand for 3 minutes, and preheated at 80° C. for 10 minutes. Clear coating composition (B-1) was applied over the uncured coating layer of base coating composition (A-1) to a thickness of 30 μm (when cured), using a Minibell rotary electrostatic spray coater at 30,000 rpm, shaping pressure of 1.5 kg/cm2, gun distance of 30 cm, booth temperature of 20° C. and booth humidity of 75%, allowed to stand for 7 minutes and heated at 140° C. for 30 minutes to simultaneously cure the two uncured coating layers of base coating composition (A-1) and clear coating composition (B-1). A coated sheet was thus obtained in which a luster multilayer coating film was formed on a substrate by a four-coat two-bake method. EXAMPLE 2 Aqueous luster base coating composition (A-1) obtained in Production Example 4 was applied in two stages to the substrate obtained in Production Example 6, using a Metabell rotary electrostatic coater at 30,000 rpm, shaping pressure of 1.7 kg/cm2, gun distance of 30 cm, booth temperature of 20° C. and booth humidity of 75%, in such a manner that the thickness of the coating composition applied in the first stage became about 5 μm (when cured), the thickness of the coating composition applied in the second stage became about 2.5 μm (when cured), and the total thickness of the coating composition applied in the two stages became 7.5 μm (when cured). The applied coating composition was allowed to stand for 1 minute between the stages. The solids content of the applied composition one minute after the application in the first stage was 45%. The solids content of the applied composition one minute after the application in the second stage was 60%. After the two stages of application, the applied composition was allowed to stand for 3 minutes and preheated at 80° C. for 10 minutes. Clear coating composition (B-1) was applied over the uncured coating layer of base coating composition (A-1) to a thickness of 30 μm (when cured), using a Minibell rotary electrostatic coater at 30,000 rpm, shaping pressure of 1.5 kg/cm2, gun distance of 30 cm, booth temperature of 20° C. and booth humidity of 75%, allowed to stand for 7 minutes and heated at 140° C. for 30 minutes to simultaneously cure the two uncured coating layers of base coating composition (A-1) and clear coating composition (B-1). Aqueous luster base coating composition (A-1) was applied in two stages over the cured coating layer of clear coating composition (B-1), using a Metabell rotary electrostatic coater at 30,000 rpm, shaping pressure of 1.7 kg/cm2, gun distance of 30 cm, booth temperature of 20° C. and booth humidity of 75° C., in such a manner that the thickness of the coating composition applied in each stage became about 2.5 μm (when cured) and the total thickness of the coating composition applied in the two stages became 5 μm (when cured). The applied coating composition was allowed to stand for 1 minute between the stages. The solids contents of the applied composition one minute after the application in the first and second stages were each 60%. After the two stages of application, the applied composition was allowed to stand for 3 minutes, and preheated at 80° C. for 10 minutes. Clear coating composition (B-1) was applied over the uncured coating layer of base coating composition (A-1) to a thickness of 30 μm (when cured) using a Minibell rotary electrostatic spray coater at 30,000 rpm, shaping pressure of 1.5 kg/cm2, gun distance of 30 cm, booth temperature of 20° C. and booth humidity of 75%. The applied composition was allowed to stand for 7 minutes, and heating was performed at 140°0 C. for 30 minutes to simultaneously cure the two uncured coating layers of base coating composition (A-1) and clear coating composition (B-1). A coated sheet was thus obtained in which a luster multilayer coating film was formed on a substrate by a four-coat two-bake method. COMPARATIVE EXAMPLE 1 The procedure of Example 1 was followed except that each of the first and third coating layers was formed by applying aqueous luster base coating composition (A-1) in a single stage to a thickness of about 7 μm (when cured), to obtain a coated sheet in which a luster multilayer coating film was formed on a substrate by a four-coat two-bake method. COMPARATIVE EXAMPLE 2 Aqueous luster base coating composition (A-1) was applied in two stages to the substrate obtained in Production Example 6, using a Metabell rotary electrostatic coater at 30,000 rpm, shaping pressure of 1.7 kg/cm2, gun distance of 30 cm, booth temperature of 20° C. and booth humidity of 75%, in such a manner that the thickness of the coating composition applied in the each stage became about 6 μm (when cured), and the total thickness of the coating composition applied in the two stages became 12 μm (when cured). The applied coating composition was allowed to stand for 1 minute between the stages. The solids contents of the applied composition one minute after the application in the first and second stages were each 40%. After the two stages of application, the applied composition was allowed to stand for 3 minutes and preheated at 80° C. for 10 minutes. Clear coating composition (B-1) was applied to the uncured coating layer of base coating composition (A-1) to a thickness of 30 μm (when cured), using a Minibell rotary electrostatic spray coater at 30,000 rpm, shaping pressure of 1.5 kg/cm2, gun distance of 30 cm, booth temperature of 20° C., and booth humidity of 75%. The applied composition was allowed to stand for 7 minutes, and heating was performed at 140° C. for 30 minutes to simultaneously cure the two uncured coating layers of base coating composition (A-1) and clear coating composition (B-1). A coated sheet was thus obtained in which a luster multilayer coating film was formed on a substrate by a two-coat one-bake method. Performance Evaluation Tests The coated sheets obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were tested for density of texture and flip-flop property by the following methods. Density of texture: The highlight of the coating surface of each coated sheet was observed by the naked eye, and evaluated according to the following criteria. A: The coating surface was only slightly grainy and had a highly dense texture; B: The coating surface was very grainy and had a poor density of texture. As another evaluation of the density of texture, the HG (Highlight Graininess) value of the coating surface of each coated sheet was measured using a micro-brilliance measuring instrument (product of Kansai Paint Co., Ltd.). The micro-brilliance measuring instrument is equipped with a light source, a CCD (Charge Coupled Device) camera and an image analyzer, and is disclosed in Japanese Unexamined Patent Publication No. 2001-221690. The HG value is a parameter of micro-brilliance obtained by the microscopic observation of a coating surface, and indicates the graininess of the highlight of the coating surface. The HG value is calculated as follows. First, the coating surface is photographed with a CCD camera at a light incidence angle of 15° and receiving angle of 0°, and the obtained digital image data (two-dimensional brilliance distribution data) is subjected to two-dimensional Fourier transformation to obtain a power spectrum image. Subsequently, the spatial frequency area corresponding to graininess is extracted from the power spectrum image, and the obtained measurement parameter is converted to an HG value from 0 to 100 that has a linear relation with graininess. An HG value of 0 indicates no graininess of the luster pigment at all, and an HG value of 100 indicates the highest possible graininess of the luster pigment. Flip-flop property: The highlight and shade of the coating surface of each coated sheet were observed by the naked eye, and evaluated according to the following criteria. A: A large difference in brightness between the highlight and shade; B: A small difference in brightness between the highlight and shade; C: Almost no difference in brightness between the highlight and shade. Further, using a multi-angle spectrocolorimeter (tradename “MA68II”, product of X-Rite in the U.S.), the color of the coating surface of each coated sheet was determined, and the reflectance at receiving angles of 15° and 110° C. from the regular reflection light was measured at a light incidence angle of 45°. The ratio of the reflectance at a receiving angle of 15° to that at a receiving angle of 110° (FF value) was calculated. The higher the FF value, the higher the flip-flop property. Table 1 shows the results of the evaluation tests of density of texture and flip-flop property. TABLE 1 Example Comp. Ex. 1 2 1 2 Density of Naked eye A A B B texture observation HG value 45 48 55 57 Flip-flop Naked eye A A B C property observation FF value 1.8 1.8 1.5 1.3 Table 1 reveals that the method of the present invention is capable of forming on a substrate a luster multilayer coating film with a highly dense texture and excellent flip-flop property.

<SOH> BACKGROUND OF THE INVENTION <EOH>Luster coating films usually contain flaky luster pigments, such as aluminum flakes, mica flakes, etc., and have various color tones. Such luster coating films shine brilliantly as the luster pigments reflect incident light from outside the coating films, and exhibit a unique and variable aesthetic appearance achieved by the combination of the reflected light and the color tones of the coating films. In recent years, luster coating films, in particular those formed on automotive bodies or the like, are being required to exhibit high-quality appearance characteristics, such as a highly dense texture, high flip-flop property, etc. As used herein, dense texture means uniform, continuous luster created by a luster pigment in a coating film. A highly dense texture can be achieved when a coating film has little graininess caused by the luster pigment contained therein. Flip-flop property is produced by the orientation of the flaky luster pigment in a coating film, parallel to the coating film surface. A coating film with that property reflects light well and has high brightness in the highlight (i.e., when viewed from the front), but has low brightness in the shade (i.e., when viewed at an angle). That is, flip-flop property is a property that produces a difference in brightness depending on the angle of vision. Japanese Unexamined Patent Publication No. 2002-273333 discloses a method of forming a luster coating film, in which a luster base coating is formed on a substrate in two stages, followed by forming a clear coating, the thickness ratio of the base coating composition applied in the first stage to that applied in the second stage being 2/1 to 4/1. This method can prevent unevenness in the luster of luster coating films. However, especially when an aqueous luster base coating composition is used, the above method is likely to result in insufficient orientation of the flaky luster pigment used, and is not capable of forming a luster coating film with a highly dense texture and high flip-flop property.

20060417

20121113

20070705

68842.0

B05D700

WALTERS JR, ROBERT S

METHOD OF FORMING LUSTER COATING FILM

UNDISCOUNTED

ACCEPTED

B05D

ACCEPTED

Spectrum coding apparatus, spectrum decoding apparatus, acoustic signal transmission apparatus, acoustic signal reception apparatus and methods thereof

A spectrum coding apparatus capable of performing coding at a low bit rate and with high quality is disclosed. This apparatus is provided with a section that performs the frequency transformation of a first signal and calculates a first spectrum, a section that converts the frequency of a second signal and calculates a second spectrum, a section that estimates the shape of the second spectrum in a band of FL≦k<FH using a filter having the first spectrum in a band of 0≦k<FL as an internal state and a section that codes an outline of the second spectrum determined based on a coefficient indicating the characteristic of the filter at this time.

1. A spectrum coding apparatus comprising: an acquisition section that acquires a spectrum whose frequency band is at least divided into a low-frequency band and high-frequency band; an estimation section that estimates the shape of the spectrum of said high-frequency band using a filter having the spectrum of said low-frequency band as an internal state; a first coding section that codes a coefficient indicating the characteristic of said filter; and a second coding section that codes an outline of the spectrum determined based on said coefficient. 2. The spectrum coding apparatus according to claim 1, further comprising a division section that divides the spectrum of said high-frequency band into a plurality of subbands, wherein said first coding section codes said coefficient for each of said subbands. 3. A spectrum decoding apparatus comprising: a first decoding section that decodes a coefficient indicating a filter characteristic from coding information; an acquisition section that acquires a spectrum in a low-frequency band out of a spectrum whose frequency band is at least divided into a high-frequency band and low-frequency band; a generation section that generates an estimated spectrum of the spectrum of said high-frequency band using a filter having the spectrum of said low-frequency band as an internal state; and a second decoding section that decodes an outline of a spectrum determined based on said decoded coefficient. 4. The spectrum decoding apparatus according to claim 3, wherein said first decoding section decodes said coefficient for each of said plurality of subbands of the spectrum of said high-frequency band. 5. A spectrum coding method comprising the steps of: performing a frequency transformation of a signal whose frequency k is in a band of 0≦k<FL and calculating a first spectrum; performing a frequency transformation of a signal whose frequency k is in a band of 0≦k<FH and calculating a second spectrum; estimating the shape of said second spectrum in a band of FL≦k<FH using a filter having said first spectrum as an internal state; coding a coefficient indicating said filter characteristic; and coding an outline of the second spectrum determined based on a coefficient indicating said filter characteristic together. 6. The spectrum coding method according to claim 5, wherein said second spectrum is divided into a plurality of subbands and the coefficient indicating the characteristic of said filter is coded for each of said subbands. 7. The spectrum coding method according to claim 5, wherein the filter is expressed by the following expression P ⁡ ( z ) = 1 1 - ∑ i = - M M ⁢ β i ⁢ z - T + i where M is an arbitrary integer, T is a pitch coefficient and βi is a filter coefficient and estimation is performed using a zero-input response of said filter. 8. The spectrum coding method according to claim 7, wherein M=0, β0=1 are assumed in said filter. 9. The spectrum coding method according to claim 5, wherein an outline of the spectrum is determined for each subband determined by pitch coefficient T. 10. The spectrum coding method according to claim 5, wherein said first signal is a signal coded and then decoded in a lower layer or a signal obtained by upsampling said signal and said second signal is an input signal. 11. A spectrum decoding method comprising the steps of: decoding a coefficient indicating a filter characteristic; performing the frequency transformation of a first signal to obtain a first spectrum and generating an estimated value of a second spectrum whose frequency k is in a band of FL≦k<FH using a filter having the first spectrum in a band of 0≦k<FL as an internal state; and decoding a spectral outline of the second spectrum determined based on a coefficient indicating said filter characteristic together. 12. The spectrum decoding method according to claim 11, further comprising a step of dividing said second spectrum into a plurality of subbands and decoding a coefficient indicating said filter characteristic for each of said subbands. 13. The spectrum decoding method according to claim 11, wherein the filter is expressed by the following expression P ⁡ ( z ) = 1 1 - ∑ i = - M M ⁢ β i ⁢ z - T + i where M is an arbitrary integer, T is a pitch coefficient and βi is a filter coefficient and an estimated value is generated using a zero-input response of said filter. 14. The spectrum decoding method according to claim 13, wherein M=0, β0=1 are assumed in said filter. 15. The spectrum decoding method according to claim 11, wherein the outline of the spectrum is decoded for each subband determined by pitch coefficient T. 16. The spectrum decoding method according to claim 11, wherein said first signal is generated from a signal decoded in a lower layer or a signal obtained by upsampling said signal. 17. An acoustic signal transmission apparatus comprising: an acoustic input section that converts an acoustic signal to an electric signal; an A/D conversion section that converts a signal output from said acoustic input section to a digital signal; a coding apparatus that performs coding on the digital signal output from said A/D conversion section using the spectrum coding method according to claim 5; an RF modulation section that modulates the code output from said coding apparatus into a signal of a radio frequency; and a transmission antenna that converts the signal output from said RF modulation section to a radio wave and transmits the radio wave. 18. An acoustic signal reception apparatus comprising: a reception antenna that receives a radio wave; an RF demodulation section that demodulates the signal received from said reception antenna; a decoding apparatus that performs decoding from information obtained by said RF demodulation section using the spectrum decoding method according to claim 11; a D/A conversion section that converts the signal output from said decoding apparatus to an analog signal; and an acoustic output section that converts an electric signal output from said D/A conversion section to an acoustic signal. 19. A communication terminal apparatus comprising the acoustic signal transmission apparatus according to claim 17. 20. A communication terminal apparatus comprising the acoustic signal reception apparatus according to claim 18. 21. A base station apparatus comprising the acoustic signal transmission apparatuses according to claim 17. 22. A base station apparatus comprising the acoustic signal reception apparatuses according to claim 18.

TECHNICAL FIELDS The present invention relates to a method of extending a frequency band of an audio signal or voice signal and improving sound quality, and further to a coding method and decoding method of an audio signal or voice signal applying this method. BACKGROUND ART A voice coding technique and audio coding technique which compresses a voice signal or audio signal at a low bit rate are important for the effective utilization of a transmission path capacity of radio wave or the like in a mobile communication and a recording medium. Voice coding for coding a voice signal includes schemes such as G726 and G729 standardized in the ITU-T (International Telecommunication Union Telecommunication Standardization Sector). These schemes target narrow band signals (300 Hz to 3.4 kHz) and can perform high quality coding at 8 kbits/s to 32 kbits/s. However, because such a narrow band signal has a frequency band as narrow as a maximum of 3.4 kHz, and as for quality, sound is muffled and lacks a sense of realism. On the other hand, in the field of voice coding, there is a scheme which targets a wideband signal (50 Hz to 7 kHz) for coding. Typical examples of such a method include G722, G722.1 of the ITU-T and AMR-WB of the 3GPP (The 3rd Generation Partnership Project) and soon. These schemes can perform coding on a wideband voice signal at a bit rate of 6.6 kbits/s to 64 kbits/s. When the signal to be coded is a voice, a wideband signal has relatively high quality, but it is not sufficient when an audio signal is the target or when a quality with a high sense of realism is required for the voice signal. Generally, when a maximum frequency of a signal is approximately 10 to 15 kHz, a sense of realism equivalent to that of FM radio is obtained and quality comparable to that of a CD is obtained if the frequency is on the order of 20 kHz. Audio coding represented by the layer 3 scheme and the AAC scheme standardized in MPEG (Moving Picture Expert Group) and so on is suitable for such a signal. However, in case of these audio coding schemes, the bit rate increases because the frequency band to be coded is widened. The National Publication of International Patent Application No. 2001-521648 describes a technique of reducing an overall bit rate by dividing an input signal into a low-frequency band and a high-frequency band and substituting the high-frequency band by a low-frequency band spectrum as the method of coding a wideband signal at a low bit rate and with high quality. The state of processing when this conventional technique is applied to an original signal will be explained using FIGS. 1A to D. Here, a case where a conventional technique is applied to an original signal will be explained to facilitate explanations. In FIGS. 1A to D, the horizontal axis shows a frequency and the vertical axis shows a logarithmic power spectrum. Furthermore, FIG. LA shows a logarithmic power spectrum of the original signal when a frequency band is limited to 0≦k<FH, FIG. 1B shows a logarithmic power spectrum when the band of the same signal is limited to 0≦k<FL (FL<FH), FIG. 1C shows a case where a spectrum in a high-frequency band is substituted by a spectrum in a low-frequency band using the conventional technique and FIG. 1D shows a case where the substituted spectrum is reshaped according to spectral outline information. According to the conventional technique, the spectrum of the original signal (FIG. 1A) is expressed based on a signal having a spectrum of 0≦k<FL (FIG. 1B), and therefore the spectrum of the high-frequency band (FL≦K<FH in this figure) is substituted by the spectrum of the low-frequency band (0≦k<FL) (FIG. 1C). For simplicity, a case assuming that there is a relationship of FL=FH/2 is explained. Next, the amplitude value of the substituted spectrum in the high-frequency band is adjusted according to the spectrum envelope information of the original signal and a spectrum obtained by estimating the spectrum of the original signal is determined (FIG. 1D). DISCLOSURE OF INVENTION Generally, the spectrum of a voice signal or an audio signal is known to have a harmonic structure in which a spectral peak appears at an integer multiple of a certain frequency as shown in FIG. 2A. The harmonic structure is important information in maintaining quality and when a gap occurs in the harmonic structure, a quality degradation is perceived. FIG. 2 A shows a spectrum when the spectrum of some audio signal is analyzed. As seen in this figure, a harmonic structure with interval T is observed in the original signal. Here, a diagram showing that the spectrum of the original signal is estimated according to the conventional technique is shown in FIG. 2B. When these two figures are compared, it is observed that while the harmonic structure is maintained in the low-frequency band spectrum in the substitution source (area A1) and the high-frequency band spectrum (area A2) in the substitution destination in FIG. 2B, the harmonic structure collapses in the connection section (area A3) of the low-frequency band spectrum of the substitution source and the high-frequency band spectrum in the substitution destination. This is attributable to the fact that the conventional technique performs substitution without considering the shape of the harmonic structure. The subjective quality deteriorates due to such disturbance of the harmonic structure when an estimated spectrum is converted to a time signal and listened. Furthermore, when FL is smaller than FH/2, that is, when it is necessary to substitute the low-frequency band spectrum twice or more in the band of FL≦k<FH, another problem occurs in adjustment of the spectral outline. The problem will be explained using FIG. 3A and FIG. 3B. The spectrum of a voice signal or audio signal is generally not flat and the energy of either the low-frequency band or the high-frequency band is larger. In this way, there is an tilt in the spectrum of a voice signal or audio signal and the energy of the high-frequency band is often smaller than the energy of the low-frequency band. When substitution of the spectrum is performed in such a situation, discontinuity of the spectral energy occurs (FIG. 3A). As shown in FIG. 3A, when a spectral outline is adjusted every predetermined period (subband), the discontinuity of the energy is not canceled (area A4 and area A5 in FIG. 3B), annoying sound occurs in the decoded signal because of this phenomenon and subjective quality deteriorates. In view of the above described problems, the present invention proposes a technique of coding a signal of a wide frequency band at a low bit rate and with high quality. The present invention provides a spectrum coding method of estimating the shape of the spectrum of the high-frequency band using a filter having the low-frequency band as the internal state and coding the coefficient representing the characteristic of the filter at that time to adjust a spectral outline of the estimated high-frequency band spectrum. This makes it possible to improve quality of a decoded signal. BRIEF DESCRIPTION OF DRAWINGS FIG. 1A shows a conventional bit rate compression technique; FIG. 1B shows a conventional bit rate compression technique; FIG. 1C shows a conventional bit rate compression technique; FIG. 1D shows a conventional bit rate compression technique; FIG. 2A shows a harmonic structure of a spectrum of a voice signal or audio signal; FIG. 2B shows a harmonic structure of a spectrum of a voice signal or audio signal; FIG. 3A shows discontinuity of energy produced when adjusting the spectral outline; FIG. 3B shows discontinuity of energy produced when adjusting the spectral outline; FIG. 4 illustrates a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 1; FIG. 5 illustrates a process of calculating an estimated value of a second spectrum through filtering; FIG. 6 illustrates a processing flow at the filtering section, search section and pitch coefficient setting section; FIG. 7A shows an example of the state of filtering; FIG. 7B shows an example of the state of filtering; FIG. 7C shows an example of the state of filtering; FIG. 7D shows an example of the state of filtering; FIG. 7E shows an example of the state of filtering; FIG. 8A shows another example of the harmonic structure of a first spectrum stored in the internal state; FIG. 8B shows a further example of the harmonic structure of the first spectrum stored in the internal state; FIG. 8C shows a still further example of the harmonic structure of the first spectrum stored in the internal state; FIG. 8D shows a still further example of the harmonic structure of the first spectrum stored in the internal state; FIG. 8E shows a still further example of the harmonic structure of the first spectrum stored in the internal state; FIG. 9 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 2; FIG. 10 illustrates a state of filtering according to Embodiment 2; FIG. 11 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 3; FIG. 12 illustrates a state of processing of Embodiment 3; FIG. 13 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 4; FIG. 14 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 5; FIG. 15 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 6; FIG. 16 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 7; FIG. 17 is a block diagram showing the configuration of a hierarchic coding apparatus according to Embodiment 7; FIG. 18 is a block diagram showing the configuration of a hierarchic coding apparatus according to Embodiment 8; FIG. 19 is a block diagram showing the configuration of a spectrum decoding apparatus according to Embodiment 9; FIG. 20 illustrates the state of a decoded spectrum generated from the filtering section according to Embodiment 9; FIG. 21 is a block diagram showing the configuration of a spectrum decoding apparatus according to Embodiment 10; FIG. 22 is a flow chart of Embodiment 10; FIG. 23 is a block diagram showing the configuration of a spectrum decoding apparatus according to Embodiment 11; FIG. 24 is a block diagram showing the configuration of a spectrum decoding apparatus according to Embodiment 12; FIG. 25 is a block diagram showing the configuration of a hierarchic decoding apparatus according to Embodiment 13; FIG. 26 is a block diagram showing the configuration of the hierarchic decoding apparatus according to Embodiment 13; FIG. 27 is a block diagram showing the configuration of an acoustic signal coding apparatus according to Embodiment 14; FIG. 28 is a block diagram showing the configuration of an acoustic signal decoding apparatus according to Embodiment 15; FIG. 29 is a block diagram showing the configuration of an acoustic signal transmission coding apparatus according to Embodiment 16; and FIG. 30 is a block diagram showing the configuration of an acoustic signal reception decoding apparatus according to Embodiment 17 of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION With reference now to the accompanying drawings, embodiments of the present invention will be explained in detail below. Embodiment 1 FIG. 4 is a block diagram showing the configuration of spectrum coding apparatus 100 according to Embodiment 1 of the present invention. A first signal whose effective frequency band is 0≦k<FL is input from input terminal 102 and a second signal whose effective frequency band is 0≦k<FH is input from input terminal 103. Next, frequency domain transformation section 104 performs a frequency transformation on the first signal input from input terminal 102, calculates first spectrum S1(k) and frequency domain transformation section 105 performs a frequency transformation on the second signal input from input terminal 103 and calculates second spectrum S2(k) Here, discrete Fourier transform (DFT), discrete cosine transform (DCT), modified discrete cosine transform (MDCT) or the like can be applied as the frequency transformation method. Next, internal state setting section 106 sets an internal state of a filter used in filtering section 107 using first spectrum S1(k). Filtering section 107 performs filtering based on the internal state of the filter set by internal state setting section 106 and pitch coefficient T given from pitch coefficient setting section 109 and calculates estimated value D2(k) of the second spectrum. The process of calculating estimated value D2(k) of the second spectrum through filtering will be explained using FIG. 5. In FIG. 5, suppose the spectrum of 0≦k<FH is called “S(k)” for convenience. As shown in FIG. 5, first spectrum S1(k) is stored in the area of 0≦k<FL in S(k) as the internal state of the filter and estimated value D2(k) of the second spectrum is generated in the area of FL≦k<FH. This embodiment will explain a case where a filter expressed by the following Expression (1) is used and T here denotes the coefficient given from coefficient setting section 109. Furthermore, suppose M=1 in this explanation. P ⁡ ( z ) = 1 1 - ∑ i = - M M ⁢ ⁢ β i ⁢ z - T + i ( 1 ) In the filtering processing, an estimated value is calculated by multiplying each frequency by corresponding coefficient βi centered on a spectrum which is lower by frequency T in ascending order of frequency and adding up the multiplication results. S ⁡ ( k ) = ∑ i = - 1 1 ⁢ ⁢ β i · S ⁡ ( k - T - i ) ( 2 ) Processing according to Expression (2) is performed between FL≦k<FH. S(k) (FL≦k<FH) calculated as a result is used as estimated value D2(k) of the second spectrum. Search section 108 calculates a degree of similarity between second spectrum S2(k) given from frequency domain transformation section 105 and estimated value D2(k) of the second spectrum given from filtering section 107. There are various definitions of the degree of similarity and this embodiment will explain a case where filter coefficients β-1 and β1 are assumed to be 0 and the degree of similarity calculated according to the following Expression (3) defined based on a minimum square error is used. In this method, filter coefficient βi is determined after calculating optimum pitch coefficient T. E = ∑ k = FL FH - 1 ⁢ ⁢ S ⁢ ⁢ 2 ⁢ ( k ) 2 - ( ∑ k = FL FH - 1 ⁢ ⁢ S ⁢ ⁢ 2 ⁢ ( k ) · D ⁢ ⁢ 2 ⁢ ( k ) ) 2 ∑ k = FL FH - 1 ⁢ ⁢ D ⁢ ⁢ 2 ⁢ ( k ) 2 ( 3 ) Here, E denotes a square error between S2(k) and D2(k). Because the first term on the right side of Expression (3) is a fixed value regardless of pitch coefficient T, pitch coefficient T which generates D2(k) corresponding to a maximum of the second term on the right side of Expression (3) is searched. In this embodiment, the second term on the right side of Expression (3) will be referred to as a “degree of similarity.” Pitch coefficient setting section 109 has the function of outputting pitch coefficient T included in a predetermined search range TMIN to TMAX to filtering section 107 sequentially. Therefore, every time pitch coefficient T is given from pitch coefficient setting section 109, filtering section 107 clears S(k) in the range of FL≦k<FH to zero and then performs filtering and search section 108 calculates a degree of similarity. Search section 108 determines pitch coefficient Tmax corresponding to a maximum degree of similarity calculated between TMIN and TMAX and gives pitch coefficient Tmax to filter coefficient calculation section 110, second spectrum estimated value generation section 115, spectral outline adjustment subband determining section 112 and multiplexing section 111. FIG. 6 shows the processing flow of filtering section 107, search section 108 and pitch coefficient setting section 109. FIGS. 7A to E show an example of filtering state for ease in understanding of this embodiment. FIG. 7A shows the harmonic structure of the first spectrum stored in the internal state. FIGS. 7B to D show the relationship between the harmonic structures of the estimated values of the second spectrum calculated by performing filtering using three types of pitch coefficients T0, T1, T2. According to this example, T1 whose shape is similar to second spectrum S2(k) is selected as pitch coefficient T whereby the harmonic structure is maintained (see FIG. 7C and FIG. 7E). Furthermore, FIGS. 8A to E show another example of the harmonic structure of the first spectrum stored in the internal state. In this example also, an estimated spectrum whereby the harmonic structure is maintained is calculated when pitch coefficient T1 is used and it is T1 that is output from search section 108 (see FIG. 8C and FIG. 8E). Next, filter coefficient calculation section 110 determines filter coefficient βi using pitch coefficient Tmax given from search section 108. Filter coefficient βi is determined so as to minimize square distortion E which follows the following Expression (4). E = ∑ k = FL FH - 1 ⁢ ⁢ ( S ⁢ ⁢ 2 ⁢ ( k ) - ∑ i = - 1 1 ⁢ ⁢ β i ⁢ S ⁡ ( k - T max - i ) ) 2 ( 4 ) Filter coefficient calculation section 110 stores a plurality of combinations of βi (i=−1,0,1) as a table beforehand, determines a combination of βi (i=−1,0,1) which minimizes square error E of Expression (4) and gives the code to second spectrum estimated value generation section 115 and multiplexing section 111. Second spectrum estimated value generation section 115 generates estimated value D2(k) of the second spectrum according to Expression (1) using pitch coefficient Tmax and filter coefficient βi and gives it to spectral outline adjustment coefficient coding section 113. Pitch coefficient Tmax is also given to spectral outline adjustment subband determining section 112. Spectral outline adjustment subband determining section 112 determines a subband for spectral outline adjustment based on pitch coefficient Tmax. A jth subband can be expressed by the following Expression (5) using pitch coefficient Tmax. { BL ⁡ ( j ) = FL + ( j - 1 ) · T max BH ⁡ ( j ) = FL + j · T max ⁢ ( 0 ≤ j < J ) ( 5 ) Here, BL(j) denotes a minimum frequency of the jth subband and BH(j) denotes a maximum frequency of the jth subband. Furthermore, the number of subbands J is expressed as a minimum integer corresponding to maximum frequency BH(J-1) of the (j−1)th subband that exceeds FH. The information about the spectral outline adjustment subband determined in this way is given to spectral outline adjustment coefficient coding section 113. Spectral outline adjustment coefficient coding section 113 calculates a spectral outline adjustment coefficient and performs coding using the spectral outline adjustment subband information given from spectral outline adjustment subband determining section 112, estimated value D2(k) of the second spectrum given from second spectrum estimated value generation section 115 and second spectrum S2(k) given from frequency domain transformation section 105. This embodiment will explain a case where the relevant spectrum outline information is expressed with spectral power for each subband. At this time, the spectral power of the jth subband is expressed by the following Expression (6). B ⁡ ( j ) = ∑ k = BL ⁡ ( j ) BH ⁡ ( j ) ⁢ ⁢ S ⁢ ⁢ 2 ⁢ ( k ) 2 ( 6 ) Here, BL(j) denotes a minimum frequency of the jth subband and BH(j) denotes a maximum frequency of the jth subband. The subband information of the second spectrum determined in this way is regarded as the spectral outline information of the second spectrum. Likewise, subband information b(j) of estimated value D2(k) of the second spectrum is calculated according to the following Expression (7), b ⁡ ( j ) = ∑ k = BL ⁡ ( j ) BH ⁡ ( j ) ⁢ ⁢ D ⁢ ⁢ 2 ⁢ ( k ) 2 ( 7 ) and amount of variation V(j) is calculated for each subband according to the following Expression (8). V ⁡ ( j ) = B ⁡ ( j ) b ⁡ ( j ) ( 8 ) Next, amount of variation V(j) is coded and the code is sent to multiplexing section 111. To calculate more detailed spectral outline information, the following method may also be applied. A spectral outline adjustment subband is further divided into subbands of a smaller bandwidth and a spectral outline adjustment coefficient is calculated for each subband. For example, when the jth subband is divided by division number N, V ⁡ ( j , n ) = B ⁡ ( j , n ) b ⁡ ( j , n ) ⁢ ⁢ ( 0 ≤ j < J , 0 ≤ n < N ) ( 9 ) a vector of the Nth order spectrum adjustment coefficient is calculated for each subband using Expression (9), this vector is vector-quantized and an index of a representative vector corresponding to minimum distortion is output to multiplexing section 111. Here, B(j,n) and b(j,n) are calculated as follows: B ⁡ ( j , n ) = ∑ k = BL ⁡ ( j , n ) BH ⁡ ( j , n ) ⁢ ⁢ S ⁢ ⁢ 2 ⁢ ( k ) 2 ⁢ ⁢ ( 0 ≤ j < J , 0 ≤ n < N ) ⁢ ( 10 ) b ⁡ ( j , n ) = ∑ k = BL ⁡ ( j , n ) BH ⁡ ( j , n ) ⁢ ⁢ D ⁢ ⁢ 2 ⁢ ( k ) 2 ⁢ ⁢ ( 0 ≤ j < J , 0 ≤ n < N ) ( 11 ) Furthermore, BL (j,n), BH (j, n) denote a minimum frequency and a maximum frequency of the nth division section of the jth subband respectively. Multiplexing section 111 multiplexes information about optimum pitch coefficient Tmax obtained from search section 108, information about the filter coefficient obtained from filter coefficient calculation section 110 and information about the spectral outline adjustment coefficient obtained from spectral outline adjustment coefficient coding section 113 and outputs the multiplexing result from output terminal 114. This embodiment has explained when M=1 in Expression (1), but M is not limited to this value and any integer equal to or more than 0 can be used. Furthermore, this embodiment has explained the case where frequency domain transformation sections 104, 105 are used, but these are the components which are necessary when a time domain signal is input and the frequency domain transformation section is not necessary in a configuration in which a spectrum is input directly. Embodiment 2 FIG. 9 is a block diagram showing the configuration of spectrum coding apparatus 200 according to Embodiment 2 of the present invention. Since this embodiment adopts a simple configuration for a filter used at a filtering section, it requires no filter coefficient calculation section and produces the effect that a second spectrum can be estimated with a small amount of calculation. In FIG. 9, components having the same names as those in FIG. 4 have identical functions, and therefore detailed explanations of such components will be omitted. For example, spectral outline adjustment subband determining section 112 in FIG. 4 has a name “spectral outline adjustment subband determining section” identical to the spectral outline adjustment subband determining section 209 in FIG. 9, and therefore it has an identical function. The configuration of the filter used at filtering section 206 is a simplified one as shown in the following expression. P ⁡ ( z ) = 1 1 - z - T ( 12 ) Expression (12) corresponds to a filter expressed assuming M=0, β0=1 based on Expression (1). The state of filtering in this case is shown in FIG. 10. In this way, estimated value D2(k) of the second spectrum can be obtained by sequentially copying spectra in the low-frequency band located apart by T. Furthermore, search section 207 determines optimum pitch coefficient Tmax by searching pitch coefficient T which corresponds to a minimum value in Expression (3) as in the case of Embodiment 1. Pitch coefficient Tmax obtained in this way is given to multiplexing section 211. This configuration assumes that a value temporarily generated by search section 207 for the search is used as estimated value D2(k) of the second spectrum given to spectral outline adjustment coefficient coding section 210. Therefore, second spectrum estimated value D2(k) is given to spectral outline adjustment coefficient coding section 210 from search section 207. Embodiment 3 FIG. 11 is a block diagram showing the configuration of spectrum coding apparatus 300 according to Embodiment 3 of the present invention. The features of this embodiment include dividing a band FL-≦k<FH is into a plurality of subbands beforehand, performing a search for pitch coefficient T, calculation of a filter coefficient and adjustment of a spectral outline for each subband and coding these pieces of information. This avoids the problem with discontinuity of spectral energy caused by a spectral tilt included in the spectrum in a band of 0≦k<FL which is the substitution source. In addition, coding is performed independently for each subband, and therefore it is possible to produce the effect of realizing an extension of a band of higher quality. Because the components in FIG. 11 having the same names as those in FIG. 4 have identical functions, detailed explanations of such components will be omitted. Subband division section 309 divides band FL≦k<FH of second spectrum S2(k) given from frequency domain transformation section 304 into predetermined J subbands. This embodiment will be explained assuming J=4. Subband division section 309 outputs spectrum S2(k) included in a 0th subband to terminal 310a. In the same way, spectra S2(k) included in a first subband, second subband and third subband are output to terminals 310b, 310c and 310d respectively. Subband selection section 312 controls switching section 311 in such a way that the switching section 311 selects terminal 310a, terminal 310b, terminal 310c and terminal 310d sequentially. In other words, subband selection section 312 sequentially selects the 0th subband, first subband, second subband and third subband and gives spectrum S2(k) to search section 307, filter coefficient calculation section 313 and spectral outline adjustment coefficient coding section 314. Hereinafter, processing is performed in subband units, pitch coefficient Tmax, filter coefficient βi and spectral outline adjustment coefficient are calculated for each subband and given to multiplexing section 315. Therefore, information about J pitch coefficients Tmax, information about J filter coefficients and information about J spectral outline adjustment coefficients are given to multiplexing section 315. Furthermore, since subbands are predetermined in this embodiment, the spectral outline adjustment subband determining section is not necessary. FIG. 12 illustrates the state of processing according to this embodiment. As shown in this figure, band FL≦k<FH is divided into predetermined subbands, Tmax, βi, Vq are calculated for each subband and sent to the multiplexing section respectively. This configuration matches the bandwidth of a spectrum substituted from a low-frequency band spectrum with the bandwidth of the subband for spectral outline adjustment, which results in preventing discontinuity of spectral energy and improving sound quality. Embodiment 4 FIG. 13 is a block diagram showing the configuration of spectrum coding apparatus 400 according to Embodiment 4 of the present invention. A feature of this embodiment includes simplifying the configuration of a filter used at a filtering section based on above described Embodiment 3. This eliminates the necessity for a filter coefficient calculation section and has the effect that a second spectrum can be estimated with a smaller amount of calculation. In FIG. 13, components having the same names as those in FIG. 11 have identical functions, and therefore detailed explanations of such components will be omitted. The configuration of the filter used at filtering section 406 is simplified as shown in the following expression. P ⁡ ( z ) = 1 1 - z - T ( 13 ) Expression (13) corresponds to a filter which is expressed based on Expression (1) assuming M=0, β0=1. The state of filtering at this time is shown in FIG. 10. In this way, estimated value D2(k) of the second spectrum can be determined by sequentially copying spectra in the low-frequency band located apart by T. Furthermore, search section 407 searches for pitch coefficient T which corresponds to a minimum value in Expression (3) and determines it as optimum pitch coefficient Tmax as in the case of Embodiment 1. Pitch coefficient Tmax obtained in this way is given to multiplexing section 414. This configuration assumes that a value temporarily generated for a search by search section 407 is used as estimated value D2(k) of the second spectrum given to spectral outline adjustment coefficient coding section 413. Therefore, second spectrum estimated value D2(k) is given to spectral outline adjustment coefficient coding section 413 from search section 407. Embodiment 5 FIG. 14 is a block diagram showing the configuration of spectrum coding apparatus 500 according to Embodiment 5 of the present invention. Features of this embodiment include correcting spectral tilts of first spectrum S1(k) and second spectrum S2(k) using an LPC spectrum respectively, and determining estimated value D2(k) of the second spectrum using the corrected spectra. This produces the effect of solving the problem of discontinuity of spectral energy. In FIG. 14, components having the same names as those in FIG. 13 have identical functions, and therefore detailed explanations of such components will be omitted. Moreover, this embodiment will explain a case where a technique of correcting spectral tilts is applied to above described Embodiment 4, but this technique is not limited to this and is also applicable to each of above described Embodiments 1 to 3. Here, LPC coefficients calculated by an LPC analysis section (not shown here) or LPC decoding section is input from input terminal 505 and given to LPC spectrum calculation section 506. Apart from this, the configuration may also be adapted such that the LPC coefficients is determined by performing an LPC analysis on the signal input from input terminal 501. In this case, input terminal 505 is not necessary and the LPC analysis section is newly added instead. LPC spectrum calculation section 506 calculates a spectrum envelope according to Expression (14) shown below based on the LPC coefficients. e ⁢ ⁢ 1 ⁢ ( k ) =  1 1 - ∑ i = 1 NP ⁢ α ⁡ ( i ) · ⅇ - j ⁢ 2 ⁢ ⁢  ⁢ ⁢ k ⁢ ⁢ ⅈ K  ( 14 ) Or the spectrum envelope may also be calculated according to the following Expression (15). e ⁢ ⁢ 1 ⁢ ( k ) =  1 1 - ∑ i = 1 NP ⁢ α ⁡ ( i ) · γ i · ⅇ - j ⁢ 2 ⁢ ⁢  ⁢ ⁢ k ⁢ ⁢ ⅈ K  ( 15 ) Here, α denotes LPC coefficients, NP denotes the order of the LPC coefficients and K denotes a spectral resolution. Furthermore, γ is a constant equal to or greater than 0 and less than 1 and the use of this γ can smooth the shape of the spectrum. Spectrum envelope e1(k) obtained in this way is given to spectral tilt correction section 507. Spectral tilt correction section 507 corrects spectral tilt which is present in first spectrum S1(k) given from frequency domain transformation section 503 using spectrum envelope e1(k) obtained from LPC spectrum calculation section 506 according to the following Expression (16). S ⁢ ⁢ 1 ⁢ ⁢ new ⁡ ( k ) = S ⁢ ⁢ 1 ⁢ ( k ) e ⁢ ⁢ 1 ⁢ ( k ) ( 16 ) The corrected first spectrum obtained in this way is given to internal state setting section 511. On the other hand, similar processing will also be performed when calculating the second spectrum. A second signal input from input terminal 502 is given to LPC analysis section 508 and performed an LPC analysis to obtain LPC coefficients. The LPC coefficients obtained here are converted to parameters which are suitable for coding such as LSP coefficients, then coded and an index thereof is given to multiplexing section 521. Simultaneously, the LPC coefficients are decoded and the decoded LPC coefficients are given to LPC spectrum calculation section 509. LPC spectrum calculation section 509 has a function similar to that of above described LPC spectrum calculation section 506 and calculates spectrum envelope e2(k) for the second signal according to Expression (14) or Expression (15). Spectral tilt correction section 510 has a function similar to that of above described spectral tilt correction section 507 and corrects the spectral tilt which is present in the second spectrum according to the following Expression (17). S ⁢ ⁢ 2 ⁢ ⁢ new ⁡ ( k ) = S ⁢ ⁢ 2 ⁢ ( k ) e ⁢ ⁢ 2 ⁢ ( k ) ( 17 ) The corrected second spectrum obtained in this way is given to search section 513 and at the same time given to spectral tilt assignment section 519. Spectral tilt assignment section 519 assigns a spectral tilt to estimated value D2(k) of the second spectrum given from search section 513 according to the following Expression (18). D2new(k)=D2(k)·e2(k) (18) Estimated value s2new(k) of the second spectrum calculated in this way is given to spectral outline adjustment coefficient coding section 520. Multiplexing section 521 multiplexes information about pitch coefficient Tmax given from search section 513, information about an adjustment coefficient given from spectral outline adjustment coefficient coding section 520 and coding information about the LPC coefficients given from the LPC analysis section, and outputs the multiplexing result from output terminal 522. Embodiment 6 FIG. 15 is a block diagram showing the configuration of spectrum coding apparatus 600 according to Embodiment 6 of the present invention. Features of this embodiment include detecting a band in which the shape of a spectrum is relatively flat from within first spectrum S1(k) and searching pitch coefficient T from this flat band. This makes it less likely that the energy of the spectrum after substitution may become discontinuous and produces the effect of avoiding the problem of discontinuity of spectral energy. In FIG. 15, components having the same names as those in FIG. 13 have identical functions, and therefore detailed explanations of such components will be omitted. Furthermore, this embodiment will explain a case where a technique of correcting spectral tilts is applied to aforementioned Embodiment 4, but this technique is not limited to this and is also applicable to each of the aforementioned embodiments. First spectrum S1(k) is given to spectral flat part detection section 605 from frequency domain transformation section 603 and a band in which the spectrum has the flat shape is detected from first spectrum S1(k). Spectral flat part detection section 605 divides first spectrum S1(k) in band 0≦k<FL into a plurality of subbands, quantifies the amount of spectral variation of each subband and detects a subband with the smallest amount of spectral variation. The information indicating the subband is given to pitch coefficient setting section 609 and multiplexing section 615. This embodiment will explain a case where a variance of a spectrum included in a subband is used as means for quantifying the amount of spectral variation. Band 0≦k<FL is divided into N subbands and variance u(n) of spectrum S1(k) included in each subband is calculated according to the following Expression (19). u ⁡ ( n ) = ∑ k = BL ⁡ ( n ) BH ⁡ ( n ) ⁢ (  S ⁢ ⁢ 1 ⁢ ( k )  - S ⁢ ⁢ 1 mean ) 2 BH ⁡ ( n ) + BL ⁡ ( n ) + 1 ( 19 ) Here, BL(n) denotes a minimum frequency of an nth subband, BH(n) denotes a maximum frequency of the nth subband, S1 mean denotes an average of the absolute value of the spectrum included in the nth subband. Here, the absolute value of the spectrum is taken because it is intended to detect a flat band from the standpoint of the amplitude value of the spectrum. Variances u(n) of the respective subbands obtained in this way are compared, a subband with the smallest variance is determined and variable n indicating the subband is given to pitch coefficient setting section 609 and multiplexing section 615. Pitch coefficient setting section 609 limits the search range of pitch coefficient T into the band of the subband determined by spectral flat part detection section 605 and determines a candidate of pitch coefficient T within the limited range. Because pitch coefficient T is determined from within the band where the variation of spectral energy is small in this way, the problem of discontinuity of spectral energy is reduced. Multiplexing section 615 multiplexes information about pitch coefficient Tmax given from search section 608, information about an adjustment coefficient given from spectral outline adjustment coefficient coding section 614 and information about a subband given from spectral flat part detection section 605, and outputs the multiplexing result from output terminal 616. Embodiment 7 FIG. 16 is a block diagram showing the configuration of spectrum coding apparatus 700 according to Embodiment 7 of the present invention. A feature of this embodiment includes adaptively changing the range for searching pitch coefficient T according to the degree of periodicity of an input signal. In this way, since no harmonic structure exists for a less periodic signal such as a silence part, problems are less likely to occur even when the search range is set to be very small. Furthermore, for a more periodic signal such as a voiced sound part, the range for searching pitch coefficient T is changed according to the value of the pitch period at that time. This makes it possible to reduce the amount of information for expressing pitch coefficient T and reduce the bit rate. In FIG. 16 components having the same names as those in FIG. 13 have identical functions and therefore detailed explanations of such components will be omitted. Furthermore, this embodiment will explain a case where this technique is applied to above described Embodiment 4, but this technique is not limited to this and is also applicable to each of the embodiments described so far. At least one of a parameter indicating the degree of the pitch periodicity and a parameter indicating the length of the pitch period is input from input terminal 706. This embodiment will explain a case where a parameter indicating the degree of the pitch periodicity and a parameter indicating the length with pitch period are input. Furthermore, this embodiment will be explained assuming that pitch period P and pitch gain Pg obtained by an adaptive codebook search by CELP (not shown) are input from input terminal 706. Search range determining section 707 determines a search range using pitch period P and pitch gain Pg given from input terminal 706. First, search range determining section 707 judges the degree of the periodicity of the input signal based on the magnitude of pitch gain Pg. When pitch gain Pg is larger than a threshold, the input signal input from input terminal 701 is regarded as a voiced sound part and TMIN and TMAX indicating the search range of pitch coefficient T are determined so as to include at least one harmonic of the harmonic structure expressed by pitch period P. Therefore, when the frequency of pitch period P is large, the search range of pitch coefficient T is set to be wide, and on the contrary when the frequency of pitch period P is small, the search range of pitch coefficient T is set to be narrow. When pitch gain Pg is smaller than the threshold, the input signal input from input terminal 701 is assumed to be a silence part and no harmonic structure is assumed to exist, and therefore the search range for searching pitch coefficient T is set to be very narrow. Embodiment 8 FIG. 17 is a block diagram showing the configuration of hierarchical coding apparatus 800 according to Embodiment 8 of the present invention. This embodiment applies any one of above described Embodiments 1 to 7 to hierarchical coding, and can thereby code a voice signal or audio signal at a low bit rate Acoustic data is input from input terminal 801 and a low sampling rate signal is generated by downsampling section 802. The downsampled signal is given to first layer coding section 803 and the relevant signal is coded. The code of first layer coding section 803 is given to multiplexing section 807 and is also given to first layer decoding section 804. First layer decoding section 804 generates a first layer decoded signal based on the code. Next, upsampling section 805 raises the sampling rate of the decoded signal of first layer coding section 803. Delay section 806 gives a delay of a specific length to the input signal input from input terminal 801. The magnitude of this delay is set to the same value as the time delay produced by downsampling section 802, first layer coding section 803, first layer decoding section 804 and upsampling section 805. Any one of above described Embodiments 1 to 7 is applied to spectrum coding section 101, spectrum coding is performed using the signal obtained from upsampling section 805 as a first signal and the signal obtained from delay section 806 as a second signal and the codes are output to multiplexing section 807. The code obtained from first layer coding section 803 and the code obtained from spectrum coding section 101 are multiplexed by multiplexing section 807 and are output from output terminal 808 as the output code. When the configuration of spectrum coding section 101 is the one shown in FIG. 14 and FIG. 16, the configuration of hierarchical coding apparatus 800a according to this embodiment (lowercase alphabet is appended to distinguish it from hierarchical coding apparatus 800 shown in FIG. 17) is as shown in FIG. 18. The difference between FIG. 18 and FIG. 17 is that a signal line which is directly input from first layer decoding section 804a is added to spectral coding section 101. This shows that the LPC coefficients decoded by first layer decoding section 804 or pitch period P and pitch gain Pg are given to spectral coding section 101. Embodiment 9 FIG. 19 is a block diagram showing the configuration of spectrum decoding apparatus 1000 according to Embodiment 9 of the present invention. In this embodiment, it is possible to estimate the high-frequency component of a second spectrum by a filter based on a first spectrum and decode a generated code, thereby decode an accurately estimated spectrum, adjust a spectral outline of the estimated spectrum of the high-frequency band with an appropriate subband and thereby achieve the effect of improving the quality of the decoded signal. The code coded by a spectrum coding section (not shown here) is input from input terminal 1002 and is given to separation section 1003. Separation section 1003 gives information about a filter coefficient to filtering section 1007 and spectral outline adjustment subband determining section 1008. At the same time, it gives information about a spectral outline adjustment coefficient to spectral outline adjustment coefficient decoding section 1009. Moreover, a first signal whose effective frequency band is 0≦k<FL is input from input terminal 1004 and frequency domain transformation section 1005 performs a frequency transformation on a time domain signal input from input terminal 1004 and calculates first spectrum S1(k). Here, as the frequency transformation method, a discrete Fourier transform (DFT), discrete cosine transform (DCT), modified discrete cosine transform (MDCT) and so on can be used. Next, internal state setting section 1006 sets the internal state of a filter used at filtering section 1007 using first spectrum S1(k). Filtering section 1007 performs filtering based on the internal state of the filter set by internal state setting section 1006, pitch coefficient Tmax given from separation section 1003 and filter coefficient β and calculates estimated value D2(k) of the second spectrum. In this case, at filtering section 1007, the filter described in Expression (1) is used. Furthermore, when the filter described in Expression (12) is used, it is only pitch coefficient Tmax that is given from separation section 1003. Which filter should be used corresponds to the type of the filter used by the spectrum coding section (not shown here) and the filter identical to that filter is used. The state of decoded spectrum D(k) generated from filtering section 1007 is shown in FIG. 20. As shown in FIG. 20, decoding spectrum D(k) consists of first spectrum S1(k) in frequency band 0≦k<FL and estimated value D2(k) of the second spectrum in frequency band FL=<k<FH. Spectral outline adjustment subband determining section 1008 determines the subband for adjusting a spectral outline using pitch coefficient Tmax given from separation section 1003. A jth subband can be expressed as shown in the following Expression (20) using pitch coefficient Tmax. { BL ⁡ ( j ) = FL + ( j - 1 ) · T max BH ⁡ ( j ) = FL + j · T max ⁢ ( 0 ≤ j < J ) ( 20 ) Here, BL(j) denotes a minimum frequency of the jth subband and BH(j) denotes a maximum frequency of the jth subband. Furthermore, the number of subbands J is expressed as a minimum integer corresponding to maximum frequency BH(J-1) of the (J−1)th subband that exceeds FH. The information about the spectral outline adjustment subband determined in this way is given to spectrum adjustment section 1010. Spectral outline adjustment coefficient decoding section 1009 decodes a spectral outline adjustment coefficient based on the information about the spectral outline adjustment coefficient given from separation section 1003 and gives this decoded spectral outline adjustment coefficient to spectrum adjustment section 1010. Here, the spectral outline adjustment coefficient quantizes the amount of variation for each subband expressed by Expression (8) and then expresses the decoded value Vq(j). Spectrum adjustment section 1010 multiplies decoded spectrum D(k) obtained from filtering section 1007 by decoded value Vq(j) of the amount of variation for each subband decoded by spectral outline adjustment coefficient decoding section 1009 on the subband given from spectral outline adjustment subband determining section 1008 according to the following Expression (21), thereby adjusts the spectral shape of frequency band FL≦k<FH of decoded spectrum D(k) and generates decoded spectrum S3(k) after adjustment. S3(k)=D(k)·Vq(j)(BL(j)≦k≦BH(j), for all j) (21) This decoded spectrum S3(k) is given to time domain conversion section 1011, converted to a time domain signal and output from output terminal 1012. When converting decoded spectrum S3(k) to a time domain signal, time domain conversion section 1011 performs appropriate processing such as windowing and overlap-add as required and avoids discontinuity which occurs among frames. Embodiment 10 FIG. 21 is a block diagram showing the configuration of spectrum decoding apparatus 1100 according to Embodiment 10 of the present invention. A feature of this embodiment includes dividing a band of FL≦k<FH into a plurality of subbands beforehand so that a spectrum can be decoded using information about each subband. This avoids the problem of discontinuity of spectral energy caused by spectral tilts included in the spectrum in a band of 0≦k<FL which is the substitution source. In addition, it is possible to decode a code which is coded for each subband independently and generate a high quality decoded signal. In FIG. 21, components having the same names as those in FIG. 19 have identical functions, and therefore detailed explanations of such components will be omitted. In this embodiment, band FL≦k<FH is divided into predetermined J subbands as shown in FIG. 12, and pitch coefficient Tmax, filter coefficient β and spectral outline adjustment coefficient Vq which are coded for each subband are decoded to generate a voice signal. Or pitch coefficient Tmax and spectral outline adjustment coefficient Vq which are coded for each subband are decoded to generate a voice signal. Which technique should be adopted depends on the kind of the filter used at the spectral coding section (not shown here). The filter in Expression (1) is used in the former case and the filter in Expression (12) is used in the latter case. First spectrum S1(k) is stored in band 0≦k<FL from spectrum adjustment section 1108 and as for band FL≦k<FH, the spectrum after spectral outline adjustment which has been divided into J subbands is given to subband integration section 1109. Subband integration section 1109 combines these spectra and generates decoded spectrum D(k) as shown in FIG. 20. Decoding spectrum D(k) generated in this way is given to time domain conversion section 1110. The flow chart of this embodiment is shown in FIG. 22. Embodiment 11 FIG. 23 is a block diagram showing the configuration of spectrum decoding apparatus 1200 according to Embodiment 11 of the present invention. Features of this embodiment include correcting spectral tilts of first spectrum S1(k) and second spectrum S2(k) using an LPC spectrum respectively and decoding a code that can be obtained by calculating estimated value D2(k) of the second spectrum using the corrected spectra. This makes it possible to obtain a spectrum free of the problem of discontinuity of spectral energy and produces the effect of generating a high quality decoded signal. In FIG. 23, components having the same names as those in FIG. 21 have identical functions, and therefore detailed explanations of such components will be omitted. Furthermore, this embodiment will explain a case where a technique of correcting spectral tilts is applied to above described Embodiment 10, but this technique is not limited to this and is also applicable to above described Embodiment 9. LPC coefficient decoding section 1210 decodes LPC coefficients based on information about the LPC coefficients given from separation section 1202 and gives the LPC coefficients to LPC spectrum calculation section 1211. The processing by LPC coefficient decoding section 1210 depends on the coding processing on the LPC coefficients which is performed inside the LPC analysis section of a coding section (not shown here) and processing of decoding the code obtained through the coding processing there is performed. LPC spectrum calculation section 1211 calculates the LPC spectrum according to Expression (14) or Expression (15). The same method as that used by the LPC spectrum calculation section of the coding section (not shown here) can be used to determine which method should be used. The LPC spectrum calculated by LPC spectrum calculation section 1211 is given to spectral tilt assignment section 1209. On the other hand, the LPC coefficients calculated by the LPC decoding section (not shown here) or the LPC calculation section is input from input terminal 1215 and is given to LPC spectrum calculation section 1216. LPC spectrum calculation section 1216 calculates the LPC spectrum according to Expression (14) or Expression (15). Which expression should be used depends on what method is used by the coding section (not shown here). Spectral tilt assignment section 1209 multiplies decoded spectrum D(k) given from filtering section 1206 by the spectral tilt according to the following Expression (22), and then gives decoded spectrum D(k) assigned a spectral tilt to spectrum adjustment section 1207. In Expression (22), e1(k) denotes the output of LPC spectrum calculation section 1216 and e2(k) denotes the output of LPC spectrum calculation section 1211. D ⁢ ⁢ 2 ⁢ ⁢ new ⁡ ( k ) = D ⁢ ⁢ 2 ⁢ ( k ) e ⁢ ⁢ 1 ⁢ ( k ) · e ⁢ ⁢ 2 ⁢ ( k ) ( 22 ) Embodiment 12 FIG. 24 is a block diagram showing the configuration of spectrum decoding apparatus 1300 according to Embodiment 12 of the present invention. Feature of this embodiment include detecting a band in which the spectrum has a relatively flat shape from within first spectrum S1(k) and decoding a code obtained by searching pitch coefficient T from this flat band. This prevents the energy of the spectrum after substitution from becoming discontinuous, can obtain a decoded spectrum free of the problem of discontinuity of spectral energy and produce the effect of generating a high quality decoded signal. In FIG. 24, components having the same names as those in FIG. 21 have identical functions, and therefore detailed explanations of such components will be omitted. Furthermore, this embodiment will explain a case where this technique is applied to above described Embodiment 10, but this technique is not limited to this and is also applicable to above described Embodiment 9 and Embodiment 11. Separation section 1302 gives subband selection information n indicating which subband is selected out of the N subbands into which band 0≦k<FL is divided and information indicating which position is used as the start point of the substitution source out of the frequencies included in the nth subband to pitch coefficient Tmax generation section 1303. Pitch coefficient Tmax generation section 1303 generates pitch coefficient Tmax used at filtering section 1307 based on these two pieces of information and gives pitch coefficient Tmax to filtering section 1307. Embodiment 13 FIG. 25 is a block diagram showing the configuration of hierarchical decoding apparatus 1400 according to Embodiment 13 of the present invention. This embodiment applies any one of above described Embodiments 9 to 12 to a hierarchical decoding method, and can thereby decode a code generated by the hierarchical coding method of above described Embodiment 8 and decode a high quality voice signal or audio signal. A code that is coded using a hierarchy signal coding method (not shown here) is input from input terminal 1401, separation section 1402 separates the above described code and generates a code for the first layer decoding section and a code for the spectrum decoding section. First layer decoding section 1403 decodes the decoded signal of sampling rate 2·FL using the code obtained at separation section 1402 and gives the decoded signal to upsampling section 1405. Upsampling section 1405 raises the sampling frequency of the first layer decoded signal given from first layer decoding section 1403 to 2·FH. According to this configuration, when the first layer decoded signal generated by first layer decoding section 1403 needs to be output, the first layer decoded signal can be output from output terminal 1404. When the first layer decoded signal is not necessary, output terminal 1404 can be deleted from the configuration. The code separated by separation section 1402 and first layer decoded signal after upsampling generated by upsampling section 1405 are given to spectrum decoding section 1001. Spectrum decoding section 1001 performs spectrum decoding based on one of the methods according to above described Embodiments 9 to 12, generates a decoded signal of sampling frequency 2·FH and outputs the signal from output terminal 1406. Spectrum decoding section 1001 performs processing assuming the first layer decoded signal after the upsampling given from upsampling section 1405 as a first signal. When the configuration of spectrum decoding section 1001 is the one shown in FIG. 23, the configuration of hierarchical decoding apparatus 1400a according to this embodiment is as shown in FIG. 26. The difference between FIG. 25 and FIG. 26 is in that the signal line directly input from separation section 1402 is added to spectrum decoding section 1001. This shows that the LPC coefficients decoded by separation section 1402 or pitch period P and pitch gain Pg are given to spectrum decoding section 1001. Embodiment 14 Next, Embodiment 14 of the present invention will be explained with reference to drawings. FIG. 27 is a block diagram showing the configuration of acoustic signal coding apparatus 1500 according to Embodiment 14 of the present invention. This embodiment is characterized in that acoustic coding apparatus 1504 in FIG. 27 is constructed of hierarchical coding apparatus 800 shown in above described Embodiment 8. As shown in FIG. 27, acoustic signal coding apparatus 1500 according to Embodiment 14 of the present invention is provided with input apparatus 1502, A/D conversion apparatus 1503 and acoustic coding apparatus 1504 which is connected to network 1505. The input terminal of A/D conversion apparatus 1503 is connected to the output terminal of input apparatus 1502. The input terminal of acoustic coding apparatus 1504 is connected to the output terminal of A/D conversion apparatus 1503. The output terminal of acoustic coding apparatus 1504 is connected to network 1505. Input apparatus 1502 converts sound wave 1501 which is audible to human ears to an analog signal which is an electric signal and gives it to A/D conversion apparatus 1503. A/D conversion apparatus 1503 converts an analog signal to a digital signal and gives it to acoustic coding apparatus 1504. Acoustic coding apparatus 1504 codes an input digital signal, generates a code and outputs it to network 1505. According to Embodiment 14 of the present invention, it is possible to obtain the effect as shown in above described Embodiment 8 and provide an acoustic coding apparatus which codes an acoustic signal efficiently. Embodiment 15 Next, Embodiment 15 of the present invention will be explained with reference to drawings. FIG. 28 is a block diagram showing the configuration of acoustic signal decoding apparatus 1600 according to Embodiment 15 of the present invention. This embodiment is characterized in that acoustic decoding apparatus 1603 shown in FIG. 28 is constructed of hierarchical decoding apparatus 1400 shown in above described Embodiment 13. As shown in FIG. 28, acoustic signal decoding apparatus 1600 according to Embodiment 15 of the present invention is provided with reception apparatus 1602 which is connected to network 1601, acoustic decoding apparatus 1603, D/A conversion apparatus 1604 and output apparatus 1605. The input terminal of reception apparatus 1602 is connected to network 1601. The input terminal of acoustic decoding apparatus 1603 is connected to the output terminal of reception apparatus 1602. The input terminal of D/A conversion apparatus 1604 is connected to the output terminal of voice decoding apparatus 1603. The input terminal of output apparatus 1605 is connected to the output terminal of D/A conversion apparatus 1604. Reception apparatus 1602 receives a digital coded acoustic signal from network 1601, generates a digital reception acoustic signal and gives it to acoustic decoding apparatus 1603. Voice decoding apparatus 1603 receives a reception acoustic signal from reception apparatus 1602, performs decoding processing on this reception acoustic signal, generates a digital decoded acoustic signal and gives it to D/A conversion apparatus 1604. D/A conversion apparatus 1604 converts the digital decoded voice signal from acoustic decoding apparatus 1603, generates an analog decoded voice signal and gives it to output apparatus 1605. Output apparatus 1605 converts the analog decoded acoustic signal which is an electric signal to vibration of the air and outputs it as sound wave 1606 audible to human ears. According to Embodiment 15 of the present invention, it is possible to obtain the effect as shown in above described Embodiment 13 and efficiently perform decoding the coded acoustic signal with a small number of bits and thereby output a high quality acoustic signal. Embodiment 16 Next, Embodiment 16 of the present invention will be explained with reference to drawings. FIG. 29 is a block diagram showing the configuration of acoustic signal transmission coding apparatus 1700 according to Embodiment 16 of the present invention. Embodiment 16 of the present invention is characterized in that acoustic coding apparatus 1704 in FIG. 29 is constructed of hierarchical coding apparatus 800 shown in above described Embodiment 8. As shown in FIG. 29, Acoustic signal transmission coding apparatus 1700 according to Embodiment 16 of the present invention is provided with input apparatus 1702, A/D conversion apparatus 1703, acoustic coding apparatus 1704, RF modulation apparatus 1705 and antenna 1706. Input apparatus 1702 converts sound wave 1701 which is audible to human ears to an analog signal which is an electric signal and gives it to A/D conversion apparatus 1703. A/D conversion apparatus 1703 converts an analog signal to a digital signal and gives it to acoustic coding apparatus 1704. Acoustic coding apparatus 1704 codes the input digital signal, generates a coded acoustic signal and gives it to RF modulation apparatus 1705. RF modulation apparatus 1705 modulates the coded acoustic signal, generates a modulated coded acoustic signal and gives it to antenna 1706. Antenna 1706 transmits the modulated coded acoustic signal as radio wave 1707. According to Embodiment 16 of the present invention, it is possible to obtain the effect as shown in above described Embodiment 8 and efficiently code the acoustic signal with a small number of bits. The present invention can be applied to a transmission apparatus, transmission coding apparatus or acoustic signal coding apparatus that uses an audio signal. Furthermore, the present invention can also be applied to a mobile station apparatus or base station apparatus. Embodiment 17 Next, Embodiment 17 of the present invention will be explained with reference to drawings. FIG. 30 is a block diagram showing the configuration of acoustic signal reception decoding apparatus 1800 according to Embodiment 17 of the present invention. Embodiment 17 of the present invention is characterized in that acoustic decoding apparatus 1804 in FIG. 30 is constructed of hierarchical decoding apparatus 1400 shown in above described Embodiment 13. As shown in FIG. 30, acoustic signal reception decoding apparatus 1800 according to Embodiment 17 of the present invention is provided with antenna 1802, RF demodulation apparatus 1803, acoustic decoding apparatus 1804, D/A conversion apparatus 1805 and output apparatus 1806. Antenna 1802 receives a digital coded acoustic signal as radio wave 1801, generates a digital reception coded acoustic signal which is an electric signal and gives it to RF demodulation apparatus 1803. RF demodulation apparatus 1803 demodulates the reception coded acoustic signal from antenna 1802, generates a demodulated coded acoustic signal and gives it to acoustic decoding apparatus 1804. Acoustic decoding apparatus 1804 receives a digital demodulated coded acoustic signal from RF demodulation apparatus 1803, performs decoding processing, generates a digital decoded acoustic signal and gives it to D/A conversion apparatus 1805. D/A conversion apparatus 1805 converts the digital decoded voice signal from acoustic decoding apparatus 1804, generates an analog decoded voice signal and gives it to output apparatus 1806. Output apparatus 1806 converts the analog decoded voice signal which is an electric signal to vibration of the air and outputs it as sound wave 1807 audible to human ears. According to the Embodiment 17 of the present invention, it is possible to obtain the effect as shown in above described Embodiment 13, decode a coded acoustic signal efficiently with a small number of bits and thereby output a high quality acoustic signal. As explained above, according to the present invention, by estimating a high-frequency band of a second spectrum using a filter having a first spectrum as its internal state, coding a filter coefficient when the degree of similarity to the estimated value of the second spectrum becomes a maximum and adjusting a spectral outline with an appropriate subband, it is possible to code the spectrum at a low bit rate and with high quality. Moreover, by applying the present invention to hierarchical coding, a voice signal and audio signal can be coded at a low bit rate and with high quality. The present invention can be applied to a reception apparatus, reception decoding apparatus or voice signal decoding apparatus using an audio signal. Furthermore, the present invention can also be applied to a mobile station apparatus or base station apparatus. Furthermore, each function block employed in the description of each of the aforementioned embodiments may typically be implemented as an LSI constituted by an integrated circuit. These may be individual chips or partially or totally contained on a single chip. Furthermore, LSI is adopted here, but this may also be referred to as “IC”, “system LSI”, “super LSI” or “ultra LSI” depending on the differing extents of integration. Further, the method of circuit integration is not limited to LSI's, and implementation using dedicated circuitry or general purpose processors is also possible. After LSI manufacture, utilization of an FPGA (Field Programmable Gate Array) or a reconfigurable processor where connections and settings of circuit cells within an LSI can be reconfigured is also possible. Further, if integrated circuit technology comes out to replace LSI's as a result of the advancement of semiconductor technology or a derivative other technology, it is naturally also possible to carry out function block integration using this technology. The adaptation of a biotechnology and so on may be considered as possibilities. A first mode of the spectrum coding method of the present invention is a spectrum coding method comprising a section for performing the frequency transformation of a first signal and calculating a first spectrum, a section for performing the frequency transformation of a second signal and calculating a second spectrum, a step of estimating the shape of the second spectrum in a band of FL≦k<FH using a filter which has the first spectrum in a band of 0≦k<FL as an internal state and a step of coding a coefficient indicating the filter characteristic at this time, wherein the outline of the second spectrum determined based on the coefficient indicating the filter characteristic is coded together. According to this configuration, it is only necessary to code the coefficient indicating the characteristic of the filter by estimating the high-frequency component of second spectrum S2(k) using the filter based on first spectrum S1(k) and it is possible to estimate the high-frequency component of second spectrum S2(k) at a low bit rate and with high accuracy. Moreover, since a spectral outline is coded based on the coefficient indicating the characteristic of the filter, no discontinuity of energy of the spectrum occurs and thereby it is possible to improve quality. Furthermore, a second mode of the spectrum coding method of the present invention divides the second spectrum into a plurality of subbands and codes the coefficient indicating the characteristic of the filter and the outline of the spectrum for each subband. According to this configuration, by estimating the high-frequency component of second spectrum S2(k) using the filter based on first spectrum S1(k), it is only necessary to code the coefficient indicating the characteristic of the filter and estimate the high-frequency component of second spectrum S2(k) at a low bit rate and with high accuracy. Furthermore, a plurality of subbands are predetermined and the coefficient indicating the filter characteristic and the outline of the filter are coded for each subband, and therefore it is possible to prevent discontinuity of energy of the spectrum and thereby improve quality. Furthermore, a third mode of the spectrum coding method of the present invention adopts the above described configuration in which the filter can be expressed by P ⁡ ( z ) = 1 1 - ∑ i = - M M ⁢ β i ⁢ z - T + i ( 23 ) and estimation is performed using a zero-input response of the filter. According to this configuration, it is possible to prevent collapse of the harmonic structure caused with the estimated value of S2(k) and obtain the effect of improving quality. Moreover, a fourth mode of the spectrum coding method of the present invention adopts the above described configuration in which M=0, β0=1 are assumed. According to this configuration, the characteristic of the filter is determined only by pitch coefficient T and it is possible to obtain the effect that the spectrum can be estimated at a low bit rate. Furthermore, a fifth mode of the spectrum coding method of the present invention adopts the above described configuration in which the outline of the spectrum is determined for each subband determined by pitch coefficient T. According to this configuration, since the band width of the subband is determined appropriately, it is possible to prevent discontinuity of energy of the spectrum and improve quality. Furthermore, a sixth mode of the spectrum coding method of the present invention adopts the above described configuration, in which the first signal is a signal coded and then decoded in a lower layer or a signal obtained by upsampling this signal and the second signal is an input signal. According to this configuration, it is possible to apply the present invention to hierarchical coding which is composed of a coding section with a plurality of layers and obtain the effect that an input signal can be coded at a low bit rate and with high quality. A first mode of the spectrum decoding method of the present invention is a spectrum decoding method comprising the steps of decoding a coefficient indicating the characteristic of a filter, performing the frequency transformation of a first signal to obtain a first spectrum and generating an estimated value of a second spectrum in a band of FL≦k<FH using the filter which has the first spectrum in a band of 0≦k<FL as the internal state, in which the spectral outline of the second spectrum determined based on the coefficient indicating the characteristic of the filter is decoded together. According to this configuration, it is possible to decode the code obtained by estimating the high-frequency component of second spectrum S2(k) using the filter based on first spectrum S1(k) and thereby obtain the effect that the estimated value of the high-frequency component of second spectrum S2(k) can be decoded with high accuracy. Furthermore, since the spectral outline coded based on the coefficient indicating the characteristic of the filter can be decoded, discontinuity of energy of the spectrum no longer occurs and a high quality decoded signal can be generated. Furthermore, a second mode of the spectrum decoding method of the present invention comprises the steps of dividing the second spectrum into a plurality of subbands and decoding a coefficient indicating the characteristic of the filter and the outline of the spectrum for each subband. According to this configuration, it is possible to decode the code which is coded by estimating the high-frequency component of second spectrum S2(k) using the filter based on first spectrum S1(k) and thereby obtain the effect that the estimated value of the high-frequency component of second spectrum S2(k) can be decoded with high accuracy. Furthermore, it is possible to predetermine a plurality of subbands and decode the coefficient indicating the characteristic of the filter coded and outline of the spectrum for each subband, and thereby discontinuity of energy of the spectrum is prevented and a high quality decoded signal can be generated. Moreover, a third mode of the spectrum decoding method of the present invention adopts the above described configuration in which the filter is expressed P ⁡ ( z ) = 1 1 - ∑ i = - M M ⁢ β i ⁢ z - T + i ( 23 ) and an estimated value is generated using a zero-input response of the filter. According to this configuration, it is possible to decode a code that is coded using the method of preventing collapse of the harmonic structure caused with the estimated value of S2(k) and thereby obtain the effect that decodes the estimated value of the spectrum with improved quality. Moreover, a fourth mode of the spectrum decoding method of the present invention adopts the above described configuration in which M=0, β0=1 are assumed. According to this configuration, since it is possible to decode a code that is coded by estimating the spectrum based on the filter whose characteristic is defined only by pitch coefficient T and thereby obtain the effect that the estimated value of the spectrum can be decoded at a low bit rate. Furthermore, a fifth mode of the spectrum decoding method of the present invention has a configuration in which the outline of the spectrum is decoded for each subband determined by pitch coefficient T. According to this configuration, the spectral outline calculated for each subband having an appropriate bandwidth can be decoded, and therefore it is possible to prevent discontinuity of energy of the spectrum and improve quality. Furthermore, a sixth mode of the spectrum decoding method of the present invention adopts the above described configuration in which the first signal is generated from a signal decoded in a lower layer or a signal obtained by upsampling this signal. According to this configuration, it is possible to decode a code that is coded through hierarchical coding made up of a coding section with a plurality of layers and thereby obtain the effect that a decoded signal can be obtained at a low bit rate and with high quality. The acoustic signal transmission apparatus of the present invention adopts a configuration comprising an acoustic input apparatus that converts an acoustic signal such as a music sound and voice to an electric signal, an A/D conversion apparatus that converts a signal output from an acoustic input section to a digital signal, a coding apparatus that performs coding using a method including one spectral coding scheme according to one of claims 1 to 6 which performs coding on the digital signal output from this A/D conversion apparatus, an RF modulation apparatus that performs modulation processing or the like on the code output from this acoustic coding apparatus and a transmission antenna that converts a signal output from this RF modulation apparatus to a radio wave and transmits the signal. According to this configuration, it is possible to provide a coding apparatus that performs coding efficiently with a small number of bits. The acoustic signal decoding apparatus of the present invention adopts a configuration including a reception antenna that receives a reception radio wave, an RF demodulation apparatus that performs demodulation processing on the signal received from the reception antenna, a decoding apparatus that performs decoding processing on information obtained by the RF demodulation apparatus using the method including one spectrum decoding method according to claims 7 to 12, a D/A conversion apparatus that D/A-converts the digital acoustic signal decoded by the acoustic decoding apparatus and an acoustic output apparatus that converts an electric signal output from the D/A conversion apparatus to an acoustic signal. According to this configuration, it is possible to decode a coded acoustic signal efficiently with a small number of bits and thereby output a high quality hierarchical signal. The communication terminal apparatus of the present invention adopts a configuration comprising at least one of the above described acoustic signal transmission apparatuses or above described acoustic signal reception apparatuses. The base station apparatus of the present invention adopts a configuration comprising at least one of the above described acoustic signal transmission apparatuses or above described acoustic signal reception apparatuses. According to this configuration, it is possible to provide a communication terminal apparatus or a base station apparatus that codes an acoustic signal efficiently with a small number of bits. Furthermore, this configuration can also provide a communication terminal apparatus or base station apparatus capable of decoding a coded acoustic signal efficiently with a small number of bits. This application is based on Japanese Patent Application No. 2003-363080 filed on Oct. 23, 2003, entire content of which is expressly incorporated by reference herein. INDUSTRIAL APPLICABILITY The present invention can code a spectrum at a low bit rate and with high quality and is suitable for use in a transmission apparatus or reception apparatus or the like. Further, applying the present invention to hierarchical coding enables a voice signal or audio signal to be coded at a low bit rate and with high quality, which is suitable for use in a mobile station apparatus, base station apparatus or the like in a mobile communication system.

<SOH> BACKGROUND ART <EOH>A voice coding technique and audio coding technique which compresses a voice signal or audio signal at a low bit rate are important for the effective utilization of a transmission path capacity of radio wave or the like in a mobile communication and a recording medium. Voice coding for coding a voice signal includes schemes such as G726 and G729 standardized in the ITU-T (International Telecommunication Union Telecommunication Standardization Sector). These schemes target narrow band signals (300 Hz to 3.4 kHz) and can perform high quality coding at 8 kbits/s to 32 kbits/s. However, because such a narrow band signal has a frequency band as narrow as a maximum of 3.4 kHz, and as for quality, sound is muffled and lacks a sense of realism. On the other hand, in the field of voice coding, there is a scheme which targets a wideband signal (50 Hz to 7 kHz) for coding. Typical examples of such a method include G722, G722.1 of the ITU-T and AMR-WB of the 3GPP (The 3rd Generation Partnership Project) and soon. These schemes can perform coding on a wideband voice signal at a bit rate of 6.6 kbits/s to 64 kbits/s. When the signal to be coded is a voice, a wideband signal has relatively high quality, but it is not sufficient when an audio signal is the target or when a quality with a high sense of realism is required for the voice signal. Generally, when a maximum frequency of a signal is approximately 10 to 15 kHz, a sense of realism equivalent to that of FM radio is obtained and quality comparable to that of a CD is obtained if the frequency is on the order of 20 kHz. Audio coding represented by the layer 3 scheme and the AAC scheme standardized in MPEG (Moving Picture Expert Group) and so on is suitable for such a signal. However, in case of these audio coding schemes, the bit rate increases because the frequency band to be coded is widened. The National Publication of International Patent Application No. 2001-521648 describes a technique of reducing an overall bit rate by dividing an input signal into a low-frequency band and a high-frequency band and substituting the high-frequency band by a low-frequency band spectrum as the method of coding a wideband signal at a low bit rate and with high quality. The state of processing when this conventional technique is applied to an original signal will be explained using FIGS. 1A to D. Here, a case where a conventional technique is applied to an original signal will be explained to facilitate explanations. In FIGS. 1A to D, the horizontal axis shows a frequency and the vertical axis shows a logarithmic power spectrum. Furthermore, FIG. LA shows a logarithmic power spectrum of the original signal when a frequency band is limited to 0≦k<FH, FIG. 1B shows a logarithmic power spectrum when the band of the same signal is limited to 0≦k<FL (FL<FH), FIG. 1C shows a case where a spectrum in a high-frequency band is substituted by a spectrum in a low-frequency band using the conventional technique and FIG. 1D shows a case where the substituted spectrum is reshaped according to spectral outline information. According to the conventional technique, the spectrum of the original signal ( FIG. 1A ) is expressed based on a signal having a spectrum of 0≦k<FL ( FIG. 1B ), and therefore the spectrum of the high-frequency band (FL≦K<FH in this figure) is substituted by the spectrum of the low-frequency band (0≦k<FL) ( FIG. 1C ). For simplicity, a case assuming that there is a relationship of FL=FH/2 is explained. Next, the amplitude value of the substituted spectrum in the high-frequency band is adjusted according to the spectrum envelope information of the original signal and a spectrum obtained by estimating the spectrum of the original signal is determined ( FIG. 1D ).

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1A shows a conventional bit rate compression technique; FIG. 1B shows a conventional bit rate compression technique; FIG. 1C shows a conventional bit rate compression technique; FIG. 1D shows a conventional bit rate compression technique; FIG. 2A shows a harmonic structure of a spectrum of a voice signal or audio signal; FIG. 2B shows a harmonic structure of a spectrum of a voice signal or audio signal; FIG. 3A shows discontinuity of energy produced when adjusting the spectral outline; FIG. 3B shows discontinuity of energy produced when adjusting the spectral outline; FIG. 4 illustrates a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 1; FIG. 5 illustrates a process of calculating an estimated value of a second spectrum through filtering; FIG. 6 illustrates a processing flow at the filtering section, search section and pitch coefficient setting section; FIG. 7A shows an example of the state of filtering; FIG. 7B shows an example of the state of filtering; FIG. 7C shows an example of the state of filtering; FIG. 7D shows an example of the state of filtering; FIG. 7E shows an example of the state of filtering; FIG. 8A shows another example of the harmonic structure of a first spectrum stored in the internal state; FIG. 8B shows a further example of the harmonic structure of the first spectrum stored in the internal state; FIG. 8C shows a still further example of the harmonic structure of the first spectrum stored in the internal state; FIG. 8D shows a still further example of the harmonic structure of the first spectrum stored in the internal state; FIG. 8E shows a still further example of the harmonic structure of the first spectrum stored in the internal state; FIG. 9 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 2; FIG. 10 illustrates a state of filtering according to Embodiment 2; FIG. 11 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 3; FIG. 12 illustrates a state of processing of Embodiment 3; FIG. 13 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 4; FIG. 14 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 5; FIG. 15 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 6; FIG. 16 is a block diagram showing the configuration of a spectrum coding apparatus according to Embodiment 7; FIG. 17 is a block diagram showing the configuration of a hierarchic coding apparatus according to Embodiment 7; FIG. 18 is a block diagram showing the configuration of a hierarchic coding apparatus according to Embodiment 8 ; FIG. 19 is a block diagram showing the configuration of a spectrum decoding apparatus according to Embodiment 9; FIG. 20 illustrates the state of a decoded spectrum generated from the filtering section according to Embodiment 9; FIG. 21 is a block diagram showing the configuration of a spectrum decoding apparatus according to Embodiment 10; FIG. 22 is a flow chart of Embodiment 10; FIG. 23 is a block diagram showing the configuration of a spectrum decoding apparatus according to Embodiment 11; FIG. 24 is a block diagram showing the configuration of a spectrum decoding apparatus according to Embodiment 12; FIG. 25 is a block diagram showing the configuration of a hierarchic decoding apparatus according to Embodiment 13; FIG. 26 is a block diagram showing the configuration of the hierarchic decoding apparatus according to Embodiment 13; FIG. 27 is a block diagram showing the configuration of an acoustic signal coding apparatus according to Embodiment 14; FIG. 28 is a block diagram showing the configuration of an acoustic signal decoding apparatus according to Embodiment 15; FIG. 29 is a block diagram showing the configuration of an acoustic signal transmission coding apparatus according to Embodiment 16; and FIG. 30 is a block diagram showing the configuration of an acoustic signal reception decoding apparatus according to Embodiment 17 of the present invention. detailed-description description="Detailed Description" end="lead"?

20060418

20110524

20070329

64568.0

H04K110

VO, DON NGUYEN

SPECTRUM CODING APPARATUS, SPECTRUM DECODING APPARATUS, ACOUSTIC SIGNAL TRANSMISSION APPARATUS, ACOUSTIC SIGNAL RECEPTION APPARATUS AND METHODS THEREOF

UNDISCOUNTED

ACCEPTED

H04K

ACCEPTED

Securing digital content system and method

A system and method of encrypting digital content in a digital container and securely locking the encrypted content to a particular user and/or computer or other computing device is provided. The system uses a token-based authentication and authorization procedure and involves the use of an authentication/authorization server. This system provides a high level of encryption security equivalent to that provided by public key/asymmetric cryptography without the complexity and expense of the associated PKI infrastructure. The system enjoys the simplicity and ease of use of single key/symmetric cryptography without the risk inherent in passing unsecured hidden keys. The secured digital container when locked to a user or user's device may not open or permit access to the contents if the digital container is transferred to another user's device. The digital container provides a secure technique of distributing electronic content such as videos, text, data, photos, financial data, sales solicitations, or the like.

1. A method of securely delivering data, comprising the steps of: creating a container having electronic content and a container identifier; encrypting at least one data block of the electronic content using a symmetric encryption technique and encrypting a header associated with a first data block of the electronic content using an asymmetric encryption technique, the header including a symmetric decryption key; and re-keying the header using data associated with a user or a user's device to lock at least a portion of the electronic content to the user or the user's device, wherein the locked at least a portion of the electronic content can only be decrypted and accessed by the user or on the user's device when the user or user's device has been authenticated against at least the container identifier. 2. A system for securely delivering data, comprising at least one component to: create a container having electronic content and a container identifier; encrypt at least one data block of the electronic content using a symmetric encryption technique and to encrypt a header associated with a first data block of the electronic content using an asymmetric encryption technique, the header including a symmetric decryption key; and re-key the header using data associated with a user or a user's device to lock at least a portion of the electronic content to the user or the user's device, wherein the locked at least a portion of the electronic content can only be decrypted and accessed by the user or on the user's device when the user or user's device has been authenticated against at least the container identifier. 3. A computer program product comprising a computer usable medium having readable program code embodied in the medium, the computer program product includes at least one component to: create a container having electronic content and a container identifier; determining at least one data block for partitioning the electronic content; encrypt the at least one data block of the electronic content using a symmetric encryption technique and to encrypt a header associated with a first data block of the electronic content using an asymmetric encryption technique, the header including a symmetric decryption key; re-key the header using data associated with a user or a user's device to lock at least a portion of the electronic content to the user or the user's device, wherein the locked at least a portion of the electronic content can only be decrypted and accessed by the user or on the user's device when the user or user's device has been authenticated against at least the container identifier; and decrypt the locked portion of the electronic content when the user or user's device has been authenticated.

BACKGROUND OF THE INVENTION 1. Field of the Invention The invention generally relates to encrypting digital content, and more specifically, to securely locking encrypted digital media to a particular user, computer or other computing device. 2. Background Description Any owner or distributor of secure or copyrighted digital content, i.e., electronic data in any form, may face several problems concerning the encryption of the data and the method of access that is provided to an end user. The owner or distributor typically is compelled to provide a robust method of encryption while remaining within a system that is relatively easy and simple for users to operate. In order to be relatively effective and/or easy to use, the system provided by owners or distributors must typically allow users to repeatedly access the material while requiring that they undergo an authentication, approval or payment process under a set of rules determined by the content owner. For example, the user may access the content an unlimited number of times after approval, or the user may have to regain approval after a certain number of accesses and/or a after a certain amount of time has passed. Normally, content owners require substantial confidence and assurance that once approved for access by a particular user on a particular device the content cannot be freely accessed by another user especially if the content is transmitted to another machine or device. Currently, most content originators and distributors utilize a Public Key Infrastructure, or PKI system, to accomplish these functions. The PKI system utilizes public key or asymmetric cryptography in which a public key and a private key are produced at the time that the content file is encrypted. This PKI system typically has the following properties or requires the use of: (i) A certificate authority that issues and verifies a digital certificate. A digital certificate includes the public key, information about the public key or other licensing information. (ii) A registration authority that acts as the verifier for the certificate authority before a digital certificate is issued to a requestor. (iii) One or more directories where the certificates (with their public keys) are held. (iv) A certificate management system. This PKI system is quite complex and very often is an operational and financial burden for content originators, distributors and users. An alternative encryption system is symmetric cryptography. A symmetric system utilizes a secret or hidden key that is shared by both the sender and recipient of the encrypted data. While much simpler to use and substantially less costly to implement, a common drawback may be that if the secret key is discovered or intercepted, the encrypted data can easily be decrypted and stolen. However, if a method and system for protecting the secret key, itself, can be provided so that the secret key is not exposed to discovery or interception, including an end user, then a very reliable and effective procedure and system for securely delivering electronic content is possible while avoiding the significant burdens of a PKI infrastructure. SUMMARY OF THE INVENTION An aspect of the invention provides a method for creating a digital container and encrypting the contents of the digital container with a symmetric encryption technique. The method also provides for protecting the symmetric decryption keys by inserting the symmetric decryption keys into header associated with a data block in the digital container and encrypting the header using an asymmetric encryption algorithm. Upon an attempted access of the container by a user, the header is re-encrypted using data from the user's device and/or the user so that the contents of the digital container are now locked to the user's device or to the user. Transaction data such as credit card information or account information may also be obtained from the user, perhaps for paying for the contents of the container or other service, which may be verified and used to gain access to the contents. Once the container has been locked to the user's device or user, the container may only be opened and accessed on that device or by that user. If the digital container were to be transmitted to another device, the digital container recognizes that the footprint of the device has changed or the user is different and may not open until a re-authorization has been performed which may involve a financial transaction. A further aspect of the invention includes a system for creating a digital container and encrypting the contents of the digital container with a symmetric encryption technique. The system also provides for protecting the systemic decryption keys by inserting the symmetric decryption keys into header associated with a data block in the digital container and encrypting the header using an asymmetric encryption algorithm. Upon an attempted access of the container by a user, the system re-encrypts the header using data from the user's device such as a machine footprint and/or the user such as a client fingerprint so that the contents of the digital container are now locked to the user's device or to the user. The system may also acquire transaction data such as credit card information or account information from the user, perhaps for paying for the contents of the container or other service, which may be verified and used to gain access to the contents. Once the container has been locked to the user's device or user, the system provides that the container may only be opened and accessed on that device or by that user. If the digital container were to be transmitted to another device, the system recognizes that the footprint of the device has changed or the user is different and may not open until a re-authorization has been performed which may involve a financial transaction. In another aspect of the invention, a computer program product comprising a computer usable medium having readable program code embodied in the medium is provided. The computer program product includes at least one component to create a digital container and to encrypt the contents of the digital container with a symmetric encryption technique. The at least one component also protects the symmetric decryption keys by inserting the symmetric decryption keys into header associated with a data block in the digital container and encrypting the header using an asymmetric encryption algorithm. Upon an attempted access of the container by a user, the at least one component re-encrypts the header using data from the user's device and/or the user so that the contents of the digital container are now locked to the user's device or to the user. The at least one component may also obtain transaction data such as credit card information or account information from the user, perhaps for paying for the contents of the container or other service, which may be verified and used to gain access to the contents. Once the container has been locked to the user's device or user, the container may only be opened and accessed on that device or by that user. DESCRIPTION OF THE DRAWINGS FIG. 1 is a functional block diagram of an embodiment of the system of the invention; FIG. 2 is a functional block of an embodiment showing registration and encryption of a secure digital container (SDC), according to the invention; FIG. 3 is a functional block diagram of a user's device, according to the invention; FIG. 4 is an illustrative embodiment of a Graphical User Interface (GUI), according to the invention; FIG. 5 is a functional block diagram of an embodiment of a container authentication and permission token generation process, according to the invention; FIG. 6 is an illustration of an embodiment of a permission token, according to the invention; FIG. 7 is a functional block diagram of an embodiment of a decryption process, according to the invention; FIGS. 8A and 8B are flow diagrams of an embodiment showing steps of using the invention; and FIG. 9 is a flow diagram of an embodiment showing steps of using the invention. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION The invention provides a system and method of encrypting electronic content using symmetric encryption without exposing the decryption key to discovery or interception. In embodiments, delivery of the electronic content from a creator to an end user may be accomplished by digital containers that employ protected key symmetric encryption. The invention combines the robustness equivalent to PKI encryption but with the simplicity and cost effectiveness of symmetric/secret key cryptography. U.S. Provisional Application Ser. No. 0/512,091, filed October 20, 2003 is incorporated by reference herein in its entirety. An aspect of the invention involves a unique process that is used to “re-key” the “hidden” keys sent with the electronic content, often in digital containers, with a value that contains data specific to the user and/or the user's device. This “re-keying” (i.e., re-encrypting) is typically performed on the user's device without ever exposing the content in an unencrypted form, thus the keys themselves are maintained securely and eliminates the potential for compromising the electronic data and/or the keys. During “re-keying”, the “re-keyed” keys may also be associated with the original user's device in such a way as to effectively inhibit any unauthorized assess to the electronic content. This is especially useful, if and when, the electronic content might be further propagated to other user's devices, such as by email, copied disks, or peer-to-peer communications, for example. These other users are effectively denied access to the electronic content since the electronic content has been re-keyed and associated with the original user and/or original user's device. After the “re-keying” process executes, the content inside the container is “locked” to a particular device and/or a particular user. FIG. 1 is a functional block diagram of an embodiment of the system of the invention, generally denoted by reference numeral 100. FIG. 1 also illustrates several steps associated with processes of the invention. The system 100 includes a content originator device 105 which includes a container creation application 110 (which may alternatively execute on a server or separate container creation computer) and content file or files 115 such as video, text, streaming media, audio, animation, music, financial transaction data, or any other type of data for inclusion in the production of a secure digital container (SDC) 120. The container creation application 110 also provides for encrypting electronic content such as the content files 115. Further included in the system 100 is a user's device 125 (e.g., a computer controlled device such as a personal computer, a cable receiver box, compact disk (CD) player, television, digital video disk (DVD) player, satellite receiver, personal digital assistant (PDA), or the like) that may receive the electronic content 115, typically via a SDC 120. In embodiments, the SDC 120 may be delivered to a user's computer via a CD or DVD. The user's device 125 may be interconnected via a network 150, such as the Internet, for transmission of the SDC 120 to the user's device 125. The network may be any type of network such as wired, wireless, phone system, or the like. The SDC 120 may be delivered via any number of various known techniques including website download, peer-to-peer download, email, instant messaging (IM), file transfer protocols, or the like. (For clarity, once the SDC 120 has been transmitted or is otherwise present on the user's device, the SDC on the user's device is denoted by reference numeral 120′) The user's device 125 also includes memory 130 for storing various data items such as digital rights management (DRM) data and a Client Fingerprint Mode Flag (CFMF), also described in more detail below. The user's device 125 may also include a hard drive, compact disk (CD) drives or a digital video disk (DVD) drive, generally denoted by reference numeral 135. The user's device 125 may also include an external hardware identification device 140 for providing input for authenticating a user such as a biometric authentication device or card reader, for example. The system 100 may also include a container authentication server 160, which in embodiments, may oversee operations of a container registration database 165. In embodiments, database 165 may be distributed. The container authentication server also manages attempts to open the container by a user and coordinates permissions, authentications and portions of the re-keying sequences of a digital container using the container ID and container registration database 165. This may also include managing financial transactions associated with the container assess. Also included in the system 100 may be a transaction server 180 (e.g., an IPayment, Inc. Gateway server) for receiving financial transaction requests such as credit card or debit transactions when a user chooses to purchase a service or item controlled by the SDC 120′, and for providing a response to the request which validates a purchase, as described more fully below. In one application, the container creation application 110 encrypts the one or more content files 105 (or any subset of the content files) and incorporates the one or more content files 105 into the secure digital container 120. Once the SDC 120 has been constructed, usage rights parameters as selected by the content originator, along with other SDC registration data, may be stored in the container registration database 165, as denoted by reference numeral 170. The usage rights may include, but not limited to, limiting accesses to the content files to a certain number of occurrences, limiting access to a period of time, limiting copying of the content files (or portions thereof), limiting the copying to a secondary device, limiting the burning of the content file to storage media such as CD or DVD or controlling printing, to name a few. Once the SDC 120 is transmitted or released to a user (or users), or perhaps to an Internet site to be discovered and downloaded by users or potential customers of the electronic content, a user may attempt to open the SDC 120′ on their device 125 (or attempts to open portions of the SDC 120′). When the attempt to access or open the SDC 120′ occurs, executable code either in the SDC 120′ or already on the user's device opens a secure link to the container verification server 160 and sends an authorization request message 190. This authorization request message 190 includes data specific to the user or the user's device. This authorization request message 190 may also include financial transaction information, such as credit/debit card data or user identification data (e.g., account numbers, social security numbers, telephone numbers, alias names, or the like) perhaps for Internet payment services such as online payment services provided by PayPal™, Inc, or the like. If a financial transaction is involved, then this data may be sent to the transaction server 180 (e.g., an iPayment, Inc. Gateway server, or the like) in a financial transaction request message 192. Once this request is processed, transaction approval or denial data may be returned to the container authentication server 160 in a financial transaction response message 194. After receiving the financial transaction response message 194, the container authentication server 160 may create an authentication request response called a permission token message, as denoted by reference numeral 196. This permission token message contains a permission token that is typically a relatively small bit string that includes the financial transaction approval or denial data, the contents usage rights data, permission flags and re-encryption data that is now unique to both the SDC 120′ and the user and/or the user's device, as explained more fully below. When the permission token 196 is returned to the SDC 120′ on the user's device 125, the container executable code may read the token bit string and may write the usage rights data and a permission flag called a client fingerprint mode flag (CFMF) to a confidential (e.g., unpublished or hidden) location such as memory 130 on the user's device 125. Alternatively, this confidential location may be a storage device such as a disk, DVD, or external storage device. Once this CFMF and usage rights data have been stored, any future or subsequent attempt to re-open the container causes the container executable code to detect the stored CFMF resulting in the SDC 120′ opening, potentially limited by the usage rights data, without having to repeat the authentication process. The function of the CFMF and the usage rights data will be discussed in greater detail below. Also, when the container executable code receives the re-encryption data, the container executable code uses the re-encryption data (i.e., returned with the permission token) to re-encrypt a core or selected part of the encrypted content file(s). This re-encryption process (described more fully below) provides unique aspects to controlling and shielding the electronic content and encryption/decryption process when the selected segment of the content file(s) is re-encrypted with a value that contains data specific to the SDC 120′ and the user and/or the user's device 125. This re-encryption process is performed on the user's device without ever exposing the contents in an unencrypted form and shields the contents and the encryption keys from piracy, unauthorized access, theft or intrusion with a high degree of confidence. Since all user devices are considered to be insecure environments, it may be said that this process re-encrypts the data in a secure way in an insecure environment. After this process is executed, the content inside the SDC 120′ is “locked” to a particular device (e.g., device 125) and/or a particular user. Thereafter, the SDC 120′ can never be sent (perhaps by email, physical delivery, or other electronic delivery) to a different user and/or another user device and opened successfully without undergoing a new authentication process. FIG. 2 is a functional block diagram of an embodiment showing registration and encryption of a SDC, according to the invention, generally denoted by reference numeral 200. FIG. 2 also illustrates certain steps of the registration and encryption process, according to the invention. The container creation application 105 evaluates the content file(s) 115 as selected or composed by a container creator and determines an appropriate number of data blocks for partitioning the content files and to be used to encrypt these files. The number of data blocks to be encrypted may be related to the type of device being targeted (e.g., a cable box, personal computer, or other type of device), number of files being encrypted, or overall amount of data being encrypted, or as requested by a container creator, for example. The data block concept typically increases speed and efficiency of the decryption process. Also, the data block concept provides an ability to encrypt only parts of the electronic content instead of the entirety and also permits portions of the content to be optionally accessed by a user prior to any decryption. For example, if a large media file, such as a feature length motion picture is being decrypted, the user may be able to use a media player to jump to any point in the film and begin to view it without waiting for the entire file to be decrypted. Another example may be when advertisement segments, such as previews, are presented to a user prior to decryption. It should be clear by these examples that essentially any portion of the electronic material may be selected by the container creator and marked as “unencrypted,” as appropriate. Once the content file or files 115 are divided into data blocks, a symmetric encryption algorithm 112 may be used to encrypt each individual data block resulting in one or more encrypted data blocks 1-N, 230a-230c. The encryption process and insertion into the SDC 120 for each encrypted data block 230a-230c is represented by reference numerals 245a-245c, respectively. Commercially available symmetric encryption algorithms such as, for example, Blowfish™, Twofish™, Rijndael™, Serpent™ or Triple DES™ may be used. The container creation application 105 may be designed in a modular fashion, so that the encryption algorithm modules can be upgraded as new encryption technology becomes available. As part of the symmetric encryption process, the symmetric key used to encrypt the data blocks 230a-230c, and which subsequently is to be used to decrypt these data blocks, is then inserted or “hidden” in the header of the first data block 230a, as denoted by reference numeral 240. In embodiments, this convention might include using another data block other than the first data block. After the data block(s) encryption is completed, an asymmetric encryption algorithm 205 is used to encrypt the header 231 of the first data block and render the hidden symmetric key inaccessible and secure during transmission, delivery or use. This process is denoted by reference numeral 235. Any secure asymmetric encryption algorithm, such as ElGamal, may be used for this function. The asymmetric encryption algorithm 205 generates two decryption keys, called the primary and secondary keys 250 and 252, respectively, and are stored in a record 225 in the container registration database 165 on the container verification server 160. The primary 250 and secondary key 252 are associated with the corresponding unique SDC 120 via digital container ID 210 (e.g., 12345). Reference numeral 220 denotes the logical association of the digital container ID 210, the primary key 250 and the secondary key 252 for each unique record in the container registration database 165. There may be a plurality of entries in the container registration database for many different digital containers and associated keys, as one of ordinary skill in the art would recognize. This illustration shows but one example. These keys may be produced based on data, in whole or in part, from the particular container ID 210. In this way, these decryption keys are made unique to that particular container. The digital container ID may be of various lengths such as, for example, 32-64 bytes, but any appropriate length may be used depending on anticipated total numbers of digital containers that may be created overall. The digital container ID may also be organized by series such that different producers of digital containers may acquire or purchase unique series (or a range) of digital container IDs, thus avoiding potential conflicts in digital container IDs. In embodiments, the data block concept might be modified to insert different symmetric keys into the encrypted headers of multiple data blocks. For example, the data blocks may be divided into uniquely encrypted sets. Each set would be encrypted with a symmetric key unique to that set. A number of data blocks equal to the number of uniquely encrypted data block sets may then be used to store these unique symmetric keys in their header. These headers may, in turn, be encrypted with a similar number of asymmetric encryption keys sets. These keys sets may all be stored in the container registration database record for the container in question. As a result, a similar number of fingerprint keys may be created for the token assembly and eventual decryption process. Hence, this technique may be used to effectively eliminate reverse engineering and/or “hacking.” This technique may also be used to allow various content files to be decrypted independently of the other content files in the container such that this scheme may be used to limit access to various independent content files within a container according to date, sequence, user or any combination of these factors. FIG. 3 is a functional block diagram of a user's device, according to the invention, generally denoted by reference numeral 125. FIG. 3 is also discussed in relation to FIGS. 1 and 2. The user's device 125 may include a SDC 120′ (which may have been received via a transmission, for example) having a digital container ID 210 and may also include a container code module 302 (i.e., executable code). The user device 125 also includes appropriate system hardware 310 such as a central processing unit (CPU), network interface, power, etc. for general operations. Also included in the user's device 125 may be an operating system (OS) 315 suitable for the type of user device, a special security chipset 320 for securely storing keys, a smart card 305 and smart card reader 306 for alternatively providing user identification data, a memory 130 for storage of encrypted usage rules 325 and the CFMF 330. The memory 130 may be logically segregated or unique to the user device 125 and may or may not be under control of the OS 315, depending on the device type and OS type. When the digital container 120′ is received at a user's computer or device 125 and the user attempts to access the protected content of the SDC 120′, executable instructions 302 resident in the SDC (or perhaps already present on the user's device) searches for the CFMF 330. The CFMF 330 may already be present if the container had been previously approved to be opened on the device 125. If the SDC 120′ has not been approved previously, the CFMF 330 is not found and the container code module 302 begins an approval process. In embodiments, the user might also be prompted to input various biometric measurement parameters such as fingerprints and/or retina scans in place of or in addition to the manual data input via a biometric measurement device 140. In this fashion, a variety of multi-factor authentication modes is possible for increasing the security of the authentication process The executable instructions of the container code module 302 may also read data from the user's device 125 to create a machine footprint 335. The machine footprint 335 is derived from sources on the user's computer or device such as, but not limited to, the following: Bios version OS version Network Interface Card (NIC) ID System Name System Manufacturer System Model Processor Name or ID number User Name Physical memory identification data Disk drive model name or ID Display name In embodiments, unique user identification data may also be read from an “smart” card 305 that is inserted into the user's CD-ROM drive or other external memory reading device 306. This card 305 has a read/write memory capacity and may be used to store user identification data and secure financial transaction data. The container code module 302 may be programmed to read data from this card 305 and include this information in the machine footprint 335, if the card 305 is available. Data from this card 305 may be used to lock the contents of the SDC 120′ to a particular user instead of a particular device. In this manner the user may securely pay for and access protected contents on any machine such as a device made available for multiple users or public use. transaction data, such as account numbers, that may be used to purchase the contents of the container and/or products/services represented by the contents of the SDC 120′. When the user has completed entering the form data 405 in the data input/e-commerce screen (e.g., GUI 400) and presses the “Send” button 410 on the GUI 400, the SDC 120′ opens up a secure SSL link 350 to the container authentication server 160 and transmits the client fingerprint 340 and the secure user input data 345 (i.e., from user input data 405) as part of the authorization request 190. In embodiments, the user input data 405 is never stored on the user's device and is therefore securely protected throughout processing. In other SDC embodiments, user data input is not required and the process is initiated when the user attempt to open the container, by-passing prompting for user input. In this case, no user input data is sent to the container authentication server 160 with the client fingerprint 340. FIG. 5 is a functional block diagram of an embodiment of a container authentication and permission token generation process, according to the invention, generally denoted by reference numeral 500. FIG. 5 also shows certain steps of the process, which may be considered in view of FIGS. 1-4. When the container verification server receives the authorization request, any secure user input data 345 (e.g., financial transaction data) that may be included is sent to a transaction processing module 555. This transaction processing module 555 assembles a financial transaction request, if appropriate, and securely transmits it to the transaction server for transaction processing, as represented by reference numeral 192. The container authentication server also reads the client fingerprint data 340 as received from the SDC executable code and sends it to a CFMF algorithm module 550. This CFMF algorithm module randomly selects a portion of the machine footprint data creating a machine footprint subset 335′, and separately creates a In another version of the invention, the container code module 302 may be programmed to read unique identification data from specialized security chipset 320 on the user's device 125. This unique identification data may be written to a protected area of the chipset 320 which cannot be accessed or altered by the user. This kind of protected identification data may be included in the machine footprint 335 and may be used to maximize security. An example of this type of application may be the secure distribution of data to a predetermined set of recipients. Each of these recipients might be furnished with a device that utilizes a specialized chipset 320 containing protected identification data so that when the machine footprint 335, computed during an authenticating phase, does not reflect the special identification data read from these protected chips, access to the contents is denied or restricted. User data may also be used to capture user data via a data input screen (e.g., GUI) 400 to create secure user input data 345. An example of GUI 400 is described below in reference to FIG. 4. Once the appropriate machine footprint data has been selected and read, the executable instructions of the container code module 302 creates the “client fingerprint” 340. The client fingerprint 340 includes the machine footprint data 335 and the unique container ID 210. FIG. 4 is an illustrative embodiment of a Graphical User Interface (GUI), according to the invention, generally denoted by reference numeral 400. The approval process may include displaying the data input/e-commerce GUI 400 to the user. This GUI 400 may be tailored according to particular targeted users or applications and may include prompts for user input data 405 such as credit/debit card numbers, expiration dates, name, address, email address or other identifying information, as appropriate. The user may also be prompted to enter demographic data or financial CFMF 330. The CFMF 330 value may be made unique by using the container ID read from the client fingerprint 340 via a randomizing function. The CFMF 330 is then processed by a fingerprint key algorithm module 560. This module 560 first concatenates the CFMF 330 value, the machine footprint subset 335′ data and the container ID 210 into a single value. This value may be processed by a cryptographic one-way hashing function to create a fingerprint key 565. Examples of suitable hashing functions include Secure Hash Algorithm (SHA-1) and Message-Digest algorithm (MD5), as generally known by a skilled artisan. The primary and secondary decryption keys, respectively, for the encrypted first data block 230a of the SDC 120 are then retrieved from the container registration database that were previously stored during the container registration process. An atomic proxy encryption algorithm 570, a generally known technique, combines these keys (e.g., 250, 252) with the fingerprint key 565 to produce an atomic proxy re-key value 580. An atomic proxy algorithm is typically an encryption function that can re-encrypt data on any insecure machine in a secure manner. Thus, the encrypted data (e.g., data blocks 230a-230c) may be re-encrypted while data remains secure at all times. The data is never left unprotected or exposed. Further, the usage rights parameters for the container may be read from the container registration database 165. These parameters describe usage rules such as the number of times the user may access the contents, a period of time in which the user may access the contents, as applied to portions or the entire contents. The usage parameters may also include any subscription data that might allow the user to access other containers involved in a subscription grouping. This may be accomplished by grouping ranges of containers in to a series. These usage rights parameters may be encrypted by a symmetric encryption algorithm 575. The previously created fingerprint key 565 may be used as the encryption key for this process. The resulting encrypted usage rules 585 data may then be provided to the token assembler 590. The previously created atomic proxy re-key value 580 may also be sent to the token assembler 590 along with a permission flag data string 594 (also known as an installation flag) and any encrypted financial transaction response 194 data, previously created by the transaction server 180. The permission flag data string 594 determines whether the container code module (i.e., executable code) grants or denies access to the protected container (e.g., SDC 120′) contents. Other functions might include determining what approval, denial or error message may be presented to the user. The financial transaction response data provides data that might be displayed in transaction approval or denial message when presented to the user. This financial transaction response data may include credit/debit card acceptance or rejection codes as well as purchase confirmation data. The token assembler 590 also constructs a permission token 600. The permission token is typically a string of bytes that may include, but is not limited to: i) header bytes that identify the start of the permission token data string and perform a handshake function. ii) the installation permission flag. iii) the atomic proxy re-key value. iv) the Client Fingerprint Mode Flag. v) the encrypted usage rights data. vi) the encrypted financial transaction response data. vii) trailer bytes that identify the end of the permission token data string. FIG. 6 is an illustration of an embodiment of a permission token, according to the invention, generally denoted by reference numeral 600. The exemplary permission token 600 includes fields for a header 605 to indicate the beginning of the token, an installation permission flag 610, an atomic proxy re-key value 615, a client fingerprint mode flag 620, digital rights management rules data 625, a financial transaction response data 630, and a trailer 635 to indicate the end of the token. These fields of the permission token 600 are built by the token assembler 590, previously described, for transmission in a message to the SDC on the user's device. The use of these fields at the user's device is described in relation to FIG. 7. FIG. 7 is a functional block diagram of an embodiment of a decryption process, according to the invention. FIG. 7 also shows certain steps of the decryption process. The permission token 600 is returned to the user's device via a permission token message (e.g., message 196 of FIG. 1) and read by the container executable instructions. The encrypted usage rules data 625 and the CFMF 620 are then stored in a confidential or “hidden” location 130 located on or associated with the user's device 125 as encrypted usage rules data 585 and CFMF 330, respectively. The executable instructions of the container code module may read the atomic proxy re-key value 615 from the token 600. An atomic proxy algorithm 705 uses this re-key value 615, along with the unique container ID 210 read from the container, to securely re-encrypt the encrypted header of data block 1, as denoted by reference numeral 715. This one-time operation locks the encrypted content data to the user and/or the user's device 125 and takes place without ever exposing the content data in unencrypted form. The executable instructions employ a machine footprint algorithm 720 that uses the CFMF 330 value to determine what subset 722 of the original machine footprint sources is used to create the machine footprint subset 720 that matches the similar subset created on the container authentication server 160 during the token assembly process. Once the machine footprint subset 722 is determined, it is used by the machine footprint module 720 to create the fingerprint key 730. The fingerprint key 730 is used by an asymmetric encryption algorithm 735 to decrypt the re-encrypted header of the first content data block 231. Once the header decryption process is completed, the fingerprint key 730 may be discarded and therefore no decryption key is stored on the user's machine and available for hacking or reverse engineering. Throughout this process, the container and its content(s) are securely locked to the user's machine 125. Since the fingerprint key 730 is not stored on the user's device 125, it is re-created every time the user attempts to open the container. When the header 231 is decrypted, the symmetric key hidden in the header is extracted as denoted by reference numeral 740 and used by a symmetric decryption algorithm 750 to decrypt the encrypted content data blocks 230a-230c. Once these data blocks are decrypted, the user may access, view, or otherwise use the content based on usage rights. The symmetric decryption algorithm 750 may be resident with the executable instruction set (i.e., container code module 302) that resides in the SDC 120′ or may already be present on the user's device. This algorithm may be upgraded as new technology becomes available. Moreover, when the user attempts to access the encrypted data in the SDC 120′ at a later time, the executable instructions of the container code module 302 can locate the CFMF that was written to a hidden or confidential location during the first decryption effort. If this flag is found, the process used to create the fingerprint key 730 is repeated and this key is used to decrypt the usage rules data 130 to determine if the usage rules allow further access to the protected contents. In this way, the user may access the content without having to repeat the over container authorization process. If the CFMF 330 is not found or if the usage rules contained in the usage rights data 130 prohibit access to the protected contents, then the executable instructions will prompt the user to repeat the authorization procedure. Depending on what elements of the user's device or user input that were used to create the original machine footprint 335, the user may be prompted to recreate certain conditions that were in effect when the original machine foot print was created. For example, the user may be prompted to re-enter certain security codes or biometric measurements. If the Smart Card scenario was being used, the user may be prompted to re-insert this card in order to successfully reopen the container. The machine footprint module 720 that re-creates the machine footprint subset 722 may be programmed with a variable tolerance which permits some degree of flexibility if changes in the machine footprint of the user's device occur. For example, if the machine footprint subset was created by reading eight pieces of data from the user's device, the machine footprint module 720 may be programmed to ignore changes in three of the pieces of data and still recreate the fingerprint key 730 used to decrypt the container contents. As a result of the re-encryption technique, if the digital container is ever transmitted to a different computer or device, the executable instructions will fail to locate the CFMF when the new user attempts to access the content. If this condition is detected, the authorization process re-initiates so that the container might be associated with another user. FIGS. 8A and 8B are flow diagrams of an embodiment showing steps of using the invention, starting at step 800. FIGS. 8A, 8B and 9 may equally represent a high-level block diagram of components of the invention implementing the steps thereof. The steps of FIGS. 8A, 8B and 9 (and other block diagrams) may be implemented on computer program code in combination with the appropriate hardware. This computer program code may be stored on storage media such as a diskette, hard disk, CD-ROM, DVD-ROM or tape, as well as a memory storage device or collection of memory storage devices such as read-only memory (ROM) or random access memory (RAM). Additionally, the computer program code can be transferred to a workstation over the Internet or some other type of network. The steps of the flow diagrams may be implemented on the system of FIG. 1. Continuing with FIGS. 8A and 8B, at step 805 a digital container creator or originator selects one or more files to be placed in a digital container and chooses which files are to be encrypted. At step 810, content data is analyzed for data block sizing and those chosen files are encrypted by corresponding data blocks. At step 815, symmetric encryption algorithm encrypts data blocks. The symmetric decryption key may be stored or “hidden” in the header of the first data block (alternatively, in embodiments other blocks may be used). At step 820, an asymmetric encryption algorithm may be used to encrypt the header of the first data block. At step 825, the primary and secondary asymmetric keys for the first data block may be stored in a container verification server. At step 830, the newly constructed digital container is transmitted or otherwise made available to a user's device. At step 835, a user attempts to open the container and/or access the encrypted files. At step 840, the container attempts to locate and read a CFMF on the user's device. At step 845, a check is made if the CFMF has been located. If so, then processing continues at step 872. Otherwise, if not, then at step 850, a machine footprint may be created by reading data from various sources associated with the user and/or the user's device. At step 852, the machine footprint data is combined (e.g., by hashing) with the digital container ID to form a client footprint. At step 854, a check is made whether user input is required as determined by the digital container executable instructions. If not, then processing continues at step 856. However, if yes, then at step 855, the user may be prompted for financial transaction data, a password, an account number, or other unique access permission information. At step 856, the client footprint and user input data, if any, may be securely transmitted to a container verification server. At step 858, the container verification server reads the client footprint and creates an atomic proxy re-key value, encrypted usage rights data, permission flag and CFMF. At step 860, a check is made whether a financial transaction is involved with container access. If not, processing continues at step 864. If yes, then at step 862, the container verification server transmits financial data to a transaction server for authenticating or processing financial data and a transaction response is generated by the transaction server to the container verification server. At step 864, a permission token may be assembled with the permission flag, atomic proxy re-key value, CFMF, encrypted usage rule (or rights) data and any available transaction response data. At step 866, the container verification server securely returns the permission token to the digital container on the user's device. At step 868, the digital container reads the permission token and stores encrypted usage rule (i.e., rights) data and CFMF in a confidential location on the user's device or associated storage. At step 870, an atomic proxy algorithm uses the atomic proxy re-key value to securely re-encrypt the first data block header which locks the digital content to the user or user's device. At step 872, the digital container executable instructions uses the CFMF to read appropriate machine footprint data and construct a fingerprint key. At step 874, the symmetric decryption algorithm uses the fingerprint key to decrypt usage rules data. At step 876, a check is made whether the usage rules allow access to the digital contents or potions of the digital content. If access is not permitted, processing continues at step 850, where it may be assumed that the digital container is now present on another or different device from the original device from which the client footprint was initially created and for which a re-keying (i.e., re-encrypting) under proper validations and approval (perhaps including a financial transaction) may occur for establishing the new device or user. Alternatively, processing may also terminate. However, if access is permitted at step 876, then at step 878, an asymmetric decryption algorithm uses the fingerprint key to decrypt the first data block header and extract the “hidden” symmetric key. At step 880, a symmetric decryption algorithm uses the symmetric key to decrypt all the encrypted data blocks. At step 882, the contents of the container may be accessed by a user according to usage rules such as one-time access, execute only, print prohibited, copy prohibited, print prohibited, time-limited access, access count, or the like. At step 884, the user may close the container to end the session and all decrypted contents are deleted by the container executable instructions. The process may resume at step 835, if the user attempts to access or open the digital container. FIG. 9 is a flow diagram of an embodiment showing steps of using the invention, starting at step 900. At step 905, a new container may be created and the contents (e.g., files) partitioned (e.g., organized into data blocks). Each data block (or each data block of a subset of the total number of data blocks) may be encrypted using a symmetric encryption algorithm. At step 910, a content decryption key may be hidden in the header of the first data block. At step 915, an asymmetric encryption algorithm may be used to encrypt the first data block header. The asymmetric keys (e.g., primary and secondary keys) may be stored in a container registration database for later recall. Typically the database would be an independently maintained facility and securely protected. At step 920, the digital container is sent, delivered, or otherwise made available to a user's device such as a phone, personal digital assistant (PDA), PC, cable box, or other computer controller device. At step 925, a user may attempt to open and/or access the digital container and its contents. At step 930, machine footprint data and, optionally, user input data (such as, for example, financial data, account data, credit data, a social security number, or other identifying data) may be sent to a container authentication server along with the digital container ID, typically accomplished using a secure network connection. At step 935, the container authentication server combines data from the user, user's device and digital container ID, as available, to produce a fingerprint key. At step 940, the container authentication server uses an atomic proxy algorithm to combine the fingerprint key with the encryption keys previously stored in the container registration database for the digital container ID to create an atomic proxy re-key value. At step 945, the fingerprint key and atomic proxy re-key value may be inserted into a permission token and sent as a message to the digital container. At step 950, the atomic proxy algorithm uses the re-key value from the toke to re-encrypt the first data block header. The content of the container is now locked to the user's device and/or user. At step 955, executable instructions associated with the digital container combines the data from the original machine footprint sources and data from the permission token to re-create the fingerprint key. At step 960, an asymmetric decryption function uses the fingerprint key to decrypt the first data block header of the digital container. Once this occurs, the fingerprint key is discarded or purged to prevent unauthorized acquisition of the fingerprint key. At step 965, the symmetric decryption function may use the key retrieved from the decrypted header to decrypt any encrypted content data blocks. The digital container may also include non-encrypted data blocks as constructed originally by the container creator which would, of course, not required any decryption when accessed by a user. At step 970, the user may access the contents of the container as regulated by the usage rules. The user may also be prevented from accessing certain or all parts of the content based on the usage rules, or if the fingerprints do not support decryption on the user's device. At step 980, the process ends. ENVIRONMENTS AND EXAMPLES OF USING THE INVENTION This product brings unique capabilities to a number of digital goods distribution, e-commerce and rights management markets. These markets include, but are not limited to: i) The secure distribution of digital entertainment goods to the general consumer market. Since the digital container and the related encryption function described by this invention are designed to operate in a variety of device and operating system environments, the product is well suited to this market. The container may be used distribute and sell such products as movies and videos, games, software, books (including audio books) periodical or the like. These items may be securely distributed to cable television set-top boxes, personal computers, tablet computers, handheld computing devices and mobile phones, just to name a few. ii) The legal distribution of digital goods in a Peer-To-Peer (P2P) environment. The on-board e-commerce and access tracking features of the product make it especially useful in the P2P marketplace. iii) The self publishing marketplace. The digital container product allows users to create and e-commerce-enable their own publishing and media distribution objects. Authors can publish and sell their own books, stories and articles at a fraction of the price of current publishing requirements. Musicians can create multimedia containers which promote and sell their music without having to deal with any expensive record labels. iv) The personal records privacy and regulations compliance marketplace. Hospitals, private doctors and law firms can containerize and store the private records of patients and clients. These records may be retrieved and securely transmitted to authorized recipients such as government agencies or insurance firms as needed. v) The secure distribution of documents and files for corporations and government agencies. The pre-registration of distribution lists on the Container Authentication Server combined with the multi-factor authentication features of this invention provide for an extremely effective method of secure document distribution. The containerization concept allows this secure distribution to take place outside of corporate LANs and across multiple devices and operating systems. vi) Secure financial transactions using the Smart Card concept. The Smart Card is an intelligent card that may be inserted into a non-specialized reader device such as a CD-ROM drive. The card is designed to hold secure personal identification data along with financial account data. Customers may use ATMs to deposit money onto the card and it can be used to purchase items in brick and mortar establishments like any bank debit card. But it could also be inserted into a computing device to execute secure purchases of containerized digital goods. Identification data from the card may be used in the authentication process described by the invention to lock digital goods to a user and not just to a device. In this way, a customer may access secure containerized files on any device, such as work computers setup for multiple users or public use devices such as computers at public libraries. In this manner a Personal Media Virtual Library concept can be created. The Smart Card can be used to purchase containerized digital goods which are then stored in an individualized “virtual library.” This library would consist of storage space purchased from an internet vendor. The Smart Card would contain the secure URL of this individualized library which would allow the user to access previously purchased containers from any device in any location. While the invention has been described in terms of embodiments, those skilled in the art will recognize that the invention can be practiced with modifications and in the spirit and scope of the appended claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The invention generally relates to encrypting digital content, and more specifically, to securely locking encrypted digital media to a particular user, computer or other computing device. 2. Background Description Any owner or distributor of secure or copyrighted digital content, i.e., electronic data in any form, may face several problems concerning the encryption of the data and the method of access that is provided to an end user. The owner or distributor typically is compelled to provide a robust method of encryption while remaining within a system that is relatively easy and simple for users to operate. In order to be relatively effective and/or easy to use, the system provided by owners or distributors must typically allow users to repeatedly access the material while requiring that they undergo an authentication, approval or payment process under a set of rules determined by the content owner. For example, the user may access the content an unlimited number of times after approval, or the user may have to regain approval after a certain number of accesses and/or a after a certain amount of time has passed. Normally, content owners require substantial confidence and assurance that once approved for access by a particular user on a particular device the content cannot be freely accessed by another user especially if the content is transmitted to another machine or device. Currently, most content originators and distributors utilize a Public Key Infrastructure, or PKI system, to accomplish these functions. The PKI system utilizes public key or asymmetric cryptography in which a public key and a private key are produced at the time that the content file is encrypted. This PKI system typically has the following properties or requires the use of: (i) A certificate authority that issues and verifies a digital certificate. A digital certificate includes the public key, information about the public key or other licensing information. (ii) A registration authority that acts as the verifier for the certificate authority before a digital certificate is issued to a requestor. (iii) One or more directories where the certificates (with their public keys) are held. (iv) A certificate management system. This PKI system is quite complex and very often is an operational and financial burden for content originators, distributors and users. An alternative encryption system is symmetric cryptography. A symmetric system utilizes a secret or hidden key that is shared by both the sender and recipient of the encrypted data. While much simpler to use and substantially less costly to implement, a common drawback may be that if the secret key is discovered or intercepted, the encrypted data can easily be decrypted and stolen. However, if a method and system for protecting the secret key, itself, can be provided so that the secret key is not exposed to discovery or interception, including an end user, then a very reliable and effective procedure and system for securely delivering electronic content is possible while avoiding the significant burdens of a PKI infrastructure.

<SOH> SUMMARY OF THE INVENTION <EOH>An aspect of the invention provides a method for creating a digital container and encrypting the contents of the digital container with a symmetric encryption technique. The method also provides for protecting the symmetric decryption keys by inserting the symmetric decryption keys into header associated with a data block in the digital container and encrypting the header using an asymmetric encryption algorithm. Upon an attempted access of the container by a user, the header is re-encrypted using data from the user's device and/or the user so that the contents of the digital container are now locked to the user's device or to the user. Transaction data such as credit card information or account information may also be obtained from the user, perhaps for paying for the contents of the container or other service, which may be verified and used to gain access to the contents. Once the container has been locked to the user's device or user, the container may only be opened and accessed on that device or by that user. If the digital container were to be transmitted to another device, the digital container recognizes that the footprint of the device has changed or the user is different and may not open until a re-authorization has been performed which may involve a financial transaction. A further aspect of the invention includes a system for creating a digital container and encrypting the contents of the digital container with a symmetric encryption technique. The system also provides for protecting the systemic decryption keys by inserting the symmetric decryption keys into header associated with a data block in the digital container and encrypting the header using an asymmetric encryption algorithm. Upon an attempted access of the container by a user, the system re-encrypts the header using data from the user's device such as a machine footprint and/or the user such as a client fingerprint so that the contents of the digital container are now locked to the user's device or to the user. The system may also acquire transaction data such as credit card information or account information from the user, perhaps for paying for the contents of the container or other service, which may be verified and used to gain access to the contents. Once the container has been locked to the user's device or user, the system provides that the container may only be opened and accessed on that device or by that user. If the digital container were to be transmitted to another device, the system recognizes that the footprint of the device has changed or the user is different and may not open until a re-authorization has been performed which may involve a financial transaction. In another aspect of the invention, a computer program product comprising a computer usable medium having readable program code embodied in the medium is provided. The computer program product includes at least one component to create a digital container and to encrypt the contents of the digital container with a symmetric encryption technique. The at least one component also protects the symmetric decryption keys by inserting the symmetric decryption keys into header associated with a data block in the digital container and encrypting the header using an asymmetric encryption algorithm. Upon an attempted access of the container by a user, the at least one component re-encrypts the header using data from the user's device and/or the user so that the contents of the digital container are now locked to the user's device or to the user. The at least one component may also obtain transaction data such as credit card information or account information from the user, perhaps for paying for the contents of the container or other service, which may be verified and used to gain access to the contents. Once the container has been locked to the user's device or user, the container may only be opened and accessed on that device or by that user.

20060419

20080902

20070208

98704.0

H04L900

CALLAHAN, PAUL E

SECURING DIGITAL CONTENT SYSTEM AND METHOD

UNDISCOUNTED

ACCEPTED

H04L

ACCEPTED

High security device for capturing electric energy on the ground for supplying a landborne vehicle

The device for capturing electrical energy having a capturing plough-type element (10), an arm for holding the capturing plough-type element on the frame of the vehicle, a mechanism for lifting up the plough-type element and the way for electrical connection to the supply circuit of a vehicle. The plough-type element is electrically insulated in relation to the ground and the trackway. One part of the plough-type element separates two profiled part holders (23, 24) which are arranged beside each other in another opposite manner and are supported a support. The conducting elements of the lower end of the plough-type element are maintained in electrical contact, sliding along polar parts born by each part holder. Along the entire length of each part holder (23, 24), each part holder is mounted in an elastically recoiling manner such that it moves towards its adjacent opposite number with the aid of an elastic mechanism.

1-19. (canceled) 20. A reinforced safety device for collecting electrical energy at ground level for a land-borne ground level electrical feed type vehicle by a sliding contact with at least one polar part, the safety device comprising: a collection blade (10) having a vehicle support holder (11) on an upper part of the collection blade (10); means for raising the blade (10) and means for electrically connecting the blade (10) to a feed circuit of the vehicle, the blade (10) being electrically insulated from ground and any lane structures, a part of the blade (10) can spread apart two holding fixtures (23,24), which are placed side-by-side opposite to one another, the two holding fixtures (23, 24) run either on the ground or in the ground along a lane, and are supported by a support carrier (21) having a bottom that is approximately flat and two lateral walls to form a collection assembly (9), collecting parts or areas of the blade (10) are maintained in electrical contact by sliding along one of conductors or conducting parts (19, 20) which are supported by each holding fixture (23, 24), each of the holding fixtures (23, 24) is provided along an entire length with elastic recall return towards an adjacent counterpart by elastic compressibility means engendering locally an elastic recall force to bring the holding fixtures (23, 24) together after one of lateral compression or a series of separate recall devices. 21. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein the elastic compressibility means engendering locally the elastic recall force for one of the two holding fixtures (23, 24) is a tubular elastic body (25, 26) that is subjected to lateral compression and is housed in a space existing between the holding fixture ( 23, 24) and the corresponding lateral wall of the carrier support (21) of the collection assembly (9). 22. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein a body of the blade (10 ) is a flat piece (12) with a forward beveled edge (14) and a lower extremity in a form of a bulge in a shape of a longitudinal block (15), the longitudinal block (15) having two flat lateral edges (17, 18), at least one of the two flat lateral edges (17, 18) has a sliding contact on one of an opposing conductor or a conducting part (19, 20) supported by the corresponding holding fixture (23, 24). 23. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein each conductor (19, 20) is connected to a different electrical phase and feeds the blade (10) via two electrical pathways. 24. The reinforced safety device for collecting electrical energy at ground level according to claim 23, wherein the collection blade (10) has two electrical conductors that are insulated from one another and are each connected to a different electrical phase. 25. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein the holding fixtures (23, 24) are made of a flexible insulating material so as to permit a local gap for clear passage of the blade (10). 26. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein the conductors (19, 20) are inserted into a slot provided in a cavity of a face of an edge of one of the holding fixtures (23, 24) facing an other one of the holding fixtures (23, 24). 27. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein the support section (21) is buried and the surface of the ground is protected by a protection (28) based on an insulating opening which is opened by passage of the blade (10), and the insulating opening closes after the blade (10) pass thereby. 28. The reinforced safety device for collecting electrical energy at ground level according to claim 27, wherein an upper surface of the support section (21), equipped with the protector (28) in the insulation cover, opens with the passage of the blade (10) and the insulating opening closes after the blade (10) passes thereby. 29. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein the device for electrical collection feeds a vehicle guided by a central rail of a guidance assembly at ground level (8). 30. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein the blade (10) is connected to a guidance arm (42) of the vehicle. 31. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein the safety device further comprises a guide rail having two semi-rails (29, 30) installed side-by-side, a guide roller (40, 41) of a guidance assembly (42) of the vehicle rolls on each of the two semi-rails (29, 30). 32. The reinforced safety device for collecting electrical energy at ground level according to claim 31, wherein each of the two semi-rails (29, 30) has a general transverse shape in the form of a U consisting of a rail riser wing (31) terminated at a top in a rail conformation (32), a base (33) and a longitudinal return toward the top forming a lateral wall (34) which terminates in an upper edge (35) that turns back in toward an interior. 33. The reinforced safety device for collecting electrical energy at ground level according to claim 32, wherein the rail riser wing (31) has a thick core (36) and a head (37) which, when viewed in cross-section, has a shape of a hook comprised on an external side of a linear projection formed of a rolling track(39) on which rolls one of the guide rollers (40, 41) on a load-bearing surface, the rolling track (39) is sloped toward a bottom of an inclined ramp (43) and on an other side, with a flat, horizontal edge (44) and on an inner side, the conformation consists of a flat horizontal bearing edge (45) followed by a perpendicular edge with a middle receiver slot (46), the conformation constituting the reception surface for a linear watertight joint (47). 34. The reinforced safety device for collecting electrical energy at ground level according to claims 32, wherein a space between the lateral wall and the thick core (36) is filled by a flexible joint (38) with an upper face inclined, the flexible joint (38) is immobilized between walls and an upper edge (35), which turns back toward an interior. 35. The reinforced safety device for collecting electrical energy at ground level according to claim 31, wherein the collection blade (10) traverses the guide rail and a composite joint (47), two parts of the composite joint (47) spread apart or are raised locally when the blade (10) passes, and recoil after passage of the blade (10). 36. The reinforced safety device for collecting electrical energy at ground level according to claim 35, wherein the composite joint (47) is formed of two linear joints (48, 49) which are installed in a side-by-side manner and which meet at an edges a middle section, and constitute a linear pivoting articulation by means of opposite edges with conformation with an extremity of the corresponding semi-rail (29, 30). 37. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein the reinforced safety device is intended for a vehicle guided by the ground level electrical energy collection assembly moving along a guide rail. 38. The reinforced safety device for collecting electrical energy at ground level according to claim 20, wherein the reinforced safety device is intended for a vehicle guided by other than the ground level electrical energy collection assembly moving along a guide rail.

This application is a national stage completion of PCT/FR2004/002607 filed Oct. 13, 2004 which claims priority from French Application Serial No. 0312259 filed Oct. 20, 2003. FIELD OF THE INVENTION The present invention concerns a double security device for collection of electrical energy at ground level for feeding a land-borne vehicle, notably a land-borne vehicle for the transportation of passengers or merchandise, urban public transportation on wheels or on rails, or an industrial maintenance car. BACKGROUND OF THE INVENTION The invention is particularly adapted to the electrical feed of an urban public transportation vehicle on a fixed guideway with electric propulsion. This vehicle being either of the rail or tire type. However, the invention is not limited to this preferred application. This type of electrical propulsion or traction vehicle is normally supplied with energy by above-ground cables or catenaries set out above its traffic lanes. However, the current trend is, for aesthetic or other reasons, to get rid of these electrified aerial lines and replace them by feed systems at ground level or by buried lines. We are thus confronted with a major safety problem. In fact, these vehicles require for their feed, a continuous current at relatively high voltage which can be extremely dangerous for human beings. The system for collecting electrical energy at ground level must therefore of necessity be protected so as to render impossible a voluntary or accidental contact with the feed conductors and the polar parts, and thus ensure the safety of passengers, pedestrians, other users of the roadway or personnel in the case of a plant car. SUMMARY OF THE INVENTION The objective of the invention is to provide a system for collecting electrical energy at ground level which is perfectly safe, and usable for these types of vehicles. Already known from patent FR 2.735.728 in the name of the applicant, is an electrical feed and guidance assembly along a rail at ground level for an urban transportation vehicle on wheels. This assembly consists of a visiting, raiseable guidance support, which carries a pair of guide rollers in a <<“V”>> shape, co-operating with a rail in the ground which has a central core that is used as a rolling track by the guide rollers and the electrical feed conductors. The central core has flexible covering parts which constitute a linear closing of the space enclosing the conductors outside of the area for the passage of the guidance support which causes the momentary opening of this closing to the passage of the contact parts supported by the conductors. The conducting parts of the former electrical feed systems are protected by flexible covering parts which only rise locally when the vehicle's guidance head passes. Though it offers increased insulation of the energy collection system, this earlier device is not perfectly secure. In fact, the parts under voltage could be reached without too much difficulty in the event of malicious or accidental insertion of a long metallic item under one of the flexible covering parts. In order to ensure a greater level of safety, the device for the collection of electrical energy at ground level according to the invention consists of a collection blade carried by a stay arm connected to the vehicle, which has, at its lower extremity, parts that are electrically connected to the vehicle's feed circuit, this blade being electrically insulated from the ground in the lane structures. In addition, buried in the ground it has two linear polar parts in two holding fixture sections installed side-by-side opposite, running along the lane and carried by a carrier type support with a bottom that is more or less flat, and with two lateral walls. According to one essential characteristic of the invention, each of these holding fixtures is equipped over its entire length with elastic recall return towards its adjacent counterpart by means of a linear elastic compressible device housed between the holding fixture and the corresponding lateral wall of the carrier support device. The passage of the vehicle results in the local spreading of the two holding fixtures by the lower part of the collection blade, and during the entire run, the conducting parts of the blade are maintained in continuous electrical contact by sliding along the linear polar parts. Preferably, the linear elastic means which generates the recall force by bringing the two opposing holding fixtures together is, in each case an elastic tubular body, capabable of being compressed laterally, housed in the existing space between the holding fixture and the corresponding lateral wall of the carrier support. This method of elastic recall forces the two holding fixtures to approach one another. It thus ensures good contact between the polar parts and the conducting parts of the blade when it is present. In the absence of the vehicle or in the areas where the blade is absent, it pushes these two holding fixtures against one another until they come into contact and lock fully, thus closing off access to the dangerous polar components. The isolation and protection of the parts under voltage already ensures the first level of safety. In order to further enhance safety, it could in addition be arranged that the ground level above the polar parts be protected electrically by an insulation covering which would open locally by the passage of the blade and then close again. The energy collecting device according to the invention thus presents a double level of safety, thereby rendering it perfectly reliable. BRIEF DESCRIPTION OF THE DRAWINGS Other characteristics and advantages of the invention will become apparent in the description which follows, given by way of example and accompanied by drawings in which; FIG. 1 is a general perspective view of the ground level collection device according to the invention when the collection blade is passing in the case of a variation which uses two guidance semi-rails; FIG. 2 is an identical view to that of FIG. 1 without the collection blade; FIG. 3 is a cross-section view of FIG. 1; FIG. 4 is a general cross-section view of the lane showing by means of dotted lines the lead train of the guided vehicle with its guidance assembly inclined in support on the guide rail; and FIG. 5 is a schematic perspective view of a segment of length of the lane shown from a certain distance the deformation of the protection and watertightness joint between the two guidance semi-rails. DETAILED DESCRIPTION OF THE INVENTION The ground level electrical energy collecting device according to the invention can be used in numerous applications in the field of transportation and that of maintenance, for example, electric cars fed from ground level circulating about in shops, and urban public transportation vehicles on rails or fixed guideways on tires being fed with electrical energy at ground level. The device according to the invention is mounted directly on the ground or in a trench dug into the ground between two rails, or between the two rolling tracks of an electric land-borne vehicle. It can also be mounted on an infrastructure, secured at a shallow depth on prepared ground, with this infrastructure being developed longitudinally to comprise an actual lane 1 formed of two rails, or of two paths 2 and 3, a lane on which vehicles travel and comprised of two caissons 4 and 5 connected at intervals, for example regular, by cross members such as 6. The caissons 4 and 5 are opened on the upper part to receive as a covering, plates such as 7 for example, ribbed or grooved which, by their succession, form paths 2 and 3. These caissons preferably contain the different electrical cables for feeding the vehicle traction energy, but also for safety and signaling. These cables run through the length of the caissons and can exit them at determined locations. According to the implementation method represented, the cross members 6 carry in the upper central part, a ground level guidance assembly 8 and below through their core, a collection assembly 9 carrying the polar parts. The device according to the invention has the following general attributes. A conductor element in the form of a blade 10 is carried in an insulated manner by a holding support 11, arm or other, supplied with an articulated joint on the vehicle, and connected in a removable manner, for example by a connector, to the extremity of an electrical connection with the feed circuits of the vehicle's electrical motive source. This technical characteristic of the electrical connection is not represented in the drawings. This blade 10 constitutes the main element for the collection of electrical energy while the vehicle is moving, as a result of its continuous electrical contact with the polar parts. Based on this fact, it will henceforth be called the collection blade. For this purpose, a part of the blade, for example the base of this component or its lower extremity, is shaped or adjusted to produce continuous sliding contact along the polar parts integrated in a set-back fashion in the linear flexible bodies of the holding fixture, which spread apart when the blade passes, then fully lock up against one another laterally after the blade has passed, as a result of a linear elastic recall return. More specifically, according to the preferred implementation represented, the blade 10 is in the form of a vertical piece 12 in the shape of a blade, of a sufficient thickness to ensure good mechanical rigidity, but remaining flexible, and having a flat back edge 13, and a front beveled edge 14. The blade 10 must, however, have a flexibility that is sufficient to resist possible movements due to rolling and other causes that occur when the vehicle is moving. The shape of the upper extremity of this blade 10 depends upon the type of electrical and mechanical connection to the vehicle's carrier support 11. A part of this blade, for example the lower extremity, is used for the collection of electrical energy. Its exact shape depends on that of the polar parts with which it must come into continuous electrical contact when the vehicle is in motion. Support 11, or its mechanical connection, is formed or designed in such a way that the blade can be raised. According to the non-limiting example of the shape represented in the Figs., the lower extremity is solid and spreads out in the form of a longitudinal block 15 with a polygonal cross-section, for example with six sections or faces, four of the large faces of which are inclined as in 16, and two edge faces 17 and 18 are conducting and in both cases, offer flat contact surfaces with one of the linear polar surfaces opposite to the polar parts or the respective conductors 19 and 20 for the purpose of capturing the electrical energy by a continuous sliding contact with them. The polar parts or conductors 19 and 20 are electrically connected to the same phase, but can just as well be supplied individually from two different phases as from the same source. This presumes a composite structure of the blade according to which each part is insulated electrically and is connected to a distinct conductor component. The collection assembly at ground level 9 of the device according to the invention is developed linearly along the lane and is installed in a support section 21 which has electrical feed connections at intervals the electrical feed connections to two polar parts 19 and 20, for example, from cables that are strung in, and along the caissons 4 and 5. The support section 21 is in the form, for example, as illustrated in the drawings, of a flat-bottomed trough 22 with a more or less rectangular cross-section opened upward, or partially closed. To reduce the risks of accident, this support section 21 is preferably buried to a reasonable depth in relation to the vehicle's travel lane. Advantageously, a water evacuation system connected to drainage to the ground can be provided in the bottom wall 22 of the trough 21. Polar parts 19 and 20, connected or not to the same phase, are made, for example, of conductive bars, each of which is immobilized in the corresponding slot holding fixture 23 and 24 running along the support 21 of the trough. The conductive bars shown in the slots of the holding fixture are each offset in relation to the adjacent face of the trough. These holding fixtures are mounted unattached in the trough support 21 and can thus be moved laterally, being supported by the bottom of this element. The holding fixture sections 23 and 24 are linear blocks produced in insulating material with a cross-section, for example that is more or less square or rectangular, occupying the major part of the interior space of the trough 21 between the two lateral walls which delimit its interior space. Within the interior space of the trough, between each holding fixture 23 and 24 and the adjacent lateral wall is a housed an elastic recall return for the holding fixtures, 25 or 26, for example a hollow tube made of an elastomer or other equivalent material, which can withstand a local lateral crushing or compression and generate in return a lateral reaction force producing an elastic recall return of the two holding fixtures 23 and 24 installed side-by-side, until the faces of the opposite edges are fully locked together. Needless to say, other appropriate methods of elastic recall, for example, point source methods installed at regular intervals in elastic or spring materials or other. In the case of the vehicle on tires, guidance is effected by the ground level guidance assembly 8, for example, using a central monorail guidance system. For reasons of additional safety and watertightness, the ground level guidance assembly 8 or the ground level collection assembly 27 alone in the case of a non-guided vehicle or one which is a guided otherwise, will be covered by a permanent protection 28 at ground level, which can be opened by the blade or otherwise, for example by the vehicle's guidance assembly, and which closes after the passage of the collection blade by the blade itself, or by another means. This permanent protection 28 at ground level forming a water-tight covering must, however, be sufficiently rigid to support, without opening or buckling under, the weight of any vehicle, for example, at a level crossing. This ground level protection 28 could, for example, be made in the form of two linear slats or wings that overlapped or not in the middle. Advantageously, the slats or wings could open due to the action of the front part of the blade and then be locked fully closed by the simple effect of elastic recall. This permanent protection at ground level 28 also provides watertightness against the runoff of water toward the electrical contacts. In the case of any vehicle, whether guided or not, other than a vehicle on tires guided by a central monorail, for example, a rail vehicle, the ground level guidance assembly by monorail does not exist. In this case, it is the ground level collection assembly, or the one installed flush with the ground that will have the permanent protection 28. When the implementation includes a ground level guidance assembly 8 like the one represented, it is this ground level guidance assembly 8 which is covered by the permanent ground level protection 28. Advantageously, it can be envisioned that the upper surface of the carrier has the insulation coverage which opens with the passing of the blade. The functioning of the electrical energy capturing safety system according to the invention flows in an obvious manner from the preceding description. In the absence of a vehicle, the elastic recall elements force the two holding fixtures 23 and 24 to close against one another until the opposite edge faces are fully locked together, thus impeding access to the polar parts 19 and 20 under voltage. If it is present, the ground level permanent protection 28 is in the closed position, thereby providing an additional level of safety. When the vehicle passes, the collection blade 10 or another means ahead of it, opens the permanent ground level protection 28 automatically and spreads the two holding fixture sections 23 and 24 locally as the vehicle advances, in such a way as to maintain continuous electrical contact with polar parts 19 and 20. The conducting parts of the blade 10 are kept in permanent electrical contact sliding along these linear polar parts as a result of the compression force exercised by the elastic recall elements 25 and 26. After the vehicle passes, the ground level permanent protection 28 closes again, and the elastic recall elements 25 and 26 push on the holding fixtures 23 and 24 until the interior space of the trough 21 is sealed. Within the overall process of normal vehicle functioning, the system for collecting electrical energy at ground level according to the invention is designed so that the collection blade 10 is inserted into position at the beginning of the line, and will not come out again before the end of the line. However, the system according to the invention is sufficiently flexible and offers a sufficient degree of play to allow the extraction of the collection blade from the entire line by lifting it, for example in the case of a breakdown or in the event that a vehicle safety device is activated. The methods described above can vary in their form without deviating from the scope of the invention. Thus, for example, the collection assembly 9 is supported by the trough 21 opened upward, but it could just as well be nearly totally closed permanently by means of removable stops, except for a central slot for the passage of the collection blade 10 as is shown in the drawings. In the case of the application of the collection system according to the invention to a public transportation fixed guideway vehicle on tires using a central guide rail, the lower support section 21 of the collection assembly 9 will preferably be buried under the central guide rail and the collection blade 10 to then advantageously be carried by the vehicle's guidance assembly. The ground level energy collecting device according to the invention can be connected to a ground level controller, but also to an assembly guided by the monorail for the electrical feed of a vehicle that is guided in another manner. The ground level energy collecting device according to the invention is shown as being connected to a ground level control assembly, of which one method of implementation represented in FIGS. 1 and 2 consists of a guidance device formed of two side-by-side identical and symmetrical guidance semi-rails 29 and 30, spaced transversally from one another by a distance sufficient to allow a free flat space for the passage of collecting blade 10, without the risk of electrical contact with one or the other of the two semi-rails 29 and 30. The two semi-rails 29 and 30 being identical, it is sufficient to describe one of them. According to the variation represented, each semi-rail 29 or 30 has a transversal shape in the general form of a U comprised of a rail riser wing 31 ending at the top in a rail conformation 32, a bottom 33 and a longitudinal return towards the top forming a lateral wall 34 terminating in an upper edge 35 which turns back towards the interior. The rail riser wing 31 is comprised of a thick core 36 and a head 37 presenting in cross-section the shape of a hook. The space located between the thick core 36 and the corresponding lateral wall 34 is occupied by a flexible filler joint 38 with a hollow tubular body encased between the wall and the upper edge 35 that returns towards the interior. The guide rails are affixed to each cross member 6, for example, by bolting. More precisely, the conformation (shape) of the rail 32 consists of the external side of a linear ridge formed by a rolling track 39, on the load-bearing surface of which rolls one of the two guide rollers 40 and 41 (FIGS. 1, 3 and 4) of the vehicle's guidance assembly 42, this track being flared downward by an inclined ramp 43, and on the other side by a flat, horizontal edge 44. On the inside, the conformation is particular. It consists of a flat, horizontal abutment edge 45, followed by a perpendicular edge which creates a middle reception throat 46. This conformation constitutes the receiving surface for an inter-rail linear composite water-tight joint 47, which constitutes in this variation, the permanent ground-level cover 28. This composite joint 47 is divided into two identical and symmetrical horizontal joints 48 and 49 that can be raised by the passage of the collection blade 10 as represented in FIG. 1. The two joints 48 and 49 are immobilized flat at rest, edge to edge and right up against the flat, horizontal abutment edge 45 of the head 37 of the corresponding semi-rail 29 or 30, as represented in FIG. 2. each joint 48 or 49 has a hollow, tubular volume in the proximity of the opposite edges to give it a certain level of flexibility to deformation. The opposite edge consists of a longitudinal tongue 50 and an upper lip 51 as represented in FIGS. 1 and 2. The longitudinal tongue 50 occupies the middle reception throat 46 of the corresponding semi-rail 29 or 30 and the upper lip 51 bearing down on the upper flat horizontal edge of the corresponding semi-rail 29 or 30. This association of shapes which are combined with the elasticity of joint 48 or 49 constitutes the functional equivalent of an articulation enabling each joint 48 or 49 to raise locally on passage of the collection blade 10 by turning on the deformation of each joint at the level of its tab 50 and its longitudinal lip 51 in proximity to the blade 10 as represented in FIG. 1, and closing up again behind the blade due to the effect of elastic recall.

<SOH> BACKGROUND OF THE INVENTION <EOH>The invention is particularly adapted to the electrical feed of an urban public transportation vehicle on a fixed guideway with electric propulsion. This vehicle being either of the rail or tire type. However, the invention is not limited to this preferred application. This type of electrical propulsion or traction vehicle is normally supplied with energy by above-ground cables or catenaries set out above its traffic lanes. However, the current trend is, for aesthetic or other reasons, to get rid of these electrified aerial lines and replace them by feed systems at ground level or by buried lines. We are thus confronted with a major safety problem. In fact, these vehicles require for their feed, a continuous current at relatively high voltage which can be extremely dangerous for human beings. The system for collecting electrical energy at ground level must therefore of necessity be protected so as to render impossible a voluntary or accidental contact with the feed conductors and the polar parts, and thus ensure the safety of passengers, pedestrians, other users of the roadway or personnel in the case of a plant car.

<SOH> SUMMARY OF THE INVENTION <EOH>The objective of the invention is to provide a system for collecting electrical energy at ground level which is perfectly safe, and usable for these types of vehicles. Already known from patent FR 2.735.728 in the name of the applicant, is an electrical feed and guidance assembly along a rail at ground level for an urban transportation vehicle on wheels. This assembly consists of a visiting, raiseable guidance support, which carries a pair of guide rollers in a <<“V”>> shape, co-operating with a rail in the ground which has a central core that is used as a rolling track by the guide rollers and the electrical feed conductors. The central core has flexible covering parts which constitute a linear closing of the space enclosing the conductors outside of the area for the passage of the guidance support which causes the momentary opening of this closing to the passage of the contact parts supported by the conductors. The conducting parts of the former electrical feed systems are protected by flexible covering parts which only rise locally when the vehicle's guidance head passes. Though it offers increased insulation of the energy collection system, this earlier device is not perfectly secure. In fact, the parts under voltage could be reached without too much difficulty in the event of malicious or accidental insertion of a long metallic item under one of the flexible covering parts. In order to ensure a greater level of safety, the device for the collection of electrical energy at ground level according to the invention consists of a collection blade carried by a stay arm connected to the vehicle, which has, at its lower extremity, parts that are electrically connected to the vehicle's feed circuit, this blade being electrically insulated from the ground in the lane structures. In addition, buried in the ground it has two linear polar parts in two holding fixture sections installed side-by-side opposite, running along the lane and carried by a carrier type support with a bottom that is more or less flat, and with two lateral walls. According to one essential characteristic of the invention, each of these holding fixtures is equipped over its entire length with elastic recall return towards its adjacent counterpart by means of a linear elastic compressible device housed between the holding fixture and the corresponding lateral wall of the carrier support device. The passage of the vehicle results in the local spreading of the two holding fixtures by the lower part of the collection blade, and during the entire run, the conducting parts of the blade are maintained in continuous electrical contact by sliding along the linear polar parts. Preferably, the linear elastic means which generates the recall force by bringing the two opposing holding fixtures together is, in each case an elastic tubular body, capabable of being compressed laterally, housed in the existing space between the holding fixture and the corresponding lateral wall of the carrier support. This method of elastic recall forces the two holding fixtures to approach one another. It thus ensures good contact between the polar parts and the conducting parts of the blade when it is present. In the absence of the vehicle or in the areas where the blade is absent, it pushes these two holding fixtures against one another until they come into contact and lock fully, thus closing off access to the dangerous polar components. The isolation and protection of the parts under voltage already ensures the first level of safety. In order to further enhance safety, it could in addition be arranged that the ground level above the polar parts be protected electrically by an insulation covering which would open locally by the passage of the blade and then close again. The energy collecting device according to the invention thus presents a double level of safety, thereby rendering it perfectly reliable.

20060601

20091013

20061221

86502.0

H01R13648

LE, MARK T

HIGH SECURITY DEVICE FOR CAPTURING ELECTRIC ENERGY ON THE GROUND FOR SUPPLYING A LANDBORNE VEHICLE

UNDISCOUNTED

ACCEPTED

H01R

ACCEPTED

1-Benzoyl Substituted Diazepine Derivatives As Selective Histamine H3 Receptor Agonists

The present invention relates to novel diazepanyl derivatives of formula (I) having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.

1-8. (canceled) 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: R1 represents branched C3-6 alkyl, C3-5 cycloalkyl or —C1-4 alkylC3-4 cycloalkyl; R2 represents halogen, C1-6 alkyl, C1-6 alkoxy, cyano, amino or trifluoromethyl; n represents 0, 1 or 2; R3 represents -X-aryl, -X-heteroaryl, -X-heterocyclyl, -X-aryl-aryl, -X-aryl-heteroaryl, -X-aryl-heterocyclyl, -X-heteroaryl-aryl, -X-heteroaryl-heteroaryl, -X-heteroaryl-heterocyclyl, -X-heterocyclyl-aryl, -X-heterocyclyl-heteroaryl or -X-heterocyclyl-heterocyclyl; such that when R3 represents -X-piperidinyl, -X-piperidinyl-aryl, -X-piperidinyl-heteroaryl or -X-piperidinyl-heterocyclyl said piperidinyl group is attached to X via a nitrogen atom; wherein R3 is attached to the phenyl group of formula (I) at the 3 or 4 position; X represents a bond, O, CO, SO2, CH2O, OCH2, NR4, NR4CO or C1-6 alkyl; R4 represents hydrogen or C1-6 alkyl; wherein said aryl, heteroaryl or heterocyclyl groups of R3 may be optionally substituted by one or more halogen, hydroxy, cyano, nitro, oxo, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkyl, C1-6 alkoxy, arylC1-6 alkoxy, C1-6 alkylthio, C1-6 alkoxyC1-6 alkyl, C3-7 cycloalkylC1-6 alkoxy, C3-7 cycloalkylcarbonyl, —COC1-6 alkyl, C1-6 alkoxycarbonyl, arylC1-6 alkyl, heteroarylC1-6 alkyl, heterocyclylC1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyloxy, C1-6 alkylsulfonylC1-6 alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC1-6 alkyl, aryloxy, —CO-aryl, —CO-heterocyclyl, —CO-heteroaryl, C1-6 alkylsulfonamidoC1-6 alkyl, C1-6 alkylamidoC1-6 alkyl, arylsulfonamido, arylaminosulfonyl, arylsulfonamidoC1-6 alkyl, arylcarboxamidoC1-6 alkyl, aroylC1-6 alkyl, arylC1-6 alkanoyl, or a group NR15R16, —NR15CO-aryl, —NR15CO-heterocyclyl, —NR15CO-heteroaryl, —CONR15R16, —NR15COR16, —NR15SO2R16 or —SO2NR15R16 groups, wherein R15 and R16 independently represent hydrogen or C1-6 alkyl; or solvates thereof. 10. A compound according to claim 9 which is: 4′-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]-4-biphenylcarbonitrile; 1-{4′-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]-4-biphenylyl}ethanone; 1-(4-Biphenylylcarbonyl)-4-cyclobutylhexahydro-1H-1,4-diazepine; {4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}(phenyl)methanone; 1-Cyclobutyl-4-{[4-(phenyloxy)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-({4-[(phenylmethyl)oxy]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-tetrazol-1-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-({4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(1,1-dioxido-4-thiomorpholinyl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-(Isopropyl)-4-{[4-(tetrahydro-2H-pyran4-yloxy)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-({4-[6-(trifluoromethyl)-3-pyridinyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 6-{4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-3-cyanopyridine; 5-{4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-N-methyl-2-pyridinecarboxamide; 5-{4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-2-cyanopyridine; 5-(4-{[4-(1-Isopropyl)hexahydro-1H-1,4-diazepin-1-yl]carbonyl}phenyl)-2-cyanopyridine; N-Methyl-5-(4-{[4-(1-isopropyl)hexahydro-1H-1,4-diazepin-1-yl]carbonyl}phenyl)-2-pyridinecarboxamide; 1-(1-Methylethyl)-4-({4-[2-(trifluoromethyl)-5-pyrimidinyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-(1-Methylethyl)-4-({4-[6-(trifluoromethyl)-3-pyridazinyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-(1-Methylethyl)-4-({4-[6-(trifluoromethyl)-3-pyridinyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; N,N-Dimethyl-5-(4-{[4-(1-methylethyl)hexahydro-1H-1,4-diazepin-1-yl]carbonyl}phenyl)-2-pyridinecarboxamide; 6-(4-{[4-(1-Methylethyl)hexahydro-1H-1,4-diazepin-1-yl]carbonyl}phenyl)-3-pyridinecarbonitrile; 1-Cyclobutyl-4-({4-[6-(trifluoromethyl)-3-pyridazinyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-({4-[2-(trifluoromethyl)-5-pyrimidinyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 4′-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]-3-biphenylcarboxamide; 1-55 4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-3-(trifluoromethyl)-1H-pyrazole-4-carbonitrile; 1-({4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}methyl)-5-(trifluoromethyl)-2(1H)-pyridinone; 4′-{[4-(1-Methylethyl)hexahydro-1H-1,4-diazepin-1-yl]carbonyl}-4-biphenylcarbonitrile; N-{4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-N,4,6-trimethyl-2-pyrimidinamine; 1-Cyclobutyl-4-[(3′-fluoro-4-biphenylyl)carbonyl]hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(2-pyridinyl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(3-pyridinyl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 4-({4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}oxy)benzonitrile; 1-Cyclobutyl-4-({4-[(phenyloxy)methyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(3,5-dimethyl-4-isoxazolyl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-{[4-(3,5-Dimethyl-4-isoxazolyl)phenyl]carbonyl}4-(1-methylethyl)hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(1,3-oxazol-5-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(2-ethyl-2H-tetrazol-5-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(1H-pyrrol-1-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-({4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(4-morpholinyl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-(1-Methylethyl)-4-{[4-(4-morpholinyl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine hydrochloride 1-Cyclobutyl-4-({3-[(phenyloxy)methyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-({3-[(3-pyridinylmethyl)oxy]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-({3-[(3-pyridinylmethyl)oxy]phenyl}carbonyl)hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[3-(5-methyl-1H-tetrazol-1-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1- {3-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-2-pyrrolidinone; N-{3-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-3-pyridinecarboxamide; N-{3-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-4-pyridinecarboxamide; 1-Cyclobutyl-4-{[3-(3-pyridinyl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4′-(1,3-oxazol-2-yl)-4-biphenylyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4′-(2-methyl-1,3-oxazol4-yl)-4-biphenylyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4′-(2-methyl-1,3-oxazol-5-yl)-4-biphenylyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4′-(5-methyl-1,2,4-oxadiazol-3-yl)-4-biphenylyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(1,3-oxazol-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-(1-Methylethyl)-4-{[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; 1-Cyclobutyl-4-{[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine; or a pharmaceutically acceptable salt or solvate thereof. 11. A pharmaceutical composition which comprises the compound of formula (I) as defined in claim 9 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient. 12. A method of treatment of neurological diseases which comprises administering to a host in need thereof an effective amount of a compound of formula (I) as defined in claim 9 or a pharmaceutically acceptable salt or solvate thereof.

The present invention relates to novel diazepanyl derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders. WO 03/00480 (Novo Nordisk A/S and Boehringer Ingleheim International GMBH) describes a series of substituted piperazines and diazepanes as H3 antagonists. WO 02/08221 (Neurogen Corporation) describes a series of substituted piperazines and diazepanes as capsaicin receptor antagonists which are claimed to be useful in the treatment of neuropathic pain. WO 98/37077 and WO 99/42107 (Zymogenetics Inc) both describe a series of substituted heterocyclic derivatives which are claimed to act as calcitonin mimics to enhance bone formation. The histamine H3 receptor is predominantly expressed in the mammalian central nervous system (CNS), with minimal expression in peripheral tissues except on some sympathetic nerves (Leurs et al., (1998), Trends Pharmacol. Sci. 19, 177-183). Activation of H3 receptors by selective agonists or histamine results in the inhibition of neurotransmitter release from a variety of different nerve populations, including histaminergic and cholinergic neurons (Schlicker et al., (1994), Fundam. Clin. Pharmacol. 8, 128-137). Additionally, in vitro and in vivo studies have shown that H3 antagonists can facilitate neurotransmitter release in brain areas such as the cerebral cortex and hippocampus, relevant to cognition (Onodera et al., (1998), In: The Histamine H3 receptor, ed Leurs and Timmerman, pp 255-267, Elsevier Science B.V.). Moreover, a number of reports in the literature have demonstrated the cognitive enhancing properties of H3 antagonists (e.g. thioperamide, clobenpropit, ciproxifan and GT-2331) in rodent models including the five choice task, object recognition, elevated plus maze, acquisition of novel task and passive avoidance (Giovanni et al., (1999), Behav. Brain Res. 104, 147-155). These data suggest that novel H3 antagonists and/or inverse agonists such as the current series could be useful for the treatment of cognitive impairments in neurological diseases such as Alzheimer's disease and related neurodegenerative disorders. The present invention provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: R1 represents branched C3-6 alkyl, C3-5 cycloalkyl or —C1-4 alkyl C3-4 cycloalkyl; R2 represents halogen, C1-6 alkyl, C1-6 alkoxy, cyano, amino or trifluoromethyl; n represents 0, 1 or 2; R3 represents -X-aryl, -X-heteroaryl, -X-heterocyclyl, -X-aryl-aryl, -X-aryl-heteroaryl, -X-aryl-heterocyclyl, -X-heteroaryl-aryl, -X-heteroaryl-heteroaryl, -X-heteroaryl-heterocyclyl, -X-heterocyclyl-aryl, -X-heterocyclyl-heteroaryl or -X-heterocyclyl-heterocyclyl; such that when R3 represents -X-piperidinyl, -X-piperidinyl-aryl, -X-piperidinyl-heteroaryl or -X-piperidinyl-heterocyclyl said piperidinyl group is attached to X via a nitrogen atom; wherein R3 is attached to the phenyl group of formula (I) at the 3 or 4 position; X represents a bond, O, CO, SO2, CH2O, OCH2, NR4, NR4CO or C1-6 alkyl; R4 represents hydrogen or C1-6 alkyl; wherein said aryl, heteroaryl or heterocyclyl groups of R3 may be optionally substituted by one or more (e.g. 1, 2 or 3) halogen, hydroxy, cyano, nitro, oxo, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkyl, C1-6 alkoxy, arylC1-6 alkoxy, C1-6 alkylthio, C1-6 alkoxyC1-6 alkyl, C3-7 cycloalkylC1-6 alkoxy, C3-7 cycloalkylcarbonyl, —COC1-6 alkyl, C1-6 alkoxycarbonyl, arylC1-6 alkyl, heteroarylC1-4 alkyl, heterocyclylC1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyloxy, C1-6 alkylsulfonylC1-6 alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC1-6 alkyl, aryloxy, —CO-aryl, —CO-heterocyclyl, —CO-heteroaryl, C1-6 alkylsulfonamidoC1-6 alkyl, C1-6 alkylamidoC1-6 alkyl, arylsulfonamido, arylaminosulfonyl, arylsulfonamidoC1-6 alkyl, arylcarboxamidoC1-6 alkyl, aroylC1-6 alkyl, arylC1-6 alkanoyl, or a group NR15R16, —NR15CO-aryl, —NR15CO-heterocyclyl, —NR15CO-heteroaryl, —CONR15R16, —NR15COR16, —NR15SO2R16 or —SO2NR15R16 groups, wherein R15 and R16 independently represent hydrogen or C1-6 alkyl; or solvates thereof. In one particular aspect of the present invention, there is provided a compound of formula (I) as defined above wherein X represents a bond, O, CO, SO2, CH2O, OCH2 or C1-6 alkyl. The term ‘C1-6 alkyl’ as used herein as a group or a part of the group refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like. The term ‘C1-6 alkoxy’ as used herein refers to an —O—C1-6 alkyl group wherein C1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like. The term ‘C3-8 cycloalkyl’ as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like. The term ‘halogen’ as used herein refers to a fluorine, chlorine, bromine or iodine atom. The term ‘haloC1-6 alkyl’ as used herein refers to a C1-6 alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like. The term ‘halo C1-6 alkoxy’ as used herein refers to a C1-6 alkoxy group as herein defined wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include difluoromethoxy or trifluoromethoxy and the like. The term ‘aryl’ as used herein refers to a C6-12 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or tetrahydronaphthalenyl and the like. The term ‘aryloxy’ as used herein refers to an —O-aryl group wherein aryl is as defined herein. Examples of such groups include phenoxy and the like. The term ‘heteroaryl’ as used herein refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur. Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like. Examples of such fused aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like. The term ‘heterocyclyl’ refers to a 4-7 membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or partially unsaturated containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur. Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, azepanyl and the like. Examples of such bicyclic rings include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1H-3-benzazepine, tetrahydroisoquinolinyl and the like. Preferably, R1 represents branched C3-6 alkyl (e.g. isopropyl) or C3-5 cycloalkyl (e.g. cyclopropyl or cyclobutyl), more preferably cyclobutyl. Preferably, n represents 0. Preferably, R3 represents -X-aryl (e.g. -phenyl, —CO-phenyl, —O-phenyl, —OCH2-phenyl or —CH2O-phenyl) optionally substituted by one or more halogen (e.g. fluorine), cyano, —COC1-6 alkyl (e.g. —COMe) or —CONR15R16 (e.g. —CONH2) groups; -X-heteroaryl (e.g. -tetrazolyl, -pyrazolyl, -pyrrolyl, -oxazolyl, -isoxazolyl, -oxadiazolyl, -pyridyl, —OCH2-pyridyl, —NHCO-pyridyl, -pyrimidinyl, —N(Me)-pyrimidinyl, -pyridazinyl or —OCH2-pyrazinyl) optionally substituted by one or more haloC1-6 alkyl (e.g. —CF3), cyano, oxo, C1-6 alkyl (e.g. methyl or ethyl) or —CONR15R16 (e.g. —CONHMe or —CON(Me)2) groups; -X-heteroaryl-aryl (e.g. -thiazolyl-phenyl) optionally substituted by one or more halogen (e.g. fluorine) atoms; -X-aryl-heteroaryl (e.g. -phenyl-oxazolyl or -phenyl-oxadiazolyl) optionally substituted by one or more C1-6 alkyl (e.g. methyl) groups; or -X-heterocyclyl (e.g. -thiomorpholinyl, -morpholinyl, -pyrrolidinyl or —O-tetrahydro-2H-pyran4-yl) optionally substituted by one or more oxo groups. More preferably, R3 represents -X-aryl (e.g. -phenyl or —CO-phenyl) optionally substituted by one or more halogen (e.g. fluorine), cyano or —COC,- alkyl (e.g. —COMe) groups; -X-heteroaryl (e.g. -oxazolyl, -isoxazolyl, -oxadiazolyl, -pyridyl, -pyrimidinyl or -pyridazinyl) optionally substituted by one or more haloC1-6 alkyl (e.g. —CF3), cyano, C1-6 alkyl (e.g. methyl) or —CONR15R16 (e.g. —CONHMe) groups; -X-heteroaryl-aryl (e.g. -thiazolyl-phenyl) optionally substituted by one or more halogen (e.g. fluorine) atoms; or -X-heterocyclyl (e.g. -morpholinyl). Most preferably, R3 represents -X-aryl (e.g. -phenyl) optionally substituted by one or more cyano or —COC1-6 alkyl (e.g. —COMe) groups; or -X-heteroaryl (e.g. -pyridyl) optionally substituted by one or more haloC1-6 alkyl (e.g. —CF3) or cyano groups. Especially preferably, R3 represents -pyridyl optionally substituted by one or more haloC1-6 alkyl (e.g. —CF3) or cyano groups. Preferably, R3 is attached to the phenyl group of formula (I) at the 4 position. Preferably, X represents a bond, CO, O, NR4, NR4CO, CH2O or OCH2 more preferably a bond. Preferably, R4 represents hydrogen or methyl. Preferably, R3 is attached to the phenyl group of formula (I) at the 4 position. Preferred compounds according to the invention include examples E1-E58 as shown below, or a pharmaceutically acceptable salt thereof. Compounds of formula (I) may form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, sulphate, citric, lactic, mandelic, tartaric and methanesulphonic. Salts, solvates and hydrates of histamine H3 receptor antagonists or inverse agonists therefore form an aspect of the invention. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of these compounds and the mixtures thereof including racemates. Tautomers also form an aspect of the invention. The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: (a) reacting a compound of formula (II) wherein R2, n and R3 are as defined above and L1 represents OH or a suitable leaving group, such as a halogen atom (e.g. chlorine), with a compound of formula (III) wherein R1a is as defined above for R1 or is a group convertible to R1; or (b) reacting a compound of formula (IV) with a compound of formula R3-L2, wherein R1a, R2, R3 and n are as defined above, L2 represents a suitable leaving group such as a halogen atom and Z represents a boronic acid ester group attached at the 3 or 4 position of the phenyl ring, such as a pinacol ester e.g. a group of formula Za: (c) deprotecting a compound of formula (I) which is protected; and optionally thereafter (d) interconversion to other compounds of formula (I). Process (a) typically comprises activation of the compound of formula (II) wherein L1 represents OH with a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of 1-hydroxybenzotriazole (HOBT) in a suitable solvent such as dichloromethane followed by reaction with the compound of formula (III). Process (a) may also involve halogenation of the compound of formula (II) wherein L1 represents OH with a suitable halogenating agent (e.g. thionyl chloride or oxalyl chloride) followed by reaction with the compound of formula (III) in the presence of a suitable base such as triethylamine or a solid supported base such as diethylaminomethylpolystyrene in a suitable solvent such as dichloromethane. Process (b) typically comprises the use of a catalyst such as tetrakis(triphenylphosphine)palladium(0) in a solvent such as acetonitrile with a base e.g. sodium carbonate. In process (c), examples of protecting groups and the means for their removal can be found in T. W. Greene ‘Protective Groups in Organic Synthesis’ (J. Wiley and Sons, 1991). Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl, 2′,2′,2′-trichloroethoxycarbonylv benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid) or reductively (e.g. hydrogenolysis of a benzyl group or reductive removal of a 2′,2′,2′-trichloroethoxycarbonyl group using zinc in acetic acid) as appropriate. Other suitable amine protecting groups include trifluoroacetyl (—COCF3) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid. Process (d) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation. Compounds of formula (II) and (III) are either known in the literature or can be prepared by analogous methods. Compounds of formula (IV) may be prepared by reacting a compound of formula (V) wherein R2, n and Z are as defined above, with a compound of formula (III) as defined above. This process typically comprises activation of the compound of formula (V) with a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of 1-hydroxybenzotriazole (HOBT) in a suitable solvent such as DMF. Compounds of formula (V) are either known in the literature or can be prepared by analogous methods. Compounds of formula (I) and their pharmaceutically acceptable salts have affinity for and are antagonists and/or inverse agonists of the histamine H3 receptor and are believed to be of potential use in the treatment of neurological diseases including Alzheimer's disease, dementia (including Lewy body dementia and vascular dementia), age-related memory dysfunction, mild cognitive impairment, cognitive deficit, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke and sleep disorders (including narcolepsy and sleep deficits associated with Parkinson's disease); psychiatric disorders including schizophrenia (particularly cognitive deficit of schizophrenia), attention deficit hypereactivity disorder, depression, anxiety and addiction; and other diseases including obesity and gastro-intestinal disorders. It will be appreciated that certain compounds of formula (I) believed to be of potential use in the treatment of Alzheimer's disease and cognitive deficit of schizophrenia will advantageously be CNS penetrant, e.g. have the potential to cross the blood-brain barrier. It will also be appreciated that compounds of formula (I) are expected to be selective for the histamine H3 receptor over other histamine receptor subtypes, such as the histamine H1 receptor. Generally, compounds of the invention may be at least 10 fold selective for H3 over H1, such as at least 100 fold selective. Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the above disorders, in particular cognitive impairments in diseases such as Alzheimer's disease and related neurodegenerative disorders. The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders. When used in therapy, the compounds of formula (I) are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures. Thus, the present invention further provides a pharmaceutical composition for use in the treatment of the above disorders which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The present invention further provides a pharmaceutical composition which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Compounds of formula (I) may be used in combination with other therapeutic agents, for example medicaments claimed to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease. Suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HT6 antagonists, M1 muscarinic agonists, M2 muscarinic antagonists or acetylcholinesterase inhibitors. When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants. For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months. The following Descriptions and Examples illustrate the preparation of compounds of the invention. It will be appreciated that hydrochloride salt compounds may be converted into the corresponding free base compounds by treatment with saturated aqueous potassium carbonate solution followed by extraction into a suitable solvent such as diethyl ether or DCM. Description 1 (Method A) 1-tert-Butyl-4-(isopropyl)-hexahydro-1H-1,4-diazepine-1-carboxylate (D1) tert-Butyl-hexahydro-1H-1,4-diazepine-1-carboxylate (10.0 g) was dissolved in DCM (200 ml). Acetone (7.33 ml) was added and the reaction was left to stir for 5 min. Sodium triacetoxyborohydride (21.0 g) was then added and the reaction was stirred at rt for 16 h. The reaction mixture was washed with saturated potassium carbonate solution (2×200 ml). The organic layer was dried (magnesium sulphate) and evaporated to give the title compound (D1) as a clear oil (11.0 g). Description 1 (Method B) 1-tert-Butyl-4-(isopropyl)-hexahydro-1H-1,4-diazepine-1-carboxylate (D1) tert-Butyl-hexahydro-1H-1,4-diazepine-1-carboxylate (25.06 g) was dissolved in acetonitrile (250 ml). Anhydrous potassium carbonate (34.5 g) and 2-iodopropane (63 g, 37 ml) were added and the mixture was heated at reflux for 18 h. The cooled mixture was filtered and the solids were washed with acetonitrile. The combined filtrates were evaporated and the residual oil was dissolved in diethyl ether, washed with water, sodium thiosulphate solution and brine, dried (Na2SO4) and evaporated to give the title compound (D1) as a light brown oil (29.8 g). Description 2 1-(Isopropyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D2) 1-tert-Butyl-4-(isopropyl)-hexahydro-1H-1,4-diazepine-1-carboxylate (D1) (11.0 g) was dissolved in methanol (200 ml) and 4N HCl in dioxan (100 ml) was added. The reaction was stirred at rt for 2 h and then evaporated to give the title compound (D2) as a white solid (9.6 g). 1H NMR δ (CDCl3): 11.35 (1H, s), 10.22 (1H, s), 9.72 (1H, s), 4.15-3.52 (9H, m), 2.83-2.40 (2H, m), 1.47 (6H, d, J=6.24 Hz). Description 3 1-tert-Butyl-4-(cyclobutyl)-hexahydro-1-H1,4-diazepine-1-carboxylate (D3) tert-Butyl-hexahydro-1H-1,4-diazepine-1-carboxylate (10.0 g) was dissolved in DCM (300 ml). Cyclobutanone (7.5 ml) was added and the reaction was left to stir for 5 min. Sodium triacetoxyborohydride (21.1 g) was then added and the reaction was stirred at rt for 16 h. The reaction mixture was washed with saturated potassium carbonate solution (2×200 ml). The organic layer was dried (magnesium sulphate) and evaporated to give the title compound (D3) as a clear oil (11.3 g). Description 4 1-(Cyclobutyl)hexahydro-1H-1,4-diazepine dihydrochloride (D4) 1-tert-Butyl4-(cyclobutyl)-hexahydro-1-H-1,4-diazepine-1-carboxylate (D3) (11.3 g) was dissolved in methanol (200 ml) and 4N HCl in dioxan (100 ml) was added. The reaction was stirred at rt for 3 h and then co-evaporated from toluene (3×50 ml) to give the title compound (D4) as a white solid (9.8 g). 1H NMR δ (DMSO-d6): 11.95 (1H, s), 9.55 (1H, s), 9.64 (1H, s), 3.78-3.08 (9H, m), 2.51-2.07 (6H, m), 1.80-1.51 (2H, m). Description 5 Ethyl 4-(tetrahydro-2H-pyran-4-yloxy)benzoate (D5) An ice-cold solution of ethyl 4-hydroxybenzoate (0.82 g), 4-hydroxy-tetrahydro-2H-pyran (0.5 g) and triphenylphosphine in THF (50 ml) was treated dropwise with diisopropyl azodicarboxylate (1.69 ml). After 15 min the cooling bath was removed and the reaction stood overnight at rt. The mixture was evaporated, redissolved in toluene and successively washed with 2N sodium hydroxide (2×20 ml), water (2×20 ml) and brine (20 ml). After drying (magnesium sulfate) the solution was loaded directly on to a silica flash column (step gradient 10-30% EtOAc in light petroleum 40-60) to give the title compound (D5) (0.75 g). 1H NMR δ (CDCl3): 7.98 (2H, d, J=8.5Hz), 6.91 (2H, d, J=8.5 Hz), 4.60 (1H, m), 4.35 (2H, q, J=9.8 Hz), 3.98 (2H, m), 3.57 (2H, m), 2.05 (2H, m), 1.80 (2H, m), 1.38 (3H, t, J=9.8 Hz). Description 6 4-(Tetrahydro-2H-pyran-4-yloxy)benzoic acid (D6) A solution of ethyl 4-(tetrahydro-2H-pyran-4-yloxy)benzoate (D5) (0.73 g) in EtOH (10 ml) was treated with 1 M NaOH (5.84 ml) and the mixture stirred at 60° C. for 5 h. The solution was cooled to rt and the EtOH was evaporated. The aqueous was washed with DCM (2×10 ml) and acidified. The solid was filtered off, washed with water and dried to give the title compound (D6) (0.55 g). MS electrospray (-ion) 221 (M-H). 1H NMR δ (DMSO-d6): 7.87 (2H, d, J=8.5 Hz), 7.05 (2H, d, J=8.5 Hz), 4.69 (1H, m), 3.85 (2H, m), 3.50 (2H, m), 1.98 (2H, m), 1.59 (2H, m). Description 7 1-Cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1-H1,4-diazepine (D7) 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.24 g) in dry DMF (30 ml) was treated with EDC (1.48 g) and HOBT (0.67 g). The reaction mixture was stirred at rt for 5 min, followed by the addition of 1-(cyclobutyl)hexahydro-1H-1,4-diazepine dihydrochloride (D4) (1.13 g) and triethylamine (2.7 ml). The mixture was stirred at rt overnight. The reaction mixture was then poured into water (250 ml) and extracted with EtOAc (2×35 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate (2×30 ml) followed by water (5×30 ml). After drying (magnesium sulphate) the solution was evaporated to give the title compound (D7) as an oil (0.84 g).MS electrospray (+ve ion) 385 (MH+). Description 8 Methyl 4-(6-cyano-3-pyridinyl)benzoate (D8) 4-Methoxycarbonylphenyl boronic acid (0.5 g) and 5-bromo-2-pyridinecarbonitrile (0.5 g) in a mixture of THF (5 ml) and water (5 ml) were treated with tetrakis(triphenyl phosphine)palladium(0) (0.32 g) and potassium carbonate (1 g). A further amount of THF (5 ml) was added and the reaction was heated at 80° C. for 1 h. After cooling the reaction mixture was diluted with EtOAc (30 ml) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried (magnesium sulfate) and concentrated to give a crude residue that was purified by column chromatography (silica-gel, gradient 0-100% EtOAc in hexane) to give the title compound (D8) as a white solid (0.5 g). LCMS electrospray (+ve) 239 (MH+). Description 9 4-(6-Cyano-3-pyridinyl)benzoic acid (D9) Methyl 4-(6-cyano-3-pyridinyl)benzoate (D8) (0.5 g) in dioxane (30 ml) was treated with 1.1 eq aqueous LiOH solution (2.3 ml), 1N) and stirred at rt for 2 days. Solvent was removed by evaporation to give a white solid which was dissolved in water (10 ml) and acidified with 2N HCl to give a white solid which was filtered and dried to give the title compound (D9) (0.35 g). LCMS electrospray (+ve) 224 (MH+). Description 10 5-Bromo-2-pyridinecarboxylic acid (D10) 4-Bromobenzonitrile (4.45 g) was heated at reflux in concentrated hydrochloric acid (60 ml) for 3 h. After cooling, white crystals were filtered off and dried in a vacuum oven to give the title compound (D10) (3.46 g). LCMS electrospray (+ve) 203 (MH+). Description 11 5-Bromo-N-methyl-2-pyridinecarboxamide (D11) 5-Bromo-2-pyridinecarboxylic acid (D10) (1 g) was dissolved in dry DMF (50 ml) and treated with methylamine hydrochloride (0.42 g), EDC (1.29), HOBT (0.56 g) and Et3N (2.4 ml). The reaction was stirred at rt overnight then poured into water (200 ml) and extracted with DCM (50 ml). The organic extract was washed with brine (5×50 ml), dried (magnesium sulfate) and evaporated to give the title compound (D11) as a yellow crystalline solid (0.45 g). LCMS electrospray (+ve) 349 (MH+). Description 12 1-(Isopropyl)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D12) The tile compound (D12) was prepared in a similar manner to Description 7 from 1-(isopropyl)-hexahydro-1H-1,4-diazepine (free base of D2) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and isolated as a brown oil. LCMS electrospray (+ve) 373 (MH+). Description 13 5-Bromo-2-trifluoromethylpyrimidine (D13) A mixture of potassium fluoride (1.77 g) and cuprous iodide (5.79 g) was stirred and heated together using a heat gun under vacuum (˜1 mm) for 20 min. After cooling, dimethyl formamide (20 ml) and N-methyl pyrrolidinone (20 ml) were added followed by (trifluoromethyl)trimethylsilane (4.1 ml) and 5-bromo-2-iodopyrimidine (6.5 g). The mixture was stirred at rt for 5 h and then the brown solution was poured into 6N ammonia solution. The product was extracted into ethyl acetate and the extracts were washed with sodium bicarbonate solution and brine and then dried (Na2SO4) and evaporated. Chromatography on silica gel (elution with 20-50% dichloromethane in pentane) gave the title compound (D13) as a white solid (2.4 g). 1H NMR (CDCl3): 8.97 (2H, s). Description 14 4-(4-Bromophenyl)-2-methyl-oxazole (D14) 4-Bromophenacyl bromide (21.3 g) and acetamide (11.3 g) were heated together at 130° C. under argon. After 2.5 h the reaction mixture was allowed to cool, and partitioned between water (150 ml) and Et2O (150 ml). The organic phase was washed with aqueous NaOH (0.5N), aqueous HCl (0.5M) and saturated aqueous NaCl solution (100 ml) of each), dried (MgSO4) and evaporated to give a brown solid which was recrystallised from hexanes to give the title compound (D14) as an orange solid (4.1 g). LCMS electrospray (+ve) 239 (MH+). Description 15 5 5-(4-Bromophenyl)-2-methyl-oxazole (D15) Trifluoromethanesulfonic acid (6.6 ml) was added to a flask containing iodobenzene diacetate (12.2 g) and MeCN (200 ml) at rt. After 25 min. a solution of 4′-bromoacetophenone (5 g) in MeCN (50 ml) was added and the resultant mixture heated at reflux for 6 h. The reaction was allowed to cool to rt before the solvent was evaporated and the residue partitioned between saturated aqueous Na2CO3 (150 ml) and EtOAc (150 ml). The organic phase was washed with saturated brine (150 ml), dried (MgSO4) and evaporated to give an orange solid. The crude product was purified by column chromatography (silica gel, 50% EtOAc in hexane) to give the title compound (D15) as a pale yellow solid (3.5 g). LCMS electrospray (+ve) 239 (MH+). Description 16 3-(4-Bromophenyl)-5-methyl-1,2,4-oxadiazole (D16) Step 1: 4-Bromo-N-hydroxy-benzenecarboximidamide 4-Bromophenylcarbonitrile (10.2 g), hydroxylamine hydrochloride (7.8 g) and Et3N (11.3 g) were dissolved in EtOH (250 ml) and the reaction mixture was heated at reflux for 3 h, after which it was evaporated to form a white precipitate of the desired amidoxime, which was filtered off and washed with water (25 ml). The filtrate was extracted into EtOAc (2×25 ml), and the combined organic extracts were dried (Na2SO4) and evaporated to give a second crop of the subtitle compound (combined yield=11.1 g). LCMS electrospray (+ve) 216 (MH+). Step 2: 3-(4-Bromophenyl)-5-methyl-1,2,4-oxadiazole The product from D16, step 1 was suspended in acetic anhydride and heated to 100° C. for 4 h, then 120° C. for 3 h. After cooling the reaction mixture was evaporated to give a brown solid. This was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic phase was washed with saturated aqueous NaCl, dried (Na2SO4) and evaporated to give a yellow solid. The crude product was purified by column chromatography (silica gel, 10-100% gradient of EtOAc in hexane) to give the title compound (D16) as a white solid (6.2 g). LCMS electrospray (+ve) 240 (MH+). Description 17 2-(4-Bromophenyl)-oxazole (D17) Step 1: 4-Bromo-N-(2,2-dimethoxyethyl)-benzamide Potassium carbonate (8.0 g) was added to a solution of 2,2-dimethoxyethylamine in water (90 ml) and acetone (40 ml) at rt. The reaction mixture was cooled in an ice-water bath and 4-bromobenzoyl chloride (16.4 g) dissolved in acetone (70 ml) was added drop-wise over 90 min. The stirred reaction mixture was allowed to warm to rt. After a further 2 h the reaction mixture was extracted into EtOAc (3×75 ml), the combined organics were washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and evaporated to give the amide as an off white solid (18.5 g). LCMS electrospray (+ve) 289 (MH+). Step 2: 2-(4-Bromophenyl)-oxazole The product of D17, step 1 was suspended in Eaton's reagent (200 ml), the reaction mixture was purged with argon and heated to 240° C. for 9 h. The reaction mixture was then allowed to cool and stirred for 65 h at rt. The crude mixture was poured over ice (1 L) and stirred for 1 h. The aqueous mixture was extracted into EtOAc (2×250 ml), dried (MgSO4) and evaporated to give a grey powder. This crude solid was dissolved in THF (300 ml) and EtOH (300 ml), and Hunig's base (21.1 ml) was added. MP-carbonate resin (40.1 g) and PS-thiophenol resin (69.7 g) were suspended in the reaction mixture, which was stirred for 24 h. The suspension was filtered and the solid phase resins washed with 1:1 THF:EtOH (3×600 ml), and the combined organics evaporated to give the title compound (D17) as a white solid (9.0 g). LCMS electrospray (+ve) 225 (MH+). Description 18 4-(3-Methyl-1,2,4-oxadiazol-5-yl)benzoic acid (D18) Methyl 4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate (J. R. Young and R. J. DeVita, Tetrahedron Lett., 1998, 39, 3931) was dissolved in a mixture of dioxan (110 ml), water (70 ml) and isopropanol (30 ml), and lithium hydroxide (1.38 g) was added. The mixture was stirred at room temperature for ca 5 h and then the mixture was acidified to ca pH 4 by addition of Amberlyst 15 H+ resin. The resin was removed by filtration and the filtrate was concentrated in vacuo. The solid white precipitate which was obtained was collected by filtration, washed with water on the filter and dried in vacuo at 40° C. for 48 h to give the title compound (D18) (4.23 g). EXAMPLE 1 4′-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]-4-biphenylcarbonitrile hydrochloride (E1) 1-(Cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.15 g) was stirred with diethylaminomethyl polystyrene (1.0 g), HOBT (0.045 g), 4′-cyano-4-biophenylcarboxylic acid (0.16 g) in DCM (5 ml). EDC (0.16 g) was then added and the reaction was stirred at rt for 16 h. The polymer supported base was filtered off and the filtrate was diluted with DCM (10 ml) and washed with saturated sodium hydrogen carbonate (2×15 ml). The organic layer was then loaded directly onto a silica column eluting with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM. The isolated free base product was dissolved in DCM (5 ml) and treated with excess 1N HCl/diethyl ether solution (1 ml) and stirred for 10 min. The mixture was evaporated (co-evaporated with acetone 2×10 ml), triturated with acetone, then dried at 50° C. under high vacuum for 16 h to yield the title compound (E1) as a pale solid (0.119 g). MS electrospray (+ion) 360 (MH+). 1H NMR δ (DMSO-d6): 10.60 (1H, s), 7.97 (4H, m), 7.86 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=7.6 Hz), 4.18 (1H, m), 3.89-3.37 (6H, m), 3.10 (2H, m), 2.40-1.59 (8H, m). EXAMPLE 2 1-{4′-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]-4-biphenylyl}ethanone hydrochloride (E2) 1-(Cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.15 g) was stirred with diethylaminomethyl polystyrene (1.0 g), HOBT (0.045 g) and 4′-acetyl-4-biphenylcarboxylic acid (0.13 g) in DCM (5 ml). EDC (0.16 g) was then added and the reaction stirred at rt for 16 h. The polymer supported base was filtered off and the filtrate was diluted with DCM (10 ml) and washed with saturated sodium hydrogen carbonate (2×15 ml). The organic layer was loaded directly onto a silica column eluting with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM. The isolated free base product was dissolved in DCM (5 ml) and treated with excess 1N HCl/diethyl ether solution (1 ml) and stirred for 10 min. The mixture was evaporated (co-evaporated with acetone 2×10 ml), triturated with acetone, then dried at 50° C. under high vacuum for 16 h to yield the title compound (E2) as a pale solid (0.055 g). MS electrospray (+ion) 377 (MH+). 1H NMR δ (DMSO-d6): 10.57 (1H, s), 9.07 (2H, d, J=6.4 Hz), 7.88 (4H, m), 7.60 (2H, d, J=7.6 Hz), 4.15 (1H, m), 3.82-3.33 (6H, m), 3.02 (2H, m), 2.62 (3H, s), 2.41-1.62 (8H, m). EXAMPLES 3-6 (E3-E6) Examples 3-6 were prepared from 1-(cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) and the appropriate carboxylic acid, using the procedure described in Example 1 and displayed 1H NMR and mass spectral data that were consistent with structure. Example No R Mass Spectrum (ES+) E3 [MH]+ 335 E4 [MH]+ 363 E5 [MH]+ 351 E6 [MH]+ 365 EXAMPLE 7 1-Cyclobutyl-4-{[4-tetrazol-1-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine hydrochloride (E7) 1-(Cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.15 g) was stirred with diethylaminomethyl polystyrene (1.0 g), HOBT (0.045 g) and 4-(tetrazol-1-yl)-benzoic acid (0.14 g) in DCM (5 ml). EDC (0.165 g) was then added and the reaction was stirred at rt for 16 h. The polymer supported base was filtered off and the filtrate was diluted with DCM (10 ml) and washed with saturated sodium hydrogen carbonate (2×15 ml). The organic layer was then loaded directly onto a silica column eluting with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM. The isolated free base product was dissolved in DCM (5 ml) and treated with excess 1N HCl/diethyl ether solution (1 ml) and stirred for 10 min. The mixture was evaporated (co-evaporated with acetone 2×10 ml), triturated with acetone, then dried at 50° C. under high vacuum for 16 h to yield the title compound (E7) as a pale solid (0.096 g). MS electrospray (+ion) 327 (MH+). 1H NMR δ (DMSO-d6): 11.11 (1H, s), 10.18 (1H, s), 8.02 (2H, d, J=8.4 Hz), 7.76 (2H, d, J=8.0 Hz), 4.17 (1H, m), 3.81-3.27 (6H, m), 3.11 (2H, m), 2.47-1.95 (6H, m), 1.80-1.59 (2H, m). EXAMPLE 8 1-Cyclobutyl-4-({4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]phenyl}carbonyl) hexahydro-1H-1,4-diazepine hydrochloride (E8) The title compound (E8) was prepared from 1-(cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) and 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]benzoic acid using the procedure described in Example 7. MS APCl 436 (MH+). EXAMPLE 9 1-Cyclobutyl-4-{[4-(1,1-dioxido-4-thiomorpholinyl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine hydrochloride (E9) 1-(Cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.15 g) was stirred with diethylaminomethyl polystyrene (1.0 g), HOBT (0.045 g), 4-(1,1-dioxido-4-thiomorpholinyl)benzoic acid (0.186 g) in DCM (5 ml). EDC (0.165 g) was then added and the reaction was stirred at rt for 16 h. The polymer supported base was filtered off and the filtrate was diluted with DCM (10 ml) and washed with saturated sodium hydrogen carbonate (2×15 ml). The organic layer was then loaded directly onto a silica column and eluted with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM. The isolated free base product was dissolved in DCM (5 ml) and treated with excess 1N HCl/diethyl ether solution (1 ml) and stirred for 10 min. The mixture was evaporated (co-evaporated with acetone 2×10 ml), triturated with acetone, then dried at 50° C. under high vacuum for 16 h to yield the title compound (E9) as a pale solid (0.086 g). MS electrospray (+ion) 392 (MH+). 1H NMR δ (DMSO-d6): 10.5 (1H, s), 7.37 (2H, d, J=8.4 Hz), 7.07 (2H, d, J=8.8 Hz), 4.18-3.24 (10H, m), 3.11 (4H, m), 3.10-2.85 (2H, m), 2.45-1.98 (7H, m), 1.80-2.54 (2H, m). EXAMPLE 10 1-(Isopropyl)-4-{[14-(tetrahydro-2H-pyran-4-yloxy)phenyl]carbonyl)hexahydro-1H-1,4-diazepine hydrochloride (E10) A stirred suspension of 4-(tetrahydro-2H-pyran4-yloxy)benzoic acid (D6) (222 mg) in DCM (5 ml) at rt was treated with oxalyl chloride (0.28 ml) and 10% DMF in DCM (1 drop). After 1 h the solution was evaporated and then re-evaporated from DCM (2×5 ml). The acid chloride was redissolved in DCM (10 ml) and treated with 1-(isopropyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D2) (178 mg) and diethylaminomethyl polystyrene (3.2 mmol/g, 938 mg). After stirring overnight the mixture was loaded directly on to a silica gel flash column [step gradient 6-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, then redissolved in DCM and treated with excess 4M HCl in dioxan. Crystallisation from acetone afforded the title compound (E10) (225 mg). MS electrospray (+ion) 347 (MH+). 1H NMR δ (DMSO-d6): 10.45 (1H, m), 7.41 (2H, d, J=8.5 Hz), 7.02 (2H, d, J=8.5 Hz), 4.63 (2H, m), 4.02 (1H, m), 3.02-3.93 (13H, m), 2.32 (1H, m), 1.96 (2H, m), 1.61 (2H, m), 1.27 (6H, d, J=6.5 Hz). EXAMPLE 11 1-Cyclobutyl-4-({4-[6-(trifluoromethyl)-3-pyridinyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine hydrochloride (E11) A mixture of 1-cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D7) (0.28 g) and 5-bromo-2-(trifluoromethyl)pyridine (F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327) in dry and degassed acetonitrile (3.5 ml) was treated with tetrakis(triphenyl phosphine)palladium(0) (0.050 g), and 2M aqueous Na2CO3 solution (0.6 ml). The reaction mixture was heated at 140° C. for 5 min in an Emrys Optimiser microwave reactor. The crude reaction mixture was then diluted with MeOH (10 ml) and the solution was poured directly onto an SCX column (10 g) and washed first with MeOH (60 ml) and then eluted with 2M ammonia in MeOH solution (60 ml). The ammonia/methanol fractions were concentrated and further purified on a Waters mass directed preparative HPLC. The required fractions were concentrated and the residual gum was redissolved in MeOH (1 ml) and treated with ethereal HCl (1 ml), 1N). After evaporation of solvent the residue was triturated with diethyl ether to give the title hydrochloride salt (E11) as a white solid (0.088 g). 1H NMR δ (methanol-d4): 1.76-1.89 (2H, m), 2.18-2.38 (6H, m), 3.09-3.18 (2H, m), 3.47-3.9 (6H, m), 4.31-4.35 (1H, m), 7.64 (2H, d, J=8 Hz), 7.88 (1H, d, J=8 Hz), 7.92 (2H, d, J=8 Hz), 8.33 (1H, d, J=8 Hz), 9.02 (1H, s). LCMS electrospray (+ve) 404 (MH+). EXAMPLE 12 6-{4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-3-cyanopyridine hydrochloride (E12) The title compound (E12) was prepared in a similar manner to Example 11 from 1-cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D7) (0.15 g) and 6-chloronicotinonitrile (0.054 g). The crude reaction mixture was purified by flash chromatography [silica gel, step gradient 0-15% MeOH (containing 10% 0.88 ammonia solution) in DCM]. The free base compound was converted into the HCl salt in dry DCM (2 ml) with ethereal HCl (1 ml), 1N). Evaporation of solvent afforded the title compound (E12) as a white solid (0.046 g). 1H NMR δ (methanol-d4): 1.78-1.90 (2H, m), 2.1-2.4 (6H, m), 3.03-3.2 (2H, m), 3.5-3.9 (6H, m), 4.28-4.35 (1H, m), 7.65 (2H, d, J=8 Hz), 8.13 (1H, d, J=8 Hz), 8.23-8.26 (3H, m), 8.99 (1H, d, J=2.4 Hz). LCMS electrospray (+ve) 361 (MH+). EXAMPLE 13 5-{4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-N-methyl-2-pyridinecarboxamide hydrochloride (E13) The title compound (E13) was prepared in a similar manner to Example 11 from 1-cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D7) (0.22 g) and 5-bromo-N-methyl-2-pyridinecarboxamide (D11) (0.11 g). The crude mixture after SCX work-up was purified on a Waters mass directed preparative HPLC. Pure fractions were concentrated, redissolved in dry DCM (2 ml) and treated with 1N ethereal HCl. After evaporation of solvents the title compound (E13) was obtained as a white solid (0.062 g). 1H NMR δ (methanol-d4): 1.77-2.00 (2H, m), 2.15-2.45 (6H, m), 3.0 (3H, s), 3.07-3.25 (2H, m), 3.45-3.85 (6H, m), 4.28-4.39 (1H, m), 7.67-7.69 (2H, d, J=8 Hz), 7.90-7.88 (2H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 8.42 (1H, d, J=8 Hz), 8.99 (1H, d, J=1.2 Hz). LCMS electrospray (+ve) 393 (MH+). EXAMPLE 14 5-{4-[(4-Cyclobutylhexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl}-2-cyanopyridine hydrochloride (E14) The title compound (E1 4) was prepared in a similar manner to Example 11 from 5-bromo-2-cyanopyridine (0.043 g) and 1-cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D7) ( 0.1 g). 1H NMR δ (methanol-d4): 1.8-1.9 (2H, m), 2.18-2.38 (6H, m), 3.05-3.20 (2H, m), 3.48-3.90 (6H, m), 4.28-4.38 (1H, m), 7.64 (2H, d, J=8.4 Hz), 7.83 (2H, d, J=8.4 Hz), 7.92 (1H, d, J=8 Hz), 8.24 (1H, dd, J=8 Hz), 9.04 (1H, d, J=1.6 Hz). LCMS electrospray (+ve) 361 (MH+). EXAMPLE 15 5-(4-{[4-(1-Isopropyl)hexahydro-1H-1,4-diazepin-1-yl]carbonyl}phenyl)-2-cyanopyridine hydrochloride (E15) 4-(6-Cyano-3-pyridinyl)benzoic acid (D9) (0.35 g) was dissolved in dry DMF and treated with EDC (0.51 g) and a catalytic quantity of HOAT. The reaction mixture was stirred at rt for 5 min, followed by the addition of 1-(isopropyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D2) (0.28 g) and N,N-diisopropylethylamine (1 ml), and allowed to stir at rt overnight. After evaporation of solvent the residue was partitioned between DCM (15 ml) and water (15 ml). The DCM layer was dried (magnesium sulfate) and concentrated to leave a crude residue which was purified by flash chromatography [silica gel, step gradient 0-15% MeOH (containing 10% 0.88 ammonia solution) in DCM]. Pure fractions were combined and concentrated to give the free base which was converted into the HCl salt in DCM (2 ml) with 1N ethereal HCl (1 ml). Evaporation of the solvents afforded the title compound (E15) (8 mg). 1H NMR δ (methanol-d4): 1.4 (6H, d, J=6.4 Hz), 2.16 (2H, bs), 3.47-4.2 (8H, m), 4.2-4.4 (1H, m), 7.68 (2H, d, J=8 Hz), 7.85 (2H, d, J=8 Hz), 7.98 (1H, d, J=8 Hz), 8.29 (1H, dd, J=8 Hz), 9.04 (1H, d, J=1.6 Hz). LCMS electrospray (+ve) 349 (MH+). EXAMPLE 16 N-Methyl-5-(4-{[4-(1-isopropyl)hexahydro-1H-1,4-diazepin-1-yl]carbonyl}phenyl)-2-pyridinecarboxamide hydrochloride (E16) The title compound (E16) was prepared in a similar manner to Example 11 from 1-(isopropyl)-4-{([4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D12) (0.15 g) and 5-bromo-N-methyl-2-pyridine carboxamide (D11) (0.086 g). After SCX work-up the product was purified using flash chromatography [silica gel, step gradient 0-15% MeOH (containing 10% 0.88 ammonia solution) in DCM]. The free base product was dissolved in dry DCM (2 ml) and treated with 1N ethereal HCl (1 ml). Evaporation of solvents afforded the title compound (E16) as a white solid (0.1 g). 1H NMR δ (DMSO-d6): 1.25-1.30 (6H, m), 1.99-2.2 (1H, m), 2.27-2.45 (1H, m), 2.84-2.85 (3H, d, J=4.8 Hz), 3.2-4.18 (9H, m), 7.65 (2H, d, J=8 Hz), 7.90 (2H, d, J=8 Hz), 8.12 (1H, d, J=8 Hz), 8.32 (1H, dd, J=8 Hz), 8.82 (1H, q, J=4.8 Hz), 8.98 (1H, d, J=1.6 Hz). LCMS electrospray (+ve) 381 (MH+). EXAMPLES 17-21 (E17-E21) Examples 17-21 were prepared in a similar manner to Example 11 from 1-(isopropyl)-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D12) and the appropriate heteroaryl bromide or chloride. All compounds displayed 1H NMR and mass spectral data that were consistent with structure. Example No R Mass Spectrum (ES+) 17 (MH+) 393 18 (MH+) 393 19 (MH+) 392 20 (MH+) 395 21 (MH+) 349 EXAMPLE 22 1-Cyclobutyl-4-({4-[6-(trifluoromethyl)-3-pyridazinyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine hydrochloride (E22) The title compound (E22) was prepared in a similar manner to Example 11 from 1-cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl)hexahydro-1H-1,4-diazepine (D7) and 3-chloro-6-(trifluoromethyl)pyridazine (Goodman, Stanforth and Tarbit, Tetrahedron, 1999, 55, 15067). The crude product after work-up was by purified by flash chromatography [silica gel, gradient 0-100% EtOAc-MeOH) and the free base was converted into the title hydrochloride salt (E22). 1H NMR δ (methanol-d4): 1.8-1.95 (2H, m), 2.15-2.48 (6H, m), 3.07-3.25 (2H, m), 3.48-3.95 (6H, m), 4.3-4.5 (1H, m), 7.72 (2H, d, J=8 Hz), 8.21 (1H, d, J=8 Hz), 8.32 (2H, d, J=8 Hz), 8.45 (1H, d, J=8 Hz). EXAMPLE 23 1-Cyclobutyl-4-({4-[2-(trifluoromethyl)-5-pyrimidinyl]phenyl}carbonyl)hexahydro-1H-1,4-diazepine hydrochloride (E23) The title compound (E23) was prepared in a similar manner to Example 11 from 1-cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D7) and 5-bromo-2-trifluoromethylpyrimidine (D13). The crude product after work-up was by purified by flash chromatography [silica gel, gradient 0-100% EtOAc-MeOH] and the free base was converted into the title hydrochloride salt (E23). 1H NMR δ (DMSO-d6): 1.6-1.75 (2H, m), 2.0-2.4 (6H, m), 2.97-3.05 (2H, m), 3.35-3.70 (6H, m), 4.14-4.19 (1H, m), 7.67 (2H, d, J=8 Hz), 8.0 (2H, d, J=8 Hz), 9.45 (2H, s),10.8-11.0 (1H, bs). LCMS electrospray (+ve) 405 (MH+). EXAMPLE 24-28 (E24-E28) Examples 24-28 were prepared in a similar manner to Example 15 from either 1-(cyclobutyl)hexahydro-1H-1,4-diazepine dihydrochloride (D4) or 1-(isopropyl)hexahydro-1H-1,4-diazepine dihydrochloride (D2) and the appropriate benzoic acid. The free base products were converted into the corresponding hydrochloride salts with ethereal HCl. Example No R R1 Mass Spectrum 24 [MH]+ 378 (ES+) 25 [MH]+ 418 (ES+) 26 [MH]+ 434 (ES+) 27 [MH]+ 348(APCI) 28 [MH]+ 394 (ES+) EXAMPLE 29-43 (E29-E43) Examples 29-43 were prepared from either 1-(cyclobutyl)hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.19) or 1-(isopropyl)hexahydro-1H-1,4-diazepine dihydrochloride (D2) (0.1 g) in a 1:1 mixture of DCM/DMF (5 ml). To this solution diethylaminomethyl-polystyrene (3.2 mmole/g) (0.4 g, 3 eq) was added and stirred at rt for 10 min, followed by the addition of N-cyclohexylcarbodiimide-N-methylpolystyrene (200-400 mesh, 2.3 mmole/g) (0.2 g), catalytic HOBT and 1 equivalent of the appropriate benzoic acid. The reaction mixture was shaken at rt for 48 h. Tris-(2-aminoethyl) aminomethyl polystyrene (PS-Trisamine) (0.050 g) was added and the reaction mixture was shaken at rt for further 4 h. The resins were filtered off and the filtrate was evaporated to dryness. The crude residue was purified by flash chromatography [silica gel, step gradient 0-15% MeOH (containing 10% 0.88 ammonia solution) in DCM]. The free base compounds were converted into the HCl salts in dry DCM (2 ml) with ethereal HCl (1 ml), 1N). Compounds showed 1H NMR and mass spectra that were consistent with structure. Example Mass No R R1 Spectrum E29 [MH]+ 353 (APCI) E30 [MH]+ 353 (APCI) E31 [MH]+ 336 (ES+) E32 [MH]+ 336 (ES+) E33 [MH]+ 376 (ES+) E34 [MH]+ 365 (APCI) E35 [MH]+ 354 (APCI) E36 [MH]+ 342 (APCI) E37 [MH]+ 326 (ES+) E38 [MH]+ 355 (APCI) E39 [MH]+ 324 (ES+) E40 [MH]+ 353 (APCI) E41 [MH]+ 367 (APCI) E42 [MH]+ 344 (ES+) E43 [MH]+ 332 (ES+) EXAMPLES 44-51 (E44-E51) Examples 44-51 were prepared in a similar manner to Examples 29-43 from 1-(cyclobutyl)hexahydro-1H-1,4-diazepine dihydrochloride (D4) and the appropriate benzoic acid. Example No R Mass Spectrum E44 [MH]+ 365 (APCI) E45 [MH]+ 366 (APCI) E46 [MH]+ 367 (APCI) E47 [MH]+ 341 (APCI) E48 [MH]+ 342 (APCI) E49 [MH]+ 379 (ES+) E50 [MH]+ 379 (ES+) E51 [MH]+ 336 (ES+) EXAMPLES 52-55 (E52-E55) Examples 52-55 were prepared in a similar manner to Example 11 from 1-cyclobutyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine (D7) and the appropriate aryl bromides (e.g. D14-D16 for E53-E55, respectively), except that THF/H2O was used as solvent and potassium carbonate as base, and the reaction was heated at 80-85° C. for 1 h. Compounds showed 1H NMR and mass spectra that were consistent with structure. Example Mass No R Spectrum E52 [MH]+ 402 (ES+) E53 [MH]+ 416 (ES+) E54 [MH]+ 416 (ES+) E55 [MH]+ 417 (ES+) EXAMPLE 56 1-Cyclobutyl-4-{[4-(1,3-oxazol-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine hydrochloride (E56) Step 1: 1,1-Dimethylethyl 4-([4-(1,3-oxazol-2-yl)phenyl]carbonyl)hexahydro-1H-1,4-diazepine carboxylate A microwave vial was charged with 2-(4-bromophenyl)-oxazole (D17) (0.224 g), molybdenum hexacarbonyl (0.111 g), trans-Di-μ-acetatobis[2-(di-o-tolylphosphino)benzyl]palladium(II) (0.04 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.08 g) and purged with argon. Diglyme (4 ml), toluene (2 ml) and 4M aqueous potassium carbonate (0.74 ml) were added, and the reaction mixture was degassed by argon saturation. tert-Butyl-hexahydro-1H-1,4-diazepine carboxylate (0.22 g) was added and the reaction vial was heated at 150° C. for 20 min in the microwave reactor. The reaction mixture was filtered, dried (Na2SO4) and evaporated. Chromatography of the crude product (silica gel, eluting with EtOAc/hexanes, 50-100%) afforded the subtitle compound (0.141 g). Step 2: 4-{[4-(1,3-Oxazol-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine The product from E56, Step 1 was dissolved in DCM (5 ml) and TFA (0.5 ml) was added. After 7 h saturated aqueous potassium carbonate (5 ml) was added and the aqueous phase extracted into DCM (3×10 ml). The combined organics were washed with brine (20 ml), dried (MgSO4) and evaporated to give the subtitle compound as a yellow oil (0.064 g). Step 3: 1-Cyclobutyl-4-{[4-(1,3-oxazol-2-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine hydrochloride Cyclobutanone (0.04 ml) was added to a solution of the product of E56 Step 2 (0.064 g) and triethylamine (0.12 ml) in DCM (2.5 ml). After 5 min sodium triacetoxyborohydride (0.111 g) was added and the reaction mixture was stirred for 16 h. Saturated aqueous sodium hydrogen carbonate (5 ml) was added and the aqueous phase extracted into DCM (10 ml). The organic phase was filtered through a PhaseSep® cartridge and evaporated. Chromatography of the crude mixture [silica gel, eluting with 2N NH3 in MeOH/DCM, 0-15%] afforded the required amine free base, which was dissolved in DCM (2 ml) and treated with HCl (1 ml), 1M in diethyl ether). The precipitate was filtered and dried to give the title compound (E56) (0.07 g). MS electrospray (+ion) 326 (MH+). EXAMPLE 57 1-(1-Methylethyl)-4-{[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine hydrochloride 4-(3-Methyl-1,2,4-oxadiazol-5-yl)benzoic acid (D18) (0.415 g), 1-(isopropyl)hexahydro-1H-1,4-diazepine (free base of D2) (0.294 g), EDC (0.425 g) and HOBT (0.282 g) were dissolved in DMF (10 ml) and stirred under argon. Hunig's base (1.43 ml) was added and the reaction mixture stirred for 15 h. The solvent was evaporated and the yellow residue partitioned between DCM (10 ml) and saturated sodium hydrogen carbonate (10 ml). The aqueous phase was extracted into DCM (2×10 ml), dried (MgSO4) and evaporated to give the crude amide as a brown solid. Chromatography of the crude mixture [silica gel, eluting with MeOH/DCM, 0-20%] afforded the desired amine free base, which was dissolved in DCM (2 ml) and treated with HCl (1 ml), 1M in diethyl ether). The precipitate was filtered and dried to give the title compound (E57) (0.07 g). MS electrospray (+ion) 329 (MH+). 1H NMR δ (CDC13, free base): 8.16 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.4 Hz), 3.79-3.77 (2H, m), 3.44-3.40 (2H, m), 2.93 (1H, app pent, J=6.8 Hz), 2.82 (1H, app tr, J=5.2 Hz), 2.70 (1H, app tr, J=5.8 Hz), 2.65-2.59 (2H, m), 2.48 (3H, s), 1.96-1.90 (1H, m), 1.77-1.71 (1H, m), 1.04 (3H, d, J=6.4 Hz) and 0.99 (3H, d, J=6.4 Hz). EXAMPLE 58 1-Cyclobutyl-4-{[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}hexahydro-1H-1,4-diazepine hydrochloride (E58) 4-(3-Methyl-1,2,4-oxadiazol-5-yl)benzoic acid (D18) (0.365 g), 1-(cyclobutyl)hexahydro-1H-1,4-diazepine (free base compound from D4) (0.28 g), EDC (0.374 g) and HOBT (0.248 g) were dissolved in DMF (10 ml) and stirred under argon. Hunig's base (1.26 ml) was added and the reaction mixture stirred for 15 h. The solvent was evaporated and the yellow residue partitioned between DCM (10 ml) and saturated sodium hydrogen carbonate (10 ml). The aqueous phase was extracted into DCM (2×10 ml), dried (MgSO4) and evaporated to give the crude amide as a brown solid. Chromatography of the crude mixture [silica gel, eluting with MeOH/DCM, 0-20%] afforded the desired amine free base, which was dissolved in DCM (2 ml) and treated with HCl (1 ml), 1M in diethyl ether). The precipitate was filtered and dried to give the title compound (E58) (0.07 g). MS electrospray (+ion) 341 (MH+). 1H NMR δ (CDCl3, free base): 8.16 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 3.81-3.78 (2H, m), 3.48-3.42 (2H, m), 2.97-2.85 (1H, m), 2.65-2.63 (1H, m), 2.54-2.42 (3H, m), 2.50 (3H, s), 2.11-1.95 (3H, m), 1.90-1.75 (3H, m) and 1.71-1.58 (2H, m). Abbreviations Boc tert-butoxycarbonyl EtOAc ethyl acetate h hour min minutes DCM dichloromethane MeOH methanol rt room temperature DMF dimethylformamide TFA trifluoroacetic acid HOBT 1-hydroxybenzotriazole EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. Biological Data A membrane preparation containing histamine H3 receptors may be prepared in accordance with the following procedures: (i) Generation of Histamine H3 Cell Line DNA encoding the human histamine H3 gene (Huvar, A. et al. (1999) Mol. Pharmacol. 55(6), 1101-1107) was cloned into a holding vector, pCDNA3.1 TOPO (InVitrogen) and its cDNA was isolated from this vector by restriction digestion of plasmid DNA with the enzymes BamH1 and Not-1 and ligated into the inducible expression vector pGene (InVitrogen) digested with the same enzymes. The GeneSwitch™ system (a system where in transgene expression is switched off in the absence of an inducer and switched on in the presence of an inducer) was performed as described in U.S. Pat. Nos. 5,364,791; 5,874,534; and 5,935,934. Ligated DNA was transformed into competent DH5α E. coli host bacterial cells and plated onto Luria Broth (LB) agar containing Zeocin™ (an antibiotic which allows the selection of cells expressing the sh ble gene which is present on pGene and pSwitch) at 50 μg ml−1. Colonies containing the re-ligated plasmid were identified by restriction analysis. DNA for transfection into mammalian cells was prepared from 250 ml) cultures of the host bacterium containing the pGeneH3 plasmid and isolated using a DNA preparation kit (Qiagen Midi-Prep) as per manufacturers guidelines (Qiagen). CHO K1 cells previously transfected with the pSwitch regulatory plasmid (InVitrogen) were seeded at 2×10 e6 cells per T75 flask in Complete Medium, containing Hams F12 (GIBCOBRL, Life Technologies) medium supplemented with 10% v/v dialysed foetal bovine serum, L-glutamine, and hygromycin (100 μg ml−1), 24 hours prior to use. Plasmid DNA was transfected into the cells using Lipofectamine plus according to the manufacturers guidelines (InVitrogen). 48 hours post transfection cells were placed into complete medium supplemented with 500 μg ml−1 Zeocin™. 10-14 days post selection 10 nM Mifepristone (InVitrogen), was added to the culture medium to induce the expression of the receptor. 18 hours post induction cells were detached from the flask using ethylenediamine tetra-acetic acid (EDTA; 1:5000; InVitrogen), following several washes with phosphate buffered saline pH 7.4 and resuspended in Sorting Medium containing Minimum Essential Medium (MEM), without phenol red, and supplemented with Earles salts and 3% Foetal Clone II (Hyclone). Approximately 1×10 e7 cells were examined for receptor expression by staining with a rabbit polyclonal antibody, 4a, raised against the N-terminal domain of the histamine H3 receptor, incubated on ice for 60 minutes, followed by two washes in sorting medium. Receptor bound antibody was detected by incubation of the cells for 60 minutes on ice with a goat anti rabbit antibody, conjugated with Alexa 488 fluorescence marker (Molecular Probes). Following two further washes with Sorting Medium, cells were filtered through a 50 μm Filcon™ (BD Biosciences) and then analysed on a FACS Vantage SE Flow Cytometer fitted with an Automatic Cell Deposition Unit. Control cells were non-induced cells treated in a similar manner. Positively stained cells were sorted as single cells into 96-well plates, containing Complete Medium containing 500 μg ml−1 Zeocin™ and allowed to expand before reanalysis for receptor expression via antibody and ligand binding studies. One clone, 3H3, was selected for membrane preparation. (ii) Membrane Preparation from Cultured Cells All steps of the protocol are carried out at 4° C. and with pre-cooled reagents. The cell pellet is resuspended in 10 volumes of buffer A2 containing 50 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) (pH 7.40) supplemented with 10 e-4M leupeptin (acetyl-leucyl-leucyl-arginal; Sigma L2884), 25 μg/ml bacitracin (Sigma B0125),1 mM ethylenediamine tetra-acetic acid (EDTA), 1 mM phenylmethylsulfonyl fluoride (PMSF) and 2×10 e-6M pepstain A (Sigma). The cells are then homogenised by 2×15 second bursts in a 1 litre glass Waring blender, followed by centrifugation at 500 g for 20 minutes. The supernatant is then spun at 48,000 g for 30 minutes. The pellet is resuspended in 4 volumes of buffer A2 by vortexing for 5 seconds, followed by homogenisation in a Dounce homogeniser (10-15 strokes). At this point the preparation is aliquoted into polypropylene tubes and stored at −70° C. (iii) Generation of Histamine H1 Cell Line The human H1 receptor was cloned using known procedures described in the literature [Biochem. Biophys. Res. Commun. 1994, 201(2), 894]. Chinese hamster ovary cells stably expressing the human H1 receptor were generated according to known procedures described in the literature [Br. J. Pharmacol. 1996, 117(6), 1071]. Compounds of the invention may be tested for in vitro biological activity in accordance with the following assays: (I) Histamine H3 Binding Assay For each compound being assayed, in a white walled clear bottom 96 well plate, is added: (a) 10 μl of test compound (or 10 μl of iodophenpropit (a known histamine H3 antagonist) at a final concentration of 10 mM) diluted to the required concentration in 10% DMSO; (b) 10 μl 125I 4-[3-(4-iodophenylmethoxy)propyl]-1H-imidazolium (iodoproxyfan) (Amersham; 1.85MBq/μl or 50 μCi/ml; Specific Activity ˜2000 Ci/mmol) diluted to 200 pM in assay buffer (50 mM Tris(hydroxymethyl)aminomethane buffer (TRIS) pH 7.4, 0.5mM ethylenediamine tetra-acetic acid (EDTA)) to give 20 pM final concentration; and (c) 80 μl bead/membrane mix prepared by suspending Scintillation Proximity Assay (SPA) bead type WGA-PVT at 100 mg/ml in assay buffer followed by mixing with membrane (prepared in accordance with the methodology described above) and diluting in assay buffer to give a final volume of 80 μl which contains 7.5 μg protein and 0.25 mg bead per well-mixture was pre-mixed at room temperature for 60 minutes on a roller. The plate is shaken for 5 minutes and then allowed to stand at room temperature for 3-4 hours prior to reading in a Wallac Microbeta counter on a 1 minute normalised tritium count protocol. Data was analysed using a 4-parameter logistic equation. (II) Histamine H3 Functional Antagonist Assay For each compound being assayed, in a white walled clear bottom 96 well plate, is added: (a) 10 μl of test compound (or 10 μl of guanosine 5′-triphosphate (GTP) (Sigma) as non-specific binding control) diluted to required concentration in assay buffer (20 mM N-2-Hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)+100 mM NaCl+10 mM MgCl2, pH7.4 NaOH); (b) 60 μl bead/membrane/GDP mix prepared by suspending wheat germ agglutinin-polyvinyltoluene (WGA-PVT) scintillation proximity assay (SPA) beads at 100 mg/ml in assay buffer followed by mixing with membrane (prepared in accordance with the methodology described above) and diluting in assay buffer to give a final volume of 60 μl which contains 100 μg protein and 0.5 mg bead per well-mixture is pre-mixed at 4° C. for 30 minutes on a roller and just prior to addition to the plate, 10 μM final concentration of guanosine 5′ diphosphate (GDP) (Sigma; diluted in assay buffer) is added; The plate is incubated at room temperature to equilibrate antagonist with receptor/beads by shaking for 30 minutes followed by addition of: (c) 10 μl histamine (Tocris) at a final concentration of 0.3 μM; and (d) 20 gl guanosine 5′[y35-S] thiotriphosphate, triethylamine salt (Amersham; radioactivity concentration=37 kBq/μl or 1 mCi/ml; Specific Activity 1160 Ci/mmol) diluted to 1.9nM in assay buffer to give 0.38nM final. The plate is then incubated on a shaker at room temperature for 30 minutes followed by centrifugation for 5 minutes at 1500 rpm. The plate is read between 3 and 6 hours after completion of centrifuge run in a Wallac Microbeta counter on a 1 minute normalised tritium count protocol. Data is analysed using a 4-parameter logistic equation. Basal activity used as minimum i.e. histamine not added to well. (III) Histamine H1 Functional Antagonist Assay Compounds are assayed in a black walled clear bottom 384-well plate with cells seeded at 10000 cells/well. Tyrodes buffer is used throughout (NaCl 145 mM, KCl 2.5 mM, HEPES 10 mM, glucose 10 mM, MgCl2 1.2 mM, CaCl2 1.5 mM, probenecid 2.5 mM, pH adjusted to 7.40 with NaOH 1.0 M). Each well is treated with 10 μl of a solution of FLUO4AM (10 μM in Tyrodes buffer at pH 7.40) and plates are then incubated for 60 minutes at 37° C. Wells are then washed with Tyrodes buffer using a EMBLA cell washer system, leaving 40 μl buffer in each well, and then treated with 10 μl of test compound in Tyrodes buffer. Each plate is incubated for 30 min to allow equilibration of the test compound with the receptor. Each well is then treated with 10 μl of histamine solution in Tyrodes buffer. Functional antagonism is indicated by a suppression of histamine induced increase in fluorescence, as measured by the FLIPR system (Molecular Devices). By means of concentration effect curves, functional potencies are determined using standard pharmacological mathematical analysis. Results The compounds of Examples E1-E58 were tested in the histamine H3 functional antagonist assay and exhibited pKb values>8.0. More particularly, the compounds of Examples 1-9, 11-14, 16, 22-28, 30-42, 44, 47, 52-56 and 58 exhibited pKb values≧9.0. Most particularly, the compounds of Examples 1, 2, 11, 12 and 58 exhibited pKb values>9.5. The compounds of Examples E1 42, 44, 46-48 and 51-55 were tested in the histamine H1 functional antagonist assay and exhibited antagonism<7.0 pKb. More particularly, the compounds of Examples E1-25, 27-42, 44, 46-48 and 51-55 exhibited antagonism<6.0 pKb.

20070206

20101207

20080221

94716.0

A61K31551

COLEMAN, BRENDA LIBBY

1-BENZOYL SUBSTITUTED DIAZEPINE DERIVATIVES AS SELECTIVE HISTAMINE H3 RECEPTOR AGONISTS

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Magnetic gearing of permanent magnet brushless motors

A permanent magnet brushless 3-phase motor comprises windings R, Y, B, each divided into a plurality of sections 1-5 and switch means S1-S12 for selectively connecting the section of the respective winding e.g. R in series and/or parallel with all other sections of that winding R. Control means are provided for actuating the switch means S1-S12 to connect the winding sections 1-5 in different configurations whilst the motor is running to alter the speed/torque characteristics of the motor.

1. A permanent magnet brushless motor comprising a winding divided into a plurality of sections and switch means for selectively connecting the sections of the winding in one of a plurality of different configurations, wherein each section is connected in series and/or parallel with all other sections of the winding. 2. A permanent magnet brushless motor as claimed in claim 1, in which the switch means is arranged to connect all of the winding sections in parallel. 3. A permanent magnet brushless motor as claimed in claim 1, in which the switch means is arranged to connect all of the winding sections in series. 4. A permanent magnet brushless motor as claimed in claim 1, in which the switch means is arranged to connect some of the winding sections in parallel, with at least one other section being connected in series with the parallel-connected sections. 5. A permanent magnet brushless motor as claimed in claim 1, in which the voltage applied to the winding is pulse-width modulated. 6. A permanent magnet brushless motor as claimed in claim 5, in which the voltage applied to the winding is pulse-width modulated by selectively energising said switch means. 7. A permanent magnet brushless motor as claimed in claim 1, comprising means for repeatedly actuating said switch means to change said winding sections between different connection configurations to obtain a motor characteristic intermediate that of the configurations between which the windings are repeatedly switched. 8. A permanent magnet brushless motor as claimed in claim 1, comprising control means for actuating the switch means to vary the configuration of the winding connections whilst the motor is running, in accordance with predetermined operating parameters. 9. A permanent magnet brushless motor as claimed in claim 8, in which the control means is able to vary the configuration of the winding connections whilst the motor is running, in accordance with the output of means for sensing an operating parameter of the motor. 10. A permanent magnet brushless motor as claimed in claim 8, in which the control means is able to vary the configuration of the winding connections whilst the motor is running, in accordance with the output of means for sensing an operating parameter of the article being driven by the motor. 11. A permanent magnet brushless motor as claimed in claim 8, in which the control means is able to vary the configuration of the winding connections of a conducting phase whilst the motor is running, in accordance with the back emf measured across the winding of non-conducting phase or a section thereof. 12. A permanent magnet brushless motor as claimed in claim 8, in which the control means is able to vary the configuration of the winding connections whilst the motor is running, in accordance with time or an operating cycle or program. 13. A permanent magnet brushless motor as claimed in claim 8, in which the control means comprises means for manually changing the configuration of the winding connections. 14. A permanent magnet brushless motor as claimed in claim 1, in which all of the sections of the or each winding are wound in parallel to each other. 15. A permanent magnet brushless motor as claimed in claim 1, in which the sections of the winding are connected such that current flows through each section in the same direction. 16. A permanent magnet brushless motor as claimed in claim 1, in which one of the sections of the winding comprises a different number of turns from another section. 17. A permanent magnet brushless motor as claimed in claim 1, in which one of the sections of the winding comprises a conductor having a different cross- sectional area than the conductor of another section.

This invention relates to the magnetic gearing of permanent magnet brushless motors. Permanent magnet brushless motors are known which are capable of providing variable speed outputs. The motor characteristics are linear, generating high torque at low speeds and high speed at low torque levels. In certain applications, the range of speed and torque characteristics of a particular motor may not be sufficient to cover the desired range, even though the output power of the motor may be sufficient. In such circumstances two options are available. Firstly, a more powerful motor could be used to cover the entire range or secondly, mechanical gears could be provided for the motor. Both of these methods add cost and weight to the system. Canadian Patent Application No. 2341095 discloses an alternative to the above-mentioned methods which uses a technique in which the speed and torque can be varied inside the motor and the only additional item required is a switching circuit. A prerequisite of this technique is that the stator coils of the motor must be segmented into at least two or more sections, which are evenly or perhaps unevenly distributed throughout the stator slots. The switching circuit can then be used to change the number of coil segments which are connected to the supply. Such an arrangement utilises the control of the induced back electromotive force (back emf) to control the speed by selectively altering the number of conductors which are connected to the supply. This in effect also alters the torque with changing speed of the motor. In the main embodiment of Canadian Patent Application No. 2341095, each of the motor windings comprises a plurality of series-connected sections provided by tappings in the winding, which can be selectively connected across the supply. With just one of the coil segments connected across the supply, the motor will produce a high speed but a low torque. However, with a higher proportion of coils connected in series across the supply, the motor will produce a lower speed at the same torque. In this manner, the speed but not the torque of the motor can be varied by selectively connecting the windings in series. In an alternative embodiment, each of the motor windings comprises a plurality of parallel-connected sections, which sections can be selectively connected in parallel across the supply. With just one of the coil segments connected across the supply, the motor will produce a high speed but a low torque as previously described. However, with a higher proportion of coils connected in parallel across the supply, the motor will produce high torque at the same speed. In this manner, the torque but not the speed of the motor can be varied by selectively connecting the windings in parallel. A disadvantage of either arrangement is that sections are redundant when running the motor during some configurations and thus copper (I2R) losses will be higher because the crass-sectional area of copper utilised decreases as the number of active sections decreases. Also, the presence of redundant sections means that the net resistance of the coils is not optimised in all configurations and hence the supply current or voltage has to be controlled to avoid damaging the connected coils. Since speed and torque are functions of the current, any limitation of the current affects the performance of the motor. In most situations, the supply current to the motor is limited (for example in domestic mains to 13 amps), and thus the attainable speed and torque will not be optimised when some coils are out of circuit. We have now devised a permanent magnet brushless motor which alleviates the above-mentioned problem. In accordance with this invention, there is provided a permanent magnet brushless motor comprising a winding divided into a plurality of sections and switch means for selectively connecting the sections of the winding in one of a plurality of different configurations, wherein each section is connected in series and/or parallel with all other sections of the winding. The switch means can then be used to change magnetic gears, by changing the configuration of the coil segments in series, parallel or a combination of both, which are connected to the supply. We call such an arrangement magnetic gearing because it utilises the control of the induced back electromagnetic force (back emf) to control the speed by selectively altering the winding configuration which are connected to the supply. This alters the torque with changing speed of the motor. In contrast to known methods of varying the speed or torque by coil manipulation, the present invention is distinguished in that all of the winding segments contribute towards the motor operation no matter which section configuration is being employed. In this manner, all of the available copper is utilised at all times, thereby keeping the copper loss of the motor to a minimum. The advantage of utilising all of the winding sections is the reduction of the motor's copper loss. Normally the stator slots are packed with as much copper wire as possible, either by maximising the number of turns, or by maximising the wire diameter (if the number of turns have been predetermined for the design). In this manner the cross-section area of copper is maximised for the slot, so that the resistance of the coils is kept to a minimum. Hence the copper loss for the motor will always be kept to a minimum. In a first configuration, the switch means is preferably arranged to connect all of the winding sections in parallel. In this configuration at a given current I, the motor is able to reach high speeds at relatively low torque levels. In a second configuration, the switch means is preferably arranged to connect all of the winding sections in series. In this configuration at the same current I, the motor is only able to deliver high levels of torque at relatively low speeds. In a third configuration, the switch means is preferably arranged to connect some of the winding sections in parallel, with at least one other section being connected in series with the parallel-connected sections. In this configuration at the same current, the motor is able to reach speeds between that of the first and second configurations and deliver a torque between the first and second configurations. In order to further vary the speed v torque characteristic of the motor, the voltage applied to the winding may be pulse-width modulated, for example using said switch means. The speed v torque characteristic of the motor may also be varied by rapidly switching the winding sections between different configurations to obtain a characteristic intermediate that of the configurations between which the windings are switched. Preferably the switch means is able to vary the configuration of the winding connections whilst the motor is running, in accordance with predetermined operating parameters. Preferably, the switch means is able to vary the configuration of the winding connections whilst the motor is running, in accordance with the output of means for sensing an operating parameter of the motor such as the current, voltage, speed or torque, or in accordance with the output of means for sensing an operating parameter of the article being driven by the motor such as velocity. In the case of a multi-phase motor having a plurality of windings, the switch means may vary the configuration of the winding connections of a conducting phase whilst the motor is running, in accordance with the back emf measured across the winding of non-conducting phase or a section thereof. Alternatively, the switch means is able to vary the configuration of the winding connections in accordance with time or an operating cycle or program. Alternatively, means may be provided for manually changing the configuration of the winding connections. Preferably all of the sections of the winding are wound in parallel during assembly, with the current preferably flowing through each section in the same direction. One of the sections of the winding may comprise a different number of turns from another section. Also, one of the sections of the winding may comprise a conductor having a different cross-sectional area than the conductor of another section. An embodiment of this invention will now be described by way of an example only and with reference to the accompanying drawings, in which: FIG. 1 is a schematic diagram of one phase of a 3-phase permanent magnet brushless motor in accordance with the present invention; FIGS. 2 to 6 are schematic diagrams showing various connections of sections of the motor of FIG. 1; FIG. 7 is a table showing the switch states of the motor of FIG. 1 with reference to the connections of FIGS. 2 to 6; FIG. 8 is a graph of speed v torque for the connections of FIGS. 2 to 6; and FIG. 9 is graph of speed v torque to illustrate how the ideal motor characteristics for a washing machine can be achieved using the motor of FIG. 1. Referring to FIG. 1 of the drawings, there is shown a 3-phase permanent magnet brushless DC motor comprising three star-connected phases R,Y,B 18 slots, 12 poles and a slot pitch of 1. The stator outer diameter, inner diameter and length are 110 mm, 55 mm and 75 mm, respectively. The air gap is 0.5 mm, the magnet width and thickness are 10 mm and 4 mm, respectively. Each phase comprises a winding having, for example, five conductors or so-called sections 1-5 of 0.63 mm enamelled copper which are co-wound in parallel through the relevant stator slots of the motor. The supply voltage to the motor is 180 volts DC. The first end of the first section 1 of one phase R is connected to the first ends of the first sections of the other two phases Y, B. The first end of the first section of the phase R is also connected to the first end of the second section 2 of that phase R via a switch S1. Likewise, the first ends of the other sections 3,4,5 are connected to adjacent sections via respective switches S2, S3, S4. Similarly, the second end of the first section 1 of the phase R is connected to the second end of the second section 2 of that phase R via a switch S9. Likewise, the second ends of the other sections 3,4,5 are connected to adjacent sections via respective switches S10, S11, S12. The second end of the fifth section 5 is also connected to the supply. The second end of the first section 1 of the phase R is connected to the first end of the second section 2 of that phase R via a switch S5. Likewise, the second ends of the other sections 2,3,4 are connected to the first ends of adjacent sections via respective switches S6, S7, S8. Referring to FIGS. 2, 7 and 8 of the drawings, when the motor is initially started, only the switches S5 to S8 are energised such that the sections 1-5 are connected in series. In this manner the supply current flows through each series-connected section 1-5 in the same direction with respect to each section's polar orientation (as indicated by the arrows in FIG. 1): it is imperative that this is always the case. Had one of the sections (e.g. section 4) been oriented in the opposite direction, the flux produced by section 4 would oppose the flux produced by sections 1, 2, 3 and 5. The torque of the motor is directly proportional to the current and, as long as the starting torque is high enough to overcome the load attached to the motor, the rotor begins to turn. This is accompanied by the generation of a back emf in the coils, which begins to cancel out the supply voltage, so that the current available for the phase coils begins to reduce, as does the torque produced by the motor. The back emf, is directly proportional to the number of turns in the phase coils, the magnetic flux produced by the permanent magnets, the number of permanent magnet pole pairs and the angular speed of the rotor. Other factors, such as the interconnection between the coils and the phases and the number of phases also affects the back emf generated. The consequence of this behaviour is that, the motor will continue to accelerate until the torque produced by it, equals the load. From this point on, the motor will continue to rotate at a constant speed. If at any instance the load is altered, the motor will automatically adjust its torque (and consequently, its speed) in order to balance the load. The maximum speed that can be attained by a motor, occurs when there is no load attached to the motor. Ideally, this occurs when the back emf generated in the phase coils is equal to the supply voltage, at which instance there is no current flowing through the coils to produce any torque; this situation is referred to as the no load speed. In reality, the back emf will always remain marginally lower than the supply voltage (even at no load speed). This is because a small portion of power supply is used up in overcoming frictional forces due to windage and the bearings, as well as iron losses of the motor. It is evident from the graph of FIG. 8 that the motor is limited to performance criteria within the speed v torque line for FIG. 2. The graph indicates that the motor can manage a maximum speed of 584 rpm and a maximum torque of 28.1 Nm. As a further example, it can also provide torque of 8 Nm up to a maximum speed of approximately 400 rpm, or conversely, the motor running at 400 rpm, can provide up to a maximum torque of approximately 8 Nm. If the desired motor performance falls beyond the 10 amp line, for instance 14 Nm at 600 rpm, the motor parameters need to be altered in order to cater for the additional power requirements. Referring to FIGS. 3, 7 and 8 of the drawings, the motor's performance can be changed by altering the configuration in which all of the motor's windings are connected. By energising the switches in accordance with FIG. 7, sections 1 and 2 can be connected in parallel and this parallel set is then connected in series with section 3, 4 and 5 (which are connected in series with one another). It is evident from the graph of FIG. 8 that the motor is now limited to performance criteria within the speed v torque line for FIG. 3. The graph indicates the motor will now generate a no load speed of 725 rpm and a stall torque of 34.6 Nm. Referring to FIGS. 4, 7 and 8 of the drawings, the motor's performance can be changed again by energising the switches in accordance with FIG. 7, so that sections 1, 2 and 3 are connected in parallel and this parallel set is then connected in series with sections 4 and 5 (which are connected in series with one another). It is evident from the graph of FIG. 8 that the motor is now limited to performance criteria within the speed v torque line for FIG. 4. The graph indicates the motor will now generate a no load speed of 966 rpm and a stall torque of 46.1 Nm. Referring to FIGS. 5, 7 and 8 of the drawings, the motor's performance can be changed again by energising the switches in accordance with FIG. 7, so that sections 1, 2, 3 and 4 are connected in parallel and this parallel set is then connected in series with section 5. It is evident from the graph of FIG. 8 that the motor is now limited to performance criteria within the speed v torque line for FIG. 5. The graph indicates the motor will now generate a no load speed of 1449 rpm and a stall torque of 69.0 Nm. Referring to FIGS. 6, 7 and 8 of the drawings, the motor's performance can finally be changed by energising the switches in accordance with FIG. 7, so that sections 1, 2, 3, 4 and 5 are connected in parallel. It is evident from the graph of FIG. 8 that the motor is now limited to performance within the speed v torque line for FIG. 6. The graph indicates the motor will now generate a no load speed of 2898 rpm and a stall torque of 136.7 Nm. At first sight, one may consider that the best option would be to implement the configuration of FIG. 6 (i.e. all sections in parallel), since this choice yields the greatest range in terms of both speed and torque. However, although the voltage supplied to all of the configurations is the same (180 volts DC), the current varies from one configuration to the next. In practical applications there will always be a current limit, for example most household appliances are limited to 13 amps. Referring to FIG. 8, if a notional 10 amp limit is applied to each configuration, it will be seen that the maximum torque achievable by the configuration of FIGS. 2 to 6 are 29.7, 23.7, 17.8, 11.9 and 5.9 Nm respectively. Thus, by operating the switches to change between the various configurations, whilst keeping the motor within the confines of the 10 amp limit, a performance can be achieved as shown in the shaded area of the graph. Accordingly, it will be appreciated that a gearing system for the motor can be provided by operating the switches, thereby allowing the motor to generate higher torque (at low speed) and higher speed (with low torque) than would be possible with any single configuration (with limited current supply). Thus, when the motor is initially energised, all sections can be connected in series as shown in FIG. 2, such that a high starting torque is achieved well within the confines of the 10 amp limit. The switches S1 to S12 can be relays or semiconductor devices. In the case of semiconductor devices, a plurality of devices could be included in a single package. Individual switches for example S1, S5 and S9 can be configured into a single mechanical or electronic switch. In this case when 1 and 9 are ON, then 5 is OFF. When 5 is ON, then 1 and 9 are OFF. This way only 4 switches will be required per phase instead of 12 switches. Referring to FIG. 9 of the drawings, there is shown a graph of the required speed v torque curve 20 for a domestic washing machine superimposed onto the graph of FIG. 8. At present the required speed and torque are normally achieved by using induction motors running at high speeds with appropriate mechanical gearing and drive belts, or by using a large DC direct drive motor. However, it can be seen that the required range of speed and torque can easily be achieved within the current confines using a reasonably sized direct drive brushless DC motor in accordance with this invention. It will be seen that the configurations of FIGS. 3 and 4 are not necessary to provide the required speed v torque curve for a domestic washing machine and thus some cost savings can be achieved by omitting some of the switches. It should be noted that the multi-segmented coils within a single phase need not be wound using the same wire diameter or the same number of turns, however, all the phases must be wound in an identical manner. For instance, section 1 of every phase must be wound with the same wire and have the same number of turns. Coil section 2 can have a different number of turns and it can be wound using a different wire diameter to that of section 1, but coil segment 2 of every phase must be identical and the same applies to all other segments. It will be appreciated that whilst the embodiment hereinbefore described utilises 3-phases, the invention applies to a motor having any number of phases. Furthermore, the invention also applies to permanent magnet brushless synchronous motors, which have similar speed torque characteristics. The configurations discussed in FIGS. 2 to FIGS. 6 are not the only possible combinations. For example, another possible combination is coil sections 1 and 2 connected in parallel and coil sections 3 and 4 connected in parallel, the two parallel sets being connected in series with one another and with the remaining section 5. This configuration will produce the same motor characteristics as the arrangement shown in FIG. 4. Yet another configuration can be obtained by connecting sections 1, 2 and 3 in parallel and sections 4 and 5 in parallel and then connecting the parallel sets in series with one another. This will yield motor characteristics that are the same as the one produced by the configuration shown in FIG. 5. The number of speed-torque characteristics that can be obtained is dependent on the number of winding sections provided (per phase), which is limited to some finite number. The motor operates at its most efficient level when it is running as close as possible to its no load speed. For this reason, it is undesirable to allow the motor to compensate for an increase in load, by automatically reducing its speed (on the speed-torque characteristics line). It would be far better to meet the demands of the increase in load through magnetic gearing, so that the new torque level is achieved whilst the motor continues to run close to its no load speed. However, in order to meet all possible torque levels (within the given range of the motor) the motor would require an infinite number of magnetic gears and therefore, an infinite number of winding sections and switches. In an alternative embodiment, it is possible to achieve any speed torque curve in between those obtained by altering the configuration of the windings by interchanging between the two configurations very rapidly, so that the motor is not operating at the characteristics of either configuration, but somewhere in between. The rapid switching between the two configurations can be achieved by feeding a pulse width modulated (PWM) signal to the switches (S1 to S12) and the duty cycle of the PWM is altered to achieve the desired intermediate speed and torque. For example, consider a first configuration with all winding sections connected in parallel; this gear provides the highest speed the motor can achieve and therefore, it is the highest gear. The next gear down from this, is achieved by connecting one of the winding sections in series with the remaining parallel sections; this provides the next highest speed. If the PWM has a duty cycle of 100%, the gear will change from the highest to the next lower gear and remain there. Conversely, if a duty cycle of 0% (i.e. no signal) is chosen, the motor will remain in the highest gear. Choosing a duty cycle between 0 and 100% will yield a gear and consequently, a motor speed and torque between the highest two gears; i.e. an intermediate gear. If desired, the gearing can be switched directly between the highest gear (all sections in parallel) and the lowest gear (all sections in series). The duty cycle of the PWM can then be used to select a speed/torque characteristics anywhere in between the two extremes of the motor performance. However, the resolution and consequently, the accuracy with which a desired speed can be achieved decreases as the full range of the gearing scale increases. This, to some extent can be compensated by increase in PWM frequency.

20060418

20080603

20070201

69925.0

H02P706

DUDA, RINA I

MAGNETIC GEARING OF PERMANENT MAGNET BRUSHLESS MOTORS

SMALL

ACCEPTED

H02P

ACCEPTED

Method and device for manufacturing a wire cord

A machine for manufacturing a cord consisting of twisted metallic wires comprises a pair of crimping wheels with meshing toothed surfaces for crimping a plurality of wires when they are passed between said meshing toothed surfaces, and a twisting means for twisting together the wires along a twisting path downstream of the pair of twisting wheels. The pair of crimping wheels is arranged at the beginning of the twisting path and the twisting together of the wires preferably starts between the meshing toothed surfaces.

1.-13. (canceled) 14. A method for manufacturing a wire cord, said method comprising the steps of: bundling a plurality of wires in a bundling means in such a way to form a bundle of wires wherein said wires lie closely side-by-side in one plane; crimping said wires by passing said bundle of wires between meshing toothed surfaces; and twisting together said plurality of crimped wires along a twisting path, wherein said meshing toothed surfaces are located at the beginning of said twisting path. 15. The method according to claim 14, wherein said twisting together starts between said meshing toothed surfaces. 16. The method according to claim 15, wherein: at the entrance of said meshing toothed surfaces, said wires still lie closely side-by-side in one plane; and at the outlet of said meshing toothed surfaces, said wires are crossing one another. 17. A machine for manufacturing a wire cord, said machine comprising: a bundling means for bundling a plurality of wires, wherein said bundling means is configured in such a way as to force said plurality of wires to form a bundle of wires wherein said wires lie closely side-by-side in one plane; a crimping means located downstream of said bundling means, said crimping comprising crimping wheels with meshing toothed surfaces for crimping said wires; and a twisting means for twisting together said wires along a twisting path, wherein said crimping means is located at the beginning of said twisting path. 18. The machine according to claim 17, wherein said bundling means is located between 30 mm to 60 mm from the point where said bundle of wires enters between said meshing toothed surfaces. 19. The machine according to claim 17, wherein said bundling means is a bundling die with an aperture, said aperture being dimensioned in such a way as to force said plurality of wires to lie closely side-by-side in one plane. 20. The machine according to claim 19, wherein said bundling die is located between 30 mm to 60 mm from the point where said bundle of wires enters between said meshing toothed surfaces. 21. The machine according to claim 17, wherein in said meshing toothed surfaces two successive teeth with a tooth thickness t are separated by a gap with a gap width g, and said tooth thickness t and said gap width g satisfy following relation: 2t<g<4t. 22. The machine according to claim 21, wherein said wires have a diameter D and said tooth thickness t and said diameter D satisfy following relation: 2D<t<4D. 23. The machine according to claim 22, wherein said wires have a diameter D between 0,2 and 1,0 mm. 24. The machine according to claim 17, wherein the distance between said crimping wheels in said pair is adjustable, so that the penetration of the teeth of one wheel into the gaps of the other wheel is adjustable. 25. The machine according to claim 17, wherein said twisting means comprises: a rotor that can be rotated about a rotor rotation axis; and a deflection pulley supported on said rotor, said deflection pulley forming the end of said twisting path, wherein the latter is substantially co-axial to said rotor rotation axis. 26. The machine according to claim 17, further comprising: a support structure; a rotor with a first rotor end and a second rotor end, said rotor being supported by said support structure in such a way as to be capable of rotating about a rotor rotation axis; a cradle supported between said first rotor end and said second rotor end, in such a way as to be capable of freely rocking about said rotor rotation axis, whereby said cradle remains immobile in rotation when said rotor is rotated; a plurality of wire unwinding devices supported by said cradle; guiding means on said cradle for guiding a plurality of wires from said unwinding devices towards said pair of crimping wheels, said pair of crimping wheels being mounted on said cradle in such a way as to be substantially aligned with said rotor rotation axis; a first deflection pulley supported on said first end of said rotor, in such a way as to be capable of twisting together said plurality of wires in said twisting path, which extends from said first deflection pulley to said pair of crimping wheels; a first flyer arm connected to said first rotor end an a second flyer arm connected to said second rotor end, said first and second flyer arm being capable of guiding the twisted wires about said cradle from said first rotor end to said second rotor end; a second deflection pulley supported on said second end of said rotor, in such a way as to be capable of guiding said twisted wires coming from said second flyer arm axially out of said second rotor end; and a pulling means for pulling said twisted wires out of said second rotor end.

FIELD OF THE INVENTION The present invention generally relates to a method and a machine for manufacturing a wire cord, in particular a high elongation wire cord used for reinforcing purposes and comprising crimped wires that are twisted together. BACKGROUND OF THE INVENTION Such a wire cord is commonly used for reinforcing elastomer products, such as tires. All or some of the individual wires are crimped before they are twisted together. The crimping of the wires results in a higher elongation at rupture of the cord and warrants a better elastomer penetration into the cord. There are different prior art techniques for manufacturing high elongation cords that consists of crimped steel wires that are twisted together. U.S. Pat. No. 5,707,467 discloses crimping the wires in a revolving cam-like pre-former before twisting them together. Such a cam-like pre-former comprises a plate-like or tubular rotary member with 3 to 4 staggered pins. The wire is guided in a zigzag path along the staggered pins and the pre-former is rotated along the wire axis, whereby the pre-former pre-forms a helical wavy form in the wire. Each wire is pre-formed in a separate pre-former. The crimped wires are introduced through a die and a hollow shaft into a rotating buncher type twister, inside which they are twisted together into a cord that is wound on a take-up bobbin. This method has major drawbacks. The zigzag path of the wire in the revolving pre-former requires a limitation of the pulling speed of the wire, and this results of course in a lower productivity. The pre-formers must all be driven in rotation at a controlled speed, which is difficult to achieve. Last but not least, the crimped wires are smoothened again when they are guided over guide rolls and through guide dies before being twisted together. U.S. Pat. No. 5,111,649 discloses crimping the wires between the meshing teeth of a pair of gear-like wheels. Downstream of the gear-like wheels the crimped wires pass through through-holes in a stationary plate before they are introduced into a twisting machine that twists them together into a steel cord. This method has major drawbacks, too. The toothed wheels can only provide a relatively flat deformation of the wires without risking to damage them. Furthermore, the stationary plate guiding the crimped wires into the twisting machine has a tendency to smooth them again. Also U.S. Pat. No. 6,311,466 discloses crimping the wires between toothed wheels. However, instead of using only one pair of toothed wheels, one suggests to use a second pair of toothed wheels that is placed next to the first pair in order to pre-form the wire in a plane turned by 90 degrees compared to the first crimping plane and with a different pitch than the first pair. Each wire passes through a separate toothed wheels arrangement. Thereafter, the crimped wires are bundled and introduced into a known twisting machine to be twisted together. According to U.S. Pat. No. 6,311,466, the individual steel wires should thus receive a spatial deformation before they are twisted together, which is said to improve rubber penetration, to increase elongation at rupture and to decrease the stiffness of the cord. It will, however, be appreciated that the wire has a tendency to tilt when it leaves the first pair of toothed wheels. Thus, the second pair of toothed wheels tends to generate the second wave in the same plane as the first wave, which partially ruins the expected advantages. Moreover, this method also suffers from a smoothing back of the crimped wires prior to the final twisting operation. OBJECT OF THE INVENTION The object of the present invention is to provide a method and a machine for more efficiently manufacturing a wire cord comprising crimped metallic wires that are twisted together. This object is achieved by a method as claimed in claim 1, respectively a machine as claimed in claim 5. SUMMARY OF THE INVENTION In accordance with an important aspect of the present invention, the crimping is carried out by passing a plurality of wires between meshing toothed surfaces that are located at the beginning of the twisting path, along which the wires are twisted together. This feature allows to obtain excellent results with regard to the elongation at rupture of the cord and elastomer penetration into the cord. There is no smoothing of the crimped wires before they are twisted together and there is a very homogeneous distribution of the crimping waves in the twisted cord. Furthermore, the method in accordance with the present invention can be carried out with very simple crimping equipment, it does not need complicated adjustments and it allows to obtain very good productivity results. The plurality of wires shall preferably be closely bundled before they are crimped between the meshing toothed surfaces, and the twisting together of the wires shall preferably already start between the meshing toothed surfaces of the crimping wheels. In ideal circumstances, the plurality of wires shall still lie closely side by side in one plane at the entrance of the meshing toothed surfaces of the crimping wheels, whereas at the outlet of the meshing toothed surfaces, the wires shall already be crossing one another. A machine for manufacturing a cord in accordance with the present invention has a crimping means with crimping wheels with meshing toothed surfaces for crimping the wires and a twisting means for twisting together the wires along a twisting path. In accordance with an important aspect of the present invention, the crimping means comprises a pair of crimping wheels with meshing toothed surfaces that is located at the beginning of the twisting path, and the machine also comprises bundling means located upstream of the pair of crimping wheels for closely bundling a plurality of wires before passing them between said toothed surfaces at the beginning of said twisting path. The bundling means is preferably a bundling die with an aperture that is dimensioned in such a way as to force the plurality of wires to lie closely side by side. Good results are achieved if the bundling means is located between 30 mm to 60 mm from the point where the wires enter between the meshing toothed surfaces. Within a toothed surface, two successive teeth with a tooth thickness t are separated by a gap with a gap width g, wherein the tooth thickness t and the gap width g shall preferably satisfy following relation: 2t<g<4t. Furthermore, if the wires have a diameter D, the tooth thickness t and the diameter D should satisfy following relation: 2D<t<4D, wherein the wires normally have a diameter D between 0,2 mm and 1,0 mm and most often between 0,2 mm and 0,5 mm. Advantageously, the distance between the crimping wheels is finely adjustable, so that the penetration of the teeth of one wheel into the gaps of the other wheel is adjustable. This allows to adjust the crimp amplitude, whereby it is possible to optimise mechanical properties of the cord and/or rubber penetration into the cord. In a preferred embodiment, the twisting means comprises a rotor that can be rotated about a rotor rotation axis and a deflection pulley supported on the rotor. The deflection pulley forms the end of the twisting path, which is substantially co-axial to the rotor rotation axis. The invention may be carried out on a great variety of steel cord twisting machines. However, because of the small space required for crimping the wires, it is e.g. particularly suited for twisting machines in which the wire unwinding devices for the wires are supported on a central cradle. Such a machine comprises e.g. a support structure, a rotor with a first rotor end and a second rotor end, which is supported by the support structure in such a way as to be capable of rotating about a rotor rotation axis, a cradle supported between the first rotor end and the second rotor end, in such a way as to be capable of freely rocking about the rotor rotation axis, whereby the cradle remains immobile in rotation when the rotor is rotated. The cradle supports a plurality of wire unwinding devices. The pair of crimping wheels is mounted on the cradle in such a way as to be substantially aligned with the rotor rotation axis. Guiding means are provided on the cradle for guiding a plurality of wires from the unwinding devices towards the pair of crimping wheels. A first deflection pulley is supported on the first rotor end, in such a way as to be capable of twisting together the wires in the twisting path, which extends from the first deflection pulley to the pair of crimping wheels. A first flyer arm is connected to the first rotor end and a second flyer arm is connected to the second rotor end, wherein the first and second flyer arms are capable of guiding the twisted wires about the cradle from the first rotor end to the second rotor end. A second deflection pulley is supported on the second rotor end, in such a way as to be capable of guiding the twisted wires coming from the second flyer arm axially out of the second rotor end, where a pulling means is used for pulling the twisted wires out of the second rotor end. BRIEF DESCRIPTION OF THE DRAWINGS The present invention will now be described, by way of example, with reference to the accompanying drawing, in which: FIG. 1 is a schematic general view of a machine for manufacturing a cord comprising a plurality of crimped wires; FIG. 2 is a schematic view illustrating the bundling of the wires, the crimping of the wires between meshing toothed surfaces of a pair of crimping wheels and the twisting together of the wires; FIG. 3 is a top view showing an enlarged detail of the toothed surface of a crimping wheel with wires thereon; and FIG. 4 is an enlarged section through a bundling die with wires passing through it. DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT FIG. 1 shows a machine 10 for manufacturing a cord consisting of five steel wires that are crimped and twisted together. The machine comprises, in a configuration known per se, a rotor 12 that is supported by a support structure 14, 14′ in such a way as to be capable of being rotated by a motor 15 about a rotor rotation axis 16. The rotor comprises a first rotor end 18 and a second rotor end 18′. A cradle 20 is mounted between both rotor ends 18, 18′, in such a way as to be capable of freely rocking about the rotor rotation axis 16, whereby the cradle 20 remains immobile in rotation when the rotor 12 is rotated about the rotor rotation axis 16. The cradle 20 supports five conventional unwinding devices 221, 222, 223, 224, 225. Each of these unwinding devices receives one wire spool 241, 242, 243, 244, 245, delivering one of the five steel wires 261, 262, 263, 264, 265 which will form the final cord. Five guiding pulleys 281, 282, 283, 284, 285 guide the five wires 261, 262, 263, 264, 265, which are unwound from the five wire spools 241, 242, 243, 244, 245, into a bundling die 30 that is substantially co-axial to the rotor rotation axis 16. From the bundling die 30, the wires 261, 262, 263, 264, 265, pass through a crimping device 32, which is fixed on the cradle 20 and consequently immobile in rotation about the rotor rotation axis 16, onto the first rotor end 18, which is in rotation about the rotor rotation axis 16. The crimping device 32 and the crimping operation itself will be described later. At the outlet of the crimping device 32 the wires follow a path 34 that is substantially co-axial with the rotor rotation axis 16. This path 34 will be called hereafter “twisting path”, because the individual wires 261, 262, 263, 264, 265, are twisted together along this path 34, as will now be explained. The first rotor end 18 forms a first twisting device and comprises, in a configuration known per se, a deflection pulley 36 (which is also called twisting pulley 36), a flyer arm 38 and a flyer arm deflection pulley 40. The twisting pulley 36 is directly supported on the rotor 12. The flyer arm 38 extends radially from the first rotor end 18 and supports the flyer arm pulley 40 at its free end. The second rotor end 18′ comprises, in the same way, a deflection pulley 36′, a flyer arm 38′ and a flyer arm deflection pulley 40′. When the rotor 12 is rotated by the motor 15, the cradle 20 remains immobile, so that the twisting pulley 36 twists together the wires 261, 262, 263, 264, 265 within the twisting path 34. Thus, a twisted wire cord 44 is formed. The twisting pulley 36 guides this cord 44 onto the flyer arm deflection pulley 40 of the flyer arm 38. From the flyer arm deflection pulley 40, the cord 44 passes onto the flyer arm deflection pulley 40′ of the flyer arm 38′, whereby the cord 44 is guided about the cradle 20 from the first rotor end 18 onto the second rotor end 18′. From the flyer arm deflection pulley 40′, the cord 44 passes into the second rotor end 18′. The deflection pulley 36′ in this second rotor end 18′ guides the cord 44 within the axis of rotation 16 out of the second rotor end 18′, where the cord 44 is pulled away by a conventional winding device 50 (here schematically represented by a spool). Downstream of the deflection pulley 36′, the cord 44 is subjected to a second twist, which completes its formation. The crimping device 32 will now be described with reference to FIG. 2. It comprises a pair of crimping wheels 51, 51′ with meshing toothed surfaces 52, 52′. The crimping wheels 51, 51′ are auto-rotating when the wires 26i are pulled through between the meshing toothed surfaces 52, 52′. These toothed surfaces 52, 52′ have a particular design. Indeed, two successive teeth with a tooth thickness t are separated by a gap with a gap width g that is much larger than the tooth thickness t. The gap width g shall normally satisfy the following condition: 2t<g<4t. The tooth thickness shall be fixed in function of the wire diameter D and shall normally satisfy following condition: 2D<t<4D. For a wire diameter D of 0,38 mm a tooth thickness t of 1 mm and a gap width g of 3 mm were retained. The teeth shall have a rounded profile in order not to damage the wires. The distance between the two crimping wheels 51, 51′ shall be finely adjustable, so that the penetration of the teeth of one wheel into the gaps of the other wheel can be adjusted. This can e.g. be achieved by mounting one of the crimping wheels 51, 51′ on a conventional micrometer adjustment device (not shown). On FIG. 2 one can also see the bundling die 30 arranged upstream of the crimping wheels 51, 51′. The object of this bundling die 30 is to closely bundle the wires 26i before they are crimped between the meshing toothed surfaces 52, 52′. In order to be fully effective, the bundling die 30 shall be located between 30 mm to 60 mm from the point where the wires 26i enter between the meshing toothed surfaces. FIG. 4 shows a section through the bundling die 30. It can be seen that the bundling die 30 has an aperture 60 for the wires 26i that is dimensioned in such a way as to force the five wires 26i to lie closely side by side. FIG. 2 also shows a schematic representation of the twisting means with the twisting pulley 36, the flyer arm 38 and the flyer arm deflection pulley 40. Good results have been obtained with a distance L between the crimping wheels 51, 51′ and the twisting pulley 36 in the range of 100 mm to 150 mm. An important aspect of the present invention will now be described with reference to FIG. 3, which schematically shows, as an enlarged detail, a top view on the toothed surface 52 of the crimping wheel 51, which is meshing with the toothed surface 52′ of the crimping wheel 51′ for crimping the wires 26i. Arrow 71 identifies the travelling direction of the wires 26i, which is parallel to the plane of the FIG. 3, and arrow 73 identifies the twisting sense. The dashed line 76 represents the axis of rotation of the crimping wheel 51. Reference numbers 721, 722, 723 identify three teeth of the toothed surface 52, which are separated by the gaps 741 and 742. Two teeth 72′1, 72′2 of the meshing toothed surface 52′ of crimping wheel 51′ are represented with doted lines as they penetrate into the gaps 741 and 742 of the toothed surface 52. The three teeth 721, 722, 723 of the toothed surface 52 and the two teeth 72′1, 72′2 of the meshing toothed surface 52′ co-operate to crimp the wires 26i. In accordance with an important aspect of the present invention this crimping takes place at the beginning of the twisting path 34. In FIG. 3 it can be seen that at the entrance of the meshing toothed surfaces 52, 52′, the five wires 26i lie closely side by side in one plane, whereas at the outlet of the meshing toothed surfaces 52, 52′ the wires 26i are already crossing one another, i.e. the twisting together of the wires 26i starts between the meshing toothed surfaces 52, 52′. It will be appreciated that locating the crimping of the wires at the beginning of the twisting together of the wires, allows to obtain excellent results with regard to the elongation at rupture of the cord and the elastomer penetration into the cord. Thus it has e.g. been possible to make a 5×0,38 HT HE steel cord with an elongation at rupture of more than 5%. There is no smoothing of the crimped wires before they are twisted together and there is a very homogeneous distribution of the crimping waves in the twisted cord. Furthermore, the method in accordance with the present invention can be carried out with very simple crimping equipment, it does not need complicated adjustments and allows to obtain very good productivity results.

<SOH> BACKGROUND OF THE INVENTION <EOH>Such a wire cord is commonly used for reinforcing elastomer products, such as tires. All or some of the individual wires are crimped before they are twisted together. The crimping of the wires results in a higher elongation at rupture of the cord and warrants a better elastomer penetration into the cord. There are different prior art techniques for manufacturing high elongation cords that consists of crimped steel wires that are twisted together. U.S. Pat. No. 5,707,467 discloses crimping the wires in a revolving cam-like pre-former before twisting them together. Such a cam-like pre-former comprises a plate-like or tubular rotary member with 3 to 4 staggered pins. The wire is guided in a zigzag path along the staggered pins and the pre-former is rotated along the wire axis, whereby the pre-former pre-forms a helical wavy form in the wire. Each wire is pre-formed in a separate pre-former. The crimped wires are introduced through a die and a hollow shaft into a rotating buncher type twister, inside which they are twisted together into a cord that is wound on a take-up bobbin. This method has major drawbacks. The zigzag path of the wire in the revolving pre-former requires a limitation of the pulling speed of the wire, and this results of course in a lower productivity. The pre-formers must all be driven in rotation at a controlled speed, which is difficult to achieve. Last but not least, the crimped wires are smoothened again when they are guided over guide rolls and through guide dies before being twisted together. U.S. Pat. No. 5,111,649 discloses crimping the wires between the meshing teeth of a pair of gear-like wheels. Downstream of the gear-like wheels the crimped wires pass through through-holes in a stationary plate before they are introduced into a twisting machine that twists them together into a steel cord. This method has major drawbacks, too. The toothed wheels can only provide a relatively flat deformation of the wires without risking to damage them. Furthermore, the stationary plate guiding the crimped wires into the twisting machine has a tendency to smooth them again. Also U.S. Pat. No. 6,311,466 discloses crimping the wires between toothed wheels. However, instead of using only one pair of toothed wheels, one suggests to use a second pair of toothed wheels that is placed next to the first pair in order to pre-form the wire in a plane turned by 90 degrees compared to the first crimping plane and with a different pitch than the first pair. Each wire passes through a separate toothed wheels arrangement. Thereafter, the crimped wires are bundled and introduced into a known twisting machine to be twisted together. According to U.S. Pat. No. 6,311,466, the individual steel wires should thus receive a spatial deformation before they are twisted together, which is said to improve rubber penetration, to increase elongation at rupture and to decrease the stiffness of the cord. It will, however, be appreciated that the wire has a tendency to tilt when it leaves the first pair of toothed wheels. Thus, the second pair of toothed wheels tends to generate the second wave in the same plane as the first wave, which partially ruins the expected advantages. Moreover, this method also suffers from a smoothing back of the crimped wires prior to the final twisting operation.

<SOH> SUMMARY OF THE INVENTION <EOH>In accordance with an important aspect of the present invention, the crimping is carried out by passing a plurality of wires between meshing toothed surfaces that are located at the beginning of the twisting path, along which the wires are twisted together. This feature allows to obtain excellent results with regard to the elongation at rupture of the cord and elastomer penetration into the cord. There is no smoothing of the crimped wires before they are twisted together and there is a very homogeneous distribution of the crimping waves in the twisted cord. Furthermore, the method in accordance with the present invention can be carried out with very simple crimping equipment, it does not need complicated adjustments and it allows to obtain very good productivity results. The plurality of wires shall preferably be closely bundled before they are crimped between the meshing toothed surfaces, and the twisting together of the wires shall preferably already start between the meshing toothed surfaces of the crimping wheels. In ideal circumstances, the plurality of wires shall still lie closely side by side in one plane at the entrance of the meshing toothed surfaces of the crimping wheels, whereas at the outlet of the meshing toothed surfaces, the wires shall already be crossing one another. A machine for manufacturing a cord in accordance with the present invention has a crimping means with crimping wheels with meshing toothed surfaces for crimping the wires and a twisting means for twisting together the wires along a twisting path. In accordance with an important aspect of the present invention, the crimping means comprises a pair of crimping wheels with meshing toothed surfaces that is located at the beginning of the twisting path, and the machine also comprises bundling means located upstream of the pair of crimping wheels for closely bundling a plurality of wires before passing them between said toothed surfaces at the beginning of said twisting path. The bundling means is preferably a bundling die with an aperture that is dimensioned in such a way as to force the plurality of wires to lie closely side by side. Good results are achieved if the bundling means is located between 30 mm to 60 mm from the point where the wires enter between the meshing toothed surfaces. Within a toothed surface, two successive teeth with a tooth thickness t are separated by a gap with a gap width g, wherein the tooth thickness t and the gap width g shall preferably satisfy following relation: 2t<g<4t. Furthermore, if the wires have a diameter D, the tooth thickness t and the diameter D should satisfy following relation: 2D<t<4D, wherein the wires normally have a diameter D between 0,2 mm and 1,0 mm and most often between 0,2 mm and 0,5 mm. Advantageously, the distance between the crimping wheels is finely adjustable, so that the penetration of the teeth of one wheel into the gaps of the other wheel is adjustable. This allows to adjust the crimp amplitude, whereby it is possible to optimise mechanical properties of the cord and/or rubber penetration into the cord. In a preferred embodiment, the twisting means comprises a rotor that can be rotated about a rotor rotation axis and a deflection pulley supported on the rotor. The deflection pulley forms the end of the twisting path, which is substantially co-axial to the rotor rotation axis. The invention may be carried out on a great variety of steel cord twisting machines. However, because of the small space required for crimping the wires, it is e.g. particularly suited for twisting machines in which the wire unwinding devices for the wires are supported on a central cradle. Such a machine comprises e.g. a support structure, a rotor with a first rotor end and a second rotor end, which is supported by the support structure in such a way as to be capable of rotating about a rotor rotation axis, a cradle supported between the first rotor end and the second rotor end, in such a way as to be capable of freely rocking about the rotor rotation axis, whereby the cradle remains immobile in rotation when the rotor is rotated. The cradle supports a plurality of wire unwinding devices. The pair of crimping wheels is mounted on the cradle in such a way as to be substantially aligned with the rotor rotation axis. Guiding means are provided on the cradle for guiding a plurality of wires from the unwinding devices towards the pair of crimping wheels. A first deflection pulley is supported on the first rotor end, in such a way as to be capable of twisting together the wires in the twisting path, which extends from the first deflection pulley to the pair of crimping wheels. A first flyer arm is connected to the first rotor end and a second flyer arm is connected to the second rotor end, wherein the first and second flyer arms are capable of guiding the twisted wires about the cradle from the first rotor end to the second rotor end. A second deflection pulley is supported on the second rotor end, in such a way as to be capable of guiding the twisted wires coming from the second flyer arm axially out of the second rotor end, where a pulling means is used for pulling the twisted wires out of the second rotor end.

20060420

20081014

20070412

63208.0

H01R1373

HURLEY, SHAUN R

METHOD AND DEVICE FOR MANUFACTURING A WIRE CORD

UNDISCOUNTED

ACCEPTED

H01R

ACCEPTED

Collapsible funnel

A funnel for pouring liquid into a receptacle is collapsible and is stored in the receptacle when not in use. The funnel is automatically unfolded upon opening the receptacle lid. The funnel has no risk of is unfolding in the receptacle. A tube fixed to the base plate includes displaceable means that are fastened to the lid. The tube is terminated at the top with an arrester for securing the displaceable means. The foldable funnel is disposed inside the existing receptacle, and the funnel is unfolded as soon as the lid is lifted. The opened lid is disposed at the side of the funnel completely outside the funnel circumference so as not to interfere with filling. Placing the lid upon the tube, centering the lid on the funnel and pushing downward closes the receptacle and folds the funnel, which disappears downward into the receptacle.

1. Funnel for placing in a receptacle for pouring liquid into the receptacle, primarily in connection with pouring liquids from cans or bottles, where the funnel (2, 102, 202, 302) is collapsible, where the funnel is stored in the receptacle when not in use, where the funnel is unfolded at the opening of a receptacle lid, where the receptacle lid is connected with means for pulling up the funnel from the receptacle causing the funnel to be automatically unfolded, where the means for pulling up is connected with a base plate, characterized in that the means for pulling up are formed by a tube fixed to the base plate, the tube including displaceable means that are fastened to the lid, and that tube is terminated at the top with arrester means for securing the displaceable means. 2. Funnel according to claim 1, characterized in that the displaceable means are formed by a weight contained in the tube, where a pliable connecting member is fastened to the weight and to the lid. 3. Funnel according to claim 1, characterized in that the displaceable means are formed by a rod that is contained in the tube, where the rod is terminated with a hinge member, where the hinge member interacts with the top end of the tube. 4. Funnel according to claim 3, characterized in that the hinge member contains a ball fastened to the rod, where the ball interacts with the end of the tube, and that the end of the tube includes slots for accommodating the rod. 5. Funnel according to claim 1, characterized in that the funnel in folded state is pressed down into a liquid filter provided in the receptacle. 6. Funnel according to claim 1, characterized in that the liquid filter has sealing means interacting with the stub of the receptacle which is designed with a collar, and that liquid filter forms or is provided with an annular sealing around the collar of the stub of the receptacle. 7. Funnel according to claim 1, characterized in that the liquid filter is provided with an annular recess at the top end of the filter, where the recess can engage corresponding projections on the funnel, whereby the funnel is secured during use. 8. Funnel according to claim 1, characterized in that close to its top end, the liquid filter includes an annular bayonet socket that may engage a corresponding bayonet joint on the funnel, whereby the funnel is secured during use. 9. Funnel according to claim 1, characterized in that close to its top end, the liquid filter includes an internal thread that may engage a corresponding external thread on the funnel, whereby the funnel is secured during use. 10. Funnel according to claim 1, characterized in that the top of the liquid filter forms a collar that may engage the lid of the funnel when the funnel is contained in folded state in the liquid filter. 11. Funnel according to claim 1, characterized in that the filter contains a central partly through going rod, which rod is placed partly in the tube, where the rod under the filter is connected to floating means, where the top of the rod is indicating the liquid level of the receptacle. 12. Funnel according to claim 1, characterized in that the funnel comprises spokes, which spokes supports plumes there between, where the spokes are hinged to the base plate by hinging means. 13. Funnel according to claim 12, characterized in that the spokes contain extensions, which extensions are folded towards the wall of the filter, which filter at the top comprises a surrounding constriction which constriction cooperates with the spokes extensions by forcing the extensions in radial direction towards the central axis of the filter for unfolding the funnel by pulling the funnel upwards.

The present invention concerns a funnel for placing in a receptacle for pouring liquid into the receptacle, primarily in connection with pouring liquids from cans or bottles, where the funnel is collapsible, where the funnel is stored in the receptacle when not yin use, where the funnel is unfolded at the opening of a receptacle lid, where the receptacle lid is connected with means for pulling up the funnel from the receptacle causing the funnel to be automatically unfolded, where the means for pulling up is connected with a base plate. Such a funnel is known from U.S. Pat. No. 5,857,504, disclosing a collapsible funnel with associated movable rod extending inside the funnel and is connected to a screwcap, where the movable rod is pushed down into the receptacle through a filling stub when the funnel is not in use. The folding funnel is to be pulled out of the receptacle before use for automatic unfolding for use with the spout of the receptacle for filling liquid, particularly if the movable rod together with the lid exposes the funnel opening for facilitating liquid filling. The movable rod, however, has a length greater than the funnel itself, whereby the length of the rod determines how great depth there is to be in the receptacle in order that the funnel can be used. In many receptacles, a liquid filter is provided under the filling stub, and this filter is perhaps to be removed due to the long rod. As the funnel is disposed freely in a receptacle, there is a possibility that the funnel itself will slide down under the lower edge of the stub, whereafter the funnel can be unfolded in the receptacle. A subsequent removal of the funnel may be impossible. Another drawback may be that by loading an e.g. can supported at the edge of the funnel, the funnel may be pushed down into the receptacle and liquid may be spilled, causing a fire hazard if the liquid is flammable. It is the purpose of the invention to provide a collapsible funnel that may be placed in a receptacle and readily used, where there is no risk that the funnel is unfolded in the receptacle, and where the funnel is part of a unit which is simultaneously a liquid filter. This may be achieved with a funnel as that described in the introduction, if the means for pulling up are formed by a tube fixed to the base plate, the tube including displaceable means that are fastened to the lid, and that tube is terminated at the top with arrester means for securing the displaceable means. Hereby may be achieved a very efficient collapsible funnel that may be used advantageously for filling e.g. petrol on lawn mowers or windshield washer fluid on cars, where this foldable funnel may efficiently be disposed inside the existing receptacle, and where the funnel may be unfolded effectively as soon as the lid is lifted off. Since the lid is connected with the displaceable means, the lid maybe disposed on the side of the funnel and thereby completely outside the circumference of the funnel, whereby the lid will not in any way interfere with filling liquid. Closing of the receptacle will occur by the lid being placed upon the tube at the centre of the funnel and subsequent pushing downwards with the lid, whereby the funnel is folded together and disappears down into the receptacle. The displaceable means may be formed by a weight contained in the tube, where a pliable or bendable connecting member is fastened to the weight and to the lid. Hereby is achieved that the pliable or bending connecting member allow complete removal of the lid while filling occurs, while the pliable or bending connecting member ensures that the lid does not disappear but stays close by. The pliable connecting member may advantageously be formed of e.g. a piece of steel wire, or maybe a piece of nylon cord, where the weight provided in the tube ensures retracting of cord or wire when the lid is put on. The displaceable means may alternatively be formed of a rod that is contained in the tube, where the rod is terminated with a hinge member, where the hinge member interacts with the top end of the tube. Hereby is achieved a more rigid connection in the shape of a rod, where the hinge member allows that this rod is laid down to the side in the completely drawn out condition, whereby the lid again comes outside the circumference of the funnel itself. The hinge member may contain a ball fastened to the rod, where the ball interacts with the end of the tube, and where the end of the tube includes slots for accommodating the rod. Hereby is achieved that the rod may be turned in any direction and may interact with one of the slots of the tube, whereby the rod may be laid entirely down to the side. In the folded state, the funnel may be pushed down into a liquid filter that may be provided in the receptacle. Hereby may be achieved complete control of as to where the funnel is disposed when folded in the receptacle, and at a functional failure of the funnel, the entire internal liquid filter may be removed, thus removing the funnel from the receptacle at the same time. Using the liquid filter is particularly required if a previously fitted liquid filter is to be removed for making space for the funnel. Hereby may be ensured that the same filter function is continued, but now by means of the filter surrounding the funnel on all side and at the bottom. The liquid filter may be designed with sealing means interacting with the stub of the receptacle which is designed with a collar, and where liquid filter forms or is provided with an annular sealing around the collar of the stub of the receptacle. Hereby may be achieved than the liquid filter forms its own sealing against the receptacle collar. This will be suitable if the receptacle e.g. includes a very volatile liquid like petrol, as evaporation is hindered thereby. The liquid filter may include an annular recess at the top end of the filter, where the recess can engage corresponding projections on the funnel, whereby the funnel may be secured during use. Hereby may be attained that the funnel is unmoved in unfolded state, and that the funnel can e.g. withstand a can bearing on it during pouring without the funnel thereby being pushed down into the receptacle. In a first alternative embodiment, close to its top end, the liquid filter may include an annular bayonet socket that may engage a corresponding bayonet joint on the funnel, whereby the funnel is secured during use. Hereby is achieved a stable locking of the funnel implying elimination of a risk that a funnel may capsize or fold and petrol may possibly be spilled and ignited, in the worst case. In another alternative embodiment, close to its top end, the liquid filter may include an internal thread that may engage a corresponding external thread on the funnel, whereby the funnel may be secured during use. Also, hereby may be achieved a stable locking, where a person manipulating the funnel by tightening the thread is provided great safety for the funnel being secured before filling is commenced. The top of the liquid filter may form a collar that may engage the lid of the funnel when the funnel is contained in folded state in the liquid filter. Hereby may be achieved an efficient closing of the receptacle, whereby evaporation of volatile liquids is achieved. The filter might contain a central partly through going rod, which rod is placed partly in the tube, where the rod under the filter is connected to floating means, where the top of the rod indicates the liquid level of the receptacle. Hereby, may be achieved an efficient indication of the liquid level during the filling of liquid into the receptacle. The rod will also during faulting the funnel into the filter by pressing it down, the rod will govern the base plate in direction of the centre of the filter, and as such when the funnel reaches the bottom of the filter ensure that the base plate discentrally placed inside the filter which by the next opening of the filter assures an efficient and uncomplicated opening of the funnel The funnel can comprise spokes, which spokes support plumes between, where the spokes are hinged to the base plate by hinging means. Hereby, can be achieved a very effective funnel which might be light weight because the spokes and the plumes could be made of a plastic material. The spokes might be hinged to the base plate. It can be assured that the spokes are correctly placed during folding and unfolding of the funnel, and where the unfolding takes place by a turning of the hinging means. By producing the hinging means as a plastic film directly by the production of spokes and base plate, the hinging means can be a plastic film placed between the base plate and the spoke. Hereby, is achieved a very cheap and very effective production method for most of the components for the funnel. The spokes might contain extensions, which extensions are folded towards the wall of the filter, which filter at the top comprises a surrounding constriction, which constriction cooperates with the spokes extensions by forcing the extensions in radial direction towards the central axis of the filter for unfolding the funnel by pulling the funnel upwards. Hereby, is achieved a very effective unfolding and folding method for the funnel. The necessary forces for unfolding the funnel is only needed for pulling the funnel the last few millimeters to the top of the filter. This means that it could be ensured that the spokes are outside the filter before they start opening. The use of the constriction in the top of the filter is also securing the funnel in the unfolded position where a folding can be started after the funnel has started its movement downwards into the filter, so the extensions of the spokes are no longer in contact with the constriction. In the following, the invention is explained from the drawings where: FIG. 1 shows section through a first possible embodiment, FIG. 2 shows a section through a second possible embodiment, FIGS. 3 and 4 show enlarged details of FIG. 2, FIG. 5 shows a section through a third possible embodiment, FIG. 6 shows a top view of the same embodiment as FIG. 5, FIG. 7 shows a section of a possible embodiment as shown in FIGS. 5 and 6, FIG. 8 shows a section through a fourth possible embodiment for a folded funnel, FIG. 9 shows the same embodiment as FIG. 8 but partly opened, FIG. 10 shows the same embodiment as FIG. 9 unfolded, FIG. 11 shows the embodiment as in FIG. 10 seen from the top, FIG. 12a shows an embodiment of a funnel according to the invention, equipped with a ring, FIG. 12b shows a cross sectional view of the same embodiment as shown in FIG. 12a, FIG. 12c shows the same embodiment as shown in FIG. 12a and 12b in perspective, FIG. 13 shows a cut through of the same embodiment of a funnel as shown in FIG. 12, but without the ring, FIG. 14 shows the same embodiment of a funnel as shown in FIG. 13, where the funnel is displayed fully opened, and FIG. 15 shows the same embodiment of a funnel as shown in FIG. 14, but here viewed from a different angle. FIG. 1 shows a possible embodiment of the invention with a funnel 2 interacting with a receptacle 4, where the funnel includes a tube 6 fixed on a base plate 7, where the funnel is connected to a lid 8, where the funnel has mechanical reinforcing elements 10, and where the lid 8 is connected to the tube 6 via a connecting member 12. The funnel 2 interacts with a liquid filter 14 interacting with a receptacle collar 16 at the top, as the liquid filter has a collar 18 fitting tightly around the receptacle collar 16. Also, the upper edge of the receptacle includes a clearance 20 that interact with a projection 22 on the funnel, whereby the funnel becomes fixed in the unfolded condition. At the top, the filter 14 has a collar 24 interacting with closure edge 26 on the lid 8. Simultaneously, the lid has a central projection 28 interacting with upper edge 32 of the tube 6. Inside the tube 6 is provided a weight 30 performing retracting of the connecting member 12 if the lid is put on. The connecting member 12 may be provided as a cord, e.g. a steel wire, or a nylon cord or other pliable material. Placing the lid 8 over the tube 6 will imply that the funnel 2 is folded and pressed down into the liquid filter 14. Hereby the funnel 2 is secured in the liquid filter, and there is no possibility that the funnel can be unfolded down in the receptacle, a situation arising if the connecting element 12 is broken, as the funnel may then be freely pushed down into the receptacle. Simultaneously, the liquid filter 14 has the advantage that if a liquid filter has already been mounted in the receptacle, and this is necessarily to be removed for providing space for the funnel 2, the filter 14 can take over this function automatically. If the receptacle has space enough for accommodating the funnel at the outset, it will only be an advantage to introduce an extra liquid filter. Irrespectively whether the liquid that is to be stored in the receptacle is petrol for e.g. a lawn mower or windshield washer liquid for a car, or, if the case is pouring liquid from one receptacle to another, it is suitable that contaminating particles are prevented from access to the receptacle to the greatest possible extent. On FIG. 2 is shown an alternative embodiment for a funnel 102 that interacts with a receptacle 104, where an internal tube 106 is fastened to a base plate 107, where the tube 106 is mechanically connected with a lid 108 by a connecting rod 112, and where the funnel includes reinforcing elements 110. Inside the receptacle 104 there is shown a liquid filter 114. This liquid filter interacts with the upper edge 116 of the receptacle with a turned-in collar 118. Also, the liquid filter has a clearance 120 for receiving a projection 122 provided at the lower circumference of the funnel for securing the latter. At the top, the liquid filter 114 has a collar 124 interacting with the lid 108, where the lid has a closure edge 126. The connecting member 112 is fastened onto a hinge member 130 which is designed as a ball, where the ball and the hinge member 130 interact with the end 132 of the tube 106. FIGS. 3 and 4 show in details the design of the end 132 of the tube 106, consisting of four projections that are separated by slots 134, where the slots are designed to accommodate the connecting member 112 so that the tube 106 can be laid down on the side of the funnel 102. FIG. 5 shows a section through a third possible embodiment of the funnel 202 where an internal tube 206 is fastened to a base plate 207 where the tube 206 is mechanically connected with a lid 208 by a connection rod 202. And where the funnel includes spokes 210, which spokes 210 support plumes 211. The funnel 202 comprises a liquid filter 204. The connection rod 212 is fastened into a hinge member 230 which is designed as a ball where the ball and the hinge member 230 interact with the end 232 of the tube 206. Inside the tube 206, is placed a central rod 240 which rod is through going through the filter 214. The rod 240 might be slidable in the tube 206 and through an opening at the bottom of the filter 214. Underneath the filter 214, the rod 240 might be connected to not-shown buoyancy members which buoyancy member will pull the rod 240 upwards depending of the liquid level in the surrounding receptacle. The rod 240 might in be placed in a not central opening in the bottom of the filter 214, without cooperating with the tube 206. The rod 240 might be connected by special connection means to buoyancy means placed beside or around the filter 214, in order to let the top of the rod 240 indicate the correct liquid level in the receptacle. In operation, the funnel shown in FIG. 5 will be easy to fold by help of the lid 208 and the connection means 212 which can be pushed downwards into the tube 206. Pressing the lid further downwards will at a certain moment influence the base plate 207 and move that base plate 207 downwards. The constriction 244 interacts with the outside of the spokes 210 which are pressed simultaneously towards the centre of the funnel which is folded with a reduction of the diameter so that the whole funnel now can be pressed downwards into the filter 214. By pressing down the funnel, their connection means 212 and ball means 230 will interact with the rod 240 and press this rod downwards. This will press a buoyancy element down under the liquid level and as such and upwards acting force will act on rod 240. At the end, the lid 208 can be connected to the opening of the filter 214 by connecting means. FIG. 6 shows the funnel from FIG. 5 seen from a top view. In the center is shown the top of the tube 206, and also the base plate 207 is seen from this top view. Spokes 210 are connected to the base plate 207 by hinging means 246, and between spokes 210 are placed plumes 211. The plumes 211 may for example be manufactured from a nylon-based material. On FIG. 6a is shown a side view of the funnel from FIG. 6. Spokes 210 and extensions 242 are seen together with hinging means 246 connected to a base plate 207. The base plate 207 is connected to a tube 206. The connection between the spokes 210 and the hinging means might comprise a snap functions that is activated by unfolding the funnel for keeping the funnel unfolded until a central force at the tube 206 the base plate 207 is pressing the funnel 202 downwards for folding. The spokes 210 might have a curved form for keeping the funnel 202 unfolded in use. FIG. 7 shows spokes 210 and extensions 242 and alternative plumes 211 now in a curved form. FIG. 8 shows a cut through a fourth possible funnel 302 which funnel is folded and placed totally inside a filter 314. Inside the filter 314 is seen the tube 306 and the ball member 330 is seen at the bottom. The lid 308 is seen at the top which lid 308 is connected to the connecting means 312. Spokes 310 is also seen inside the filter 314 and the spokes' extensions 342 are seen at the bottom. The extensions 342 are in close contact to the base plate 307. FIG. 9 shows the same embodiment but now partly opened. The primary difference is now that the lid is pulled upwards and the connection means 312 are now pulled out from the tube 306. Also the ball member has been moved from the bottom of the filter 314 till a top position. The spokes 310 and the extensions 342 and the base plate 307 are still in the same position as in FIG. 8. FIG. 10 shows the same embodiment as in FIG. 8 and FIG. 9, but now fully opened. The lid 308 and the connection rod 312 are now bent to the side by rotating the ball member 337 inside the top 332. The slits are not shown inside the top element 332 for the connection rod 312. The spokes 310 are unfolded, they are connected to the base plate 307 by hinging means 346. The spokes have extensions 342 cooperating with the constriction 344 where the contact between the extension 342 and their constriction 334 leads to unfolding of the spokes 310. FIG. 11 shows the same invention as FIGS. 8, 9 and 10 but here seen as a top view. Spokes 310 are by hinging means 346 connected through a base plate 307. Between spokes 310 are shown glooms 311. Between the hinging means, the spokes 310 and the base plate 307 are openings for letting your fluids flow downwards into the filter 314 as shown on FIG. 10. FIG. 12a shows a possible embodiment of the invention where the liquid filter 1214 is equipped with a ring 1250. The liquid filter 1214 has a protrusion 1260, which interacts with the upper edge 1251 of the ring 1250. FIG. 12b shows a cross sectional view of the same embodiment as shown in FIG. 12a. The ring 1250 is provided with a recess 1252, which interacts with a projection 1261 on the liquid filter 1214. The ring 1214 may be manufactured in different sizes in order to fit any given opening of a receptacle. The ring may further be exchangeable. It is, hereby, achieved that the funnel may be manufactured in a standard size and shape. If the liquid filter 1214 has a smaller cylindrical radius than the opening of the receptacle, then the liquid filter 1214 may be provided with a ring 1250 of a suitable size. The rings may be shaped in such a way that they can be mounted on the liquid filter 1214 at an oblique angle with respect to the cylinder axis of the liquid filter 1214. In this way, the funnel may be adapted to any given opening. A funnel according to the invention may for example be used for filling windshield washer fluid on a car. However, since the different types and brands of cars have different types of receptacles for windshield washer fluid, the collapsible funnel may be sold together with a set of rings so that the funnel may be adapted to any given receptacle. Due to the low manufacturing cost of the rings 1250, this will not lead to a notable increase in the price of the finished product. FIG. 12c shows the same embodiment as shown in FIG. 12a and 12b in perspective. At the bottom of the liquid filter 1214, a meshed filter 1270 is provided. It is, hereby, achieved that possible contaminants, for example small particles, may be collected and thus an eventual destruction of the liquid pump may be avoided. In another embodiment, the liquid filter 1214 may be a pipe with no filter at the bottom. Instead, the pipe may be provided with a stop-ring at the bottom, which will prevent the funnel from sliding down in the receptacle in which it is stored. Additionally, the rings 1250 may have an outer perimeter that is not ring-shaped, but instead have a polygonal edge. FIG. 13 shows a cut through of the same embodiment of a funnel as shown in FIG. 12, but without the ring 1250. The funnel is displayed fully opened. The lid 1308 is connected to the tube 1306 with a connection rod (of which only the bottom is shown). The spokes 1310 are by hinging means 1346 connected to the base plate 1307. The upper part of the liquid filter 1314 comprises a protrusion 1313 that interacts with the extensions 1342 of the spokes 1310. The extensions 1342 cooperate with the constrictions 1344 where the contact between the extensions 1342 and their constriction 1344 leads to an unfolding of the spokes 1310 and a fixing of the spokes 1310 in the unfolded position. The liquid filter additionally contains air holes 1377. The air holes 1377 ensure that liquid may be filled into a receptacle using a funnel according to the invention at a higher rate because air may escape the receptacle while filling it with liquid. An additional air hole 1358 may be placed at the top of the tube 1306. FIG. 14 shows the same embodiment of a funnel as shown in FIG. 13. The funnel is displayed fully opened. The lid 1308 is connected to the tube 1306 with a connection rod 1437. Between the hinging means, the spokes 1310 and the base plate 1307, there are openings 1348 for letting fluids flow downwards into the filter 1314. FIG. 15 shows the same embodiment of a funnel as shown in FIG. 14 where the funnel is displayed fully opened, but here viewed from a different angle so that the meshed filter 1570 at the bottom of the liquid filter 1314 can be seen. The meshed filter 1570 ensures that possible contaminants in the liquid are prevented from entering the receptacle. A funnel according to the invention may be manufactured from a material that is particularly suitable for usage in conjunction with any given liquid. A funnel for filling gasoline on for example a lawn mower may be manufactured from a different kind of material than a funnel that is used in a receptacle for wind shield washer liquid. The funnel may in an alternative embodiment be equipped with a special filter, which is specially designed for filtering of gasoline.

20060911

20080129

20070412

65183.0

B67C1104

MAUST, TIMOTHY LEWIS

COLLAPSIBLE FUNNEL

SMALL

ACCEPTED

B67C

ACCEPTED

Liftgate frame

A frame (18) for a liftgate (10) of a motor vehicle includes an upper frame member (24) and a generally U-shaped lower frame member (26). The upper frame member is adapted to be pivotally secured (33, 35) to the motor vehicle. The lower frame member (26) is fixedly secured to the upper frame member (24). The lower frame member (26) is integrally formed, and includes spaced apart vertical segments (36, 38) and a horizontal segment (40) extending therebetween for supporting the liftgate as the liftgate opens and closes.

1. A liftgate frame for a liftgate of a motor vehicle, said frame assembly comprising: an upper frame member adapted to be pivotally secured to the motor vehicle; and a generally U-shaped, integrally formed lower frame member fixedly secured to said upper frame member, said lower frame member including spaced apart, downwardly extending vertical segments and a horizontal segment extending between said vertical segments for supporting the liftgate as the liftgate opens and closes. 2. A liftgate frame as set forth in claim 1 including a reinforcement member fixedly secured to said upper frame member and to one of said vertical segments for reinforcing the attachment between said upper and lower frame members. 3. A liftgate frame as set forth in claim 2 wherein said lower frame member is formed by tubular hydroforming of a metal material. 4. A liftgate frame as set forth in claim 3 wherein said upper frame member includes an inner header panel pivotally hinged to the motor vehicle and an outer header panel fixedly secured to said inner header panel.

This application claims priority from U.S. Provisional Patent Application 60/513,653 filed Oct. 23, 2003, the entirety of which is incorporated herein by reference thereto. BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a liftgate of a motor vehicle. More particularly, the invention relates to a liftgate frame adapted to provide support for a liftgate through multiple opening positions. 2. Description of the Related Art Certain motor vehicles, including station wagons, sport utility vehicles, and minivans, have a rear opening through which access to an interior of the motor vehicle is gained. The rear opening extends between a floor and a roof of the motor vehicle to allow for loading and unloading of items. Typically, a liftgate is pivotally secured to the motor vehicle to selectively cover the rear opening. To fully cover the rear opening, the liftgate must extend between the floor and the roof of the motor vehicle. Consequently, the liftgate can be large and heavy, making it difficult for some individuals to open and close the liftgate. To ease this difficulty, liftgates have been developed that include a window or flipglass pivotally hinged thereto such that the window can be moved independent of the liftgate. A user thus has the option of opening only the window, which is relatively lightweight, in order to gain access to a portion of the rear opening. This access to a portion of the rear opening is generally sufficient for storage and removal of smaller items. As a result, the liftgate must be opened and closed only in those instances when access to the entire rear opening is needed, that is, during loading and unloading of larger items. Another consideration in liftgate design is driver visibility out the rear of the motor vehicle. Existing liftgates are typically two-piece, stamped metal components having inner and outer stampings, which restricts visibility through the rear opening. Thus, it would be desirable to provide a compact liftgate frame that supports a liftgate through multiple opening positions and increases rear visibility. SUMMARY OF THE INVENTION A frame for a liftgate of a motor vehicle includes an upper frame member and a generally U-shaped lower frame member. The upper frame member is adapted to be pivotally secured to the motor vehicle. The lower frame member is fixedly secured to the upper frame member. The lower frame member is integrally formed and includes spaced apart vertical segments and a horizontal segment extending therebetween for supporting the liftgate as the liftgate opens and closes. BRIEF DESCRIPTION OF THE DRAWINGS Advantages of the invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein: FIG. 1 is a fragmentary, rear perspective view of a motor vehicle including a liftgate in a closed position; FIG. 2 is a fragmentary, rear perspective view of the motor vehicle including the liftgate in an open position; FIG. 3 is a fragmentary, rear perspective view of the motor vehicle including the liftgate in a window open position; FIG. 4 is a fragmentary, rear perspective view of the motor vehicle including the liftgate in a tailgate open position and a liftgate frame according to the invention disposed along the motor vehicle; FIG. 5 is an exploded, rear perspective view of the liftgate frame; FIG. 6 is a rear perspective view of the liftgate frame; and FIG. 7 is a rear view of the liftgate showing a window and a tailgate disposed along the liftgate frame. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Referring to FIGS. 1 through 4, a liftgate, generally shown at 10, selectively covers an opening 12 along a rear portion 14 of a motor vehicle 16. The liftgate 10 includes a liftgate frame, generally indicated at 18, which is adapted to be pivotally secured to the motor vehicle 16. The liftgate 10 also includes a window or flipglass 20 pivotally hinged to and supported by the frame 18. The liftgate 10 further includes a tailgate 22, which is also pivotally hinged to and supported by the frame 18. The various pivoting elements allow the liftgate 10 to move between a closed position (FIG. 1), an open position (FIG. 2), a window open position (FIG. 3), and a tailgate open position (FIG. 4). It is appreciated that the various pivoting elements may be manually or power operated. Referring to FIGS. 5 and 6, the frame 18 includes an upper frame member or header, generally shown at 24, and a generally U-shaped lower frame member 26. The upper frame member 24 extends across the rear portion 14 of the motor vehicle 16 above the opening 12 thereof. The upper frame member 24 includes an inner header panel 28 and an outer header panel 30, both of which may be formed from a stamping operation. The inner header panel 28 is pivotally secured to the motor vehicle 16 by frame hinge mechanisms 33, 35 (shown in FIG. 7) of a suitable type. The outer header panel 30 is fixedly secured to the inner header panel 28 by welding or a similar method. The outer header panel 30 includes weld nuts 29 positioned therealong (shown in FIG. 6). The lower frame member 26 is fixedly secured to the upper frame member 24. Together, the upper 24 and lower 26 frame members form a ring structure extending all around the opening 12 at the rear portion 14 of the motor vehicle 16. The lower frame member 26 is integrally formed, and includes spaced apart, generally upright segments 36, 38 and a horizontal segment 40 extending therebetween. Each of the upright segments 36, 38 has a non-planar contour that allows the frame 18 to conform to the rear portion 14 of the motor vehicle 16. Referring to FIG. 6, each of the upright segments 36, 38 includes cylindrical rod sleeves 42 and cylindrical striker sleeves 44 formed therealong. The rod sleeves 42 retain one end of a prop rod 37 (shown in FIG. 2). The prop rod 37 extends between each vertical segment 36, 38 and the motor vehicle 16. The prop rod 37 assists in pivotal movement of the frame 18. More specifically, the prop rod 37 prevents overtravel of the frame 18 as the frame 18 pivots away from the motor vehicle 16. The striker sleeves 44 along each of the vertical segments 36, 38 house a frame striker 46, described in greater detail below. The horizontal segment 40 of the lower frame member 26 includes a frame latch 48. The frame latch 48 engages a rear striker (not shown) located at the rear portion 14 of the motor vehicle 16 to lock the frame 18 thereto. More specifically, the frame latch 48 is engaged by the rear striker when the liftgate 10 is in the closed position, the window open position, and the tailgate open position in order to prevent pivoting of the frame 18 relative to the motor vehicle 16. At the same time, the engagement of the frame latch 48 to the rear striker does not prevent the window 20 and the tailgate 22 from pivoting relative to the frame 18. The horizontal segment 40 also includes tailgate hinge mechanisms 50 of a suitable type for pivoting the tailgate 22 relative to the frame 18. Preferably, the lower frame member 26 is formed by tubular hydroforming, as is known to those skilled in the art. The tubular lower frame member 26 is formed from steel or aluminum. The tubular hydroforming process results in the lower frame member 26 having a cross-section that provides for rear visibility out the window 20. Still referring to FIG. 6, the tubular lower frame member 26 may house electrical wiring 51 therein. The electrical wiring 51 is routed from the motor vehicle 16 to the lower frame member 26 through openings 32, 34. The electrical wiring 51 is operably connected to a motor (not shown) for moving the frame 18 and/or the tailgate 22. In addition, the electrical wiring 51 supplies power to ancillary equipment such as tail lights and wiper motors (both not shown). Referring once again to FIGS. 5 and 6, a generally L-shaped reinforcement member 52 extends between the upper frame member 24 and one of the vertical segments 36, 38 for reinforcing the joint between the upper 24 and lower 26 frame members. More specifically, a first portion 54 of the reinforcement member 52 is fixedly secured to the inner 28 and outer 30 header panels of the upper frame member 24, and a second portion 56 of the reinforcement member 52 is fixedly secured within one of the tubular vertical segments 36, 38. Referring to FIG. 7, the window 20 includes an upper edge 58, a lower edge 60, and sides 62, 64 extending therebetween. The upper edge 58 of the window 20 is disposed along the upper frame member 24, and the sides 62, 64 of the window 20 are disposed along the vertical segments 36, 38. The window 20 is pivotally hinged to the frame 18 by window hinge mechanisms 63, 65 of a suitable type. It will be appreciated that as long as the window hinge mechanisms 63, 65 can be suitably attached to the frame 18 at various locations therealong. A window prop rod 66, shown in FIGS. 3 and 4, extends between each side 62, 64 of the window 20 and the frame 18 for limiting the path of travel of the window 20 in the upwards direction. One end of the window prop rod 66 is secured to a rod support 68 located along the window 20. The other end of the window prop rod 66 is secured to one of the weld nuts 29 along the frame 18. Referring again to FIG. 7, the tailgate 22 includes a lower edge 70, an upper edge 72, and opposing sides 74, 76 extending therebetween. The lower edge 70 of the tailgate 22 is disposed adjacent the horizontal segment 40 of the lower frame member 26; the upper edge 72 of the tailgate 22 is disposed adjacent the lower edge 60 of the window 20; and the sides 74, 76 are disposed along the vertical segments 36, 38. When the liftgate 10 is in the closed and open positions, the lower edge 60 of the window 20 overlaps the upper edge 72 of the tailgate 22 to prevent pivoting of the tailgate 22 while the window 20 is closed. To this end, the window 20 includes a window striker 75 selectively engaging a tailgate latch 77 of a suitable type to hold the window 20 and the tailgate 22 in an abutting relationship with one another. With the window 20 open, the tailgate 22 is able to be pivoted about the tailgate hinge mechanisms 50 along the horizontal segment 40. A cable 78, shown in FIG. 4, extends between the frame 18 and the tailgate 22 to prevent overtravel of the tailgate 22 as it pivots away from the frame 18. The tailgate 22 may include an internal rotational spring mechanism or strut 80 of a suitable type secured to one end of the cable 78. The spring mechanism 80 is also secured to the tailgate 22 and dampens downward movement of the tailgate 22 away from the frame 18. Referring once again to FIG. 7, the tailgate 22 optionally includes an electronic switching module or brainplate 82, which creates signals indicating the position of the liftgate 10. When the liftgate 10 is in the open position, the brainplate 82 emits a signal to a controller (not shown) to prevent movement of the window 20 and the tailgate 22 relative to the frame 18. The brainplate 82 also signals the controller to restrict movement of the window 20 until the liftgate 10 is in the closed position. In addition, the brainplate 82 will signal the controller both that the frame 18 is sealingly engaging the motor vehicle 16 and that the window 20 is open before allowing the tailgate 22 to open. Further, the brainplate 82 is able to generate a signal to initiate power release of the tailgate latch 77. The tailgate 22 may be formed from a lightweight metal, such as aluminum, or a composite material to contribute to weight reduction of the liftgate 10. Utilization of such a lightweight metal or composite material is made possible by the underlying frame 18, including the tubular hydroformed lower frame member 26, which provides the necessary structural support for the liftgate 10. The liftgate 10 includes various sealing members to provide a tight engagement between moving parts. Referring back to FIG. 2, the motor vehicle 16 includes a flange 84 extending around the opening 12. A flange seal 86 extends along the flange 84 in order to seal the frame 18 with the motor vehicle 16 when the liftgate 10 is in the closed, window open, and tailgate open positions. The sealing of the frame 18 to the motor vehicle 16 reduces noise and prevents moisture from entering the motor vehicle 16. Referring to FIG. 3, the upper edge 72 of the tailgate 22 includes a horizontal seal 88 extending therealong for sealingly engaging the window 20. Referring to FIG. 4, an outer sealing member 90 extends along an outboard surface 92 of the upper 24 and lower 26 frame members. The outer sealing member 90 is retained along the outboard surface 92 by an adhesive. The outer sealing member 90 sealingly engages the window 20 and/or the tailgate 22 when the liftgate 10 is in the open, closed, or window open positions. In a preferred embodiment, the outer sealing member 90 is a one-piece ring-shaped seal. The multiple opening positions of the liftgate 10 provide a user with various options during loading and unloading of items. For example, a user may decide to open only the window 20 for loading and unloading smaller items. Since the window 20 is relatively lightweight, a minimal amount of effort is required to open the window 20. With the window 20 open, the user may pivot the tailgate 22 relative to the frame 18 to move the liftgate 10 into the tailgate open position, as shown in FIG. 4. In the tailgate open position, the tailgate 22 is generally co-planar with a floor 94 of the motor vehicle 16, which is useful during “tailgating” or other activities. In addition, a supplemental latch mechanism (not shown) may be provided to secure the window 20 in a closed position while the liftgate 10 is in the tailgate open position in order to store and transport items that extend out past an interior length of the motor vehicle 16. The liftgate 10 may be moved into the open position, shown in FIG. 2, directly from the closed position by pivoting the frame 18 relative to the motor vehicle 16. The open position is advantageous over the tailgate open position for two reasons. First, since moving the liftgate 10 into the open position involves pivoting the frame 18, the entire opening 12 is accessible from outside the motor vehicle 16. Second, the tailgate 22 is not extending out past the floor 94. Thus, when loading or unloading particularly heavy items, the extra work involved in moving the item over the tailgate 22 and into or off of the motor vehicle 16 is eliminated. The liftgate 10 utilizes the same attachment points as a conventional liftgate. Thus, the liftgate 10, including the frame 18, the window 20, and the tailgate 22, may be utilized as a “drop in” option during the motor vehicle assembly process. The invention has been described in an illustrative manner. It is to be understood that the terminology, which has been used, is intended to be in the nature of words of description rather than of limitation. Many modifications and variations of the invention are possible in light of the above teachings. Therefore, within the scope of the appended claims, the invention may be practiced other than as specifically described.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention This invention relates to a liftgate of a motor vehicle. More particularly, the invention relates to a liftgate frame adapted to provide support for a liftgate through multiple opening positions. 2. Description of the Related Art Certain motor vehicles, including station wagons, sport utility vehicles, and minivans, have a rear opening through which access to an interior of the motor vehicle is gained. The rear opening extends between a floor and a roof of the motor vehicle to allow for loading and unloading of items. Typically, a liftgate is pivotally secured to the motor vehicle to selectively cover the rear opening. To fully cover the rear opening, the liftgate must extend between the floor and the roof of the motor vehicle. Consequently, the liftgate can be large and heavy, making it difficult for some individuals to open and close the liftgate. To ease this difficulty, liftgates have been developed that include a window or flipglass pivotally hinged thereto such that the window can be moved independent of the liftgate. A user thus has the option of opening only the window, which is relatively lightweight, in order to gain access to a portion of the rear opening. This access to a portion of the rear opening is generally sufficient for storage and removal of smaller items. As a result, the liftgate must be opened and closed only in those instances when access to the entire rear opening is needed, that is, during loading and unloading of larger items. Another consideration in liftgate design is driver visibility out the rear of the motor vehicle. Existing liftgates are typically two-piece, stamped metal components having inner and outer stampings, which restricts visibility through the rear opening. Thus, it would be desirable to provide a compact liftgate frame that supports a liftgate through multiple opening positions and increases rear visibility.

<SOH> SUMMARY OF THE INVENTION <EOH>A frame for a liftgate of a motor vehicle includes an upper frame member and a generally U-shaped lower frame member. The upper frame member is adapted to be pivotally secured to the motor vehicle. The lower frame member is fixedly secured to the upper frame member. The lower frame member is integrally formed and includes spaced apart vertical segments and a horizontal segment extending therebetween for supporting the liftgate as the liftgate opens and closes.

20060619

20090317

20070301

94038.0

B62D2510

BONIFAZI, MELISSA ANN

LIFTGATE FRAME

UNDISCOUNTED

ACCEPTED

B62D

ACCEPTED

Novel chimeric polypeptide and use thereof

A chimeric polypeptide comprising a TNF neutralizer domain, an IL-1 receptor antagonist domain, and a dimerization domain, wherein the three domains are operably linked to each other. Within the scope of this invention are (i) nucleic acids encoding the polypeptide; (ii) expression vectors and host cells containing the nucleic acids; (iii) related pharmaceutical compositions; and (iii) related preparation and treatment methods.

1. A chimeric polypeptide comprising: (1) a TNF neutralizer domain; (2) an IL-1 receptor antagonist domain; and (3) a dimerization domain, wherein the three domains are operably linked. 2. The chimeric polypeptide of claim 1, wherein the TNF neutralizer domain includes a domain that binds to mammalian TNF or IL-6. 3. The chimeric polypeptide of claim 2, wherein the TNF neutralizer domain includes an extracellular domain of mammalian TNFR or mammalian IL-6 receptor, or its functional equivalent. 4. The chimeric polypeptide of claim 3, wherein the mammalian TNFR is TNFRII or TNFRI. 5. The chimeric polypeptide of claim 3, wherein the mammalian TNFR is human TNFRII. 6. The chimeric polypeptide of claim 1, wherein the IL-1 receptor antagonist domain includes IL-1ra or its functional equivalent. 7. The chimeric polypeptide of claim 6, wherein the IL-1ra is a glycosylated mammalian polypeptide. 8. The chimeric polypeptide of claim 1, wherein the dimerization domain includes a human Ig Fc fragment. 9. The chimeric polypeptide of claim 8, wherein the human Ig Fc fragment is an IgG1 Fc fragment. 10. The chimeric polypeptide of claim 1, wherein the chimeric polypeptide includes, from the N-terminus to the C-terminus, a TNF neutralizer domain, a dimerization domain, and an IL-1 receptor antagonist domain; or functional equivalents thereof. 11. The chimeric polypeptide of claim 10, wherein the chimeric polypeptide includes an extracellular domain of human TNFRII, human IgG1 Fc, and IL-1ra; or functional equivalents thereof. 12. The chimeric polypeptide of claim 11, wherein the chimeric polypeptide includes SEQ ID NO:2. 13. A polynucleotide comprising a sequence encoding the chimeric polypeptide of claim 1. 14. A cell comprising a polynucleotide of claim 13. 15. The cell of claim 14, wherein the cell is a mammalian cell, a bacterial cell, a yeast cell, an insect cell, or a plant cell. 16. The cell of claim 15, wherein the cell is a CHO cell or a NSO cell or a SP/2/0 cell. 17. A composition comprising a chimeric polypeptide of claim 1 and a pharmaceutical acceptable carrier. 18. A composition comprising a polynucleotide of claim 13 and a pharmaceutical acceptable carrier. 19. A method of treating a TNF and IL-1 dependent disorder, comprising administering to a subject in need thereof an effective amount of a composition of claim 17. 20. The method of claim 19, wherein the disorder is an inflammatory disorder. 21. The method of claim 20, wherein the inflammatory disorder is rheumatoid arthritis or psoriasis. 22. A method of treating a TNF and IL-1 dependent disorder, comprising administering to a subject in need thereof an effective amount of a composition of claim 18. 23. The method of claim 22, wherein the disorder is an inflammatory disorder. 24. The method of claim 23, wherein the inflammatory disorder is rheumatoid arthritis or psoriasis. 25. A vector comprising a polynucleotide of claim 13. 26. A method of producing a polypeptide, comprising culturing the cell of claim 14 in a medium under conditions permitting expression of a polypeptide encoded by the polynucleotide, and purifying the polypeptide from the cultured cell or the medium of the cell.

RELATED APPLICATION This application claims priority to U.S. Provisional Application Ser. No. 60/497,988, filed Aug. 26, 2003, the content of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present invention is directed to a chimeric protein therapeutic agent useful in treatment of diseases such as acute and chronic inflammation. BACKGROUND OF THE INVENTION Inflammation is the body's defense reaction to injuries such as those caused by mechanical damage, infection or antigenic stimulation. An inflammatory reaction may be expressed pathologically when inflammation is induced by an inappropriate stimulus such as an autoantigen, expressed in an exaggerated manner or persists well after the removal of the injurious agents. Two important mediators of inflammation reaction are tumor necrosis factor (TNF) and internleukin-1 (IL-1). TNF neutralizer and IL-1 antagonist have been used to treat inflammation-dependent diseases. Tumor necrosis factor-alpha (CNF alpha) and Tumor necrosis factor beta (INF-beta) are mammalian secreted proteins capable of inducing a wide variety of effects on a large number of cell types. The great similarities in the structural and functional characteristics of these two cytokines have resulted in their collective description as “TNF”. TNF proteins initiate their biological effects on cells by binding to specific TNF receptor (TNFR) proteins expressed on the plasma membrane of a TNF-responsive cell. Two distinct forms of TNFR are known to exist: Type I TNFR (TNFRI), having a molecular weight of approximately 75 kilodaltons, and type II INFR (TNFRII), having a molecular weight of approximately 55 kilodaltons. TNFRI and TNFRII each bind to both TNF alpha and TNF beta. TNF antagonists, such as soluble TNFR and TNF binding proteins, bind to TNF and prevent TNF from binding to cell membrane bound TNF receptors. Such proteins were used to suppress biological activities caused by TNF. The role of TNF in mediated inflammatory diseases has been well established. TNFRII have been proved to be safe and effective clinically for indications of TNF dependent disorders such as rheumatoid arthritis and psoriasis. One of the most potent inflammatory cytokines is IL-1. IL-1 is manufactured by cells of the macrophage/monocyte lineage, and may be produced in two forms: IL-1 alpha and IL-1 beta. IL-1 proteins initiate their biological effects on cells by binding to specific IL-1 receptor (IL-1R), proteins expressed on the plasma membrane of an IL-1 responsive cell. IL-1 receptor antagonist (IL-1ra) is a human protein that acts as a natural inhibitor of IL-1. IL-1ra binds to cell membrane bound IL-1 receptors and prevents IL-1 from binding to the same IL-1 receptors. This protein has been used to suppress biological activities caused by IL-1. In theory, simultaneously neutralizing or blocking two important inflammatory mediators, such as TNF and IL-1, should have the best therapeutic value for treatment of inflammation dependent disorders. However, clinical trial of 242 patients and 24-weeks of concurrent use of a soluble TNFRII and non-glycosylated IL-1ra published by Immunex Inc and Amgen Inc did not increase the efficacy but lead to higher incidence of infection and neutrapenia than that of a soluble TNFRII and IL-1ra as monotherapy. SUMMARY OF INVENTION This invention relates to a novel chimeric polypeptide for treating TNF and IL-1 dependent disorders. The chimeric polypeptide includes (1) a TNF neutralizer domain, (2) an IL-1 receptor antagonist domain and (3) a dimerization domain. The three domains are operably linked to each other. The TNF neutralizer domain may include an extracellular domain of human TNFRII; the IL-1 receptor antagonist domain may include IL-1ra; and the dimerization domain may include a human IgG1 Fc fragment or a human immunoglobulin heavy chain constant region. In particular, the IL-1ra is a glycosylated mammalian polypeptide. In one embodiment, chimeric polypeptide includes, from the N-terminus to the C-terminus, a TNF neutralizer domain, a dimerization domain, and an IL-1 receptor antagonist domain. For example, the chimeric polypeptide may include an extracellular domain of human TNFRII, human IgG1 Fc, and IL-1ra (e.g., SEQ ID NO:2). In another aspect, the invention features a polynucleotide comprising a sequence encoding a chimeric polypeptide of the invention, as well as a cell producing such a polynucleotide. For example, the cell may be a mammalian cell such as CHO cells, NSO cells and SP2/0 cells. The polynucleotide and the cell of the invention can be used to produce a chimeric polypeptide of the invention. A “polynucleotide” or “nucleic acid” refers to a DNA molecule (e.g., a cDNA or genomic DNA), an RNA molecule (e.g., an mRNA), or a DNA or RNA analog. A DNA or RNA analog can be synthesized from nucleotide analogs. The nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA. An “isolated nucleic acid” is a nucleic acid the structure of which is not identical to that of any naturally occurring nucleic acid or to that of any fragment of a naturally occurring genomic nucleic acid. The term therefore covers, for example, (a) a DNA which has the sequence of part of a naturally occurring genomic DNA molecule but is not flanked by both of the coding sequences that flank that part of the molecule in the genome of the organism in which it naturally occurs; (b) a nucleic acid incorporated into a vector or into the genomic DNA of a prokaryote or eukaryote in a manner such that the resulting molecule is not identical to any naturally occurring vector or genomic DNA; (c) a separate molecule such as a cDNA, a genomic fragment, a fragment produced by polymerase chain reaction (PCR), or a restriction fragment; and (d) a recombinant nucleotide sequence that is part of a hybrid gene, i.e., a gene encoding a fusion protein. Specifically excluded from this definition are nucleic acids present in mixtures of different (i) DNA molecules, (ii) transfected cells, or (iii) cell clones, e.g., as these occur in a DNA library such as a cDNA or genomic DNA library. The nucleic acid described above can be used to express a fusion protein of this invention. For this purpose, one can operatively link the nucleic acid to suitable regulatory sequences to generate an expression vector. The invention further provides a composition containing a chimeric polypeptide or a polynucleotide of the invention and a pharmaceutically acceptable carrier. The composition can be used for treating TNF and IL-1 dependent disorders. Also within the invention is a method of treating a TNF and IL-1 dependent disorder by administering to a subject in need thereof an effective amount of a composition of the invention. For example, the disorder may be an inflammatory disorder such as rheumatoid arthritis or psoriasis. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. BRIEF DESCRIPTION OF DRAWINGS FIG. 1: 1st generation of production CHO cell clones of TNFRII-Fc and TNFRII-Fc-IL-1ra chimera: 24 well plate expression in serum-free medium; direct Coomasie blue protein staining; all recombinant proteins are visible ranging 0.5-1.0 ug; loading 10-15 microliters per lane. FIG. 2: Affinity purification of TNFRII-Fc-IL-1ra chimera: SDS page reduced and non-reduced conditions; Coomasie blue protein staining. FIG. 3: An example of our trouble-shooting capability: reducing a degradation problem for TNFRII-Fc-IL-1ra chimera by altering the first purification step—BPLC analysis of intact and partially degraded TNFRII-Fc-IL-1ra chimera with TNFRII-Fc control. FIG. 4: SEC-BPLC analysis of TNFRII-Fc-IL-1ra chimera after formulation and lyophilization. FIG. 5: IL-1 receptor binding assay indicates that TNFRII-Fc-IL-1ra chimera binds human IL-1 receptor with higher affinity than marketed non-glycosylated IL-1ra (Kineret). FIG. 6: TNF alpha binding assay indicates that TNFRII-Fc in-house (+ve control) binds to TNF alpha specifically when comparing with -ve control Tie2-Fc. FIG. 7: TNF alpha binding assay indicates that TNFRII-Fc-IL-1ra chimera binds to TNF alpha specifically to TNF alpha similar to that of TNFRII-Fc (FIG. 6). FIG. 8: Cell-based TNF alpha neutralization test indicates that similar to marketed TNFRII-Fc (Enbrel), TNFRII-Fc-IL-1ra chimera neutralizes TNF alpha's killing activity on L979 cells. FIG. 9: Cell-based IL-1 neutralization test indicates that both marketed IL-1ra (Kineret) and TNFRII-Fc-IL-1ra chimera neutralize IL-1's biological activity on D10 cell proliferation. As expected, glycosylated IL-1ra has lower in vitro activity than E-coli made non-glycosylated IL-1ra (Kineret). DETAILED DESCRIPTION OF THE INVENTION This invention is based on the discovery of a chimeric polypeptide that can be used for treating TNF and IL-1 dependent disorder. The chimeric polypeptide includes (1) a TNF neutralizer domain, (2) an IL-1 receptor antagonist domain, and (3) a dimerization domain. The three domains are operably linked to each other. Surprisingly, this chimeric molecule is produced at commercial production level in mammalian hosts using TNFRII-Fc production level as a reference. It contains intact TNF and IL-1 neutralizing activities after the chimerization. In other word, fusion of a large TNFRII-Fc molecule to N-terminus of IL-1ra does not interrupt IL-1ra's IL-1 receptor binding and IL-1 neutralizing activities. Unlike concurrent use of TNFRII-Fc and IL-1ra, this chimeric molecule is distributed more at inflammatory site through systemic administration route, making it an inflammation site directed TNFRII-Fc. Our results further indicate that this chimeric molecule made in mammalian hosts, contains glycosylated IL-1ra, and has a larger molecular weight than those of both TNFRII-Fc and IL-1ra. Therefore it has longer biological life, and less frequent effective injection dose. Due to its inflammation site directed nature and less effective dose and dosing frequency, this chimeric molecule may have less side effects when comparing with that of TNFRII-Fc and concurrent use of TNFRII-Fc and IL-1ra. A “TNF neutralizer domain” refers to a domain capable of neutralizing TNF, i.e., inhibiting the activity of TNF, e.g., TNF-alpha. For example, a TNF neutralizer domain may include an extracellular domain of human TNFRII, an extracellular domain IL-6 receptor, an antibody to TNF or a TNF receptor, or an antibody to IL-6 or an IL-6 receptor. TNF neutralizer domains are well known in the art. For example, U.S. Pat. No. 5,605,690.discloses TNF receptors (TNFRs) having amino acid sequences which are substantially similar to the native mammalian TNF receptor or TNF binding protein amino acid sequences, and which are capable of binding TNF molecules and inhibiting TNF from binding to cell membrane bound TNFR. Two distinct types of TNFR are known to exist as mentioned earlier: Type I TNFR (TNFRI) and Type II TNFR (TNFRII). The preferred TNFRs of the present invention are soluble forms of TNFRI and TNFRII, as well as soluble TNF binding proteins. Soluble TNFR molecules include, for example, analogs or subunits of native proteins having at least 20 amino acids and which exhibit at least some biological activity in common with TNFRI, TNFRII or TNF binding proteins. Soluble TNFR constructs are devoid of a transmembrane region (and are secreted from the cell) but retain the ability to bind TNF. Various bioequivalent protein and amino acid analogs have an amino acid sequence corresponding to all or part of the extracellular region of a native TNFR, for example, huTNFRI.DELTA.235, huTNFRI.DELTA.185 and huTNFRI.DELTA.163, or amino acid sequences substantially similar to the sequences of amino acids 1-163, amino acids 1-185, or amino acids 1-235 of SEQ ID NO:1 disclosed in U.S. Pat. No. 5,605,690, and which are biologically active in that they bind to TNF ligand. Equivalent soluble TNFRs include polypeptides which vary from these sequences by one or more substitutions, deletions, or additions, and which retain the ability to bind TNF or inhibit TNF signal transduction activity via cell surface bound TNF receptor proteins, for example huTNFRI.DELTA.x, wherein x is selected from the group consisting of any one of amino acids 163-235 of SEQ ID NO:1 disclosed in U.S. Pat. No. 5,605,690. Analogous deletions may be made to muTNFR. Inhibition of TNF signal transduction activity can be determined by transfecting cells with recombinant TNFR DNAs to obtain recombinant receptor expression. The cells are then contacted with TNF and the resulting metabolic effects examined. If an effect results which is attributable to the action of the ligand, then the recombinant receptor has signal transduction activity. Exemplary procedures for determining whether a polypeptide has signal transduction activity are disclosed by Idzerda et al., J. Exp. Med. 171:861 (1990); Curtis et al., Proc. Natl. Acad. Sci. U.S.A. 86:3045 (1989); Prywes et al., EMBO J. 5:2179 (1986) and Chou et al., J. Biol. Chem. 262:1842 (1987). Alternatively, primary cells or cell lines which express an endogenous TNF receptor and have a detectable biological response to TNF could also be utilized. The nomenclature for TNFR analogs as used herein follows the convention of naming the protein (e.g., TNFR) preceded by either “hu” (for human) or “mu” (for murine) and followed by a DELTA. (to designate a deletion) and the number of the C-terminal amino acid. For example, huTNFR.DELTA.235 refers to human TNFR having Asp.sup.235 as the C-terminal amino acid (i.e., a polypeptide having the sequence of amino acids 1-235 of SEQ ID NO:1 disclosed in U.S. Pat. No. 5,605,690). In the absence of any human or murine species designation, TNFR refers generically to mammalian TNFR. Similarly, in the absence of any specific designation for deletion mutants, the term TNFR means all forms of TNFR, including routants and analogs which possess TNFR biological activity. “Biologically active,” as used throughout the specification as a characteristic of TNF receptors, means that a particular molecule shares sufficient amino acid sequence similarity with the embodiments of the present invention disclosed herein to be capable of binding detectable quantities of TNF, transmitting a TNF stimulus to a cell, for example, as a component of a hybrid receptor construct, or cross-reacting with anti-TNFR antibodies raised against TNFR from natural (i.e., nonrecombinant) sources. Preferably, biologically active TNF receptors within the scope of the present invention are capable of binding greater than 0.1 nmoles TNF per nmole receptor, and most preferably, greater than 0.5 nmole TNF per umole receptor in standard binding assays. In preferred aspects of the present invention, the INF neutralizers are selected from the group consisting of soluble human TNFRI and TNFR II. The pCAV/NOT-TNFR vector, containing the human TNFRI cDNA clone 1, was used to express and purify soluble human TNFRI. pCAV/NOT-TNFR has been deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Md. 20852, U.S.A. (Accession No. 68088) under the name pCAV/NOT-TNFR. Like most mammalian genes, mammalian TNF receptors are presumably encoded by multi-exon genes. Alternative mRNA constructs which can be attributed to different mRNA splicing events following transcription, and which share large regions of identity or similarity with the cDNAs disclosed in U.S. Pat. No. 5,605,690 may also be used. Other mammalian TNFR cDNAs may be isolated by using an appropriate human TNFR DNA sequence as a probe for screening a particular mammalian cDNA library by cross-species hybridization. Mammalian TNFR used in the present invention includes, by way of example, primate, human, murine, canine, feline, bovine, ovine, equine and porcine TNFR. Mammalian TNFRs can be obtained by cross species hybridization, using a single stranded cDNA derived from the human TNFR DNA sequence as a hybridization probe to isolate TNFR cDNAs from mammalian cDNA libraries. Functional equivalents of TNFR which may be used in the present invention A “functional equivalent” refers to a polypeptide derived from the TNFR polypeptide, e.g., fusion proteins or proteins having one or more point mutations, insertions, deletions, truncations, or combination thereof. It retains substantially the activity of the TNFR polypeptide, i.e., the ability to bind to TNF. The isolated polypeptide can contain SEQ ED NO: 3 or a fragment of SEQ ID NO: 3, or can be SEQ ID NO: 3 or a fragment of SEQ ID NO: 3. The primary amino acid structure may be modified by forming covalent or aggregative conjugates with other chemical moieties, such as glycosyl groups, lipids, phosphate, acetyl groups and the like, or by creating amino acid sequence mutants. Covalent derivatives are prepared by linking particular functional groups to TNFR amino acid side chains or at the N- or C-termini. Other derivatives of TNFR include covalent or aggregative conjugates of TNFR or its fragments with other proteins or polypeptides, such as by synthesis in recombinant culture as N-terminal or C-terminal fusions. For example, the conjugated peptide may be a signal (or leader) polypeptide sequence at the N-terminal region of the protein which co-translationally or post-translationally directs transfer of the protein from its site of synthesis to its site of function inside or outside of the cell membrane or wall (e.g., the yeast .alpha.-factor leader). TNFR protein fusions can comprise peptides added to facilitate purification or identification of TNFR (e.g., poly-His). The amino acid sequence of TNF receptor can also be linked to the peptide Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys (DYKDDDDK) (Hopp et al., Bio/Technology 6:1204,1988.) The latter sequence is highly antigenic and provides an epitope reversibly bound by a specific monoclonal antibody, enabling rapid assay and facile purification of expressed recombinant protein. This sequence is also specifically cleaved by bovine mucosal enterokinase at the residue immediately following the Asp-Lys pairing. Fusion proteins capped with this peptide may also be resistant to intracellular degradation in E. coli. TNFR with or without associated native-pattern glycosylation may also be used. TNFR expressed in yeast or mammalian expression systems, e.g., COS-7 cells, may be similar or slightly different in molecular weight and glycosylation pattern than the native molecules, depending upon the expression system. Expression of TNFR DNAs in bacteria such as E. coli provides non-glycosylated molecules. Functional mutant analogs of mammalian TNFR having inactivated N-glycosylation sites can be produced by oligonucleotide synthesis and ligation or by site-specific mutagenesis techniques. These analog proteins can be produced in a homogeneous, reduced-carbohydrate form in good yield using yeast expression systems. N-glycosylation sites in eukaryotic proteins are characterized by the amino acid triplet Asn-A.sub.1-Z, where A.sub.1 is any amino acid except Pro, and Z is Ser or Thr. In this sequence, Asn provides a side chain amino group for covalent attachment of carbohydrate. Such a site can be eliminated by substituting another amino acid for Asn or for residue Z, deleting Asn or Z, or inserting a non-Z amino acid between A.sub.1 and Z, or an amino acid other than Asn between Asn and A.sub.1. TNFR derivatives may also be obtained by mutations of TNFR or its subunits. A TNFR mutant, as referred to herein, is a polypeptide homologous to TNFR but which has an amino acid sequence different from native TNFR because of a deletion, insertion or substitution. Bioequivalent analogs of TNFR proteins may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, cysteine residues can be deleted (e.g., Cys.sup.178) or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. Other approaches to mutagenesis involve modification of adjacent dibasic amino acid residues to enhance expression in yeast systems in which KEX2 protease activity is present. Generally, substitutions should be made conservatively; i.e., the most preferred substitute amino acids are those having physiochemical characteristics resembling those of the residue to be replaced. Similarly, when a deletion or insertion strategy is adopted, the potential effect of the deletion or insertion on biological activity should be considered. Substantially similar polypeptide sequences, as defined above, generally comprise a like number of amino acids sequences, although C-terminal truncations for the purpose of constructing soluble TNFRs will contain fewer amino acid sequences. In order to preserve the biological activity of TNFRs, deletions and substitutions will preferably result in homologous or conservatively substituted sequences, meaning that a given residue is replaced by a biologically similar residue. Examples of conservative substitutions include substitution of one aliphatic residue for another, such as Ile, Val, Leu, or Ala for one another, or substitutions of one polar residue for another, such as between Lys and Arg; Glu and Asp; or Gln and Asn. Other such conservative substitutions, for example, substitutions of entire regions having similar hydrophobicity characteristics, are well known. Moreover, particular amino acid differences between human, murine and other mammalian TNFRs are suggestive of additional conservative substitutions that may be made without altering the essential biological characteristics of TNFR. Subunits of TNFR may be constructed by deleting terminal or internal residues or sequences. Particularly preferred sequences include those in which the transmembrane region and intracellular domain of TNFR are deleted or substituted with hydrophilic residues to facilitate secretion of the receptor into the cell culture medium. The resulting protein is referred to as a soluble TNFR molecule which retains its ability to bind TNF. A particularly preferred soluble TNFR construct is TNFRI.DELTA.235 (the sequence of amino acids 1-235 of SEQ ID NO:1 disclosed in U.S. Pat. No. 5,605,690), which comprises the entire extracellular region of TNFRI, terminating with Asp.sup.235 immediately adjacent the transmembrane region. Additional amino acids may be deleted from the transmembrane region while retaining TNF binding activity. For example, huTNFRI.DELTA.183 which comprises the sequence of amino acids 1-183 of SEQ ID NO: 1, and INFRI.DELTA.163 which comprises the sequence of amino acids 1-163 of SEQ ID NO: 1 disclosed in U.S. Pat. No. 5,605,690, retain the ability to bind TNF ligand. TNFRI.DELTA.142, however, does not retain the ability to bind TNF ligand. This suggests that one or both of Cys.sup.157 and Cys.sup.163 is required for formation of an intramolecular disulfide bridge for the proper folding of TNFRI. Cys.sup.178, which was deleted without any apparent adverse effect on the ability of the soluble TNFRI to bind TNF, does not appear to be essential for proper folding of TNFRI. Thus, any deletion C-terminal to Cys.sup.163 would be expected to result in a biologically active soluble TNFRI. The present invention contemplates use of such soluble TNFR constructs corresponding to all or part of the extracellular region of TNFR terminating with any amino acid after Cys.sup.163. Other C-terminal deletions, such as TNPRI.DELTA.157, may be made as a matter of convenience by cutting TNFR cDNA with appropriate restriction enzymes and, if necessary, reconstructing specific sequences with synthetic oligonucleotide linkers. Soluble TNFR with N-terminal deletions may also be used in the present invention. For example, the N-terminus of TNFRI may begin with Leu.sup.1, Pro.sup.2 or Ala.sup.3 without significantly affecting the ability of TNFRI to effectively act as a TNF antagonist. The resulting soluble TNFR constructs are then inserted and expressed in appropriate expression vectors and assayed for the ability to bind TNF. Mutations in nucleotide sequences constructed for expression of analog TNFR must, of course, preserve the reading frame phase of the coding sequences and preferably will not create complementary regions that could hybridize to produce secondary mRNA structures such as loops or hairpins which would adversely affect translation of the receptor mRNA. Although a mutation site may be predetermined, it is not necessary that the nature of the mutation per se be predetermined. For example, in order to select for optimum characteristics of mutants at a given site, random mutagenesis may be conducted at the target codon and the expressed TNFR mutants screened for the desired activity. Not all mutations in the nucleotide sequence which encodes TNFR will be expressed in the final product, for example, nucleotide substitutions may be made to enhance expression, primarily to avoid secondary structure loops in the transcribed mRNA (see EPA 75,444A, incorporated herein by reference), or to provide codons that are more readily translated by the selected host, e.g., the well-known E. coli preference codons for E. coli expression. Mutations can be introduced at particular loci by synthesizing oligonucleotides containing a mutant sequence, flanked by restriction sites enabling ligation to fragments of the native sequence. Following ligation, the resulting reconstructed sequence encodes an analog having the desired amino acid insertion, substitution, or deletion. Alternatively, oligonucleotide-directed site-specific mutagenesis procedures can be employed to provide an altered gene having particular codons altered according to the substitution, deletion, or insertion required. Exemplary methods of making the alterations set forth above are disclosed by Walder et al. (Gene 42:133, 1986); Bauer et al. (Gene 37:73, 1985); Craik (BioTechniques, January 1985, 12-19); Smith et al. (Genetic Engineering: Principles and Methods, Plenum Press, 1981); and U.S. Pat. Nos. 4,518,584 and 4,737,462 disclose suitable techniques, and are incorporated by reference herein. Antibodies to TNF or TNFRs may be used as antibody therapeutics to treat TNF dependent diseases. These antibodies contain immunoglobulin heavy chain constant region similar to a dimerized IgG Fc fragment at its C-terminus and two TNF or TNFR binding Fab domains at its N-terminus. The activity of these antibodies may be determined by using TNF dependent cells such as L979 cell (ATTC). TNF-dependent cells can be killed by adding effective dose of recombinant TNF alpha. This TNF-dependent activity can be neutralized by addition of these antibodies into the reaction. The activity of these antibodies may also be determined by using TNF in vitro binding assay in 96-well plate. Soluble IL-6 receptors or antibodies to IL-6 or IL-6R with IgG heavy chain constant region similar to a dimerized IgG Fc fragment at their C-terminus may be used to replace TNFRII of this chimeric molecule. The activity of these molecules may be determined by using IL-6 receptor in vitro binding assay in 96-well plate. The activity may also be determined by using recombinant IL-6 and IL-6-dependent D10 cells. An “interleukin-1 receptor antagonist domain” refers to a domain capable of specifically binding to IL-1 receptor and preventing activation of cellular receptors to IL-1. Examples of interleukin-1 receptor antagonists include IL-1ra (U.S. Pat. No. 6,096,728) and anti-IL-1 receptor monoclonal antibodies (EP 623674), as well as their functional equivalents, i.e., polypeptides derived from IL-1ra or anti-IL-1 receptor monoclonal antibodies, e.g., fusion proteins or proteins having one or more point mutations, insertions, deletions, truncations, or combination thereof. They retain substantially the activity of specifically binding to IL-1 receptor and preventing activation of cellular receptors to IL-1. They can contain SEQ ID NO: 5 or a fragment of SEQ ID NO: 5. Preferably, the IL-1ra is a glycosylated mammalian polypeptide. The activity of an Interleukin-1 receptor antagonist may be determined by cell-based IL-1 neutralization assay using IL-1 dependent D10 cells (see Example 4). Preferred IL-1ra proteins are described in U.S. Pat. No. 5,075,222 (referred to herein as the '222 patent); WO 91/08285; WO 91/17184; AU 9173636; WO 92/16221 and WO 96/22793, the disclosures of which are incorporated herein by reference. The proteins include glycosylated as well as non-glycosylated IL-1 receptor antagonists. Specifically, three useful forms of IL-1ra and variants thereof are disclosed and described in the '222 patent. The first of these, IL-1ra.alpha., is characterized as a 22-23 kD molecule on SDS-PAGE with an approximate isoelectric point of 4.8, eluting from a Mono Q FPLC column at around 52 mM NaCl in Tris buffer, pH 7.6. The second, IL-1ra.beta., is characterized as a 22-23 kD protein, eluting from a Mono Q column at 48 mM NaCl. Both IL-1ra alpha and IL-1ra.beta are glycosylated. The third, IL-1rax, is characterized as a 20 kD protein, eluting from a Mono Q column at 48 mM NaCl, and is non-glycosylated. All three of these inhibitors possess similar functional and immunological activities. The present invention also includes modified forms of IL-1ra. The modified forms of IL-1ra as used herein include variant polypeptides in which amino acids have been (1) deleted from (“deletion variants”), (2) inserted into (“addition variants”) or (3) substituted for (“substitution variants”) residues within the amino acid sequence of IL-1ra. For IL-1ra deletion variants, each polypeptide may typically have an amino sequence deletion ranging from about 1 to 30 residues, more typically from about 1 to 10 residues and most typically from about 1 to 5 contiguous residues. N-terminal, C-terminal and internal intrasequence deletions are contemplated. Deletions within the IL-1ra amino acid sequence may be made in regions of low homology with the sequences of other members of the IL-1 family. Deletions within the IL-1ra amino acid sequence may be made in areas of substantial homology with the sequences of other members of the IL-1 family and will be more likely to significantly modify the biological activity. For IL-1ra addition variants, each polypeptide may include an amino- and/or carboxyl-terminal fusion ranging in length from one residue to one hundred or more residues, as well as internal intrasequence insertions of single or multiple amino acid residues. Internal additions may range typically from about 1 to 10 amino acid residues, more typically from about 1 to 5 amino acid residues and most typically from about 1 to 3 amino acid residues. Amino-terminus addition variants include the addition of a methionine (for example, as an artifact of the direct expression of the protein in bacterial recombinant cell culture) or an additional amino acid residue or sequence. A further example of an amino-terminal insertion includes the fusion of a signal sequence, as well as or with other pre-pro sequences, to facilitate the secretion of protein from recombinant host cells. Each polypeptide may comprise a signal sequence selected to be recognized and processed, i.e., cleaved by a signal peptidase, by the host cell. For prokaryotic host cells that do not recognize and process the native IL-1ra signal sequence, each polypeptide may comprise a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase or heat-stable enterotoxin II leaders. For yeast cells, each polypeptide may have a signal sequence selected, for example, from the group of the yeast invertase, alpha factor or acid phosphatase leader sequences. For mammalian cell expression, each polypeptide may have the native signal sequence of IL-1ra, although other mammalian signal sequences may be suitable, for example, sequences derived from other IL-1 family members. For IL-1ra substitution variants, each such polypeptide may have at least one amino acid residue in IL-1ra removed and a different residue inserted in its place. Substitution variants include allelic variants, which are characterized by naturally-occurring nucleotide sequence changes in the species population that may or may not result in an amino acid change. One skilled in the art can use any information known about the binding or active site of the polypeptide in the selection of possible mutation sites. Exemplary substitution variants are taught in WO 91/171 84, WO 92/16221, and WO 96/09323. One method for identifying amino acid residues or regions for mutagenesis of a protein is called “alanine scanning mutagenesis” (Cunningham and Wells (1989), Science, 244:1081-1085, the disclosure of which is hereby incorporated by reference). In this method, an amino acid residue or group of target residues of a protein is identified (e.g., charged residues such as Arg, Asp, His, Lys and Glu) and replaced by a neutral or negatively-charged amino acid (most preferably alanine or polyalanine) to effect the interaction of the amino acids with the surrounding aqueous environment in or outside the cell. Those residues demonstrating functional sensitivity to the substitutions are then refined by introducing additional or alternate residues at the sites of substitution. Thus, the site for introducing an amino acid sequence modification is predetermined and, to optimize the performance of a mutation at a given site, alanine scanning or random mutagenesis may be conducted and the resulting variant polypeptide is screened for the optimal combination of desired activity and degree of activity. The sites of greatest interest for substitutional mutagenesis include sites where the amino acids found in IL-ra are substantially different in terms of side-chain bulk, charge and/or hydrophobicity from IL-1ra-like proteins such as IL-1ra's of other various species or of other members of the IL-1 family. Other sites of interest include those in which particular residues of IL-1ra are identical with those of such IL-1ra-like proteins. Such positions are generally important for the biological activity of a protein. Initially, these sites are modified by substitution in a relatively conservative manner. Such conservative substitutions are shown in Table 1 under the heading of “Preferred Substitutions”. If such substitutions result in a change in biological activity, then more substantial changes (Exemplary Substitutions) are introduced and/or other additions/deletions may be made and the resulting polypeptides screened. TABLE 1 Amino Acid Substitutions Original Preferred Exemplary Residue Substitutions Substitutions Ala (A) Val Val; Leu; Ile Arg (R) Lys Lys; Gln; Asn Asn (N) Gln Gln; His; Lys; Arg Asp (D) Glu Glu Cys (C) Ser Ser Gln (Q) Asn Asn Glu (E) Asp Asp Gly (G) Pro Pro His (H) Arg Asn; Gln; Lys; Arg Ile (I) Leu Leu; Val; Met; Ala; Phe; norleucine Leu (L) Ile norleucine; Ile; Val; Met; Ala; Phe Lys (K) Arg Arg; Gln; Asn Met (M) Leu Leu; Phe; Ile Phe (F) Leu Leu; Val; Ile; Ala Pro (P) Gly Gly Ser (S) Thr Thr Thr (T) Ser Ser Trp (W) Tyr Tyr Tyr (Y) Phe Trp; Phe; Thr; Ser Val (V) Leu Ile; Leu; Met; Phe; Ala; norleucine Conservative modifications to the amino acid sequence (and the corresponding modifications to the encoding nucleic acid sequence) of IL-1ra are expected to produce proteins having similar functional and chemical characteristics. In contrast, substantial modifications in the functional and/or chemical characteristics of IL-1ra may be accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the protein at the target site or (c) the bulk of the side chain. Naturally-occurring residues are divided into groups based on common side chain properties: 1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; 2) neutral hydrophilic: Cys, Ser, Thr; 3) acidic: Asp, Glu; 4) basic: Asn, Gln, His, Lys, Arg; 5) aromatic: Trp, Tyr, Phe; and 6) residues that influence chain orientation: Gly, Pro. Non-conservative substitutions may involve the exchange of a member of one of these groups for another. Such substituted residues may be introduced into regions of IL-1ra that are homologous or non-homologous with other IL-1 family members. Specific mutations in the sequence of IL-1ra may involve substitution of a non-native amino acid at the N-terminus, C-terminus or at any site of the protein that is modified by the addition of an N-linked or O-linked carbohydrate. Such modifications may be of particular utility, such as in the addition of an amino acid (e.g., cysteine), which is advantageous for the linking of a water soluble polymer to form a derivative. Further, the sequence of IL-1ra may be modified to add glycosylation sites or to delete N-linked or O-linked glycosylation sites. An asparagine-linked glycosylation recognition site comprises a tripeptide sequence which is specifically recognized by appropriate cellular glycosylation enzymes. These tripeptide sequences are either Asn-Xaa-Thr or Asn-Xaa-Ser, where Xaa can be any amino acid other than Pro. In a specific embodiment, the variants are substantially homologous to the amino acid of IL-1ra (SEQ ID NO:5). The term “substantially homologous” as used herein means a degree of homology that is preferably in excess of 70%, more preferably in excess of 80%, even more preferably in excess of 90% or most preferably even 95%. The percentage of homology as described herein is calculated as the percentage of amino acid residues found in the smaller of the two sequences which align with identical amino acid residues in the sequence being compared when four gaps in a length of 100 amino acids may be introduced to assist in that alignment, as set forth by Dayhoff in Atlas of Protein Sequence and Structure, 5:124 (1972), National Biochemical Research Foundation, Washington, D.C., the disclosure of which is hereby incorporated by reference. Also included as substantially homologous are variants of IL-1ra which may be isolated by virtue of cross-reactivity with antibodies to the amino acid sequence of SEQ ID NO:5 or whose genes may be isolated through hybridization with a DNA encoding SEQ D NO:5 or with segments thereof. IL-1ra variants may be prepared by introducing appropriate nucleotide changes into the DNA encoding variants of IL-1ra or by in vitro chemical synthesis of the desired variants of IL-1ra. It will be appreciated by those skilled in the art that many combinations of deletions, insertions and substitutions can be made, provided that the final variants of IL-1ra are biologically active. Mutagenesis techniques for the replacement, insertion or deletion of one or more selected amino acid residues are well known to one skilled in the art (e.g., U.S. Pat. No. 4,518,584, the disclosure of which is hereby incorporated by reference). There are two principal variables in the construction of each amino acid sequence variant, the location of the mutation site and the nature of the mutation. In designing each variant, the location of each mutation site and the nature of each mutation will depend on the biochemical characteristic(s) to be modified. Each mutation site can be modified individually or in series, e.g., by (1) substituting first with conservative amino acid choices and then with more radical selections, depending upon the results achieved, (2) deleting the target amino acid residue or (3) inserting one or more amino acid residues adjacent to the located site. A “dimerization domain” refers to a domain capable of engaging two copies of a polypeptide of the invention in one molecule. For example, a dimerization domain may include a dimerized IgG Fc fragment or human IgG heavy chain constant region. An example of such a Fc fragment includes SEQ ID No:4. IgG Fc fragment dimmerizes through its cystaine residues for formation of inter-chain disulfide bonds (covalent). Sometime non-covalent dimerization also occurs without involving disulfide bond. Dimerized IgG Fc fragment in this chimeric molecule is capable of presenting two functional TNFRII molecules at its N-terminus and two functional IL-1ra molecules at its C-terminus. This arrangement increases in vivo receptor/ligand binding chances for neutralizing both TNF alpha and IL-1 receptors. The activity of a covalent dimerization through disulfide bond may be determined by using reduced and non-reduced SDS page electroporesis. Molecular weight of the protein should be reduced in half when reduced condition is used. Non-covalent dimerization may be determined by using native and denatured conditions for electroporesis. Molecular weight of the protein should be reduced in half when denatured condition is used. In a polypeptide of the invention, the TNF neutralizer domain, dimerization domain, and IL-1 receptor antagonist domain are operably linked. As used herein, “operably linked” refers to the structural configuration of the polypeptide that does not interfere with the activities of each domain, i.e., the TNF neutralizer domain retains its capability of neutralizing TNF, the interleukin-1 receptor antagonist domain retains its capability of specifically binding IL-1 receptor and preventing activation of cellular receptors to IL-1, and the dimerization domain retains its capability of engaging two copies of a polypeptide of the invention in one molecule and presenting two functional TNFRII molecules at its N-terminus and two functional IL-1ra molecules at its C-terminus. For example, a chimeric polypeptide of the invention may include, from the N-terminus to the C-terminus, a TNF neutralizer domain, a dimerization domain, and an IL-1 receptor antagonist domain. An example of such a TNF neutralizer domain includes SEQ ID NO:3. Specifically, the chimeric polypeptide includes an extracellular domain of human TNFRII, human IgG1 Fc, and IL-1ra. An example of such a chimeric polypeptide includes SEQ ID NO:2. The invention also provides an isolated polynucleotide containing a DNA sequence encoding a chimeric polypeptide of the invention. Such a polynucleotide may be constructed using recombinant DNA technology well known in the art. For example, a polynucleotide of the invention may be a vector containing a DNA sequence encoding a chimeric polypeptide of the invention. The vector can be used for production of the polypeptide. As used herein, the term “vector” refers to a polynucleotide capable of transporting another polynucleotide to which it has been linked. Various types of vectors are well known in the art. See, e.g., U.S. Pat. No. 6,756,196. One type of vector is a “plasmid”, which refers to a circular double stranded DNA loop into which additional DNA'segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors, expression vectors, are capable of directing the expression of genes to which they are operatively linked. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids (vectors). However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions. The recombinant expression vectors of the invention comprise a polynucleotide of the invention in a form suitable for expression of the polynucleotide in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operatively linked to the polynucleotide sequence to be expressed. Within a recombinant expression vector, “operably linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term “regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in many types of host cell and those which direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or polypeptides, encoded by polynucleotides as described herein. The recombinant expression vectors of the invention can be designed for expression of a polyeptide of the invention in prokaryotic or eukaryotic cells, e.g., bacterial cells such as E. coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase. In one embodiment, a polynucleotide of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed (1987) Nature 329:840), pCI (Promega), and pMT2PC (Kaufman et al. (1987) EMBO J. 6:187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see chapters 16 and 17 of Sambrook et al. eds., Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989. In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the polynucleotide preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the polynucleotide). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert et al. (1987) Genes Dev. 1:268-277), lymphoid-specific promoters (Calame and Eaton (1988) Adv. Immunol. 43:235-275), in particular promoters of T cell receptors (Winoto and Baltimore (1989) EMBO J. 8:729-733) and immunoglobulins (Banerji et al. (1983) Cell 33:729-740; Queen and Baltimore (1983) Cell 33:741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477), pancreas-specific promoters (Edlund et al. (1985) Science 230:912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, for example the murine hox promoters (Kessel and Gruss (1990) Science 249:374-379) and the alpha-fetoprotein promoter (Campes and Tilghman (1989) Genes Dev. 3:537-546). Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention or isolated polynucleotide molecule of the invention has been introduced. The terms “host cell” and “recombinant host cell” are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell can be any prokaryotic or eukaryotic cell. For example, a polypeptide of the invention can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or NSO cells). Other suitable host cells are known to those skilled in the art. Vector DNA or an isolated polynucleotide molecule of the invention can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms “transformation” and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign polynucleotide (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (supra), and other laboratory manuals. For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In some cases vector DNA is retained by the host cell. In other cases the host cell does not retain vector DNA and retains only an isolated polynucleotide molecule of the invention carried by the vector. In some cases, and isolated polynucleotide molecule of the invention is used to transform a cell without the use of a vector. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate. Polynucleotide encoding a selectable marker can be introduced into a host cell on the same vector as that encoding a polypeptide of the invention or can be introduced on a separate vector. Cells stably transfected with the introduced polynucleotide can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die). A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) a polypeptide of the invention. Accordingly, the invention further provides methods for producing a polypeptide of the invention using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of the invention (into which a recombinant expression vector or isolated polynucleotide molecule encoding a polypeptide of the invention has been introduced) in a suitable medium such that the polypeptide is produced. In another embodiment, the method further comprises isolating the polypeptide from the medium or the host cell. A polypeptide of the invention can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the polypeptide and a pharmaceutically acceptable carrier. As used herein the language “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF; Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the polypeptide in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the polypeptide into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the polypeptide can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; 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. For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. The compositions can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. In one embodiment, the polypeptide is prepared with carriers that will protect the polypeptide against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the polypeptide and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such a polypeptide for the treatment of individuals. The polypeptide of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (U.S. Pat. No. 5,328,470) or by stereotactic injection (see, e.g., Chen et al. (1994) Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g. retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. The invention further provides a method of treating TNF and IL-1 dependent disorders, including administering to a subject in need thereof an effective amount of a composition of the invention. A “TNF and IL-1 dependent disorder” refers to a disorder that is associated with an abnormal level of the gene expression or activity of TNF or IL-1. Examples of such a disease include, but are not limited to, acute and chronic inflammation (e.g., inflammatory conditions of a joint such as osteoarthritis, psoriatic arthritis and/or rheumatoid arthritis); psoriasis; acute hepatitis, cardiovascular diseases, brain injury as a result of trauma, epilepsy, hemorrhage or stroke; and graft versus disease. A subject to be treated may be identified as being in need of treatment for TNF and IL-1 dependent disorders. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). The term “treating” is defined as administration of a substance to a subject with the purpose to cure, alleviate, relieve, remedy, prevent, or ameliorate a disorder, symptoms of the disorder, a disease state secondary to the disorder, or predisposition toward the disorder. An “effective amount” is an amount of the substance that is capable of producing a medically desirable result as delineated herein in a treated subject. The medically desirable result may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). The effective amount of a composition of the invention is between 2.5 and 300 mg per person, 1-4 times every two weeks. The effective amount can be any specific amount within the aforementioned range. The effective amount is useful in a monotherapy or in combination therapy for the treatment of TNF and IL-1 dependent disorders. As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Effective amounts and treatment regimens for any particular subject (e.g., a mammal such as human) will depend upon a variety of factors, including the activity of the specific extract or its ingredients employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject's disposition to the disease, condition or symptoms, and the judgment of the treating physician or veterinarian. The examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety. EXAMPLES Example 1 Construction and expression of TNFRII-Fc-IL-1ra and control TNFRII-Fc The constructs described in SEQ ID NO:1, 6) have been successfully constructed, sequenced, and expressed in mammalian cell lines. Expression titers in serum-free medium in 24-well plate are 50 mg-100 mg/L (FIG. 1) respectively for native signal—human TNFRII extracellular domain—human IgG1 Fc gene—human IL-1ra (SEQ ID No:1) as well as native signal—human TNFRII extracellular domain—human IgG1 Fc gene (SEQ ID No:6). Higher expression of TNFRII-Fc-IL-1ra than TNFRII-Fc in CHOK1 cells (estimated by direct Coomasie blue protein staining to conditional medium) has been found in our recent production clone screening experiments. Sequence Listing (1) General information: (i) Applicant: Hui, Mizhou. (ii) Title of invention: A novel method of treating TNF and IL-1 dependent related application. (iii) Number of sequence: 7. (iv) Correspondence address: (A) Amprotien Corporation (B) Street: 355 N Lantana Street #220 (C) City: Camarillo (D) State: California (E) Country: United States (F) ZIP: 93010 (2) Information for SEQ ID No: 1: (i) Sequence characteristics: (A) Length: 1923 bp; (B) Type: nucleic acid; (C) Strandedness: single; (D) Topology: linear. (ii) Molecular Type: cDNA (iii) Anti-sense: no. (iv) Original source: homo sapiens. (v) Immediate source: synthetic. (vi) Feature: full length coding sequence. (vii) Feature: signal peptide 1-66. (viii) Sequence description: SEQ ID No:1: (full length nucleotide coding sequence of TNFRII-Fc4L-1ra without stop codon), atggcgcccgtcgccgtctgggccgcgctggccgtcggactggagctctgggctgcggcgcacgccttgcccgcc caggtggcatttacaccctacgccccggagcccgggagcacatgccggctcagagaatactatgaccagacagctc agatgtgctgcagcaaatgctcgccgggccaacatgcaaaagtcttctgtaccaagacctcggacaccgtgtgtgact cctgtgaggacagcacatacacccagctctggaactgggttcccgagtgcttgagctgtggctcccgctgtagctctg accaggtggaaactcaagcctgcactcgggaacagaaccgcatctgcacctgcaggcccggctggtactgcgcgc tgagcaagcaggaggggtgccggctgtgcgcgccgctgcgcaagtgccgcccgggcttcggcgtggccagacca ggaactgaaacatcagacgtggtgtgcaagccctgtgccccggggacgttctccaacacgacttcatccacggatatt tgcaggccccaccagatctgtaacgtggtggccatccctgggaatgcaagcatggatgcagtctgcacgtccacgtc ccccacccggagtatggccccaggggcagtacacttaccccagccagtgtccacacgatcccaacacacgcagcc aactccagaacccagcactgctccaagcacctccttcctgctcccaatgggccccagccccccagctgaagggagc actggcgacgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggac cgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagac aaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggct gaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagcc aaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaa caactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaaga gcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagag cctctccctgtctccgggtaaacgaccctctgggagaaaatccagcaagatgcaagccttcagaatctgggatgttaa ccagaagaccttctatctgaggaacaaccaactagttgctggatacttgcaaggaccaaatgtcaatttaaaagaaaag atagatgtggtacccattgagcctcatgctctgttcttgggaatccatggagggaagatgtgcctgtcctgtgtcaagtct ggtgatgagaccagactccagctggaggcagttaacatcactgacctgagcgagaacagaaagcaggacaagcgc ttcgccttcatccgctcagacagtggccccaccaccagttttgagtctgccgcctgccccggttggttcctctgcacag cgatggaagctgaccagcccgtcagcctcaccaatatgcctgacgaaggcgtcatggtcaccaaattctacttccag gaggacgag (2) Information for SEQ ID No:2: (i) Sequence characteristics: (A) Length: 619 amino acids; (B) Type: amino acid; (C) Topology: linear. (ii) Molecular type: protein. (iii) Sequence description: SEQ ID No:2: (translated mature amino acid sequence of TNFRII-Fc-IL-1ra) LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSD TVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRP GWYCALSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNT TSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVST RSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKRPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAG YLQGPNVNLKEKIDVVPIEPHALFLGIHGGKMCLSCVKSGDETRLQLEAV NITDLSENRKQDKRFAFIRSDSGPTTSFESAACPGWFLCTAMEADQPVSL TNMPDEGVMVTKFYFQEDE (2) Information for SEQ ID No:3: (amino acid sequence of mature TNFRII extracellular domain) (i) Sequence characteristics: (A) Length: 235 amino acids; (B) Type: amino acid; (C) Topology: linear. (ii) Molecular type: protein. (iii) Sequence description: SEQ ID No:3: (amino acid sequence of mature TNFRII extracellular domain) LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSD TVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRP GWYCALSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNT TSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVST RSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGD (2) Information for SEQ ID No:4: (amino acid sequence of human immunoglobulin Fc fragment) (i) Sequence characteristics: (A) Length: 232 amino acids; (B) Type: amino acid; (C) Topology: linear. (ii) Molecular type: protein. (iii) Sequence description: SEQ ID No:4: (amino acid sequence of human immunoglobulin Fc fragment) EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (2) Information for SEQ ID No:5: (amino acid sequence of mature IL-1ra) (i) Sequence characteristics: (A) Length: 152 amino acids; (B) Type:, amino acid; (C) Topology: linear. (ii) Molecular type: protein. (iii) Sequence description: SEQ ID No:5: (amino acid sequence of mature IL-1ra) RPSGRKSSKMQAFRIWDVNQKTFYLRNNQLVAGYLQGPNVNLKEKIDVVP IEPHALFLGIHGGKMCLSCVKSGDETRLQLEAVNITDLSENRKQDKRFAF IRSDSGPTTSFESAACPGWFLCTAMEADQPVSLTNMPDEGVMVTKFYFQE DE (2) Information for SEQ ID No:6: (i) Sequence characteristics: (A) Length: 1467 bp; (B) Type: nucleic acid; (C) Strandedness: single; (D) Topology: linear. (ii) Molecular Type: cDNA (iii) Anti-sense: no. (iv) Original source: homo sapiens. (v) immediate source: synthetic. (vi) Feature: full length coding sequence. (vii) Feature: signal peptide 1-66. (viii) Sequence description: SEQ ID No:6: (full length nucleotide coding sequence of TNFRII-Fc without stop codon) atggcgcccgtcgccgtctgggccgcgctggccgtcggactggagctctgggctgcggcgcacgccttgcccgcccag gtggcatttacaccctacgccccggagcccgggagcacatgccggctcagagaatactatgaccagacagctcagatgtg ctgcagcaaatgctcgccgggccaacatgcaaaagtcttctgtaccaagacctcggacaccgtgtgtgactcctgtgagga cagcacatacacccagctctggaactgggttcccgagtgcttgagctgtggctcccgctgtagctctgaccaggtggaaac tcaagcctgcactcgggaacagaaccgcatctgcacctgcaggcccggctggtactgcgcgctgagcaagcaggaggg gtgccggctgtgcgcgccgctgcgcaagtgccgcccgggcttcggcgtggccagaccaggaactgaaacatcagacgt ggtgtgcaagccctgtgccccggggacgttctccaacacgacttcatccacggatatttgcaggccccaccagatctgtaa cgtggtggccatccctgggaatgcaagcatggatgcagtctgcacgtccacgtcccccacccggagtatggccccaggg gcagtacacttaccccagccagtgtccacacgatcccaacacacgcagccaactccagaacccagcactgctccaagca cctccttcctgctcccaatgggccccagccccccagctgaagggagcactggcgacgagcccaaatcttgtgacaaaact cacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacac cctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaact ggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtg gtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctccc agcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccg ggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggg agagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagc aagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccgggtaaa (2) Information for SEQ ID No:7: (i) Sequence characteristics: (A) Length: 467 amino acids; (B) Type: amino acid; (C) Topology: linear. (ii) Molecular type: protein. (iii) Sequence description: SEQ ID No:7: (translated mature amino acid sequence of TNFRII-Fc) LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSD TVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRP GWYCALSKQEGCRLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNT TSSTDICRPHQICNVVAIPGNASMDAVCTSTSPTRSMAPGAVHLPQPVST RSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK Example 2 Scale up and purification of TNFRII-Fc-IL-1ra and control TNFRII-Fc Cell lines were serum-free suspension adapted in CHO-CD4 medium (Irvine Scientific) and in-house feed medium, and scaled up in 3 liter bioreactor (Eplikon) and roller bottles. Both TNFRII-Fc-IL-1ra (SEQ ID No: 2) and control TNFRII-Fc (SEQ ID No: 7) could be produced at commercial level (at least 180 mg/L in 3 liter bioreactor). These proteins were purified by protein-A direct capture, followed by ion-exchange and hydrophobic chromatography (FIGS. 2, 3). Bulk purified proteins were formulated, lyophilized and SEC-HPLC analyzed (FIG. 4). Example 3 The lyophilized proteins were subsequently used for TNF alpha binding and IL-1 receptor binding assays. For IL-1 receptor binding assay, recombinant human IL-1 receptor extracellular domain was first produced in house using a mammalian host. TNFRII-Fc-IL-1ra, negative control TNFRII-Fc and positive control IL-1ra (Kineret) have been coated to 96-well plate. IL-1 receptor is then incubated at 37 C for binding. The binding is detected using rabbit anti human IL-1 receptor extracellular domain antibodies, followed by goat anti rabbit IgG conjugated with HRP. FIG. 5 shows that both TNFRII-Fc-IL-1ra and IL-1ra (Kineret) bind to IL-1 receptor, and that TNFRII-Fc (Enbrel) does not bind. For TNF alpha binding assay, recombinant TNF alpha has been coated on a 96 well plate. TNFRII-Fc-IL-1ra, positive control TNFRII-Fc (Enbrel) and negative control Tie2 (ANG-1 receptor extracellular domain)-Fc was then incubated at 37 C for binding. The binding was detected by anti human IgG Fc antibodies conjugated with HRP. FIGS. 6, 7 show that both TNFRII-Fc-IL-1ra chimera and TNFRII-Fc bind to TNF alpha, and that negative control Tie2-Fc does not bind to INF alpha. Example 4 Bioassay and functional testing of TNFRII-Fc-IL-1ra, control TNFRII-Fc (Enbrel), and control IL-1ra (Kineret) For cell-based IL-1 neutralization assay, IL-1 dependent D10 cells (ATCC) have been employed to test the blocking activity of IL-1ra (Kineret) and TNFRII-Fc-IL-1ra chimera against recombinant human IL-1's proliferation stimulating activity to D10 cells. For cell-based TNF neutralization assay, L929 cells (ATCC) were employed to test TNFRII's blocking activity against TNF alpha (Biosource International). Results of cell-based assays are shown in FIGS. 8-9. Taken together, functional TNFRII-Fc-IL-1ra chimera has been produced successfully. It maintains both TNF alpha and IL-1 neutralizing activity. Due to its mammalian produced nature with glycosylation and large size of the fused molecule, it has longer biological life than TNFRII-Fc (Enbrel). Example 5 125-I labeling and animal testing of TNFRII-Fc-IL-1ra chimera and control TNFRII-Fc 125-I labeled TNFRII-Fc-IL-1ra was made by using Iodogen method and purified by size-exclusion chromatography (M Hui et al., 1989). IL-1 receptor binding assay had been established by using in-house mammalian recombinant IL-receptor extracellular domain fused (see Example 3). IL-1 receptor binding to 125-I labeled TNFRI-Fc-IL-1ra was compared side by side with non-radiolabelled TNFRII-Fc (Enbrel), and negative control TNFRII-Fc. Our data indicate that 125-I labeled TNFRII-Fc-IL-1ra is functional in terms of IL-1 receptor binding (Table 2). 125-I labeled TNFRII-FcIL-1ra was injected into skin inflammation mice model (see below) together with 125-I labeled TNFRII-Fc (Enbrel). Surprisingly, our result indicated that it was distributed more at inflammatory site than that of TNFRII-Fc (Table 3). This most probably is due to its IL-1 receptor binding affinity. Meanwhile TNFRII-Fc was also distributed more at inflammation site with lesser degree than that of TNFRII-Fc-IL-1ra. This may be explained by its TNF alpha binding affinity and high concentration of TNF alpha at inflammation site. Mice treated with 6 nmol TPA by ear painting in 200 ul acetone consistently develop skin inflammation in 2-3 days. TNFRII-Fc (5 ug and 10 ug) and TNFRII-Fc-IL-1ra (2.5 ug, 5 ug and 10 ug) were administrated over the entire period of skin inflammation development. Eight mice each group were injected with TNFRII-Fc and TNFRII-Fc-IL-1ra chimera every day from day 0-3. Administration of TNFRII-Fc systemically (intra-peritoneally) was shown effective in suppressing the symptoms of skin inflammation in mice (Table 3). Surprisingly, TNFRII-Fc-IL-1ra chimera was shown more effective than TNFRII-Fc while significantly lower effective dose for TNFRII-Fc-IL-1ra was demonstrated than that of TNFRII-Fc (Table 4). Animal tests have been used to evaluate the properties of TNFRII-Fc-IL-1ra chimera in collagen induced arthritis model. Mice previously immunized with porcine type II collagen (CII) in complete Freund adjuvant consistently develop collagen-induced arthritis (CIA). Approximately 14-17 days post-immunization, symptoms of clinical arthritis began to appear in the mice, with 90-100% of the mice displaying severe arthritis by day 28. Mice were injected intraperitoneally with TNFRII-Fc, TNFRII-Fc-IL-1ra and negative control Fc fragment to determine the effect, effective dose an defective dosing frequency on CIA. Mice were assessed for symptoms of arthritis at 12 weeks post-immunization. TNFRII-Fc (5 ug and 10 ug) and TNFRII-Fc-IL-1ra (2.5 ug, 5 ug and 10 ug) were administrated over the entire period of CIA development. Eight mice each group is injected with TNFRII-FC and TNFRII-Fc-IL-1ra every other day as well as once every 4 days from days 0-35. Administration of TNFRII-Fc systemically (intraperitoneally) is shown effective in suppressing the symptoms of CIA in mice (Table 5). Surprisingly, TNFRII-Fc-IL-1ra was shown more effective than TNFRII-Fc and had significantly reduced effective dose and effective dosing frequency (Table 5). TABLE 2 IL-1 receptor binding to 125-I labeled and non-labeled TNFRII-Fc-IL-1ra (n = 3). Name Binding OD (X ± SD) TNFRII-Fc-IL-1ra 125-I labeled 1.5 ± 0.3 TNFRII-Fc-IL-1ra 1.5 ± 0.2 TNFRII-Fc (Enbrel) 0.4 ± 0.3 TABLE 3 Distribution of 125-I labeled TNFRII-Fc-IL-1ra and TNFRII-Fc (Enbrel) in inflamed and non-inflamed skin tissues 4 hours after injection. The distribution is expressed as % of injected dose per gram of tissue (n = 6). % of injected dose per Treatment Tissue gram tissue (n = 6) TNFRII-Fc-IL-1ra 125-I Inflamed skin 3.8 ± 0.2 TNFRII-Fc-IL-1ra 125-I Normal skin 1.5 ± 0.1 TNFRII-Fc (Enbrel) 125-I Inflamed skin 2.8 ± 0.2 TNFRII-Fc (Enbrel) 125-I Normal skin 1.4 ± 0.2 TABLE 4 Effect of systemically administration of TNFRII-Fc-IL-1ra, TNFRII-Fc (Enbrel), concurrent use of TNFRII-Fc and IL-1ra and negative control Fc fragment during inductive stage on skin inflammation. The skin inflammation is expressed as ear swelling thickness × 10−2 mm (X ± SD)/incidence (% onset of total animal# at day 3) (n = 10). 5 ug 10 ug 20 ug TNFRII-Fc-IL- 4 ± 0.3/100% 3 ± 0.2/100% 3 ± 0.2/90% 1ra TNFRII-Fc 8 ± 0.2/100% 8 ± 0.2/100% 7 ± 0.2/100% (Enbrel) TNFRII-Fc + 8 ± 0.2/100% 7 ± 0.2/100% 7 ± 0.2/100% IL-1ra Fc fragment 16 ± 0.2/100% 15 ± 0.2/100% 16 ± 0.3/100% control TABLE 5 Effect of systemically administration of TNFRII-Fc-IL-1ra, TNFRII-Fc (Enbrel), concurrent use of TNFRII-Fc and IL-1ra and negative control Fc fragment during inductive stage on the onset of arthritis. The onset of arthritis is expressed as onset day (X ± SD)/incidence (% positive of total animal#) (n = 10). 2.5 ug 5 ug 10 ug TNFRII-Fc-IL-1ra 27 ± 2/80% 28 ± 2/70% 32 ± 3/70% TNFRII-Fc 24 ± 2/90% 24 ± 2/100% 24 ± 2/100% (Enbrel) TNFRII-Fc + IL- 24 ± 2/80% 25 ± 2/90% 25 ± 2/100% 1ra Fc fragment 18 ± 2/100% 19 ± 2/100% 18 ± 3/100% control Other Embodiments All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features. From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>Inflammation is the body's defense reaction to injuries such as those caused by mechanical damage, infection or antigenic stimulation. An inflammatory reaction may be expressed pathologically when inflammation is induced by an inappropriate stimulus such as an autoantigen, expressed in an exaggerated manner or persists well after the removal of the injurious agents. Two important mediators of inflammation reaction are tumor necrosis factor (TNF) and internleukin-1 (IL-1). TNF neutralizer and IL-1 antagonist have been used to treat inflammation-dependent diseases. Tumor necrosis factor-alpha (CNF alpha) and Tumor necrosis factor beta (INF-beta) are mammalian secreted proteins capable of inducing a wide variety of effects on a large number of cell types. The great similarities in the structural and functional characteristics of these two cytokines have resulted in their collective description as “TNF”. TNF proteins initiate their biological effects on cells by binding to specific TNF receptor (TNFR) proteins expressed on the plasma membrane of a TNF-responsive cell. Two distinct forms of TNFR are known to exist: Type I TNFR (TNFRI), having a molecular weight of approximately 75 kilodaltons, and type II INFR (TNFRII), having a molecular weight of approximately 55 kilodaltons. TNFRI and TNFRII each bind to both TNF alpha and TNF beta. TNF antagonists, such as soluble TNFR and TNF binding proteins, bind to TNF and prevent TNF from binding to cell membrane bound TNF receptors. Such proteins were used to suppress biological activities caused by TNF. The role of TNF in mediated inflammatory diseases has been well established. TNFRII have been proved to be safe and effective clinically for indications of TNF dependent disorders such as rheumatoid arthritis and psoriasis. One of the most potent inflammatory cytokines is IL-1. IL-1 is manufactured by cells of the macrophage/monocyte lineage, and may be produced in two forms: IL-1 alpha and IL-1 beta. IL-1 proteins initiate their biological effects on cells by binding to specific IL-1 receptor (IL-1R), proteins expressed on the plasma membrane of an IL-1 responsive cell. IL-1 receptor antagonist (IL-1ra) is a human protein that acts as a natural inhibitor of IL-1. IL-1ra binds to cell membrane bound IL-1 receptors and prevents IL-1 from binding to the same IL-1 receptors. This protein has been used to suppress biological activities caused by IL-1. In theory, simultaneously neutralizing or blocking two important inflammatory mediators, such as TNF and IL-1, should have the best therapeutic value for treatment of inflammation dependent disorders. However, clinical trial of 242 patients and 24-weeks of concurrent use of a soluble TNFRII and non-glycosylated IL-1ra published by Immunex Inc and Amgen Inc did not increase the efficacy but lead to higher incidence of infection and neutrapenia than that of a soluble TNFRII and IL-1ra as monotherapy.

<SOH> SUMMARY OF INVENTION <EOH>This invention relates to a novel chimeric polypeptide for treating TNF and IL-1 dependent disorders. The chimeric polypeptide includes (1) a TNF neutralizer domain, (2) an IL-1 receptor antagonist domain and (3) a dimerization domain. The three domains are operably linked to each other. The TNF neutralizer domain may include an extracellular domain of human TNFRII; the IL-1 receptor antagonist domain may include IL-1ra; and the dimerization domain may include a human IgG1 Fc fragment or a human immunoglobulin heavy chain constant region. In particular, the IL-1ra is a glycosylated mammalian polypeptide. In one embodiment, chimeric polypeptide includes, from the N-terminus to the C-terminus, a TNF neutralizer domain, a dimerization domain, and an IL-1 receptor antagonist domain. For example, the chimeric polypeptide may include an extracellular domain of human TNFRII, human IgG1 Fc, and IL-1ra (e.g., SEQ ID NO:2). In another aspect, the invention features a polynucleotide comprising a sequence encoding a chimeric polypeptide of the invention, as well as a cell producing such a polynucleotide. For example, the cell may be a mammalian cell such as CHO cells, NSO cells and SP2/0 cells. The polynucleotide and the cell of the invention can be used to produce a chimeric polypeptide of the invention. A “polynucleotide” or “nucleic acid” refers to a DNA molecule (e.g., a cDNA or genomic DNA), an RNA molecule (e.g., an mRNA), or a DNA or RNA analog. A DNA or RNA analog can be synthesized from nucleotide analogs. The nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA. An “isolated nucleic acid” is a nucleic acid the structure of which is not identical to that of any naturally occurring nucleic acid or to that of any fragment of a naturally occurring genomic nucleic acid. The term therefore covers, for example, (a) a DNA which has the sequence of part of a naturally occurring genomic DNA molecule but is not flanked by both of the coding sequences that flank that part of the molecule in the genome of the organism in which it naturally occurs; (b) a nucleic acid incorporated into a vector or into the genomic DNA of a prokaryote or eukaryote in a manner such that the resulting molecule is not identical to any naturally occurring vector or genomic DNA; (c) a separate molecule such as a cDNA, a genomic fragment, a fragment produced by polymerase chain reaction (PCR), or a restriction fragment; and (d) a recombinant nucleotide sequence that is part of a hybrid gene, i.e., a gene encoding a fusion protein. Specifically excluded from this definition are nucleic acids present in mixtures of different (i) DNA molecules, (ii) transfected cells, or (iii) cell clones, e.g., as these occur in a DNA library such as a cDNA or genomic DNA library. The nucleic acid described above can be used to express a fusion protein of this invention. For this purpose, one can operatively link the nucleic acid to suitable regulatory sequences to generate an expression vector. The invention further provides a composition containing a chimeric polypeptide or a polynucleotide of the invention and a pharmaceutically acceptable carrier. The composition can be used for treating TNF and IL-1 dependent disorders. Also within the invention is a method of treating a TNF and IL-1 dependent disorder by administering to a subject in need thereof an effective amount of a composition of the invention. For example, the disorder may be an inflammatory disorder such as rheumatoid arthritis or psoriasis. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

20061004

20100420

20070412

72961.0

A61K3817

LANDSMAN, ROBERT S

CHIMERIC POLYPEPTIDE AND USE THEREOF

SMALL

ACCEPTED

A61K

ACCEPTED

Method for the production of 6,6,6-tirhalo-3,5-dioxohexanoic acid esters

A method for the production of 6,6,6-trihalo-3,5-dioxohexanic acid esters of formula (I): in addition to the enols thereof and <I>E</I> and <I>Z</I> isomers, wherein X independently represents fluorine, chlorine or bromine and R1 represents alkyl, cycloalkyl, aryl or aralkyl. A method for the production of enol ethers of formula (Ib): and the enols thereof (E and Z isomers) wherein X and R1 have the above-mentioned meanings.

1. A method for preparing a compound compounds of formula: or an enol thereof or a E or Z isomer thereof, in which X is in each case independently of one another fluorine, chlorine or bromine, and in which R1 is alkyl, cycloalkyl, aryl or aralkyl, comprising (a) initially converting a compound of formula: in which X has the stated meaning, by reacting the hydroxyl group of the compound of formula II with a compound of the formula (R2O)2SO2 or with a compound of the formula Y—R2 in which Y is tosyl, chlorine, bromine or iodine, and in which R2 is in each case alkyl, cycloalkyl, allyl or benzyl, into a compound of formula: in which R2 and X each has the above-mentioned meaning, and (b) converting the compound of formula III by reaction with a metal alcoholate of the formula R1O− 1/n Mn+ in which R1 has the above-mentioned meaning and Mn+ is an alkali metal or alkaline earth metal cation and n=1 or 2, and (c) further treating with a strong acid, into a compound of formula I and/or an enol thereof and/or an E or Z isomer thereof. 2. A method for preparing an enol ether of the formula: or an enol thereof or, in each case, the E or Z isomer thereof, in which X is in each case independently of one another F, Cl or Br, and in which R1 is alkyl, cycloalkyl, aryl or aralkyl, and R2 is alkyl, cycloalkyl, allyl or benzyl, comprising (a) initially converting a compound of the formula: in which X has the stated meaning, by reaction of the hydroxyl group of the compound of formula II with a compound of the formula (R2O)2SO2 or with a compound of the formula Y—R2 in which Y is tosyl, chlorine, bromine or iodine, and in which R2 in each case has the above-mentioned meaning, into a compound of the formula in which R2 and X each has the above-mentioned meaning, and (b) converting the compound of formula III by reaction with a metal alcoholate of the formula R1O− 1/n Mn+ in which R1 is alkyl, cycloalkyl, aryl or aralkyl and Mn+ is an alkali metal or alkaline earth metal cation and n=1 or 2, and (c) optionally further treating with a weak acid into an enol ether of the formula Ib and/or an enol thereof. 3. A compound of formula: in which X is in each case independently of one another F, Cl or Br, and in which R2 is alkyl, cycloalkyl, allyl or benzyl, with the exception of the compound of formula III in which X is bromine and R2 is methyl. 4. A compound of formula: or an enol thereof or an E and Z isomer thereof, in which X is in each case independently of one another fluorine, chlorine or bromine, and in which R1 is alkyl, cycloalkyl, aryl or aralkyl, and in which R2 is alkyl, cycloalkyl, allyl or benzyl. 5. The method in claim 2 wherein conversion product of step (b) is further treated, step (c), with the weak acid into the enol ether of formula Ib and/or the enol thereof.

The invention relates to a method for preparing 6,6,6-trihalo-3,5-dioxohexanoic esters of the formula and the enols and E and Z isomers thereof or the enol ethers thereof, of the formula and the enols and E and Z isomers thereof in which the substituents X are each independently of one another fluorine, chlorine or bromine, and in which R1 is in each case alkyl, cycloalkyl, aryl or aralkyl, and R2 is alkyl, cycloalkyl, allyl or benzyl, starting from pyranones of the formula in which X has the abovementioned meaning. Ethyl 6,6,6-trihalo-3,5-dioxohexanoates of the formula I are employed for example for the production of herbicides and agrochemicals (JP-A-06-049039). Known methods for synthesizing substituted tricarbonyl compounds having a 3,5-dioxohexanoic ester basic structure start for example from ethyl acetoacetate, which is condensed with ethyl benzoate in THF in the presence of KH/BuLi (WO-A-94/11361), or with a highly substituted 3-oxopentanamide in THF in the presence of NaH/BuLi (WO-A-02/055519). A method for preparing tert-butyl 6,6,6-trifluoro-3,5-dioxohexanoate from 2,2,2-trifluoroethyl trifluoroacetate and tert-butyl acetoacetate is disclosed in WO-A-02/02547. A further alternative variant for preparing substituted tricarbonyl compounds proceeds by ring opening of a pyranone such as, for example, of dehydracetic acid, which is converted by means of Mg(OMe)2 in methanol into methyl 3,5-dioxohexanoate (Batelaan, J. G., Synthetic Commun. 1976, 6, 81-83). These known methods have the disadvantage that costly reagents such as BuLi are used. Solladié, et al., Tetrahedron: Asymmetry 1996, 7, 2371-2379, disclosed that ring opening of dehydracetic acid of the formula to give the tricarbonyl compound is possible, but leads to elimination of the acetyl substituent previously introduced during the synthesis. However, a loss of mass has disadvantageous effects on the profitability of a method in industrial process management. It was therefore an object of the present invention to provide a simple method for preparing alkyl 6,6,6-trihalo-3,5-dioxohexanoates and the enols and enol ethers thereof, which can utilize easily obtainable pyrones as starting compounds. This object is achieved according to the invention by the method claimed in claim 1. It has been found that compounds of the formula in which the substituents X are each independently of one another fluorine, chlorine or bromine, provide, after conversion of the hydroxyl group into an ether group and subsequent opening of the pyran ring with a metal alcoholate, depending on the further reaction conditions, compounds of the formula I or the enol ethers thereof of the formula Ib in good yield. The present method is distinguished by no loss of mass occurring during the ring opening, and the number of carbon atoms present in the basic structure being maintained. The method of the invention is surprising because it is known that 4-hydroxypyran-2-one cannot be converted into the open-chain tricarbonyl compound by reaction with sodium methanolate but, on the contrary, as shown in the reaction equation below is firstly methylated on the hydroxyl group and then the pyranone ether is converted into a phloroglucinol derivative (Effenberger, F. et al., Chem. Ber. 1984, 117, 3270-3279). It was thus not possible to expect the ring opening resulting in the method of the invention. The starting compounds of the formula II of the method of the invention can easily be obtained. Thus, for example, 4-hydroxy-6-trifluoromethylpyran-2-one can be prepared by reacting trifluoroacetic acid with ketene. Alkyl means here and hereinafter in particular an optionally halogen-substituted, linear or optionally branched group having 1 to 8 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl. Cycloalkyl means here and hereinafter in particular a cyclic group having 3 to 8 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Aryl means here and hereinafter in particular an optionally alkyl- and or halogen-substituted aromatic group having 6 or 8 carbon atoms, such as, for example, phenyl, p-tolyl or naphthyl. Aralkyl means here and hereinafter in particular an alkyl group substituted by an aryl group, such as, for example, phenylethyl, where the alkyl group comprises 1 to 4 carbon atoms, and the aryl group is an optionally halogen-substituted, aromatic or heteroaromatic group having 4 to 8 carbon atoms, such as, for example, phenyl, naphthyl, 2- or 3-furanyl, 2- or 3-thiophenyl or 2-, 3- or 4-pyridinyl. In the method of the invention for preparing compounds of the formula and the enols and E and Z isomers thereof or the enol ethers thereof of the formula and the enols and E and Z isomers thereof in which the substituents X are each independently of one another fluorine, chlorine or bromine, and in which R1 is in each case alkyl, cycloalkyl, aryl or aralkyl, and R2 is alkyl, cycloalkyl, allyl or benzyl, compounds of the formula in which X has the aforementioned meaning, are converted by reacting the hydroxyl group with a compound of the formula (R2O)2SO2 or with a compound of the formula Y—R2 in which Y is tosyl, chlorine, bromine or iodine, and in which R2 in each case has the abovementioned meaning, into a compound of the formula in which R2 and X have the stated meanings, and the pyranone ring of the reaction product is subsequently opened by reaction with a metal alcoholate of the formula R 1 ⁢ O - ⁢ 1 n ⁢ M n + in which R1 has the abovementioned meaning, and Mn+ is an alkali metal or alkaline earth metal cation and n=1 or 2, depending on the further reaction conditions, to give compounds of the formula I or Ib. Suitable reagents for the preparation according to the invention of compounds of the formula III are for example dimethyl sulfate, diethyl sulfate, methyl iodide, ethyl bromide, methyl tosylate, ethyl tosylate, phenyl tosylate, allyl chloride, allyl bromide, benzyl chloride or benzyl bromide. Mn+ in the metal alcoholates of the formula R 1 ⁢ O - ⁢ 1 n ⁢ M n + is preferably Li+, Na+, K+, Mg2+ or Ca2+. If a strong acid is added (pH<1) to the reaction mixture of compounds of the formula III after addition of the metal alcoholate, and the mixture is reacted further, compounds of the formula I and enols thereof can be obtained. In this method, the radical R2 is eliminated. If a weak acid, or no acid at all, is added to the reaction mixture of compounds of the formula III after addition of the metal alcoholate, and the mixture is reacted further, enol ethers of the formula Ib and enols thereof can be obtained. In this variant of the method, the radical R2 is retained. The enol ethers of the formula Ib can likewise be converted into compounds of the formula I and enols thereof in poor yields after addition of strong acids and under strongly acidic conditions with elimination of the radical R2. Strong acids mean in the method of the invention for example HCl, HBr, HI, H2SO4, trifluoroacetic acid or solid acids such as, for example, acidic zeolites such as H-ZSM-5 or acidic sheet silicates. Weak acids mean in the method of the invention for example acetic acid and dilute aqueous HCl, H3PO4 or H3SO4 acids or addition of strong acids after previous addition of water. In a preferred embodiment, compounds of the formula III are converted into compounds of the formula I in which X is fluorine and R1 is C1-8-alkyl, with elimination of the radical R2. In a further preferred embodiment, R1 is C1-4-alkyl. In a particularly preferred embodiment, R1 is methyl. Compounds of the formula I in the method of the invention also means the corresponding enols such as, for example, of the formulae singly or as mixture, and are also encompassed by the invention. The equilibrium distribution of compounds of the formula Ia to the enol forms thereof (as E and Z isomers) is influenced by various influences such as, for example, the solvent, the temperature or optionally by protonating or deprotonating additions. After kugelrohr distillation, for example, compound Ia with X=fluorine and R1=methyl without solvent is predominantly in the form of the monoenol of the formula Ia′ at room temperature. The enols of compounds of the formula I differ from one another by the enolized carbonyl group and the location and orientation of the resulting double bond(s). The carbonyl groups at C3 and/or C5 may be enolized. It is possible in this connection for there to be a double bond in each case between carbon atoms C2/C3, C3/C4, C4/C5 or conjugated double bonds between C2/C3 and C4/C5, and the double bonds may additionally be in the E or Z configuration. The enols are usually in the form of mixtures of a plurality of forms. The invention likewise encompasses compounds of the formula in which X is in each case independently of one another F, Cl or Br, and in which R2 is alkyl, cycloalkyl, allyl or benzyl. Likewise encompassed by the invention are enol ethers of the formula and enols thereof, such as, for example in which X is in each case independently of one another F, Cl or Br, and in which R1 is alkyl, cycloalkyl, aryl or aralkyl, and in which R2 is alkyl, cycloalkyl, allyl or benzyl. The compounds of the formula Ib may, just like the compounds of the formula I described above, be in the form of E and/or Z isomers. Depending on the external conditions, however, only the carbonyl group at C5 may be enolized. The number and location of the resulting double bonds at C2/C3 and/or C4/C5 correspond to the E and Z isomers of the enols of the compounds of the formula I. Alkyl 3,3,3-trihalo-3,5-dioxohexanoates can be prepared by the method described above from 4-methoxy-6-trihalomethylpyran-2-ones. Preferably, methyl 6,6,6-trifluoro-3,5-dioxo-hexanoate is prepared from 4-methoxy-6-trifluoromethylpyran-2-one. EXAMPLES The following examples illustrate the procedure for the method of the invention without this being regarded as a restriction. Example 1 4-Methoxy-6-trifluoromethylpyran-2-one (III; R2=methyl, X=fluorine) Sodium carbonate (1.35 g, 13 mmol) and dimethyl sulfate (2.17 g, 17 mmol) were added to a solution of 4-hydroxy-6-trifluoromethylpyran-2-one (3.0 g, 17 mmol) in acetone (50 mL). The mixture was heated under reflux for 3 hours and, after cooling, filtered. Concentration of the filtrate resulted in 2.9 g of crude product as a brown oil. It was possible to obtain 4-methoxy-6-trifluoromethylpyran-2-one (2.74 g, 14 mmol, 83%) as colorless needles with a melting point of 61° C. by crystallization from hexane. 1H NMR (400 MHz, DMSO-d6) δ: 7.01 (d, J=1.6 Hz, 1H), 5.98 (d, J=1.6 Hz, 1H), 3.7 (s, 3H). Example 2 Methyl 6,6,6-trifluoro-2-methoxy-5-oxo-2-hexenoate (Ib; R1═R2=methyl, X=fluorine) and the enols and E and Z isomers thereof A solution of 4-methoxy-6-trifluoromethylpyran-2-one (2.7 g, 14 mmol) in a methanolic magnesium methanolate solution (8.5% Mg(OMe)2, 8.36 g, 8 mmol) was heated under reflux for 16 hours. The solution was concentrated and taken up in water and ethyl acetate, and the organic phase was brought to pH 5 by adding dilute hydrochloric acid. The organic phase was separated off, dried and concentrated. 1.5 g of crude product were obtained as a yellow oil. Kugelrohr distillation at 0.04 mbar and about 160° C. afforded methyl 6,6,6-trifluoro-3-methoxy-5-oxo-2-hexenoate (1.50 g, 6.6 mmol, 48%) as a pale yellow oil. Data for the main compound: 1H NMR (400 MHz, DMSO-d6) δ (resonance lines of the enol form Ib, without E/Z determination): 6.05 (s, 1H), 3.9 (s, 3H), 3.82 (s, 2H), 3.62 (s, 3H). 19F-NMR (386 MHz, DMSO-d6) δ: −76.8. MS: 227 [M+H]+. Example 3 Methyl 6,6,6-trifluoro-3,5-dioxohexanoate (I; R1=methyl, X=fluorine) and the enols and E and Z isomers thereof A solution of 4-methoxy-6-trifluoromethylpyran-2-one (10 g, 52 mmol) in a methanolic magnesium methanolate solution (8.5% Mg(OMe)2, 62.8 g, 61 mmol) was heated under reflux for 2 hours. Concentrated aqueous HCl (25.5 g, 250 mmol) was added to the reaction solution, and the mixture was heated under reflux for a further 2 hours, then cooled and concentrated in vacuo to about 20% of the initial volume. The residue was mixed with 10 mL each of methylene chloride and water. The organic phase was separated off, washed with water, dried over sodium sulfate and concentrated. Kugelrohr distillation at 0.04 mbar and about 160° C. afforded methyl 6,6,6-trifluoro-3,5-dioxohexanoate (2.8 g, 13 mmol, 26%) as a pale yellow oil. Data for the main compound: 1H NMR (400 MHz, DMSO-d6) δ (resonance lines of the enol form Ia′, without E/Z determination): 6.0 (br, 2H), 3.8 (s, 2H), 3.65 (s, 3H). 13C-NMR (100 MHz, DMSO-d6) δ (resonance lines of the enol form Ia′, without E/Z determination): 181.6 (s), 167.7 (s), 116.9 (q, 1JC—F 286 Hz), 95.9 (t), 52.0 (q), 49.7 (t), C-3 not identifiable. MS: 212 (M+).

20060621

20080401

20070412

64691.0

C07C6966

SAWYER, JENNIFER C

METHOD FOR THE PRODUCTION OF 6,6,6-TRIHALO-3,5-DIOXOHEXANOIC ACID ESTERS

UNDISCOUNTED

ACCEPTED

C07C

ACCEPTED

Substrate cleaning method, substrate cleaning apparatus and computer readable recording medium

After a rinse process on a wafer W is performed by feeding pure water to the surface of the wafer W at a predetermined flow rate while rotating the wafer W in an approximately horizontal state, a feed amount of the pure water to the wafer W is reduced, and a pure-water feed point is moved outward from the center of the wafer W. In this manner, the wafer W is subjected to a spin dry process while forming a liquid film in a substantially outer region of the pure-water feed point.

1. A substrate cleaning method which comprising: performing a rinse process on a substrate to be processed with pure water supplied to a surface thereof while rotating the substrate in a substantially horizontal state; and thereafter performing a spin dry process on the substrate while forming a liquid film in a substantially outer region of a pure-water feed point to the substrate by making a feed amount of the pure water to the substrate smaller than that at a time of the rinse process and moving said pure-water feed point to the substrate outward from a center of the substrate. 2. The substrate cleaning method according to claim 1, wherein in said spin dry process, a speed of moving the pure-water feed point to the substrate outward from the center of the substrate is made faster at an outer peripheral portion of the substrate than at the center portion thereof. 3. The substrate cleaning method according to claim 1, wherein in said spin dry process, when the pure-water feed point to the substrate reaches a position separated from the center of the substrate by a predetermined distance, movement of said pure-water feed point is temporarily stopped, and a nitrogen gas is sprayed to the center portion of the substrate, after which spraying of said nitrogen gas is stopped and said pure-water feed point is moved out of the substrate again. 4. The substrate cleaning method according to claim 3, wherein in said spin dry process, the pure-water feed point to the substrate is rapidly moved to a position separated from the center of the substrate by 10 to 15 mm, where movement of said pure-water feed point is temporarily stopped, and a nitrogen gas is sprayed to the center portion of the substrate for a predetermined time, after which spraying of said nitrogen gas is stopped and said pure-water feed point is moved out of the substrate again at a speed equal to or less than 3 mm/second. 5. The substrate cleaning method according to claim 1, wherein in said spin dry process, after the pure-water feed point to the substrate is shifted from the center of the substrate by a predetermined distance, a nitrogen gas is sprayed to the center portion of the substrate, after which a spray point of said nitrogen gas is moved, together with said pure-water feed point, outward from the center portion of the substrate while spraying the nitrogen gas to the substrate. 6. The substrate cleaning method according to claim 5, wherein in said spin dry process, only spraying of the nitrogen gas is stopped while moving the spray point of said nitrogen gas, together with said pure-water feed point, outward from the center portion of the substrate. 7. The substrate cleaning method according to claim 5, wherein a number of rotations of the substrate in said rinse process is set equal to or greater than 100 rpm and equal to or less than 1000 rpm, and a number of rotations of the substrate in said spin dry process is set equal to or greater than 800 rpm and equal to or less than 2500 rpm. 8. The substrate cleaning method according to claim 1, wherein a number of rotations of the substrate at a time of the spin dry process is set greater than a number of rotations of the substrate at a time of the rinse process. 9. The substrate cleaning method according to claim 8, wherein a number of rotations of the substrate in said rinse process is set equal to or greater than 100 rpm and equal to or less than 1000 rpm, and a number of rotations of the substrate in said spin dry process is set equal to or greater than 1500 rpm and equal to or less than 2500 rpm. 10. The substrate cleaning method according to claim 1, wherein a mixture of a hydrophobic surface and a hydrophilic surface exists on the surface of the substrate. 11. A substrate cleaning apparatus comprising: a spin chuck which holds and rotates a substrate to be processed in a substantially horizontal state; a pure-water supply mechanism having a pure-water supply nozzle which discharges pure water to a surface of the substrate held by said spin chuck, and a pure-water supply section which supplies the pure water to said pure-water supply nozzle; a pure-water nozzle scan mechanism which causes said pure-water supply nozzle to scan between above a center of the substrate and above an outer edge thereof; and a control section which controls said spin chuck, said pure-water supply mechanism and said pure-water nozzle scan mechanism in such a way as to perform a rinse process of feeding the pure water to a surface of the substrate at a predetermined flow rate while rotating the substrate held by said spin chuck, and then perform a spin dry process on the substrate while forming a liquid film in a substantially outer region of a pure-water feed point to the substrate by making a feed amount of the pure water to the substrate smaller than that at a time of the rinse process and moving said pure-water feed point to the substrate outward from a center of the substrate. 12. The substrate cleaning apparatus according to claim 11, wherein in said spin dry process, said control section makes a speed of moving the pure-water feed point outward from the center of the substrate faster at an outer peripheral portion of the substrate than at the center portion thereof. 13. The substrate cleaning apparatus according to claim 11, further comprising a gas supply mechanism having a gas nozzle which sprays a nitrogen gas to a center portion of the surface of the substrate held by said spin chuck, and wherein said control section further controls said gas supply mechanism in such a way that in said spin dry process, when the pure-water feed point to the substrate reaches a position separated from the center of the substrate by a predetermined distance, movement of said pure-water feed point is temporarily stopped, and a nitrogen gas is sprayed to the center portion of the substrate, then said pure-water feed point is moved out of the substrate again after spraying of said nitrogen gas is stopped. 14. The substrate cleaning apparatus according to claim 13, wherein, said control section, in said spin dry process, rapidly moves the pure-water feed point to the substrate to a position separated from the center of the substrate by 10 to 15 mm, stops movement of said pure-water feed point there, subsequently sprays a nitrogen gas to the center portion of the substrate for a predetermined time, and then stops spraying said nitrogen gas and moves said pure-water feed point out of the substrate again at a speed equal to or less than 3 mm/second. 15. The substrate cleaning apparatus according to claim 11, further comprising a gas supply mechanism having a gas nozzle which sprays a nitrogen gas to the surface of the substrate held by said spin chuck, and a gas nozzle scan mechanism which causes said gas nozzle to scan on the target substrate, and wherein said control section further controls said gas supply mechanism and said gas nozzle scan mechanism in such a way that in said spin dry process, after the pure-water feed point to the substrate is shifted from the center of the substrate by a predetermined distance, a nitrogen gas is sprayed to the center portion of the substrate, then a spray point of said nitrogen gas is moved, together with said pure-water feed point, outward from the center portion of the substrate while spraying the nitrogen gas to the substrate. 16. The substrate cleaning apparatus according to claim 15, wherein, said control section, in said spin dry process, stops only spraying of the nitrogen gas while moving the spray point of said nitrogen gas, together with said pure-water feed point, outward from the center portion of the substrate. 17. The substrate cleaning apparatus according to claim 11, further comprising a gas supply mechanism having a gas nozzle which sprays a nitrogen gas to the surface of the substrate held by said spin chuck, and wherein said gas nozzle is held apart from said pure-water supply nozzle by a given space by said pure-water nozzle scan mechanism, and said control section further controls said gas supply mechanism in such a way that in said spin dry process, after the pure-water feed point to the substrate is shifted from the center of the substrate by a predetermined distance, a nitrogen gas is sprayed to the center portion of the substrate, then a spray point of said nitrogen gas and said pure-water feed point are simultaneously moved outward from the center portion of the substrate while spraying the nitrogen gas to the substrate. 18. The substrate cleaning apparatus according to claim 15, wherein said control section sets a number of rotations of the substrate in said rinse process equal to or greater than 100 rpm and equal to or less than 1000 rpm, and sets a number of rotations of the substrate in said spin dry process equal to or greater than 800 rpm and equal to or less than 2500 rpm. 19. The substrate cleaning apparatus according to claim 11, wherein said control section sets a number of rotations of the substrate at a time of the spin dry process greater than a number of rotations of the substrate at a time of the rinse process. 20. The substrate cleaning apparatus according to claim 19, wherein said control section sets a number of rotations of the substrate in said rinse process equal to or greater than 100 rpm and equal to or less than 1000 rpm, and sets a number of rotations of the substrate in said spin dry process equal to or greater than 1500 rpm and equal to or less than 2500 rpm. 21. A computer readable recording medium having recorded a program for allowing a computer that controls a substrate cleaning apparatus, which performs a rinse process by supplying pure water to a substrate to be processed while rotating the substrate held in an approximately horizontal state, to execute a process of (a) performing a rinse process of feeding the pure water to a surface of the substrate at a predetermined flow rate while rotating the substrate held by said spin chuck, and (b) performing spin dry on the substrate while forming a liquid film in a substantially outer region of a pure-water feed point to the substrate by making a feed amount of the pure water to the substrate smaller than that at a time of said rinse process and moving said pure-water feed point to the substrate outward from a center of the substrate. 22. The computer readable recording medium according to claim 21, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that a speed of moving the pure-water feed point to the substrate outward from the center of the substrate is made faster at an outer peripheral portion of the substrate than at the center portion thereof. 23. A computer readable recording medium having recorded a program for allowing a computer that controls a substrate cleaning apparatus, which performs a rinse process by supplying pure water to a substrate to be processed while rotating the substrate held in an approximately horizontal state, and further performs spin dry by feeding a nitrogen gas to the substrate, to execute a process of (a) performing a rinse process of feeding the pure water to a surface of the substrate at a predetermined flow rate while rotating the target substrate held by said spin chuck, (b) making a feed amount of the pure water to the substrate smaller than that at a time of said rinse process and moving a pure-water feed point to the substrate outward from a center of the substrate, (c) when the pure-water feed point to the substrate reaches a position separated from the center of the substrate by a predetermined distance, temporarily stopping movement of said pure-water feed point, and spraying a nitrogen gas to the center portion of the substrate, and (d) after spraying of said nitrogen gas is stopped, said pure-water feed point is moved out of the substrate again, thereby performing spin dry on the substrate while forming a liquid film in a substantially outer region of said pure-water feed point. 24. The computer readable recording medium according to claim 23, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that in said process (b), the pure-water feed point to the substrate is rapidly moved outward from the center of the substrate, in said process (c), movement of the pure-water feed point is stopped at a position separated from the center of the substrate by 10 to 15 mm, and a nitrogen gas is sprayed to the center portion of the substrate for a predetermined time, and in said process (d), after spraying of said nitrogen gas is stopped, the pure-water feed point is moved out of the substrate again at a speed equal to or less than 3 mm/second. 25. A computer readable recording medium having recorded a program for allowing a computer that controls a substrate cleaning apparatus, which performs a rinse process by supplying pure water to a substrate to be processed while rotating the target substrate held in a substantially horizontal state, and further performs spin dry by feeding a nitrogen gas to the substrate, to execute a process of (a) performing a rinse process of feeding the pure water to a surface of the substrate at a predetermined flow rate while rotating the substrate held by said spin chuck, (b) making a feed amount of the pure water to the substrate smaller than that at a time of said rinse process and moving a pure-water feed point to the substrate outward from a center of the substrate, (c) when the pure-water feed point to the substrate reaches a position separated from the center of the substrate by a predetermined distance, temporarily stopping movement of said pure-water feed point, and spraying a nitrogen gas to the center portion of the substrate, and (d) a spray point of said nitrogen gas is moved, together with said pure-water feed point, outward from the center portion of the substrate while spraying the nitrogen gas to the substrate. 26. The computer readable recording medium according to claim 25, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that in said process (d), only spraying of the nitrogen gas is stopped while moving the spray point of said nitrogen gas outward from the center portion of the substrate. 27. The computer readable recording medium according to claim 25, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that a number of rotations of the substrate in said process (a) is set equal to or greater than 100 rpm and equal to or less than 1000 rpm, and a number of rotations of the substrate in said processes (b) to (d) is set equal to or greater than 800 rpm and equal to or less than 2500 rpm. 28. The computer readable recording medium according to claim 21, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that a number of rotations of the substrate in and following said process (b) is set greater than a number of rotations of the substrate in said process (a). 29. The computer readable recording medium according to claim 28, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that a number of rotations of the substrate in said process (a) is set equal to or greater than 100 rpm and equal to or less than 1000 rpm, and a number of rotations of the substrate in and following said process (b) is set equal to or greater than 1500 rpm and equal to or less than 2500 rpm. 30. The computer readable recording medium according to claim 23, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that a number of rotations of the substrate in and following said process (b) is set greater than a number of rotations of the substrate in said process (a). 31. The computer readable recording medium according to claim 30, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that a number of rotations of the substrate in said process (a) is set equal to or greater than 100 rpm and equal to or less than 1000 rpm, and a number of rotations of the substrate in and following said process (b) is set equal to or greater than 1500 rpm and equal to or less than 2500 rpm. 32. The computer readable recording medium according to claim 25, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that a number of rotations of the substrate in and following said process (b) is set greater than a number of rotations of the substrate in said process (a). 33. The computer readable recording medium according to claim 32, wherein said program causes said computer to control said substrate cleaning apparatus in such a way that a number of rotations of the substrate in said process (a) is set equal to or greater than 100 rpm and equal to or less than 1000 rpm, and a number of rotations of the substrate in and following said process (b) is set equal to or greater than 1500 rpm and equal to or less than 2500 rpm.

TECHNICAL FIELD The present invention relates to a substrate cleaning method capable of suppressing generation of water marks on the surface of a substrate to be processed, such as a semiconductor wafer or a glass substrate for FPD (Flat Panel Display), a substrate cleaning apparatus and a computer readable recording medium for executing the substrate cleaning method. BACKGROUND ART In a semiconductor device fabrication process, for example, as the surface of a semiconductor wafer should always be kept clean, a cleaning process is performed on the semiconductor wafer approximately. As a typical example of a single wafer type cleaning process of processing semiconductor wafers one by one, a process method is known which feeds a predetermined cleaning liquid to a semiconductor wafer held by a spin chuck (chemical liquid cleaning process), then feeds pure water to the semiconductor wafer to rinse the cleaning liquid (rinse process), and further rotates the semiconductor wafer at a high speed to spin the pure water off the semiconductor wafer (spin dry process). Such a process method has a problem such that water marks is generated on the surface of a semiconductor wafer by adhesion of a mist of pure water, which is generated at the time of spin dry, to the dry surface of the semiconductor wafer, or the like. As a cleaning method which suppresses generation of such water marks, Unexamined Japanese Patent Application Publication No. H4-287922 discloses a substrate processing method which comprises a cleaning process step of feeding a predetermined cleaning liquid to the surface of a substrate to be processed from obliquely above, a rinse process step of then feeding pure water to the surface of the substrate from obliquely above, and a dry process step of then rotating the substrate at a high speed to spin the liquid off, and overlaps the end period of the rinse process step and the start period each other, whereby a nitrogen gas is supplied to the center portion of the substrate in the overlap step and the dry process step. Unexamined Japanese Patent Application Publication No. 2001-53051 discloses a substrate dry method which sprays an inactive gas to the center portion of a substrate after a rinse process, sprays pure water to the outer peripheral portion of the substrate, and moves the spray position of the inactive gas and the spray position of the pure water outward from the substrate in the radial direction. As the semiconductor device fabrication process progresses, however, a pattern having a mixture of a hydrophilic surface (e.g., an SiO2 surface formed by a predetermined method) and a hydrophobic surface (e.g., a bare Si surface) is formed on the surface of the semiconductor wafer. Because the hydrophilic surface and the hydrophobic surface differ from each other in the water spin-off speed at the time of the spin dry process, the aforementioned conventional spin dry method has a difficulty in avoiding generation of water marks. DISCLOSURE OF INVENTION The present invention has been made in view of the above situations, and aims at providing a substrate cleaning method capable of suppressing generation of water marks. It is an object of the present invention to provide a substrate cleaning apparatus and a computer readable recording medium for executing the substrate cleaning method. According to the first aspect of the invention, there is provided a substrate cleaning method comprising: performing a rinse process on a substrate to be processed with pure water supplied to a surface thereof while rotating the substrate in a substantially horizontal state; and thereafter performing a spin dry process on the substrate while forming a liquid film in a substantially outer region of a pure-water feed point to the substrate by making a feed amount of the pure water to the substrate smaller than that at a time of the rinse process and moving the pure-water feed point to the substrate outward from a center of the substrate. It is preferable that in such a substrate cleaning method, a speed of moving the pure-water feed point to the substrate outward from the center of the substrate should be made faster at an outer peripheral portion of the substrate than at the center portion thereof. Because it is difficult for centrifugal force to substantially act on pure water at the center portion of the substrate and drying is difficult as it is, favorably used is a method such that when the pure-water feed point to the substrate reaches a position separated from the center of the substrate by a predetermined distance, movement of the pure-water feed point is temporarily stopped, and a nitrogen gas is sprayed to the center portion of the substrate, after which spraying of the nitrogen gas is stopped and the pure-water feed point is moved out of the substrate again. Further, it is a preferable method that the pure-water feed point to the substrate is rapidly moved to a position separated from the center of the substrate by 10 to 15 mm, where movement of the pure-water feed point is temporarily stopped, and a nitrogen gas is sprayed to the center portion of the substrate for a predetermined time, after which spraying of the nitrogen gas is stopped and the pure-water feed point is moved out of the substrate again at a speed equal to or less than 3 mm/second. Furthermore, it is possible to take a method such that after the pure-water feed point to the substrate is shifted from the center of the substrate by a predetermined distance, a nitrogen gas is sprayed to the center portion of the substrate, then a spray point of the nitrogen gas is moved, together with the pure-water feed point, outward from the center portion of the substrate while spraying the nitrogen gas to the substrate. In addition, as substantial centrifugal force acts on pure water at an outer portion of the substrate, it is also preferable that after the pure-water feed point to the substrate is shifted from the center of the substrate by a predetermined distance, a nitrogen gas should be sprayed to the center portion of the substrate, after which while spraying the nitrogen gas to the substrate, a spray point of the nitrogen gas should be moved, together with the pure-water feed point, outward from the center portion of the substrate, during which only spraying of the nitrogen gas should be stopped. It is preferable that a number of rotations of the substrate in the rinse process should be set equal to or greater than 100 rpm and equal to or less than 1000 rpm. When, in the spin dry process, a nitrogen gas is sprayed to the center portion of the substrate, and a spray point of the nitrogen gas is moved, together with the pure-water feed point, outward of the substrate, a number of rotations of the substrate has only to be set equal to or greater than 800 rpm. It is preferable that the number of rotations of the substrate in the spin dry process should be equal to or less than 2500 rpm from the view point of preventing generation of particles or water marks originating from misting or pure water splashed from the substrate, or the like. When no nitrogen gas is fed to the substrate at the time of spin dry, by way of contrast, it is preferable that a number of rotations of the substrate at a time of the spin dry process should be set greater than a number of rotations of the substrate at a time of the rinse process. Specifically, it is preferable that a number of rotations of the substrate should be set equal to or greater than 100 rpm and equal to or less than 1000 rpm in the rinse process, and a number of rotations of the substrate should be set equal to or greater than 1500 rpm and equal to or less than 2500 rpm in the spin dry process. While the substrate cleaning method of the invention is used suitably when a mixture of a hydrophobic surface and a hydrophilic surface exists on the surface of the substrate, it of course can also be used when the surface of the substrate is only a hydrophobic surface or only a hydrophilic surface. The invention provides a substrate cleaning apparatus for executing the substrate cleaning method. That is, according to the second aspect of the invention, there is provided a substrate cleaning apparatus comprising: a spin chuck which holds and rotates a substrate to be processed in an approximately horizontal state; a pure-water supply mechanism having a pure-water supply nozzle which discharges pure water to a surface of the substrate held by the spin chuck, and a pure-water supply section which supplies the pure water to the pure-water supply nozzle; a pure-water nozzle scan mechanism which causes the pure-water supply nozzle to scan between above a center of the substrate and above an outer edge thereof; and a control section which controls the spin chuck, the pure-water supply mechanism and the pure-water nozzle scan mechanism in such a way as to perform a rinse process of feeding the pure water to a surface of the substrate at a predetermined flow rate while rotating the substrate held by the spin chuck, and then perform a spin dry process on the substrate while forming a liquid film in a substantially outer region of a pure-water feed point to the substrate by making a feed amount of the pure water to the substrate smaller than that at a time of the rinse process and moving the pure-water feed point to the substrate outward from a center of the substrate. To perform the spin dry using a nitrogen gas, it is preferable that the substrate cleaning apparatus should further comprise a gas supply mechanism having a gas nozzle which sprays a nitrogen gas to a center portion of the surface of the substrate held by the spin chuck. It is preferable that the gas supply mechanism should be so constructed as to be controlled by the control section from the view point of smoothly processing the substrate. It is preferable that the substrate cleaning apparatus should take such a structure as to further comprise a gas supply mechanism having a gas nozzle which sprays a nitrogen gas to the surface of the substrate held by the spin chuck, and a gas nozzle scan mechanism which causes the gas nozzle to scan on the substrate. Even in this case, as the gas supply mechanism and the gas nozzle scan mechanism take such structures as to be controlled by the control section, it is possible to smoothly process the substrate. The invention provides a computer readable recording medium having recorded a program which allows a computer that controls such a substrate cleaning apparatus to execute the substrate cleaning method. That is, according to the third aspect of the invention, there is provided a computer readable recording medium having recorded a program for allowing a computer that controls a substrate cleaning apparatus, which performs a rinse process by supplying pure water to a substrate to be processed while rotating the substrate held in an approximately horizontal state, to execute a process of (a) performing a rinse process of feeding the pure water to a surface of the substrate at a predetermined flow rate while rotating the substrate held by the spin chuck, and (b) performing spin dry on the substrate while forming a liquid film in a substantially outer region of a pure-water feed point to the substrate by making a feed amount of the pure water to the substrate smaller than that at a time of the rinse process and moving the pure-water feed point to the substrate outward from a center of the substrate. According to the fourth aspect of the invention, there is provided another recording medium according to the structure of the substrate cleaning apparatus, i.e., a computer readable recording medium having recorded a program for allowing a computer that controls a substrate cleaning apparatus, which performs a rinse process by supplying pure water to a substrate to be processed while rotating the substrate held in an approximately horizontal state, and further performs spin dry by feeding a nitrogen gas to the substrate, to execute a process of (a) performing a rinse process of feeding the pure water to a surface of the substrate at a predetermined flow rate while rotating the substrate held by the spin chuck, (b) making a feed amount of the pure water to the substrate smaller than that at a time of the rinse process and moving a pure-water feed point to the substrate outward from a center of the substrate, (c) when the pure-water feed point to the substrate reaches a position separated from the center of the substrate by a predetermined distance, temporarily stopping movement of the pure-water feed point, and spraying a nitrogen gas to the center portion of the substrate, and (d) after spraying of the nitrogen gas is stopped, the pure-water feed point is moved out of the substrate again, thereby performing spin dry on the substrate while forming a liquid film in a substantially outer region of the pure-water feed point. According to the fifth aspect of the invention, there is provided a still another recording medium according to the structure of the substrate cleaning apparatus, i.e., a computer readable recording medium having recorded a program for allowing a computer that controls a substrate cleaning apparatus, which performs a rinse process by supplying pure water to a substrate to be processed while rotating the substrate held in an approximately horizontal state, and further performs spin dry by feeding a nitrogen gas to the substrate, to execute a process of (a) performing a rinse process of feeding the pure water to a surface of the substrate at a predetermined flow rate while rotating the substrate held by the spin chuck, (b) making a feed amount of the pure water to the substrate smaller than that at a time of the rinse process and moving a pure-water feed point to the substrate outward from a center of the substrate, (c) when the pure-water feed point to the substrate reaches a position separated from the center of the substrate by a predetermined distance, temporarily stopping movement of the pure-water feed point, and spraying a nitrogen gas to the center portion of the substrate, and (d) a spray point of the nitrogen gas is moved, together with the pure-water feed point, outward from the center portion of the substrate while spraying the nitrogen gas to the substrate. According to the invention, even when a mixture a hydrophobic surface and a hydrophilic surface exists, it is possible to make the difference between the dry time for the hydrophobic surface and the dry time for the hydrophilic surface smaller, so that a high precision substrate cleaning process which suppresses generation of water marks can be executed. The invention is of course effective even when the surface of the substrate is comprised of only a hydrophobic surface, or comprised of only a hydrophilic surface. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a vertical cross-sectional view showing the schematic structure of a substrate cleaning apparatus. FIG. 2 is a plan view showing the schematic structure of the substrate cleaning apparatus. FIG. 3 is a diagram showing a schematic control system of the substrate cleaning apparatus. FIG. 4 is a flowchart illustrating a cleaning method. FIG. 5 is a diagram exemplarily illustrating the dry process for a wafer according to a conventional spin dry method. FIG. 6 is another diagram exemplarily illustrating the dry process for a wafer according to a conventional spin dry method. FIG. 7 is a still another diagram exemplarily illustrating the dry process for a wafer according to a conventional spin dry method. FIG. 8 is a diagram exemplarily illustrating the dry process for a wafer by spin dry in a cleaning method according to the present invention. FIG. 9 is a plan view showing the schematic structure of another substrate cleaning apparatus. FIG. 10 is a flowchart illustrating another cleaning method. FIG. 11 is a plan view showing the schematic structure of a still another substrate cleaning apparatus. BEST MODE FOR CARRYING OUT THE INVENTION An embodiment of the present invention will be described below with reference to the accompanying drawings. FIG. 1 presents a vertical cross-sectional view showing the schematic structure of a substrate cleaning apparatus 10 which cleans a semiconductor wafer, and FIG. 2 presents a plan view thereof. The essential portions of the substrate cleaning apparatus 10 are provided in a casing 50. FIG. 1 and FIG. 2 show only a part of the casing 50. A ring-shaped cup CP is disposed in approximately the center of the casing 50, and a spin chuck 51 is placed inside the cup CP. A chuck which vacuum-chucks and holds a wafer W, or a so-called mechanical chuck type, such as one which mechanically holds the end faces of the wafer W, is preferably used as the spin chuck 51, which is rotated while holding the wafer W by a drive motor 52. A drain 53 for discharging a cleaning liquid and pure water is provided in the bottom of the cup CP, and a feed window 56 through which a wafer is transferred from outside and is transferred to the outside is formed in the vertical wall of the casing 50 of the substrate cleaning apparatus 10. A process liquid nozzle 61 which feeds the cleaning liquid and pure water to the surface of the wafer W is structured in a substantially cylindrical shape, and is held, with its lengthwise direction set approximately vertically, by a nozzle holding member 63. The cleaning liquid or pure water is selectively fed to the process liquid nozzle 61 from a cleaning-liquid supply section 64 and a pure-water supply section 65 which is structured in such a way as to be able to change the flow rate by adjustment of the opening and closing of a valve. That is, the process liquid nozzle 61 functions as a nozzle to feed the cleaning liquid to the wafer W and a nozzle to feed the pure water to the wafer W. A so-called straight nozzle is preferably used as the process liquid nozzle 61. The nozzle holding member 63 is attached to the distal end portion of a scan arm 67. The scan arm 67 is mounted to the upper end portion of a vertical support member 69 placed on a guide rail 68 laid on the bottom plate of the casing 50 in one direction (Y direction). The vertical support member 69 can be moved horizontally by a Y-axis drive mechanism 77, and has a Z-axis drive mechanism 78 for lifting the scan arm 67 up and down. Therefore, the process liquid nozzle 61 is movable over the wafer W in the Y direction, and is retractable out of the cup CP over the upper end of the cup CP. An N2 nozzle 62 which sprays nitrogen gas (N2 gas) to the surface of the wafer W is also structured approximately cylindrically, and is placed, with its lengthwise direction set approximately vertically, above the center of the wafer W held by the spin chuck 51. The N2 nozzle 62 is liftable up and down by a lifting mechanism 79. An N2-gas supply section 66 feeds the N2 gas to the N2 nozzle 62. A cylindrical cover 54 is attached to the N2 nozzle 62 in such a way as to cover the distal end thereof. Of the cover 54 is not attached, the N2 gas sprayed from the N2 nozzle 62 would be concentrated on one point on the wafer W, scattering a mist of pure water on the wafer W upward. At this time, the mist's falling speed gets slower around the N2 gas sprayed from the N2 nozzle 62, raising a problem that the mist drops on dry portions of the wafer W to become particles. With the provision of the cover 54, however, that of the N2 gas sprayed from the N2 nozzle 62 which goes outward hits the cover 54, and downflows, so that the mist drops on a non-dried pure-water portion on the wafer W, and the pure-water portion will be removed later, thus suppressing generation of particles. When the outside diameter of the N2 nozzle 62 is 6 mmφ (the inside diameter; 4 mmφ), for example, it is preferable that the inside diameter of the cover 54 should be 10 mmφ to 20 mmφ. It is preferable to make the cover 54 and the N2 nozzle 62 independently liftable so that the distance between the distal end of the N2 nozzle 62 and the distal end of the cover 54 can be adjusted. Accordingly, the progress of drying of the wafer W can be controlled. FIG. 3 shows the structure of a schematic control system of the substrate cleaning apparatus 10. A control section (i.e., a computer) 11 for controlling the processing of the wafer W by the substrate cleaning apparatus 10 has a process controller (CPU) 12, a data input/output section 13 having a keyboard for a process operator to perform a command input operation or the like to determine the conditions or the like for the cleaning process for the wafer W, and a display or the like for displaying the results of arithmetic operations by the process controller (CPU) 12, the progress status of the cleaning process, and the like in a visible manner, and a memory section 14 where programs and recipes for controlling the substrate cleaning apparatus 10, data associated with executed processes, and so forth are recorded. Recorded in the memory section 14 are specifically, process programs 15 for allowing the process controller (CPU) 12 to execute the operation control of various drive mechanisms constituting the substrate cleaning apparatus 10 for performing a series of processes including a cleaning process with a cleaning liquid, a rinse process with pure water, and a spin dry process, which will be explained in detail later, and recipes 16 recorded with the time allocation in a series of processes, the feed amount of a cleaning liquid, pure water, or the N2 gas, the scan speed of the scan arm 67, and the like. Those process programs 15 and recipes 16 are recorded in various memory media, for example, a fixed storage medium, such as a hard disk (HD) or a memory (RAM or the like), and a portable type, such as a CD-ROM (or CD-R or the like), DVD-ROM (or DVD-R or the like) or MO disk, and are recorded in such a manner as to be readable by the process controller (CPU) 12. The memory section 14 can record data about processes executed by the substrate cleaning apparatus 10, e.g., data 17 on the lot number for wafers W, a process recipe used, a process date, whether or not there is an operational failure in various mechanisms in process, and the like. Such data 17 can be coped or transferred to various kinds of portable memory media, such as a CD-R and MO disk. According to the process program 15 and the recipe 16, the process controller (CPU) 12 sends various mechanisms or the like various controls signals on the chuck/unchuck of a wafer W by the spin chuck 51, the control of the number of rotations of the motor 52, the scan operation of the Y-axis drive mechanism 77, the lift operation of the Z-axis drive mechanism 78, the start and stop of the supply of pure water and the control of the flow rate of pure water from the pure-water supply section 65, the start and stop of the supply of the N2 gas from the N2-gas supply section 66, and so forth. Also preferable is the configuration that carries out bidirectional communications to feed data indicative of execution of the operations of various mechanisms constituting the substrate cleaning apparatus 10 back to the process controller (CPU) 12 from the mechanisms. FIG. 3 shows only the main mechanisms or the like, not all the mechanisms, that are controlled by the process controller (CPU) 12. Next, a substrate cleaning method for wafers W by the substrate cleaning apparatus 10 configured as mentioned above will be described. FIG. 4 shows a flowchart for cleaning steps to be described below. First, the wafer W is held substantially horizontal by the spin chuck 51, and the height of the wafer W is adjusted (step 1). The process liquid nozzle 61 is positioned above the center of the wafer W, a predetermined amount of cleaning liquid is fed to the surface of the wafer W while rotating the wafer W at a predetermined number of rotations, and the wafer W is processed for a predetermined time (step 2). In the process at step 2, the cleaning liquid may be fed to the surface of the wafer W set in a stationary state, forming puddles, and after a predetermined time elapses, the cleaning liquid may be further fed to the surface of the wafer W while rotating the wafer W. Next, while the wafer W is rotated by a predetermined number of rotations (e.g., 100 rpm to 1000 rpm), pure water is fed to near the center of the wafer W from the process liquid nozzle 61 at a predetermined flow rate (e.g., 1 L/minute) to rinse the wafer W (step 3). In the rinse process, the process liquid nozzle 61 may be scanned over the wafer W in the Y direction. At the end of such a rinse process, with the process liquid nozzle 61 set above the center of the wafer W, the feed amount of pure water to the wafer W (i.e., the amount of discharge of pure water from the process liquid nozzle 61) is reduced to, for example, 20 to 50 mL/minute (step 4), after which a pure-water feed point (i.e., the position of the process liquid nozzle 61) is moved outward from the center of the wafer W at a predetermined speed (step 5). The following is the reason why the feed amount of pure water to the wafer W is reduced at step 4. It is preferable that the feed amount of pure water to the wafer W should be increased at the time of the rinse process to improve the rinse efficiency. If the scanning of the process liquid nozzle 61 is initiated at the flow rate unchanged, however, the liquid film formed on the wafer W is thick, so that pure water spun off the wafer W rebounds at the cup CP, generating a lot of droplets or mist which would cause generation of particles or water marks. Accordingly, reducing the feed amount of pure water to provide a thin liquid film repress such rebounding, thereby suppressing generation of particles or water marks. This method can quicken drying. The spin dry step at steps 4 and 5 is terminated as the supply of pure water to the wafer W is stopped when the point of feeding pure water to the wafer W comes off the periphery of the wafer W. Thereafter, however, the wafer W may be rotated for a predetermined time. The wafer W whose spin dry process is finished is transferred from the spin chuck 51 to an apparatus which performs a next process (step 6). Next, a further detailed description will be given of the aforementioned spin dry step at steps 4 and 5. FIGS. 5 to 8 are diagrams illustrating the conventional spin dry methods and the spin dry method at steps 4 and 5 in comparison with one another. FIG. 5 is a diagram exemplarily illustrating the conventional spin dry process for a wafer W which has a hydrophilic SiO2 layer 21 formed on the entire surface. The left-hand figure of FIG. 5 shows pure water fed to the center of the wafer W and a puddle of pure water 22 on the surface of the wafer W. The right-hand figure of FIG. 5 shows the initial state where the supply of pure water to the wafer W is stopped and the wafer W is rotated by a predetermined number of rotations. When the entire surface of the wafer W is hydrophilic, the pure water 22 on the wafer W slowly moves outward of the wafer W so as to leave a thin liquid film (not shown) on the surface of the wafer W by the centrifugal force, so that the surface of the wafer W is slowly dried outward from the center. FIG. 6 is a diagram exemplarily illustrating the conventional spin dry process for a wafer W (bare wafer) which has a hydrophobic surface. The left-hand figure of FIG. 6 shows pure water fed to the center of the wafer W and a puddle of pure water 22 on the surface of the wafer W. The right-hand figure of FIG. 6 shows the initial state where the supply of pure water to the wafer W is stopped and the wafer W is rotated by a predetermined number of rotations. As pure water is shed on the hydrophobic surface, the pure water on the surface of the wafer W is spun off at a blast by the centrifugal force, so that the entire surface of the wafer W is dried instantaneously. That is, with the same number of rotations of the wafer W, the hydrophobic surface is dried faster than the hydrophilic surface. FIG. 7 is a diagram exemplarily illustrating the conventional spin dry process for a wafer W which has a mixture of a hydrophilic surface portion 23 and a hydrophobic surface 24. The left-hand figure of FIG. 7 shows pure water fed to the center of the wafer W and a puddle of pure water 22 on the surface of the wafer W. The right-hand figure of FIG. 7 shows the initial state where the supply of pure water to the wafer W is stopped and the wafer W is rotated by a predetermined number of rotations. As there is a difference in dry time between a hydrophilic surface and a hydrophobic surface provided that the number of rotations of the wafer W is the same, as mentioned above, the mixture of the hydrophilic surface portion 23 and the hydrophobic surface 24, if present on the wafer W, causes the hydrophobic surface 24 to be dried first, leaving the pure water on the hydrophilic surface portion 23. It seems that the pure water 22 remaining on the hydrophilic surface portion 23 this way adheres to the hydrophobic surface 24 dried when the pure water 22 moves outward due to the centrifugal force, thereby generating water marks. FIG. 8 is a diagram exemplarily illustrating the dry process for a wafer W which has a mixture of the hydrophilic surface portion 23 and the hydrophobic surface 24 according to the spin dry method at steps 4 and 5 described previously. The left-hand figure of FIG. 8 shows pure water fed to the center of the wafer W and a puddle of pure water 22 on the surface of the wafer W. The right-hand figure of FIG. 8 shows the state of the wafer W when feed amount of pure water to the wafer W is reduced and the pure-water feed point is moved outward of the wafer W from the center of the wafer W. As shown in the right-hand figure of FIG. 8, according to the invention the spin dry method at steps 4 and 5 a liquid film of the pure water 22 is formed at a substantially outer region of the pure-water feed point, and the area where the liquid film is formed becomes narrower as the position of the process liquid nozzle 61 moves outward of the wafer W. That is, the wafer W can be slowly dried outward from the center thereof. Even when there is a mixture of the hydrophilic surface portion 23 and the hydrophobic surface 24 on the surface of the wafer W, therefore, the difference in dry time between the hydrophilic surface portion 23 and the hydrophobic surface 24 becomes smaller, suppressing generation of water marks. According to the spin dry method at steps 4 and 5, it is preferable that the number of rotations of the wafer W at the time of the spin dry process should be set greater than the number of rotations of the wafer W at the time of the rinse process. For example, the number of rotations of the wafer W in the rinse process can be set equal to or greater than 100 rpm and equal to or less than 1000 rpm, in which case it is preferable that the number of rotations of the wafer W in the spin dry process should be set equal to or greater than 1500 rpm and equal to or less than 2500 rpm. This is because if the number of rotations of the wafer W is too slow, the dry times for the hydrophilic surface portion and the hydrophobic surface differ, bringing about a problem that water marks are likely to be generated, whereas if the number of rotations of the wafer W is too fast, a turbulence occurs around the wafer W and a mist of pure water scattered from the wafer W rides on the turbulence and readheres to the already-dried portion of the wafer W, thus making it easier to generate water marks. The speed of moving the pure-water feed point to the wafer W outward from the center of the wafer W, i.e., the scan speed of the process liquid nozzle 61, can be changed according to the number of rotations of the wafer W in order to avoid generation of water marks. Table 1 shows the results of checking the positions at which an interference fringe disappears at the inner portion of the liquid film formed on the wafer W when scanning the process liquid nozzle 61 outward from the center of the wafer W at a constant speed (1 to 4 mm/second) while rotating the wafer W of 300 mmφ at a constant number of rotations and while feeding pure water to the wafer W from the process liquid nozzle 61 at 50 mL/minute. TABLE 1 number of rotations (rpm) 1600 1800 2000 2200 2500 nozzle scan 1 40 mm 35 mm 30 mm 25 mm 20 mm speed 2 80 mm 70 mm 60 mm 50 mm 40 mm (mm/second) 3 NG※ NG 120 mm 100 mm 80 mm 4 NG NG NG NG NG ※NG: an interference fringe did not disappear while the process liquid nozzle was scanned up to the periphery of the wafer Table 1 shows that with the number of rotations of the wafer W being 1600 rpm, when the process liquid nozzle 61 was scanned outward from the center of the wafer W at 1 mm/second, an interference fringe disappeared at a point at which the process liquid nozzle 61 was separated by 40 mm from the center of the wafer W, after which generation of no interference fringe was noticed while the process liquid nozzle 61 was scanned up to the periphery of the wafer W. It is understood from Table 1 that when the process liquid nozzle 61 was scanned at 2 mm/second, an interference fringe disappeared at a point at which the process liquid nozzle 61 was separated by 80 mm from the center of the wafer W, after which generation of no interference fringe was noticed. When the process liquid nozzle 61 was scanned at 3 mm/second or 4 mm/second, by way of contrast, an interference fringe was always observed until the process liquid nozzle 61 reached the periphery of the wafer W. That is, it is understood that under this condition, an interference fringe did not disappear from the beginning to the end, and generation of water marks could not be suppressed. It is understood from Table 1 that with the scan speed of the process liquid nozzle 61 being constant, the position at which an interference fringe disappears comes closer to the center of the wafer W if the number of rotations of the wafer W is increased, whereas with the number of rotations of the wafer W being constant, the position at which an interference fringe disappears comes closer to the center of the wafer W if the scan speed of the process liquid nozzle 61 is slow. It is apparent from this that when the rotational speed of the wafer W is fast and when the scan speed of the process liquid nozzle 61 is slow, generation of an interference fringe can be suppressed. If the wafer W is entirely scanned with the scan speed of the process liquid nozzle 61 being, for example, 1 mm/second, however, the process time becomes long and the productivity drops. When the number of rotations of the wafer W is set constant, therefore, the process time can be shortened by making the scan speed of the process liquid nozzle 61 faster at the outer peripheral portion of the wafer W than at the center portion thereof. When the number of rotations of the wafer W (300 mmφ) is 2500 rpm, for example, the scan speed of the process liquid nozzle 61 can be set to 1 mm/second within the radius of 40 mm from the center of the wafer W, set to 2 mm/second from the radius of 40 mm to the radius of 80 mm, and set to 3 mm/second from the radius of 80 mm to the periphery (the radius: 150 mm). Instead of the method of slowing scanning the process liquid nozzle 61 outward from the center of the wafer W, a method of rapidly moving the process liquid nozzle 61 (e.g., 80 mm/second) to a position apart from the center of the wafer W by 10 to 15 mm, then quickly spraying an N2 gas from the N2 nozzle 62 to the center portion of the wafer W to accelerate drying at the center portion of the wafer W, and scanning the process liquid nozzle 61 from there to the periphery of the wafer W at a speed of 3 mm/second or less is suitably used for it can further suppress generation of water marks at the center portion of the wafer W. Although it is preferable that scanning of the process liquid nozzle 61 to the periphery of the wafer W should be started after spraying of the N2 gas to the center portion of the wafer W is finished, the scanning may be started while spraying of the N2 gas is being carried out. Next, another substrate cleaning apparatus which executes the substrate cleaning method according to the present invention will be described. FIG. 9 presents a plan view showing the schematic structure of a substrate cleaning apparatus 10′. The substrate cleaning apparatus 10′ has a structure such that a process liquid nozzle 61 which selectively feeds a chemical liquid and pure water to a wafer W, a pure water nozzle 61 which feeds pure water to the wafer W at the time of a spin dry process, and an N2 nozzle 62 which sprays an N2 gas to the wafer W are arranged on a nozzle holding member 63′ is attached to the distal end portion of a scan arm 67. Because the structure other than that around the nozzles is the same as that of the substrate cleaning apparatus 10 described previously, the explanation will be omitted. As described above, in the cleaning process for a wafer W by the substrate cleaning apparatus 10, at the transition from a rinse process to a spin dry process, the amount of pure water to be fed to the wafer W is reduced from 1 L/minute to 20 to 50 mL/minute, for example, the cleaning-liquid nozzle 61, if so structured as to be compatible with the large discharge amount of pure water at the time of the rinse process, may not be able to ensure stable supply of pure water due to the relationship between the piping diameter and the nozzle diameter when the discharge amount of pure water is reduced at the time of the spin dry process. To overcome such a problem, in the substrate cleaning apparatus 10′, it is possible to feed pure water to the wafer W from the process liquid nozzle 61 in a process using a cleaning liquid and the rinse process, and feed the pure water to the wafer W from the pure water nozzle 61a at the time of the spin dry process. In the nozzle holding member 63′, the process liquid nozzle 61 and the pure water nozzle 61a are arranged close to each other, and the pure water nozzle 61a and the N2 gas are held apart from each other by a given distance. FIG. 10 presents a flowchart illustrating a first cleaning method for a wafer W by the substrate cleaning apparatus 10′. This method is the process method that moves both the spray point of the N2 gas and the pure-water feed point outward from the center of the wafer W. That is, steps 11 to 13 which are the same processes as those at steps 1 to 3 which have been explained first referring to FIG. 4 are executed. Next, at the end of the rinse process at step 13, the supply of pure water to the wafer W from the pure water nozzle 61 (e.g., 20 to 50 mL/minute) is initiated while keeping feeding pure water to the center of the wafer W from the process liquid nozzle 61 (e.g., 1 L/minute) (step 14). Then, after the scan arm 67 is driven in the direction of +Y (see FIG. 9) in such a way that the pure water nozzle 61 is positioned above the center of the wafer W, the supply of the pure water to the wafer W from the process liquid nozzle 61 is stopped (step 15). Thereafter, the number of rotations of the wafer W is adjusted to be 800 rpm or greater (step 16). The reason why the number of rotations of the wafer W is reduced this way is because, at subsequent steps, the N2 nozzle 62 and the pure water nozzle 61 are both scanned over the wafer W while spraying the N2 gas to the wafer W from the N2 nozzle 62, thus making it possible to accelerate drying of the wafer W with the N2 gas. When the number of rotations of the wafer W is adjusted, the scan arm 67 is scanned at a predetermined speed in the direction of +Y (i.e., outward of the wafer W) while feeding the pure water from the pure water nozzle 61 (step 17). When the N2 nozzle 62 reaches above the center of the wafer W this way, driving of the scan arm 67 is temporarily stopped, and the N2 gas is sprayed to the center of the wafer W from the N2 nozzle 62, thereby accelerating uniform drying at the center portion of the wafer W (step 18). After the N2 gas is sprayed to the center of the wafer W for a predetermined time, the scan arm 67 is driven again in the direction of +Y to simultaneously scan the pure water nozzle 61 and the N2 nozzle 62 while spraying the N2 gas to the wafer W from the N2 nozzle 62 (step 19). Such a method can allow drying to gradually progress outward from the center of the wafer W while shortening the difference between the dry times of the hydrophilic surface and the hydrophobic surface, so that the entire surface of the wafer W can be dried eventually. Even with the use of the substrate cleaning apparatus 10′, a process method which does not spray the N2 gas to the wafer W from the N2 nozzle 62 at the time of scanning the N2 nozzle 62, in which case it is preferable that the number of rotations of the wafer W should be set equal to or greater than 1500 rpm. Generally, as pure water is fed to a rotating wafer W, the centrifugal force sufficiently acts on the fed pure water at an outer portion of the wafer W, so that drying progresses. Using this, in processing the wafer W using the substrate cleaning apparatus 10′, it is possible to employ a method of stopping spraying the N2 gas to the wafer W or a method of reducing the injection amount of the N2 gas when the N2 nozzle 62 approaches the outer peripheral portion of the wafer W. It is also possible to employ a process method which performs spraying of the N2 gas to the wafer W from the N2 nozzle 62 only to the center portion of the wafer W, as per the substrate cleaning apparatus 10. Further, it is possible to employ a process method which scans the scan arm 67 in the direction of +Y at a predetermined speed in such a way that the process liquid nozzle 61 moves outward from the center of the wafer W, and starts spraying the N2 gas to the wafer W when the N2 nozzle 62 reaches the center of the wafer W but does not stop driving the scan arm 67 then. In case of executing a process similar to the process method which is one of the previously explained spin dry methods, rapidly moves the process liquid nozzle 61 to a position separated from the center of the wafer W by 10 to 15 mm, then sprays the N2 gas to the center portion of the wafer W promptly, and scans the process liquid nozzle 61 to the periphery of the wafer W from there at a speed of 3 mm/second or less by using the substrate cleaning apparatus 10′, the N2 nozzle 62 can be made to reach the center of the wafer W at the same time as the pure water nozzle 61 is rapidly moved to a predetermined position if the distance between the pure water nozzle 61 and the N2 nozzle 62 is set to 10 to 15 mm beforehand. A still another substrate cleaning apparatus which executes the substrate cleaning method according to the invention will be described next. FIG. 11 presents a plan view showing the schematic structure of a substrate cleaning apparatus Ion. The substrate cleaning apparatus 10″ is the substrate cleaning apparatus 10′ modified to a structure which can allow the process liquid nozzle 61/the pure water nozzle 61a and the N2 nozzle 62 to independently scan between the center of a wafer W and the periphery thereof, and the structures of the other portions are the same as those of the substrate cleaning apparatus 10′. In the substrate cleaning apparatus 10″, the N2 nozzle 62 is mounted to a nozzle holding member 63″ provided at the distal end of a rotatable scan arm 67′. In the spin dry process for a wafer W, when the pure water nozzle 61 is scanned outward from the center of the wafer W, the N2 nozzle 62 always lies in a region within the circumference (indicating a circle about the rotational center of the wafer W) at which the pure water nozzle 61 is positioned, and as the pure water nozzle 61 moves outward of the wafer W, the N2 nozzle 62 is moved outward of the wafer W. The substrate cleaning apparatus 10″ may be modified to a structure which can allow the N2 nozzle 62 to linearly scan in the Y direction through the center of the wafer W, independently of the pure water nozzle 61. In that case, the N2 nozzle 62 may be scanned in such a way as to follow up the pure water nozzle 61, or may be scanned in the opposite direction to that of the pure water nozzle 61. Employing the structure that can independently scan the pure water nozzle 61 and the N2 nozzle 62 can provide a difference between the scan speeds of the pure water nozzle 61 and the N2 nozzle 62. Although the embodiments of the substrate cleaning method of the invention has been explained above, the invention is not limited to the embodiments. Although in the foregoing description the illustrated process liquid nozzle 61 takes such a structure as to be able to selectively feed the cleaning liquid and pure water to the wafer W, the substrate cleaning apparatus may separately have a nozzle which feeds only the cleaning liquid and a nozzle which feeds only the pure water. It is also preferable that, like the substrate cleaning apparatus 10′, the substrate cleaning apparatus 10 should be provided with a pure water nozzle which supplies pure water to the wafer W at the time of the spin dry in addition to the process liquid nozzle 61. In this case, the pure water nozzle may be provided at the nozzle holding member 63, or may be structured in such a way as to be drivable independently of the process liquid nozzle 61. Further, although the process liquid nozzle 61 illustrated has such a structure as to be movable in the direction of the Y axis, the process liquid nozzle, for example, may have a mechanism which rotates about a predetermined rotational axis drawing an arc between the center of the wafer W and the periphery. While the effect of the substrate cleaning method of the invention of suppressing generation of water marks is obtainable particularly remarkably when a mixture a hydrophobic surface and a hydrophilic surface exists on the surface of a substrate to be processed, the effect can of course be acquired too when the surface of the substrate is comprised only of a hydrophobic surface, or is comprised only of a hydrophilic surface. The substrate is not limited to a semiconductor wafer, but may be a glass substrate for FPD or a ceramic substrate or the like. The above-described embodiments are intended to clarify the technical contents of the invention, and the invention should not be interpreted as such limited specific examples only, but can be modified and worked out in various manners within the spirit of the invention and the described scope of the claims. INDUSTRIAL APPLICABILITY The substrate cleaning method of the invention is suitable for a fabrication method for a semiconductor device or an FDP apparatus.

<SOH> BACKGROUND ART <EOH>In a semiconductor device fabrication process, for example, as the surface of a semiconductor wafer should always be kept clean, a cleaning process is performed on the semiconductor wafer approximately. As a typical example of a single wafer type cleaning process of processing semiconductor wafers one by one, a process method is known which feeds a predetermined cleaning liquid to a semiconductor wafer held by a spin chuck (chemical liquid cleaning process), then feeds pure water to the semiconductor wafer to rinse the cleaning liquid (rinse process), and further rotates the semiconductor wafer at a high speed to spin the pure water off the semiconductor wafer (spin dry process). Such a process method has a problem such that water marks is generated on the surface of a semiconductor wafer by adhesion of a mist of pure water, which is generated at the time of spin dry, to the dry surface of the semiconductor wafer, or the like. As a cleaning method which suppresses generation of such water marks, Unexamined Japanese Patent Application Publication No. H4-287922 discloses a substrate processing method which comprises a cleaning process step of feeding a predetermined cleaning liquid to the surface of a substrate to be processed from obliquely above, a rinse process step of then feeding pure water to the surface of the substrate from obliquely above, and a dry process step of then rotating the substrate at a high speed to spin the liquid off, and overlaps the end period of the rinse process step and the start period each other, whereby a nitrogen gas is supplied to the center portion of the substrate in the overlap step and the dry process step. Unexamined Japanese Patent Application Publication No. 2001-53051 discloses a substrate dry method which sprays an inactive gas to the center portion of a substrate after a rinse process, sprays pure water to the outer peripheral portion of the substrate, and moves the spray position of the inactive gas and the spray position of the pure water outward from the substrate in the radial direction. As the semiconductor device fabrication process progresses, however, a pattern having a mixture of a hydrophilic surface (e.g., an SiO 2 surface formed by a predetermined method) and a hydrophobic surface (e.g., a bare Si surface) is formed on the surface of the semiconductor wafer. Because the hydrophilic surface and the hydrophobic surface differ from each other in the water spin-off speed at the time of the spin dry process, the aforementioned conventional spin dry method has a difficulty in avoiding generation of water marks.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a vertical cross-sectional view showing the schematic structure of a substrate cleaning apparatus. FIG. 2 is a plan view showing the schematic structure of the substrate cleaning apparatus. FIG. 3 is a diagram showing a schematic control system of the substrate cleaning apparatus. FIG. 4 is a flowchart illustrating a cleaning method. FIG. 5 is a diagram exemplarily illustrating the dry process for a wafer according to a conventional spin dry method. FIG. 6 is another diagram exemplarily illustrating the dry process for a wafer according to a conventional spin dry method. FIG. 7 is a still another diagram exemplarily illustrating the dry process for a wafer according to a conventional spin dry method. FIG. 8 is a diagram exemplarily illustrating the dry process for a wafer by spin dry in a cleaning method according to the present invention. FIG. 9 is a plan view showing the schematic structure of another substrate cleaning apparatus. FIG. 10 is a flowchart illustrating another cleaning method. FIG. 11 is a plan view showing the schematic structure of a still another substrate cleaning apparatus. detailed-description description="Detailed Description" end="lead"?

20060428

20110419

20070614

78476.0

B08B700

GOLIGHTLY, ERIC WAYNE

SUBSTRATE CLEANING METHOD, SUBSTRATE CLEANING APPARATUS AND COMPUTER READABLE RECORDING MEDIUM

UNDISCOUNTED

ACCEPTED

B08B

ACCEPTED

Nitrogen-containing fused heterocyclic compounds

There is provided a CRF receptor antagonist comprising a compound of the formula (I): wherein, ring A is a 5-membered ring represented by the formula (A′): wherein X is a carbon and X1 is an oxygen, a sulfur or —NR5—, or formula (A″): wherein X is a nitrogen and R6 is an optionally substituted hydrocarbyl, R1 is an amino substituted by two optionally substituted hydrocarbyl groups, R2 is an phenyl, Y1 is CR3a or a nitrogen, y2 is CR3b or a nitrogen and Y3 is CR3c or a nitrogen, provided that one or less of Y1, Y2, and Y3 is nitrogen, W is a bond, —(CH2)n-, and Z is a bond, —NR4—, etc.; or a salt thereof or a prodrug thereof.

1. A compound represented by the formula (I): wherein, ring A is a 5-membered ring represented by the formula (A′): wherein X is a carbon and X1 is an oxygen, a sulfur or —NR5— (wherein R5 is a hydrogen, an optionally substituted hydrocarbyl or an acyl), or formula (A″): wherein X is a nitrogen and R6 is a hydrogen, an optionally substituted hydrocarbyl or an acyl; R1 is (1) an amino substituted by two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, or (2) an optionally substituted cyclic amino, provided that the amino nitrogen of said cyclic amino has no carbonyl adjacent to the nitrogen; R2 is an. optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocyclic; Y1, Y2 and Y3 are. each an optionally substituted methyne or a nitrogen, provided that one or less of Y1, Y2 and Y3 is nitrogen; W is a bond, —(CH2)n— or —(CH2)m—CO— (wherein n is an integer of 1 to 4 and m is an integer of 0 to 4); Z is a bond, —CO—, an oxygen, a sulfur, —SO—, —SO2—, —NR4—, —NR4-alk-, —CONR4— or —NR4CO—(wherein alk is an optionally substituted C1-4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl); provided that (i) the compound wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X1 is a sulfur), W is a bond, Z is —NHCO— or —CONH—, and Y1 is CR3a (wherein R3a is a hydrogen, a halogen, or an alkoxy) and (ii) the compound wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X1 is an oxygen, a sulfur, or —NH—), R1 is an optionally substituted 1-piperazinyl, W is a bond, Z is a bond and R2 is an optionally substituted aryl, are excluded; or a salt thereof. 2. A prodrug of the compound according to claim 1. 3. The compound according to claim 1 wherein R1 is an amino substituted by two optionally substituted C1-4 alkyl groups. 4. The compound according to claim 1 wherein R1 is an amino substituted by an optionally substituted C1-4 alkyl and an optionally substituted phenyl or optionally substituted heterocyclic. 5. The compound according to claim 1 wherein R1 is a 5- or 6-membered cyclic amino which may be substituted with one or more substituents. 6. The compound according to claim 1 wherein Y1 is CR3a, Y2 is CR 3b, and Y3 is CR3c (wherein R3a, R3b and R3c are independently a hydrogen, a halogen, a nitro, an optionally substituted C1-4 hydrocarbyl, an optionally substituted C1-4 hydrocarbyloxy, an optionally substituted C1-4 hydrocarbylthio, an optionally substituted amino or an acyl containing up to 4 carbon atoms). 7. The compound according to claim 1 wherein one of Y1, Y2 and Y3 is nitrogen. 8. The compound according to claim 1 wherein W is a bond. 9. The compound according to claim 1 wherein R2 is an optionally substituted C6-10 aryl or an optionally substituted 5- or 10-membered heterocyclic. 10. The compound according to claim 1 wherein Z is —NR4— (wherein R4 is as defined in claim 1). 11. The compound according to claim 1 wherein ring A is a thiazole ring or an imidazole ring represented by the formula (Aa): wherein R5a is a hydrogen, an optionally substituted C1-4 alkyl or an acyl containing up to 4 carbon atoms. 12. The compound according to claim 1 wherein Y1 is CR3a, Y2 is CR3b and Y3 is CR3c (wherein R3a, R3b and R3c are independently a hydrogen, a halogen, a nitro, an optionally substituted C1-4 hydrocarbyl, an optionally substituted C1-4 hydrocarbyloxy, an optionally substituted C1-4 hydrocarbylthio, an optionally substituted amino or an acyl containing up to 4 carbon atoms); W is a bond; R2 is an optionally substituted C6-10 aryl or an optionally substituted 5- or 10-membered heterocyclic; and Z is —NR4— (wherein R4 is a hydrogen or an optionally substituted hydrocarbyl); and ring A is a thiazole ring or an imidazole ring represented by the formula (Aa): wherein R5a is a hydrogen, an optionally substituted C1-4 alkyl, or an acyl containing up to 4 carbon atoms. 13. A method for treating or preventing a disease wherein a CRF receptor is implicated, which comprises administering to a subject in need thereof an effective amount of a compound represented by the formula (Ia): wherein ring A is a 5-membered ring represented by the formula (A′): wherein X is a carbon and X1 is an oxygen, a sulfur or —NR5— (wherein R5 is a hydrogen, an optionally substituted hydrocarbyl or an acyl), or formula (A″): wherein X is a nitrogen and R6 is a hydrogen, an optionally substituted hydrocarbyl or an acyl; R1a is (1) an amino substituted by two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, or (2) an optionally substituted cyclic amino; R2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocyclic; Y1, Y2 and Y3 are each an optionally substituted methyne or a nitrogen, provided that one or less of Y1, Y2 and Y3 is nitrogen; W is a bond, —(CH2)n— or —(CH2)m—CO—, wherein n is an integer of 1 to 4 and m is an integer of 0 to 4; Z is a bond, —CO—, an oxygen, a sulfur, —SO—, —SO2—, —NR4—, —NR4-alk-, —CONR4— or —NR4CO— (wherein alk is an optionally substituted C1-4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl); provided that the compound wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X1 is a sulfur), W is a bond, Z is —NHCO— or —CONH—, and Y1 is CR3a (wherein R3a is a halogen, or an alkoxy) is excluded; or a salt thereof. 14. The method according to claim 13 wherein the disease being treated or prevented is selected from affective disorder, depression and anxiety. 15. Use of the compound (Ia) according to claim 13, or a salt thereof for manufacturing a medicament for preventing or treating a disease wherein a CRF receptor is implicated. 16. Use of the compound (Ia) according to claim 13, or a salt thereof for manufacturing a medicament for preventing or treating affective disorder, depression or anxiety. 17. An agent for preventing or treating a disease wherein a CRF receptor is implicated, which comprises the compound (Ia) according to claim 13 or a salt thereof. 18. An agent for preventing or treating affective disorder, depression or anxiety which comprises the compound (Ia) according to claim 13 or a salt thereof.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel nitrogen-containing fused heterocyclic compounds having CRF (corticotropin releasing factor) antagonistic activity and pharmaceutical compositions containing them. 2. Background Art Corticotropin-releasing factor (hereinafter, abbreviated as “CRF”) is a neuropeptide composed of 41 amino acids, and was isolated and purified as a peptide promoting release of adrenocorticotropic hormone (ACTH) from pituitary gland. First, the structure thereof was determined from sheep hypothalamus and, thereafter, the presence thereof was confirmed also in a rat or a human, and the structure thereof was determined [Science, 213, 1394(1981); Proc. Natl. Acad. Sci USA, 80, 4851(1983); EMBO J. 5, 775(1983)]. An amino acid sequence is the same in a human and a rat, but differed in 7 amino acids in ovine. CRF is synthesized as a carboxy-terminal of prepro CRF, cut and secreted. The CRF peptide and a mRNA thereof are present at the largest amount in hypothalamus and pituitary gland, and are widely distributed in a brain such as cerebral cortex, cerebellum, hippocampus and corpus amygdaloideum. In addition, in peripheral tissues, the existence has been confirmed in placenta, adrenal gland, lung, liver, pancreas, skin and digestive tract [J. Clin. Endocrinol. Metab., 65, 176(1987); J. Clin. Endocrinol. Metab., 67, 768(1988); Regul. Pept., 18, 173(1987), Peptides, 5 (Suppl. 1), 71(1984)]. A CRF receptor is a 7-transmembrane G protein-coupled receptor, and two subtypes of CRF1 and CRF2 are present. It is reported that CRF1 is present mainly in cerebral cortex, cerebellum, olfactory bulb, pituitary gland and tonsil nucleus. On the other hand, the CRF2 receptor has two subtypes of CRF2α and CRF2β. It was made clear that the CRF2α receptor is distributed much in hypothalamus, septal area and choroids plexus, and the CRF2α receptor is present mainly in peripheral tissues such as skeletal muscle and is distributed in a blood vessel in a brain [J. Neurosci. 15, 6340(1995); Endocrinology, 137, 72(1996); Biochim. Biophys. Acta, 1352, 129(1997)]. Since each receptor differs in distribution in a living body, it is suggested that a role thereof is also different [Trends. Pharmacol. Sci. 23, 71(2002)]. As a physiological action of CRF, the action on the endocrine system is known in which CRF is produced and secreted in response to stress in hypothalamus and acts on pituitary gland to promote the release of ACTH [Recent Prog. Horm. Res., 39, 245(1983)]. In addition to the action on the endocrine system, CRF acts as a neurotransmitter or a neuroregulating factor in a brain, and integrates electrophysiology, autonomic nerve and conducts to stress [Brain Res. Rev., 15, 71(1990); Pharmacol. Rev., 43, 425(1991)]. When CRF is administered in a cerebral ventricle of experimental animal such as a rat, anxiety conduct is observed, and much more anxiety conduct is observed in a CRF-overexpressing mouse as compared with a normal animal [Brain Res., 574, 70(1992); J. Neurosci., 10, 176(1992); J. Neurosci., 14, 2579(1994)]. In addition, α-helical CRF(9-41) of a peptidergic CRF receptor antagonist exerts an anti-anxiety action in an animal model [Brain Res., 509, 80(1990); J. Neurosci., 14, 2579(1994)]. A blood pressure, a heart rate and a body temperature of a rat are increased by stress or CRF administration, but the α-helical CRF(9-41) of a peptidergic CRF antagonist inhibits the increase in a blood pressure, a heart rate and a body temperature due to stress [J. Physiol., 460, 221(1993)]. The α-helical CRF(9-41) of a peptidergic CRF receptor antagonist inhibits abnormal conducts due to withdrawal of a dependent drug such as an alcohol and a cocaine [Psychopharmacology, 103, 227(1991); Pharmacol. Rev.53, 209(2001)]. In addition, it has been reported that learning and memory are promoted by CRF administration in a rat [Nature, 375, 284(1995); Neuroendocrinology, 57, 1071(1993); Eur. J. Pharmacol., 405, 225(2000)]. Since CRF is associated with stress response in a living body, there are clinical reports regarding stress-associated depression or anxiety. The CRF concentration in a cerebrospinal fluid of a depression patient is higher as compared with that of a normal person [Am. J. Psychiatry, 144, 873(1987)], and the mRNA level of CRF in hypothalamus of a depression patient is increased as compared with that of a normal person [Am. J. Psychiatry, 152, 1372(1995)]. A CRF binding site of cerebral cortex of a patient who suicide by depression is decreased [Arch. Gen. Psychiatry, 45, 577(1988)]. The increase in the plasma ACTH concentration due to CRF administration is small in a depression patient [N. Engl. J. Med., 314, 1329(1986)]. In a patient with panic disorder, the increase of plasma ACTH concentration due to CRF administration is small [Am. J. Psychiatry, 143, 896(1986)]. The CRF concentration in a cerebrospinal fluid of a patient with anxiety induced by stress such as obsessive-compulsive neurosis, post-psychic trauma stress disorder, Tourette's syndrome and the like is higher as compared with that of a normal person [Arch. Gen. Psychiatry, 51, 794(1994); Am. J. Psychiatry, 154, 624(1997); Biol. Psychiatry, 39, 776(1996)]. The CRF concentration in a cerebrospinal fluid of schizophrenics is higher as compared with that of a normal person [Brain Res., 437, 355(1987); Neurology, 37, 905(1987)]. Thus, it has been reported that there is abnormality in the living body response system via CRF in stress-associated mental disease. The action of CRF on the endocrine system can be presumed by the characteristics of CRF gene-introduced animal and actions in an experimental animal. In a CRF-overexpressing mouse, excessive secretions of ACTH and adrenal cortex steroid occur, and abnormalities analogous to Cushing's syndrome such as atrophy of muscle, alopecia, infertility and the like are observed [Endorcrinology, 130, 3378(1992)]. CRF inhibits ingestion in an experimental animal such as a rat [Life Sci., 31, 363 (1982); Neurophamacology, 22, 337(1983)]. In addition, α-helical CRF(9-41) of a peptidergic CRF antagonist inhibited decrease of ingestion due to stress loading in an experimental model [Brain Res. Bull., 17, 285(1986)]. CRF inhibited weight gain in a hereditary obesity animal [Physiol. Behav., 45, 565(1989)]. In a nervous orexia inactivity patient, the increase of ACTH in plasma upon CRF administration is small [J. Clin. Endocrinol. Metab., 62, 319(1986)]. It has been suggested that a low CRF value is associated with obesity syndrome [Endocrinology, 130, 1931(1992)]. There has been suggested a possibility that ingestion inhibition and weight loss action of a serotonin reuptake inhibiting agent are exerted via release of CRF [Pharmacol. Rev., 43, 425(1991)]. CRF is centrally or peripherally associated with the digestive tract movement involved in stress or inflammation [Am. J. Physiol. Gastrointest. Liver Physiol. 280, G315(2001)]. CRF acts centrally or peripherally, weakens the shrinkablity of stomach, and decreases the gastric excreting ability [Regulatory Peptides, 21, 173(1988); Am. J. Physiol., 253, G241(1987)]. In addition, α-helical CRF (9-41) of a peptidergic CRF antagonist has a restoring action for hypofunction of stomach by abdominal operation [Am. J. Physiol., 258, G152(1990)]. CRF inhibits secretion of a bicarbonate ion in stomach, decreases gastric acid secretion and inhibits ulcer due to cold restriction stress [Am. J. Physiol., 258, G152(1990)]. Furthermore, α-helical CRF (9-41) of a peptidergic CRF antagonist shows the inhibitory action on gastric acid secretion decrease, gastric excretion decrease, small intestinal transport decrease and large intestinal transport enhancement due to restriction stress [Gastroenterology, 95, 1510(1988)]. In a healthy person, mental stress increases a gas and abdominal pain due to anxiety and intestine dilation, and CRF decreases a threshold of discomfort [Gastroenterology, 109, 1772(1995); Neurogastroenterol. Mot., 8, 9 [1996]. In a irritable bowel syndrome patient, large intestinal movement is excessively enhanced by CRF administration as compared with a healthy person [Gut, 42, 845(1998)]. It has been reported from studies on experimental animals and clinical studies that CRF is induced by inflammation and is involved in a inflammatory reaction. In an inflammatory site of an experimental animal and in a joint fluid of a rheumatoid arthritis patient, production of CRF is topically increased [Science, 254, 421(1991); J. Clin. Invest., 90, 2555(1992); J. Immunol., 151, 1587(1993)]. CRF induces degranulation of a mast cell and enhances the blood vessel permeability [Endocrinology, 139, 403(1998); J.Pharmacol. Exp. Ther., 288, 1349(1999)]. CRF can be detected also in a thyroid gland of autoimmune thyroiditis-patient [Am. J. Pathol. 145, 1159(1994)]. When CRF is administered to an experimental autoimmune cerebrospinal meningitis rat, the progression of symptom such as paralysis was remarkably inhibited [J. Immunil., 158, 5751(1997)]. In a rat, the immune response activity such as T-lymphocyte proliferation and the natural killer cell activity is reduced by CRF administration or stress loading [Endocrinology, 128, 1329(1991)]. From the above-mentioned reports, it is expected that the CRF receptor antagonistic compound would exert an excellent effect for treating or preventing various diseases in which CRF is involved. As a CRF antagonist, for example, peptide CRF receptor antagonists are reported in which a part of an amino acid sequence of CRF or associated peptides of a human or other mammals is altered or deleted, and they are reported to show a pharmacological action such as ACTH release-inhibiting action and anti-anxiety action [Science, 224, 889(1984); J. Pharmacol. Exp. Ther., 269, 564(1994); Brain Res. Rev., 15, 71(1990)]. However, from a pharmacokinetic point of view such as chemical stability and absorbability for oral administration in a living body, bioavailability and intracerebral transferability, peptide derivatives have a low utility value as a medicine. SUMMARY OF THE INVENTION According to the present invention, there is provided: (1) A compound represented by the formula (I): wherein, ring A is a 5-membered ring represented by the formula (A′): wherein X is a carbon and X1 is an oxygen, a sulfur or —NR5— (wherein R5 is a hydrogen, an optionally substituted hydrocarbyl or an acyl), or formula (A″): wherein X is a nitrogen and R6 is a hydrogen, an optionally substituted hydrocarbyl or an acyl; R1 is (1) an amino substituted by two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, or (2) an optionally substituted cyclic amino, provided that the amino nitrogen of said cyclic amino has no carbonyl adjacent to the nitrogen; R2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocyclic; Y1, Y2 and Y3are each an optionally substituted methyne or a nitrogen, provided that one or less of Y1, Y2 and Y3 is. nitrogen; W is a bond, — (CH2)n— or —(CH2)m—CO— (wherein n is an integer of 1 to 4 and m is an integer of 0 to 4); Z is a bond, —CO—, an oxygen, a sulfur, —SO—, —SO2—, —NR4—, —NR4—alk—, —CONR4— or —NR4CO— (wherein alk is an optionally substituted C1-4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl); provided that (i) the compound wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X1 is a sulfur), W is a bond, Z is —NHCO— or —CONH—, and y1 is CR3a (wherein R3a is a hydrogen, a halogen, or an alkoxy) and (ii) the compound wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X1 is an oxygen, a sulfur, or —NH—), R1 is an optionally substituted 1-piperazinyl, W is a bond, Z is a bond and R2 is an optionally substituted aryl, are excluded; or a salt thereof; (2) A prodrug of the compound according to the above-mentioned (1); (3) The compound according to the above-mentioned (1) wherein R1 is an amino substituted by two optionally substituted C1-4 alkyl groups; (4) The compound according to the above-mentioned (1) wherein R1 is an amino substituted by an optionally substituted C1-4 alkyl and an optionally substituted phenyl or optionally substituted heterocyclic; (5) The compound according to the above-mentioned (1) wherein R1 is a 5- or 6-membered cyclic amino which may be substituted with one or more substituents; (6) The compound according to claim 1 wherein Y1 is CR3a, Y2 is CR3b, and Y3 is CR3c (wherein R3a, R3band R3c are independently a hydrogen, a halogen, a nitro, an optionally substituted C1-4 hydrocarbyl, an optionally substituted C1-4 hydrocarbyloxy, an optionally substituted C1-4 hydrocarbylthio, an optionally substituted amino or an acyl containing up to 4 carbon atoms); (7) The compound according to above-mentioned (1) wherein one of Y1, Y2 and Y3 is nitrogen; (8) The compound according to the above-mentioned (1) wherein W is a bond; (9) The compound according to the above-mentioned (1) wherein R2 is an optionally substituted C6-10 aryl or an optionally substituted 5- or 10-membered heterocyclic; (10) The compound according to the above-mentioned (1) wherein R2 is an optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclic; (11) The compound according to the above-mentioned (1) wherein Z is -NR4- (wherein R4 is as defined in the above-mentioned (1)); (12) The compound according to the above-mentioned (1) wherein ring A is a thiazole ring or an imidazole ring represented by the formula (Aa): wherein R5ais a hydrogen, an optionally substituted C1-4 alkyl or an acyl containing up to 4 carbon atoms; (13) The compound according to the above-mentioned (1) wherein Y1 is CR3a, Y2 is CR3b and Y3 is CR3c, (wherein R3a, R3b and R3c is independently a hydrogen, a halogen or an optionally substituted hydrocarbyl); W is a bond; R2 is an optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclic; and Z is —NR4— (wherein R4 is a hydrogen or an optionally substituted hydrocarbyl); (14) The compound according to the above-mentioned (1) wherein Y1 is CR3a, Y2 is CR3b and Y3 is CR3c (wherein R3a , R3b and R3c are independently a hydrogen, a halogen, a nitro,. an optionally substituted C1-4 hydrocarbyl, an optionally substituted C1-4 hydrocarbyloxy, an optionally substituted C1-4 hydrocarbylthio, an optionally substituted amino or an acyl containing up to 4 carbon atoms); W is a bond; R2 is an optionally substituted C6-10 aryl or an optionally substituted 5- or 10-membered heterocyclic; and Z is —NR4— (wherein R4 is a hydrogen or an optionally substituted hydrocarbyl); and ring A is a thiazole ring or an imidazole ring represented by the formula (Aa) wherein R5a is a hydrogen, an optionally substituted C1-4 alkyl, or an acyl containing up to 4 carbon atoms; (15) A method for treating or preventing a disease wherein a CRF receptor is implicated, which comprises administering to a subject in need thereof an effective amount of a compound represented by the formula (Ia): wherein ring A is a 5-membered ring represented by the formula (A′): wherein X is a carbon and X1 is an oxygen, a sulfur or —NR5—(wherein R5 is a hydrogen, an optionally substituted hydrocarbyl or an acyl), or formula (A″): wherein X is a nitrogen and R6 is a hydrogen, an optionally substituted hydrocarbyl or an acyl; R1a is (1) an amino substituted by two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, or (2) an optionally substituted cyclic amino; R2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocyclic; Y1, Y2 and Y3 are each an optionally substituted methyne or a nitrogen, provided that one or less of Y1, Y2 and Y3 is nitrogen; W is a bond, —(CH2)n— or —(CH2)m—CO—, wherein n is an integer of 1 to 4 and m is an integer of 0 to 4; Z is a bond, —CO—, an oxygen, a sulfur, —SO—, —SO2—, —NR4—, —NR4—alk—, —CONR4— or —NR4CO— (wherein alk is an optionally substituted C1-4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl); provided that the compound wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X1 is a sulfur), W is a bond, Z is —NHCO—or —CONH—, and Y1 is CR3a (wherein R3a is a halogen, or an alkoxy) is excluded; or a salt thereof; (16) The method according to the above-mentioned (15) wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety; (17) Use of the compound (Ia) according to the above-mentioned (15), or a salt thereof for manufacturing a medicament for preventing or treating a disease wherein a CRF receptor is implicated; (18) Use of the compound (Ia) according. to the above-mentioned (15), or a salt thereof for manufacturing a, medicament for preventing or treating affective disorder, depression or anxiety; (19) An agent for preventing or treating a disease wherein a CRF receptor is implicated, which comprises the compound (Ia) according to the above-mentioned (15) or a salt thereof; and (20) An agent for preventing or treating affective disorder, depression or anxiety which comprises the compound (Ia) according to the above-mentioned (15) or a salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In the present specification, the term “hydrocarbyl” means a univalent group containing only carbon and hydrogen. In the above formulas, ring A of the formulas (I) and (Ia) is a 5-membered ring represented by the following formula A′ or A″: In the formula (A′), X represents a carbon and X1 represents an oxygen, a sulfur or —NR5— (wherein R5 is a hydrogen or an optionally substituted hydrocarbyl or an acyl). That is, examples of the 5-membered ring of the formula (A′) include an oxazole ring, a thiazole ring and an imidazole ring. Examples of the “hydrocarbyl” of “an optionally substituted hydrocarbyl” represented by R5 of the formula: —NR5— include an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted alicyclic-aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic-aliphatic hydrocarbon group (an aralkyl group), and the like. Examples of said aliphatic hydrocarbon group include a saturated aliphatic hydrocarbon group having 1-8 carbon atoms (e.g., alkyl group) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; and an unsaturated aliphatic hydrocarbon group having 2-8 carbon atoms (e.g., alkenyl group, alkynyl group, alkadienyl group, alkadiynyl group, etc.) such as vinyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadiynyl, 1-heptynyl, 1-octynyl, etc. Examples of said alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkyl group, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like; an unsaturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkenyl group, cycloalkadienyl group, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl, etc.; a partly saturated and fused bicyclic hydrocarbon group [preferably, C9-10 partly saturated and fused bicyclic hydrocarbon group, etc. (including those where the benzene ring is combined to 5- or 6-membered non-aromatic cyclic hydrocarbon group)] such as 1-indenyl, 2-indenyl, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl, etc.; and the like. Said alicyclic hydrocarbon group may be cross-linked. Examples of said alicyclic-aliphatic hydrocarbon group include those where the above-mentioned alicyclic hydrocarbon group and the above-mentioned aliphatic hydrocarbon group are combined, for example, those having 4-14 carbon atoms such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, 2-(3,4-dihydro-2-naphtyl)ethyl, 2-(1,2,3,4-tetrahydro-2-naphtyl)ethyl, 2-(3,4-dihydro-2-naphtyl)ethenyl, etc. (e.g., C3-7 cycloalkyl-C1-4 alkyl group, C3-7 cycloalkenyl-C1-4 alkyl group, C3-7 cycloalkyl-C2-4 alkenyl group, C3-7 cycloalkenyl-C2-4 alkenyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl groups, etc.). Examples of said aromatic hydrocarbon group include an aryl group having 6-10 carbon atoms (including that where a 5- to 6-membered non-aromatic hydrocarbon ring is fused with phenyl group) such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl, etc.; and the like. Examples of said aromatic-aliphatic hydrocarbon group include an aralkyl group having 7-14 carbon atoms (C6-10 aryl-C1-4 alkyl group) such as phenyl-C1-4 alkyl group, e.g., benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.; naphthyl-C1-4 alkyl group such as α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl, etc.; C6-10 aryl-C2-4 alkenyl group such as phenyl-C2-4 alkenyl group, e.g., styryl, cinnamyl, etc.; and the like. The above-mentioned “hydrocarbyl” group may have a substituent at a substitutable position. Examples of such substituent include a halogen, nitro, cyano, oxo, (1) an optionally substituted heterocyclic group, (2) an optionally substituted sulfinyl group, (3) an optionally substituted sulfonyl group, (4) optionally substituted hydroxyl group, (5) optionally substituted thiol group, (6) an optionally substituted amino group, (7) an acyl group, (8) an optionally esterified or amidated carboxyl group, (9) an optionally substituted phosphoryl group, or the like. Examples of the substituent of above-mentioned (2) an optionally substituted sulfinyl group, (3) an optionally substituted sulfonyl group, (4) optionally substituted hydroxyl group, (5) optionally substituted thiol group and (6) an optionally substituted amino group include an optionally substituted hydrocarbyl. Examples of “hydrocarbyl” of such optionally substituted hydrocarbyl include those exemplified above. Such hydrocarbyl may be substituted by one or more substituents at a substitutable position. Examples of the substituent group of the optionally substituted hydrocarbyl as a substituent group include halogen, nitro, cyano, hydroxyl, thiol, amino and carboxyl. As the optionally substituted sulfinyl group of above-mentioned (2), specifically, C1-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl etc.) and C6-10 arylsulfinyl (e.g., phenylsulfinyl, naphthylsulfinyl etc.) are exemplified. As the optionally substituted sulfonyl group of above-mentioned (3), specifically, C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl etc.) and C6-10 arylsulfonyl (e.g., phenylsulfonyl, naphthylsulfonyl etc.) are exemplified. As the optionally substituted hydroxyl group of above-mentioned (4), specifically, hydroxyl, C1-6 alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.) and C6-10 aryloxy (e.g., phenoxy, naphthoxy, etc.) are exemplified. As the optionally substituted thiol group of above-mentioned (5), specifically, thiol, C1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, etc.) and C6-10 arylthio (e.g., phenylthio, naphthylthio etc.) are exemplified. As the optionally substituted amino group of above-mentioned (6), specifically, amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino, dipropylamino, diisopropylamino, dibutylamino etc.), and the like are exemplified. Examples of the acyl group of above-mentioned (7) include the same group as the acyl for R5. Examples of the ester group or amide group of the optionally esterified or amidated carboxyl group of above-mentioned (8) include ester group with the same optionally substituted hydrocarbyl as the substituent of optionally substituted hydroxyl group of above-mentioned (4) or amide group with optionally substituted amino group of above-mentioned (6). As the optionally esterified carboxyl group, specifically, carboxyl, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.), C6-10 aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), C7-16 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenetyloxycarbonyl etc.), and the like are exemplified. As the optionally amidated carboxyl group, specifically, carbamoyl, mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), C6-10 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), 5- to 6-membered heterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl etc.), and the like are exemplified. Examples of the “acyl” represented by R5 of the formula: —NR5— include a formyl and a group where the carbonyl group. is combined with a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-7 cycloalkyl group, a C5-7 cycloalkenyl group or an aromatic group (e.g., phenyl group, pyridyl group, etc.) (e.g., acetyl, propionyl, butyryl, isobytyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, etc.) and the like. R5 is preferably hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and more preferably hydrogen, C1-10 alkyl. In the formula (A″), X represents a nitrogen and R6 represents a hydrogen, an optionally substituted hydrocarbyl or an acyl. Examples of the “optionally substituted hydrocarbyl” and “acyl” represented by R6 include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl and acyl in R5. R6 is preferably hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and more preferably hydrogen, C1-10 alkyl. R1 and R1a in the formula (I) and (Ia) are (1) an amino substituted by two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, or (2) an optionally substituted cyclic amino, provided that the cyclic amino has no carbonyl. adjacent to the nitrogen in the formula (I). Examples of the “optionally substituted hydrocarbyl group” in the “amino substituted by two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group” include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl group of R5. Examples of the “Optionally substituted heterocyclic group” in the “amino substituted by two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group” include the same groups as those exemplified below with respect to the optionally substituted heterocyclic group of R2. Examples of the “cyclic amino” in the “optionally substituted cyclic amino” include, for example, a 3- to 7-membered cyclic amino group such as aziridino, pyrrolidino, imidazolidino, oxazolidino, thiazolidino, piperidino, 1,2-dihydropyridyl, 1,2,3,6-tetrahydropyridyl, piperazino, morpholino, thiomorpholino and the like. The cyclic amino group may be substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy-C1-6 alkyl, C5-7 cycloalkyl, C6-10 aryl (said aryl may have 1 or 2 substituents selected from halogen, C1-6 alkyl, halogeno C1-6 alkyl and C1-6 alkoxy), C7-14 aralkyl (said aralkyl may have 1 or 2 substituents selected from halogen, C1-6 alkyl, halogeno C1-6 alkyl and C1-6 alkoxy), hydroxy, hydroxy-C1-6 alkyl, C6-10 aryloxy (said aryloxy may have 1 or 2 substituents selected from halogen, C1-6 alkyl, halogeno C1-6 alkyl and C1-6 alkoxy), C7-14 aralkyloxy, C6-1 aryl-carbonyl, carboxyl, C1-6 alkoxy-carbonyl, carbamoyl, C6-10 aryl-carbamoyl, amino, C6-10 aryl-carbonylamino, C1-6 alkyl-carbonylamino, C1-6 alkoxy-carbonylamino, C6-10 arylthio, C6-10 arylsulfonyl, cyano, 5-to 7-membered heterocyclic group and oxo (provided that the oxo group is not substituted at the position adjacent to the nitrogen bonded to W of formula (I)). Among these, R1 and R1a in the formula (I) and (Ia) are preferably an amino substituted by two substituents selected from optionally substituted C1-4 alkyl and optionally substituted phenyl, more preferably amino substituted by two optionally substituted C1-4 alkyl groups. Preferred examples of the optionally substituted C1-4 alkyl and optionally substituted phenyl are those unsubstituted or those substituted with a group selected from the group consisting of hydroxy, C1-4 alkoxy; amino, mono- or di- C1-4 alkyl amino; halogen; and pyridyl. R2 in the formula (I) and (Ia) are alkyl, an optionally substituted cycloalkyl, an optionally substituted,cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocyclic. Examples of the “alkyl” for R2 include a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc. Examples of the “cycloalkyl” for “optionally substituted cycloalkyl” of R2 include a C3-7 cycloalkyl group such as. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Examples of the “cycloalkenyl” for the “optionally substituted cycloalkenyl” of R2 include a C3-7 cycloalkenyl group such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, etc. Examples of the “aryl” for the “optionally substituted aryl” of R2 include an aryl group having 6-10 carbon atoms (including that where a 5- to 6-membered non-aromatic hydrocarbon ring is fused with phenyl group) such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl, etc.; and the like. Examples of the “heterocyclic” for the “optionally substituted heterocyclic” of R2 include (i) a 5- to 7-membered heterocyclic group containing one sulfur atom, one nitrogen atom or one oxygen atom, (ii) a 5- to 6-membered heterocyclic group containing 2-4 nitrogen atoms, and (iii) a 5- to 6-membered heterocyclic group containing 1-2 nitrogen atoms and one sulfur or oxygen atom, or the like. In addition, each of the heterocyclic groups exemplified in (i) to (iii) may be a saturated or unsaturated heterocyclic group and the unsaturated heterocyclic group may be either aromatic or non-aromatic. Examples of the heterocyclic for an optionally substituted heterocyclic of R2 include an aromatic monocyclic heterocyclic group and a non-aromatic heterocyclic group. Specific examples of the heterocyclic for an optionally substituted heterocyclic include (i) an aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.) and (ii) a non-aromatic, heterocyclic group (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.). The above-mentioned “cycloalkyl”, “icycloalkenyl”, “Varyl” and “heterocyclic” in R2 may have the same substituent as those exemplified with respect to the optionally substituted hydrocarbyl group of R5 and further may have the same group as optionally substituted hydrocarbyl group of R5 as their substituent. In addition, two of the substituents of R2 may be combined each other to form a ring. Examples of the, ring include, for example, an aromatic fused heterocyclic group such as 8- to 12-membered aromatic fused heterocyclic group (preferably, heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with a benzene ring or heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with the same or different above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group), etc. (e.g. benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisooxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.); etc. Among these, R2 is preferably an optionally substituted phenyl or an optionally substituted 5- to 6-membered heterocyclic group. In the formula (I) and (Ia); y1 is CR3a or a nitrogen, Y2 is CR3b or a nitrogen, and Y3 is CR3c or a nitrogen (wherein R3a, R3b and R3c are independently a hydrogen, a halogen, a nitro, an optionally substituted hydrocarbyl, an optionally substituted hydrocarbyloxy, an optionally substituted hydrocarbylthio, an optionally substituted amino or an acyl), provided that one or less of Y1, Y2, and Y3 is nitrogen. The 6-membered ring with Y1, Y2 and Y3 of the formula (I) and (Ia) is a ring containing one or less nitrogen atom such as benzene ring and pyridine ring. Examples of halogen include fluorine, chlorine, bromine, iodine, and the like, preferably, fluorine and chlorine. Examples of the “optionally substituted hydrocarbyl” in R3a, R3b and R3c include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl group of R5. Examples of the hydrocarbyl for said “optionally substituted hydrocarbyloxy” and “optionally substituted hydrocarbylthio” of R3a, R3b and R3c include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl group of R5. Examples of the “optionally substituted amino” for R3a, R3b and R3c include amino group, an N-mono-substituted amino group, and an N,N-di-substituted amino group. Examples of said substituted amino groups include that having one or two substituents of an optionally substituted hydrocarbyl group (e.g., a C1-8 alkyl group, a C3-7 cycloalkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C3-7 cycloalkenyl group, a C6-10 aryl group that may have a C1-4 alkyl group, etc.), an optionally substituted heterocyclic group (e.g., the same group as an optionally substituted heterocyclic group of R2), or the formula: —COR3d (wherein R3drepresents hydrogen atom or an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group. As for “the hydrocarbyl group” or “the heterocyclic group” in “an optionally substituted hydrocarbyl group” or “an optionally substituted heterocyclic group” of R3d may have the same substituent as that of “the hydrocarbyl group” or “the heterocyclic group” in “an optionally substituted hydrocarbyl” of R5 or “an optionally substituted heterocyclic” of R2), preferably a C1-10 acyl group (e.g., a C2-7 alkanoyl, benzoyl, nicotinoyl, etc.). Specific examples thereof include methylamino, dimethylamino, ethylamino, diethylamino, dipropylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, and the like. In addition, the two groups in said substituted amino groups may be combined to form a nitrogen-containing 5- to 7-membered ring (e.g., piperidino, piperazino, morpholino, thiomorpholino, etc.). Examples of the acyl for R3a, R3b and R3c include the same groups as those exemplified with respect to the acyl for R5. In the formula (I) and (Ia), Y1, Y2 and Y3 are-preferably CR3a, CR3b and CR3c respectively. R3a, R3b and R3c are preferably hydrogen, C1-4 alkyl and C1-4 alkoxy. In the formula (I) and (Ia), W is a bond, —(CH2)n- or —(CH2)m—CO—, and n is 1-4 and m is 0-4. Preferably, W is a bond. In the formula (I) and (Ia), Z is a bond, —CO—, an oxygen, a sulfur, —SO—, —SO2—, —NR4—, —NR4—alk—, —CONR4— or —NR4CO—. Said alk is an optionally substituted C1-4 alkylene such as methylene, ethylene, propylene, butylene and the like. R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl. The “optionally substituted hydrocarbyl” and “acyl” for R4 include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl group and acyl for R5. Preferably, Z is —NR4— (wherein R4 is as defined above). Preferred examples of R4 are hydrogen and C1-4 alkyl. When Z is a bond, the fused ring of the formula (I) is preferably an imidazopyridine ring. Provided that the compounds wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X1 is a sulfur), W is a bond, Z is —NHCO— or —CONH— and Y1 is CR3a (wherein R3a is a hydrogen, a halogen or an alkoxy) are excluded from the compounds of the formula (I) and (Ia), and further the compounds wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X1 is an oxygen, a sulfur or —NH—), R1 is an optionally substituted 1-piperazinyl, W is a bond, Z is a bond, R2 is an optionally substituted aryl) are excluded from the compounds of the formula (I). As a preferred compound of the formula (I) and (Ia), a compound wherein Y1 is CR3a, Y2 is CR3b and Y3 is CR3c (wherein R3a, R3b and R3c are independently a hydrogen, a halogen or an optionally substituted hydrocarbyl); W is a bond; R2 is an optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclic; and Z is —NR4— (wherein R4 is a hydrogen or an optionally substituted hydrocarbyl) are exemplified. Compound (I) or (Ia) may be in the form of a prodrug thereof. The prodrug of Compound (I) or (Ia) refers to a compound that is converted into Compound (I) or (Ia) by a reaction with an enzyme, gastric acid, or the like under a physiological condition in the living body, namely, (i) a compound that is converted into Compound (I) or (Ia) by an enzymatic oxidation, reduction, hydrolysis, or the like, and (ii) a compound that is converted into Compound (I) or (Ia) by hydrolysis with gastric acid or the like. Examples of a prodrug of Compound (I) or (Ia) to be used include a compound or its salt wherein hydroxyl group in Compound (I) or (Ia) is acylated, alkylated, phosphorylated, or converted into borate (e.g., a compound or its salt wherein hydroxyl group in Compound (I) or (Ia) is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, dimethylaminomethylcarbonyloxy, etc.), a compound or its salt wherein carboxyl group in Compound (I) or (Ia) is esterified or amidated (e.g., a compound or its salt wherein carboxyl group in Compound (I) or (Ia) is subjected to ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification, cyclohexyloxycarbonyl esterification, or conversion into the methyl amide, etc.), or the like. These prodrugs can be produced according to a per se known method or its modified method. Further, a prodrug of Compound (I) or (Ia) may be a compound or its salt that is converted into Compound (I) or (Ia) under physiological conditions as described in “Development of Drugs”, Volume 7, Molecular Design, Hirokawa Shoten, 1990; pages 163-198. General Synthetic Method Production of a compound of formula (I) or a salt thereof of the present invention is discussed below. The following examples are given to illustrate the invention and are not intended to be inclusive in any manner. Alternative methods may be employed by one skilled in the art. A process for preparing compound (I) or a salt thereof of the present invention is shown in the following Methods A toE. (Method A) wherein R1a, R1b are independently optionally substituted hydrocarbyl groups, or R1a and R1b may be. optionally substituted cyclic form, R1aa, R1bb, R1cc and R1dd are independently hydrogen or optionally substituted hydrocarbyl groups, or R1aa and R1bb or R1cc and R1dd may be optionally substituted cyclic form, L1 is a leaving group (e.g. halogen atom such as chlorine, bromine and iodine, etc, sulfonyloxy group such as p-toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group, and acyloxy group. such as acetyloxy group and benzoyloxy group) and each of other symbols has a meaning defined above. In step A, compound (III) or a salt thereof can be prepared by hydrogenation of compound (II) or a salt thereof in the presence of a hydrogenation catalyst, or prepared by a reduction reaction for compound (II) or a salt thereof. As the catalyst, a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel, Raney nickel are used. In the present reaction, if needed, any solvents can be used as long as they do not inhibit the reaction. Inter alia, alcohols (e.g. C1-3 alcohol such as methanol, ethanol, propanol and the like), ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), or esters (ethyl acetate, etc.) are preferable. These solvents may be used by mixing at an appropriate ratio. The reaction temperature is 0° C. to 200° C., preferably 20° C. to 100° C. The reaction time is usually 0.5 to 48 hours, preferably 1 to 16 hours. While a reaction is usually performed at atmospheric pressure, it can be performed under pressure (3 to 10 atom) if necessary. While the amount of a catalyst employed may vary depending on the type of the catalyst employed, it is usually 0.1 to 20% by weight based on an active intermediate or a salt thereof. Compound (III) or a salt thereof can be also prepared by reduction of compound (II) or a salt thereof. A reducing agent is preferably Fe, Zn, Sn or SnCl2. This reaction may be performed under acidic conditions. An acid employed in this reduction may for example be an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid. A reaction solvent may for example be alcohols such as methanol and ethanol, etc., ethers such as dioxane and tetrahydrofuran, etc., aromatic hydrocarbons such as benzene, toluene and xylene, etc., esters such as ethyl acetate, etc., halogenated hydrocarbons such as chloroform and dichloromethane, etc., nitrites such as acetonitrile, etc., amides such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and sulfoxides such as dimethylsulfoxide, etc. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on the substrate employed as well as other conditions, it is −20 to 200° C., preferably 0 to 100° C. The reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 10 hours. Compound (II) or (III) or a salt thereof can be produced by Schemes 2 to 9. The thus obtained compound (II) or (III) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step B-1, compound (Ia) or a salt thereof, which is encompassed within compound (I) of the invention, can be prepared from compound (III) or a salt thereof and a carbonyl compound R1aaR1bbC═O or R1ccR1ddC═O by in situ production of an imine which is then reduced by an. appropriate reducing agent or hydrogenation in the presence of a hydrogenation catalyst. When R1a is equal to R1b in compound (Ia), R1aaR1bbC═O may be used in step B-1. When R1a is not equal to R1b in compound (Ia), the alkylation reactions may be performed stepwise by R1aaR1bbC═O and R1ccR1ddC═O in step B-1. A reducing agent is preferably sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. A hydrogenation catalyst is preferably a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel or Raney nickel. In this reaction, 1 to 10 moles, preferably 1 to 3 moles of the carbonyl compound R1aaR1bbC═O, R1ccR1ddC═O and 0.5 to 10 moles, preferably 0.5 to 3 moles of the reducing agent per 1 mole of compound (III) or a salt thereof are used. The reaction solvent may for example be alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. When producing an imine, use of molecular sieves or addition of an acid serves to promote the reaction. An acid employed here is preferably acetic acid and trifluoroacetic acid, etc. While the reaction temperature in this imine production may vary depending on compound (III) or a salt thereof as well as other conditions, it is 0 to 200° C., preferably 0 to 150° C. The reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature in the reducing reaction is −20 to 200° C., preferably 0 to 100° C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to 12 hours. Compound (Ia) or a salt thereof can be also prepared by reacting compound (III) with R1aL1 or R1bL1. When R1a is equal to R1a in compound (Ia), R1a L1 may be used in step B-2. When R1a is not equal to R1b in compound (Ia), the alkylation reactions may be performed stepwise by R1aL1 and R1bL1 in step B-2. In step B-2, 1 to 10 moles, preferably 1 to 5 moles of a compound represented by R1aL1 or a salt thereof and 1 to 10 moles, preferably 1 to 3 moles of a base are employed per 1 mole of compound (III) or a salt thereof. A base may for example be an, alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such. as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc. Examples of solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on compound (III) or a salt thereof employed as well as other reaction conditions, it is −20 to 200° C., preferably 0 to 150° C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours. Alkylation of compound (III) to prepare compound (Ia) may be performed by combined reactions of steps B-1 and B-2. The thus obtained compound (Ia) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein Z1 is oxygen, sulfur, —NR4—, or —NR4-alk-, Z1a is —SO— or —SO2— and W2 is NO2 or NH2, L1 is a leaving groups (e.g. halogen atom such as chlorine, bromine and iodine, etc, sulfonyloxy group such as p-toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group, and acyloxy group such as acetyloxy group and benzoyloxy group) and each of other symbols has a meaning defined above. Compound (IIa) which is encompassed within compound (II) or (III), or a salt thereof can be prepared by reacting compound (IV) with R2Z1H. Compound (IV) or a salt thereof can be prepared by Schemes 10 or 11 described below. In step C-1, 1 to 5 moles, preferably 1 to 3 moles of a compound represented by R2Z1H or a salt thereof and 1 to 5 moles, preferably 1 to 3 moles of a base are employed per 1 mole of compound (IV) or a salt thereof. A base may for example be an alkaline. metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as. trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc. Examples of solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitrites such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on compound (IV) or a salt thereof employed as well as other reaction conditions, it is −20 to 200° C., preferably 0 to 150° C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours. When Z1 is —NR4—, or —NR4-alk- in R2Z1H, compound (IIa) which is encompassed within compound (II) or (III), or a salt thereof can be also prepared by reacting compound (IV) with R2Z1H or a salt thereof in the presence of a palladium catalyst, preferably palladium (II) acetate and a catalytic amount of a phosphine ligand, preferably 2-(dicyclohexylphosphino)biphenyl, according to the procedure of Buchwald et al. (J. Am. Chem. Soc. 1998, 120, 9722) and the modified methods. When Z1 is sulfur in compound (IIa), compound (IIaa) which is encompassed within compound (II) or (III), or a salt thereof can be prepared by oxidation of compound (IIa) or a salt thereof. An oxidation agent is preferably hydrogen peroxide, organic peroxides (e.g. 3-chloroperoxybenzoic acid, peroxyacetic acid, etc.), manganese(IV) oxide, sodium metaperiodate. In step C-2, 1 to 10 moles, preferably 1 to 5 moles of oxidation agent are employed per 1 mole of compound (IIa) or a salt thereof. This reaction may be performed under acidic conditions. An acid employed in this oxidation may for example be an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid. A reaction solvent may for example be water, alcohols such as methanol and ethanol, etc., ethers such as dioxane and tetrahydrofuran, etc., aromatic hydrocarbons such as benzene, toluene and xylene, etc., esters such as ethyl acetate, etc., halogenated hydrocarbons such as chloroform and dichloromethane, etc., nitrites such as acetonitrile, etc., amides such as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and sulfoxides such as dimethylsulfoxide, etc. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on the substrate employed as well as other conditions, it is −20 to 200° C., preferably 0 to 100° C. The reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 10 hours. The thus obtained compound (IIa) and (IIaa) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein Z2 is bond and each of other symbols has a meaning defined above. Compound (IIb) which is encompassed within compound (II) or (III), or a salt thereof can be prepared by reacting compound (IV) with a boronic acid R2B(OH)2 or boronic acid esters or a salt thereof in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)palladium (0) and a base according to the procedure of Suzuki coupling (Organic Synthesis via Boranes, vol. 3: Suzuki coupling, A.Suzuki and H. C. Brown, Aldrich, 2002). Compound (IV) or a salt thereof can be prepared by Schemes 10 or 11 described below. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc. Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on compound (IV) or a salt thereof employed as well as other reaction conditions, it is −20 to 200° C., preferably 40 to 150° C. The reaction time is 5 minutes to 48 hours, preferably 1 h to 24 hours. The thus obtained compound (IIb) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein Z3 is C=O and each of other symbols has a meaning defined above. Compound (IIc) which is encompassed within compound (II) or (III), or a salt thereof can be prepared by reacting compound (IV) with an acid chloride R2COCl or a salt thereof after treating by an organic metal reagent. Compound (IV) or a salt thereof can be prepared by Schemes 10 or 11 described below. In step E, an organic metal reagent is employed in an amount of 1 to 5 moles, preferably 1 to 3 moles per 1 mole of compound (IV) or a salt thereof. An organic metal reagent may preferably be organic lithium such as n-BuLi, sec-BuLi, tert-BuLi, etc. Examples of solvent having no adverse effect on the reaction include ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on the reagent employed as well as other conditions, it is −100 to 200° C., preferably −78 to 100° C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 10 hours. The thus obtained compound (IIc) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein R4a and R4b are independently optionally substituted hydrocarbyl, L2 is leaving groups and each of symbols has a meaning defined above. In step F-1, compound (VI) or a salt thereof can be prepared from compound (V) or a salt thereof and an aldehyde compound R4CHO by an in situ production of an imine, which is then reduced by an appropriate reducing agent. The reaction can be carried out similar to step B in Scheme 1 to prepare compound (VI). Compound (V) or a salt thereof can be prepared by Scheme 10 described below. In step F-2, compound (VI) or a salt thereof can be also prepared by reacting (V) with R4L2 or a salt thereof. This reaction is carried out in the presence of a base. in a solvent having no adverse effect on the reaction according to the conventional. method. Specific examples of leaving groups L2 include halogen atom such as chlorine, bromine and iodine, sulfonyloxy group such as p-toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group, and acyloxy group such as acetyloxy group and benzoyloxy group. Example of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate and potassium carbonate; amines such as pyridine, triethylamine, N,N-dimethylaniline and 1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. An amount of these bases to be used is preferably about 1 to about 5 equivalents relative to compound (V). Examples of solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, aromatic hydrocarbon such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; amides such as N,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about −50 to about 150° C., preferably −10° C. to 120° C. A reaction time is usually 0.5 to 20 hours. The thus obtained compound (VI) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step G, compound (IId) is prepared by reacting a calboxylc acid R2COOH or a reactive derivative at a carboxyl group thereof and a salt thereof with compound (VI) or a reactive derivative at an amino group thereof or a salt thereof. Examples of the suitable reactive derivative at an amino group of compound (VI) include Schiff base type imine produced by reaction of compound (VI) with a carbonyl compound such as aldehyde, ketone and the like; silyl derivative produced by a reaction of compound (VI) and a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl) acetamide, bis(trimethylsilyl)urea and the like; derivative produced by a reaction of compound (VI) with phosphorus trichloride or phosgene. Specific examples of the suitable reactive derivative at a carboxyl group of R2COOH include acid halide, acid anhydride, activated amide, activated ester and the like. Examples of the suitable reactive. derivative include: acid chloride; acid azide; mixed acid anhydride with an acid such as substituted phosphoric acid such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid and the like, dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid such as methanesulfonic acid and the like, aliphatic carboxylic acid such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, trichloroacetic acid and the like or aromatic carboxylic acid such as benzoic acid and the like; symmetric acid anhydride; activated amide with imidazole; 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; activated ester such as cyanomethylester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl ester, p-cresyl thioester, carboxylmethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester and the like, or esters with N-hydroxy compound such as N,N-dimethylhydroxyamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole and the like. These reactive derivatives can be arbitrarily selected depending on a kind of compound (VI) to be used. Examples of the suitable reactive derivative of compound (IId) include alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, and basic salts such as organic base salts such as ammonium salt, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt and the like. Although the reaction is usually carried out in the conventional solvent such as water, alcohols such as methanol, ethanol and the like, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide and pyridine, the reaction may be carried out in any other organic solvents as long as they have no adverse effect on the reaction. These solvents may be used as-a mixture with water. When R2COOH is used as the form of a free acid or a salt thereof in this reaction, it is desirable that the reaction is carried out in the presence of the normally used condensing agent such as so-called Vilsmeier regent and the like prepared by a reaction of N,N′-dicyclohexylcarbodiimide; N-cyclohexyl-N′-morpholinoethylcarbodiimide; N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide; N,N′-diethylcarbodiimide, N,N′-diisopropylcarbodiimide, N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide; N,N′-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; polyethyl phosphate; polyisopropyl phosphate; phosphorus oxychloride; diphenylphosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate such as ethyl chloroformate; isopropyl chloroformate and the like; triphenylphosphine; 2-ethyl-7-hydroxybenzisooxazolium salt, 2-ethyl-5-(m-sulfopheny)isooxazoliumhydroxide internal salt; N-hydroxybenzotriazole; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or the like. Alternatively, the reaction may be carried out in the presence of an inorganic base or an organic base such as alkali metal bicarbonate salt, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine and the like. A reaction temperature is not particularly limited, but the reaction is carried out under cooling or under warming. An amount of R2COOH to be used is 1 to 10 mole equivalent, preferably 1 to 3 equivalent relative compound (VI). A reaction temperature is usually −30° C. to 100° C. A reaction time is usually 0.5 to 20 hours. In addition, when a mixed acid anhydride is used, R2COOH and chlorocarbonic ester (e.g. methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate etc.) are reacted in the. presence of a base (e.g. triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium bicarbonate, sodium carbonate, potassium carbonate etc.) and is further reacted with compound (VI). An amount of R2COOH to be used is usually 1 to 10 mole equivalent, preferably 1 to 3 mole equivalent relative to compound (VI). A reaction temperature is usually −30° C. to 100° C. A reaction time is usually 0.5 to 20 hours. The thus obtained compound (IId) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein each of symbols has a meaning defined above. Step H can be carried out similar to step G in Scheme 5 to prepare compound (IIe) which is encompassed within compound (II) or (III), or a salt thereof. Compound (VII) or a salt thereof can be prepared by Scheme 12 described below. wherein each of symbols has a meaning defined above. Compound (IIf) which is encompassed within compound (II) or (III), or a salt thereof can be prepared by treatment of compound (VIIIa) with a halogenation agent. Compound (VIIIa) or a salt thereof can be prepared by Schemes 13 or 14 described below. Examples of the halogenation agent include chlorine, bromine, iodine, thionyl chloride, thionyl bromide, sulfuryl chloride, oxalyl chloride, phosphorus trichloride, phosphorous pentachloride, and phosphorous oxychloride, etc. In step I, the halogenation agent is employed in an amount of 1 to 10 moles, preferably 1 to 3 moles per 1 mole of compound (VIIIa) or a salt thereof. Examples of the solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on the reagent employed as well as other conditions, it is −20 to 200° C., preferably 20 to 100° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The thus obtained compound (IIf) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein each of symbols has a meaning defined above. Compound (IIg) which is encompassed within compound (II) or (III), or a salt thereof can be prepared by treatment of compound (VIIIb) with a dehydrothiolation agent. Compound (VIIIb) or a salt thereof can be prepared by Schemes 13 or 14 described below. Examples of the dehydrothiolation agent include N,N′-dicyclohexylcarbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide, N,N′-diethylcarbodiimide, N,N′-diisopropylcarbodiimide, N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, mercury(II) chloride, mercury(II) oxide, copper(II) bromide, copper(II) chloride, silver oxide, silver(I) oxide and silver carbonate, etc. In step J, the dehydrothiolation agent is employed in an amount of 1 to 10 moles, preferably 1 to 3 moles per 1 mole of compound (VIIIb) or a salt thereof. Examples of solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitrites. such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. The reaction may be carried out in the presence of an inorganic base or an organic base such as alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate and potassium carbonate; amines such as pyridine, triethylamine, N,N-dimethylaniline and 1,8-diazabicyclo[5.4.0] undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. While the reaction temperature may vary depending on the reagent employed as well as other conditions, it is −20 to 150° C., preferably 20 to 100° C. The reaction time is 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The thus obtained compound (IIg) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein each of symbols has a meaning defined above. Compound (IIh) which is encompassed within compound (II) or (III), or a salt thereof can be prepared by treatment of compound (VIIIc) with a dehydrothiolation agent. Compound (VIIIc) or a salt thereof can be prepared by Schemes 13 or 14 described below. Step K can be carried out similar to step J in Scheme 8 to prepare compound (IIh). wherein x2 is H, OH or NHR5, L3 is a halogen atom such as chlorine, bromine, and iodine, and each of other symbols has a meaning defined above. In step L, compound (X) or a salt thereof can be prepared by treatment of compound (IX) with ammonia. Compound (IX) or a salt thereof is mainly commercially available, or can be prepared by reacting thiophosgene with the amino derivatives (XIV) described below (Scheme 13). Examples of the solvent include water, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxidse such as dimethylsulfoxide. These solvent may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on the reagent employed as well as other conditions, it is −20 to 200° C., preferably 20 to 100° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The thus obtained compound (X) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. Step M can be carried out according to steps I, J or K in the Schemes 7 to 9 to prepare compound (V). In step N, an amino group of compound (V) is converted into a diazonium salt, and halogenation agent is reacted thereon, according to the procedure of Sandmeyer reaction, to prepare compound (IVa), which is encompassed within compound (IV). Diazonization in the present method is carried out in the presence of an acid in a solvent having no adverse effect on the reaction according to the conventional method. As the acid, for example, acetic acid and hydrochloric acid are used. As a diazotizing agent, sodium nitrite, alkyl nitrite or sulfated nitrosyl is used. The thus obtained diazonium salt of compound (V) is reacted with halogenation agent to prepare compound (IV). Examples of the halogenation agent include chlorine, bromine, iodine, copper(I) bromide, copper (II) bromide, copper (I) chlolide and copper (II) chloride, etc. Examples of. the solvent include water, ethers such as. dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitrites such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxidse such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about −50° C. to about 150° C., preferably about −10° C. to about 100° C. A reaction time is usually about 0.5 to about 20 hours. The thus obtained compound (IVa) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein X3 is SH, OH or NHR5 and each of symbols has a meaning defined above. In step O, compound (XII) or a salt thereof can be prepared by treatment of, compound (XI) with 1,1′-carbonyl diimidazole, phosgene, alkyl haloformate such as ethyl chloroformate, phenyl haloformate such as phenyl chloroformate or urea, etc.Compound (XI) or a salt thereof is mainly commercially available or can be prepared from the nitro derivatives corresponded to compound (XI). Examples of the solvent include ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxidse such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on the reagent employed as well as other conditions, it is −20 to 200° C., preferably 20 to 100° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The thus obtained compound (XII) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step P, after base treatment of compound (XII), the resulting moiety may be converted to a leaving group to prepare compound (IV). Such leaving group may for example be a substituted sulfonyloxy (for example, methanesulfonyloxy and p-toluenesulfonyloxy, etc.), an acyloxy (for example, acetoxy and benzoyloxy, etc.) and an oxy group which is substituted with a heterocyclic or aryl group (such as succinimide, benzotriazole, quinoline and 4-nitrophenyl, etc.), etc. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc. In step P, compound (IV) or a salt thereof can be also prepared by treatment of compound (XII) with a halogenation agent. Examples of the halogenation agent include chlorine, bromine, iodine, thionyl chloride, thionyl bromide, sulfuryl chloride, oxalyl chloride, phosphorus trichloride, phosphorous pentachloride, and phosphorous oxychloride, etc. The halogenation agent is employed in an amount of 1 to 10 moles, preferably 1 to 3 moles per 1 mole of compound (XII) or a salt thereof. Examples of the solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on the reagent employed as well as other conditions, it is −20 to 200° C., preferably 20 to 100° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The thus obtained compound (IV) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein each of symbols has a meaning defined above. In step Q, an amino group. of compound (V) is converted into a diazonium salt, and cyanation agent is reacted thereon to prepare compound (XIII), according to the procedure of Sandmeyer reaction. Diazotization in the present method is carried out in the presence of an acid in a solvent having no adverse effect on the reaction according to the conventional method. As the acid, for example, acetic acid, sulfuric acid and hydrochloric acid are used. As a diazotizing agent, sodium nitrite, alkyl nitrite or sulfated nitrosyl is used. The thus obtained diazonium salt of compound (V) is reacted with cyanation agent to prepare compound (XIII). Examples of the cyanation agent include copper cyanide, potassium cyanide, sodium cyanide and nickel cyanide, etc. Examples of the solvent include water, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitrites such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about −50° C. to about 150° C., preferably about −10° C. to about 100° C. A reaction time is usually about 0.5 to about 20 hours. The thus obtained compound (XIII) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step R, compound (VII) or a salt thereof can be prepared by hydrolysis of compound (XIII) or a salt thereof. It is preferable. that hydrolysis is carried out in the presence of a base or an acid. An acid which may be employed may for example be an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, and a base may for example be an inorganic base (alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc.). This reaction is conducted in a 20 to 50 volumes of an aqueous solution of an inorganic acid described above (usually at 10 to 30%) per 1 g of the nitrile compound (XIII), or in an aqueous solution containing 3 to 10 moles of a base described above per 1 mole of the nitrile compound (XIII). In view of the solubility of a compound, the reaction may be performed in an aqueous solution described above which is supplemented with an organic solvent. An organic solvent which may be employed is alcohols such as methanol and ethanol, organic acids such as acetic acid, etc., ethers such as dioxane and tetrahydrofuran, a nitrile such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide and sulfoxides such as dimethylsulfoxide. While the reaction temperature may vary depending on the nitrile employed as well as other conditions, it is 0 to 200° C., preferably 20 to 150° C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours. The thus obtained compound (VII) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein each of symbols has a meaning defined above. Compound (VIII) or a salt thereof can be prepared by reacting (XIV) with R2NCS or a salt thereof. In step S, an isothiocyanate R2NCS is employed in an amount of 1 to 10 moles, preferably 1 to 3 moles per 1 mole of compound (XIV) or a salt thereof. Examples of solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such. as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on compound (XIV) employed as well as other conditions, it is 0 to 200° C., preferably 20 to 150° C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours. The thus obtained compound (VIII) can be isolated and purified by the known isolating and purifying methods, for example,, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein each of symbols has a meaning defined above. Compound (VIII) or a salt thereof can be also prepared by reacting (IX) with R2NH2 or a salt thereof. In step T, compound R2NH2 is employed in an amount of 1 to 10 moles, preferably 1 to 3 moles per 1 mole of compound (IX) or a salt thereof. Examples of the solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitrites such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on compound (IX) employed as well as other conditions, it is 0 to 200° C., preferably 20 to 150° C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours. The thus obtained compound (VIII) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. (Method B) wherein each of symbols has a meaning defined above. Step Ucan be carried out similar to step C, D, and E in the Schemes 2 to 4 to prepare compound (Ib) which is encompassed within compound (I). Compound (XV) or a salt thereof can be prepared by Scheme 16 described below. wherein each of symbols has a meaning defined above. Compound (XVIII) or a salt thereof can be prepared by reacting compound (XVI) with compound (XVII). In step V, 1 to 5 moles, preferably 1 to 3 moles of compound (XVII) or a salt thereof are employed per 1 mole of compound (XVI) or a salt thereof. Examples of the solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. This reaction may be performed under basic conditions. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc. While the reaction temperature may vary depending on compound (XVII) or a salt thereof employed as well as other reaction conditions, it is −20 to 200° C., preferably 0 to 150° C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours. The thus obtained compound (XVIII) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. Step Wcan be carried out similar to step B-1 and B-2 in Scheme 1 to prepare compound (XIX). In step X, compound (XV) or a salt thereof can be prepared by treatment of compound (XIX) with a halogenation agent. Examples of the halogenation agent include N-chlorosuccinimide, N-bromosuccinimide, chlorine, bromine, iodine, thionyl chloride, thionyl bromide, sulfuryl chloride, oxalyl chloride, phosphorus trichloride, phosphorous pentachloride, and phosphorous oxychloride, etc. In step X, the halogenation agent is employed in an amount of 1 to 10 moles, preferably 1 to 3 moles per 1 mole of compound (XIX) or a salt thereof. Examples of the solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as carbon tetrachloride, chloroform and dichloromethane, nitrites such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on the reagent employed as well as other conditions, it is −50 to 200° C., preferably 0 to 100° C. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The thus obtained compound (XV) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. (Method C) wherein each of symbols has a meaning defined above. Compound (Ic) which is encompassed within compound (I), or a salt thereof can be prepared by reacting compound (XX) with an amino compound R1aR1bNH. Compound (XX) or a salt thereof can be prepared by the procedures described in Methods A and B. In step Y, 1 to 5 moles, preferably 1 to 3 moles of a compound represented by R1aR1bNH or a salt thereof and 1 to 5 moles, preferably 1 to 3 moles of a base are employed per 1 mole of compound (XX) or a salt thereof. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as. pyridine, etc. Examples of solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on compound (XX) or a salt thereof employed as well as other reaction conditions, it is −20 to 200° C., preferably 0 to 150° C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours. When n is 0 in compound (XX), compound (Ic) can be also prepared by reacting compound (XX) with R1aR1bNH or a salt thereof in the presence of a palladium catalyst, preferably palladium (II) acetate and a catalytic amount of a phosphine ligand, preferably 2-(dicyclohexylphosphino)biphenyl, according to the procedure of Buchwald et al. (J. Am. Chem. Soc. 1998, 120, 9722) and the modified methods. The thus obtained compound (Ic) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. (Method D) wherein R3 is an optionally substituted carbon atom, and each of symbols has a meaning defined above. In step Z, compound (XXII) is prepared by removing a carboxyl-protecting group. Compound (XXI) or a salt thereof can be prepared by the procedures described in Methods A, B, E and Scheme 19. All conventional methods used in a reaction for removal of a carboxyl-protecting group, for example, hydrolysis, reduction and elimination using a Lewis acid can be applied to the present reaction. It is preferable that hydrolysis is carried out in the presence of a base or an acid. Examples of the suitable base include inorganic bases such as alkali metal hydroxide (e.g. sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxide (e.g. magnesium hydroxide and calcium hydroxide), alkali metal carbonate (e.g. sodium carbonate and potassium carbonate), alkaline earth metal carbonate (e.g. magnesium carbonate and calcium carbonate), alkali metal bicarbonate (e.g. sodium bicarbonate and potassium bicarbonate), alkali metal acetate (e.g. sodium acetate and potassium acetate), alkaline earth metal phosphate (e.g. magnesium phosphate and calcium phosphate) and alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate and dipotassium hydrogen phosphate), and organic bases such as trialkylamine (e.g. trimethylamine and triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.2]non-5-ene, 1,4-diazabicyclo[2.2.2]non-5-ene and 1,8-diazabicyclo[4.3.0]-7-undecene. Hydrolysis using a base is carried out in water or a hydrophilic organic solvent or a mixed solvent in many cases. Examples of a suitable acid include formic acid, hydrochloric acid, hydrobromic acid and sulfuric acid. The present hydrolysis reaction is usually carried out in an organic solvent, water or a mixed solvent thereof. A reaction temperature is not particularly limited, but is appropriately selected depending on a kind of a carboxyl-protecting group and an elimination method. Elimination using a Lewis acid is carried out by reacting compound (XXI) or a salt thereof with a Lewis acid, for example, trihalogenated boron (e.g. boron trichloride and boron trifluoride), tetrahalogenated titanium (e.g. titanium tetrachloride and titanium tetrabromide), and halogenated aluminium (e.g. aluminium chloride and aluminium bromide), or an organic acid (e.g. trichloroacetic acid and trifluoroacetic acid). This elimination reaction is preferably carried out in the presence of a cation scavenger (e.g. anisole and phenol) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane and nitroethane), alkylene halide (e.g. methylene chloride and ethylene chloride), diethyl ether, carbon disulfide, and a solvent having no adverse effect on the reaction. These solvents may be used as a mixture thereof. It is preferable that elimination by reduction is applied to elimination of a protecting group such as halogenated alkyl (e.g. 2-iodoethyl and 2,2,2-trichloroethyl) ester, and aralkyl (e.g. benzyl) ester. Examples of a reduction method using in the present elimination reaction include the conventional catalytic reduction in the presence of a combination of a metal (e.g. zinc and zinc amalgam) or a salt of a chromium compound (e.g. chromate chloride and chromate acetate) and an organic or inorganic acid (e.g. acetic acid, propionic acid and hydrochloric acid); or the conventional metal catalyst (e.g. palladium carbon and Raney nickel). A reaction temperature is not particularly limited, but a reaction is carried out under cooling, at room temperature of under warming. The thus obtained compound (XXII) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step AA, compound (Id) which is encompassed within compound (I), or a salt thereof is prepared by reacting compound (XXII) or a reactive derivative at a carboxyl group thereof and a salt thereof with the amino compound R1aR1bNH or a reactive derivative at an amino group thereof or a salt thereof. Step ZZ can be carried out similar to step G in Scheme 5 to prepare compound (Id) which is encompassed within compound (I). wherein each of symbols has a meaning defined above. Step AB can be carried out similar to step T in Scheme 14 to prepare compound (XXIV) or a salt thereof. Compound (XXIII) or a salt thereof can be prepared from amino derivatives corresponded to compound (XXIII). Step AC can be carried out similar to step I in the Scheme 7 to prepare compound (XXIa), which is encompassed within compound (XXI), or a salt thereof. (Method E) wherein each of symbols has a meaning defined above. Step AD can be carried out similar to step C, D, and E in the Schemes 2 to 4 to prepare compound (Ie) which is encompassed within compound (I). Compound (XXV) or a salt thereof can be prepared by the procedures described in Methods A, B and Scheme 21. wherein each of symbols has a meaning defined above. Step AE can be carried out similar to step P in Scheme 11 to prepare compound (XXVa), which is encompassed within compound (XXV). Compound (XXVI) or a salt thereof can be prepared by the procedures in Schemes 22-25 described below. wherein each of symbols has a meaning defined above. Step AF can be carried out similar to step A in Scheme 1 to prepare compound (XXVIII) or a salt thereof. Compound (XXVII) or a salt thereof can be prepared by the procedures. described in step 0 in Scheme 11. Step AG can be carried out similar to step B in Scheme 1 to prepare compound (XXVIa), which is encompassed within compound (XXVI), or a salt thereof. wherein R1e is an optionally substituted aryl or an optionally substituted heteroaryl, and each of the other symbols has a meaning defined above. Compound (XXVIb), which is encompassed within compound (XXVI), or a salt thereof can be prepared by reacting compound (XXVIII) with R1aaR1bb═O, R1aL1 or a salt thereof in the similar manner described in step B-1 and B-2 in Scheme 1 and with R1eL1 or a salt thereof in the presence of a palladium catalyst, a phosphine ligand, and a base according to the procedure of Buchwald coupling (Topics in Current Chemistry, 219, 131-209 (2002)) to prepare compound (XXVIb). The order of these two steps, AH-1 and AH-2, may be changed. Compound (XXVIII) or a salt thereof can be prepared by Scheme 22 described above. In step AH-2, a palladium catalyst may for example be bis(triphenylphosphine) palladium(II) dichloride, tris(dibenzylidineacetone)dipalladium(0), trans-dichlorobis(tri-o-tolylphosphine)palladium, palladium(II) trifluoroacetate and palladium(II) acetate, preferably tris(dibenzylidineacetone)dipalladium(0). A phosphine ligand may for example be 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl, 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl, 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl, 1,1′-bis(diphenylphosphino)ferrocene, tri-tert-butylphosphine and tricyclohexylphosphine, preferably 2-(dicyclohexylphosphino)biphenyl and 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc. In step AH-2, 1.0 to 5 moles, preferably 1.1 to 2.0 moles of R1eL1, 0.01 to 0.5 moles, preferably 0.05 to 0.2 moles of a palladium catalyst, 0.01 to 0.5 moles, preferably 0.02 to 0.2 moles of a phosphine ligand and 1.0 to 5.0 moles, preferably 1.2 to 3 moles of a base are employed per 1 mole of an amino compound or a salt thereof. Examples of solvent having no adverse effect on the reaction include ethers such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on compound (XIIa) or a salt thereof employed as well as other reaction conditions, it is 0 to 250° C., preferably 50 to 150° C. The reaction time is 5 minutes to 120 hours, preferably 1 hour to 48 hours. As an alternative route, compound (XXVIb) or a salt thereof can be prepared via compound (XXIX). In step AI, compound (XXIX) can be prepared by the similar procedure described in step N in Scheme 10 or reacting compound (XXVIII) with an alkyl nitrite and a metal halide, etc. In step AI, 1.0 to 5 moles, preferably 1.0 to 2.0 moles of an alkyl nitrite, 0.5 to 3 moles, preferably 0.5 to 2 moles of a metal halide. Examples of solvent having no adverse effect on the reaction include ethers such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, nitrites such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on compound (XXVIII) or a salt thereof employed as well as other reaction conditions, it is −10 to 200° C., preferably 0 to 100° C. The reaction time is 5 minutes to 120 hours, preferably 30 minutes to 24 hours. The thus obtained compound (XXIX) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. Step AJ can be carried out similar to step AH-2 to prepare compound (XXX) by reacting with R1eNH2 or a salt thereof. Step AK can be carried out similar to step B in Scheme 1 to prepare compound (XXVIb). The thus obtained compound (XXVIb) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein R1f is an optionally substituted alkyl, an optionally substituted carboxyl or an optionally substituted carboxamide, and each of the other symbols has a meaning defined above. Compound (XXVIc), which is encompassed within compound (XXVI), or a salt thereof can be prepared by oxidation of cycloalkene and next reductive alkylation of compound (XXVIII). Compound (XXVIII) or a salt thereof can be prepared by Scheme 22 described above. In an oxidation step, an oxidation agent is used and a base or an acid may be used. An oxidation agent may for example be potassium permanganate, potassium periodate, sodium periodate, sodium dichromate, potassium dichromate, osmium tetroxide, ruthenium tetroxide, oxygen, ozone, hydrogen peroxide, organic peroxide such as 3-chloroperoxybenzoic acid and peroxyacetic acid, etc., preferably ozone. These reagents may be used by mixing at an appropriate ratio. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc. An acid may for example be an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid. In the oxidation reaction, 1 to 10 moles, preferably 1 to 3 moles of the oxidative agent and 0.1 to 10 moles, preferably 0.3 to 2 moles of the base per 1 mole of compound (XXVIII) or a salt thereof are used. Examples of solvent having no adverse effect on the reaction include alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on compound (XXVIII) or a salt thereof employed as well as other reaction conditions, it is −100 to 200° C., preferably −100 to 100° C. The reaction time is 1 minute to 48 hours, preferably 1 minute to 24 hours. The thus obtained oxidant may be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In a reductive alkylation step, the similar manner described in step B-1 in Scheme 1 is used. The thus obtained compound (XXVIc) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. Step AM can be carried out similar to step O in Scheme 11 to prepare compound (XXVId) or a salt thereof. Compound (XXXI) or a salt thereof can be prepared from the nitro derivatives corresponded to compound (XXXI). Compound (I) obtained by any method described above as a free form may be converted in accordance with a standard procedure for example into a salt with an inorganic acid (for example, hydrochloric acid, sulfuric acid and hydrobromic acid, etc.), an organic acid (for example, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid and tartaric acid, etc.), an inorganic base (for example, alkaline metal such as sodium and potassium, etc., alkaline earth metal such as calcium and magnesium, etc., aluminum and ammonium, etc.) or an organic base (for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,N′-dibenzylethylenediamine, etc.), while compound (I) obtained as a salt may be converted into a free form or other salts according to standard procedure. Compound (I) or a salt thereof thus obtained can be purified and recovered using a separation/purification method known per se (for example, condensation, solvent extraction, column chromatography and recrystallization, etc.). A starting compound for compound (I) according to the invention may be in a form of a salt, including a salt with an inorganic acid (for example, hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid, etc.) and a salt with an organic acid (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid and benzenesulfonic acid, etc.). When any of these compounds carries an acidic group such as —COOH, etc., a salt with an inorganic base (for example, an alkaline metal or an alkaline earth metal such as sodium, potassium, calcium and magnesium, ammonia, etc.) or with an organic base (for example, tri-C1-3 alkylamine such as triethylamine, etc.) may be formed. In each of the reactions described above, when a starting compound carries as a substituent an amino group, an amide group, a urea group, a carboxyl group or a hydroxyl group, then such group may be derivatized with a protective group employed ordinarily in peptide chemistry, which is cleaved after a reaction if desired to yield an intended compound. A protective group for an amino group, an amide group and a urea group may for example be an optionally substituted C1-6 alkylcarbonyl (for example, formyl, methylcarbonyl and ethylcarbonyl, etc.), phenylcarbonyl, a C1-6 alkyloxycarbonyl (for example, methoxycarbonyl,ethoxycarbonyl and tert-butylcarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl), C7-10 aralkylcarbonyl (for example, benzyloxycarbonyl), C7-10 aralkyl (for example, benzyl and 4-methoxybenzyl, etc.), trityl, phthaloyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a C1-6 alkylcarbonyl (for example, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3 times. A protective group for a carboxyl group may for example be an optionally substituted C1-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, etc.), phenyl, trityl and silyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a C1-6 alkylcarbonyl (for example, formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3 times. A protective group for a hydroxyl group may for example be an optionally substituted C1-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl, etc.), phenyl, a C7-10 aralkyl (for example, benzyl, etc.), a C1-6 alkylcarbonyl (for example, formyl, methylcarbonyl and ethylcarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl, etc.), C7-10 aralkylcarbonyl (for example, benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a C1-6 alkyl, phenyl, a C7-10 aralkyl, nitro, etc., which may occur 1 to about 4 times. A method for cleaving a protective group is a method known per se or an analogous method, such as a treatment for example with an acid, a base, a reduction, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc. The pharmaceutical composition containing compound (I) or (Ia) of the present invention is expected to be useful in the treatment and prevention of diseases, in which CRF is involved, such as great depression, postpartum depression, suppression symptom, mania, anxiety, generalized anxiety disorder, panic disorder, phobia, obsessive-compulsive disorder, post psychic trauma stress disorder, Tourette's syndrome, autism, passion disorder, adjustment disorder, dysthymic disorder, sleep disorder, insomnia, bipolar disorder, circulatory disease, neurosis, schizophrenia, digestive ulcer, irritable bowl syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative ileus, gastrointestine dysfunction and nervous vomiting associated with stress, Alzheimer's disease, Alzheimer's type senile dementia, nervous degenerated disease such as Parkinson's disease and Huntington's disease, multi-infarct dementia, senile dementia, nervous orexia inactivity, hyperphagia and other ingestion disorder, obesity, diabetes, alcohol dependency, pharmacophinia, drug withdrawal, migraine, stress headache, tension headache, ischemic nervous disorder, nervous disorder, cerebral paralysis, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscular convulsion, chronic fatigue syndrome, glaucoma, Meniere syndrome, autonomic imbalance, alopecia, hypertension, cardiovascular disorder, tachycardia, congestive heart attack, hyperplea, bronchial asthma, apnea, infant sudden death syndrome, inflammatory disorder, pain, allergic disorder, impotence, menopausal disorder, fertilization disorder, infertility, cancer, immune function abnormality at HIV infection, immune functional abnormality due to stress, cerebrospinal meningitis, acromegaly, incontinence or osteoporosis. Compound (I) or (Ia) of the present invention can be formulated with a pharmaceutically acceptable carrier and can be orally or parenterally administered as solid formulations such as tablets, capsules, granules, powders, or the like; or liquid formulations such as syrups, injections, or the like. Also, there can be prepared formulations for transdermal administration such as patchings, cataplasms, ointments (including creams), plasters, tapes, lotions, liquids and solutions, suspensions, emulsions, sprays, and the like. As for a pharmaceutically acceptable carrier, a variety of organic or inorganic carrier substances, which have been conventionally employed as formulation materials, is used and compounded as a bulking agent, a lubricant, a binding agent, and a disintegrator in solid formulations; a vehicle, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent, and an analgesic in liquid formulations. If necessary, formulation excipients such as a preservative, an antioxidant, a stabilizer, a coloring agent, a sweetening agent, and the like can be used. Preferred examples of the bulking agent include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include magnesium stearate, potassium stearate, talc, colloidal silica, and the like. Preferred examples of the binding agent include crystalline cellulose, α-starch, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and the like. Preferred examples of the disintegrator include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and the like. Preferred examples of the vehicle include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like. If necessary, for the purpose of taste masking, enteric coating, or prolonged action, oral formulations can be prepared by coating by a per se known method. Examples of this coating agent include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68 [polyoxyethylene (160) polyoxypropylene (30) glycol], cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate phthalate, Eudragit (manufactured by Rohm Company, methacrylic acid-acrylic acid copolymer), and the like. Preferred examples of the solubilizing agent include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trisamiomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Preferred examples of the suspending agent include surface active agents such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, and the like; hydrophilic, high molecular substances such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like; and so on. Preferred examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol, and the like. Preferred examples of the buffering agent include buffer solutions of a phosphate, an acetate, a carbonate, a citrate, or the like. Preferable examples of the analgesic include benzyl alcohol and the like. Preferred examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferred examples of the antioxidant include sulfites, ascorbic acid, and the like. The following examples and experiments describe the manner and process of making and using the present invention and are illustrative rather than limiting. It is to be understood that there may be other embodiments which fall within the spirit and scope of the present invention as defined by the claims appended hereto. EXAMPLE 1 N2-Mesityl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine N2-Mesityl-7-nitro-1,3-benzothiazol-2-amine A mixture of 2.25 g (12.5 mmol) of 3-nitrophenylisothiocyanate and 1.4 mL (10 mmol) of mesityl amine in 10 mL of methanol was stirred at room temperature for 2 h. The resulting precipitate was collected by filtration and dried to give a quantitative yield of 1-(3-nitrophenyl)-3-(mesityl)thiourea. To 1.8 g (5.7 mmol) of the thiourea thus prepared slurried in 20 mL of CCl4 was added 0.35 mL (6.9 mmol) of bromine. The mixture was heated at reflux for 4 h, allowed to cool to room temperature and diluted with dichloromethane. This solution was washed successively with saturated sodium bicarbonate, water and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude title compound was obtained in quantitative yield and was used without further purification. MS Calcd.: 313; Found: 314 (M+H). N2-Mesityl-1,3-benzothiazole-2,7-diamine To a solution of 1.8 g (5.7 mmol) of N2-mesityl-7-nitro-1,3-benzothiazol-2-amine in 7.2 mL of glacial acetic acid and 25 mL of ethanol was added 1.8 g (32 mmol) of iron powder. The resulting solution was heated at reflux for 18 h before being cooled to room temperature. The slurry was filtered and the filtrate was concentrated to a brown solid. The solid was slurried in water, collected by filtration and purified by flash chromatography eluting with a 33% hexanes/ethyl acetate mixture to give 0.9 g (55%) of the title compound as a tan powder. MS Calcd.: 283; Found: 284 (M+H). N2-Mesityl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine To 0.125 g (0.44 mmol) of N2-mesityl-1,3-benzothiazole-2,7-diamine and 0.16 mL (2.2 mmol) of propionaldehyde in 5 mL of dichloroethane was added one drop of glacial acetic acid and 0.28 g (1.3 mmol) of sodium triacetoxyborohydride. The mixture was heated to 50° C. for 1 h and concentrated in vacuo. The crude solid was purified by flash chromatography eluting with a 2% methanol/dichloromethane mixture to give 0.016 g (10%) of the title compound as a tan powder. 1H NMR (CDCl3) δ 0.73 (t, J=7.4 Hz, 6H), 1.31-1.40 (m, 4H), 2.23 (s, 6H), 2.26 (s, 3H), 2.94-2.98 (m, 4H), 6.67 (t, J=2.7 Hz, 1H), 6.92 (s, 2H), 7.14-7.17 (m, 2H). MS Calcd.: 367; Found: 368 (M+H). Compounds of Examples 2-6 shown in Table 1, were prepared in a manner similar to that described in Example 1. Compounds 2 and 3 were purified by reverse phase HPLC (CH3CN containing 0.1% TFA/water containing 0.1% TFA) to obtain TFA salts. TABLE 1 Example Structure Name Physical Data 2 N7,N7-dimethyl- N2-mesityl-1,3- benzothiazole- 2,7-diamine MS Calcd.: 311; Found: 312 (M + H) 3 N7,N7- diisobutyl-N2- mesityl-1,3- benzothiazole- 2,7-diamine MS Calcd.: 395; Found: 396 (M + H) 4 N7,N7-diethyl- N2 -mesityl-1,3- benzothiazole- 2,7-diamine MS Calcd.: 339 Found: 340 (M + H) 5 N2-mesityl-N2- methyl-N7,N7- dipropyl-1,3- benzothiazole- 2,7-diamine MS Calcd.: 381 Found: 382 (M + H) 6 N2-mesityl- N7,N7-dibutyl- 1,3- benzothiazole- 2,7-diamine MS Calcd.: 395 Found: 396 (M + H) EXAMPLE 7 N2-Mesityl-N7,N7-dipropyl[1,3]thiazolo[4,5-b]pyridine-2,7-diamine 2-Chloro-N4,N4-dipropylpyridin-4-amine A mixture of 0.65 g (5.1 mmol) of 4-amino-2-chloropyridine and 1.8 mL (25 mmol) of propionaldehyde in 5 mL of dichloroethane was treated with two drops of glacial acetic acid and 3.2 g (15 mmol) of sodium triacetoxyborohydride. The mixture was heated to 50° C. for 1 h and an additional 0.9 mL (12.5 mmol) of propionaldehyde and 1.6 g (7.5 mmol) of sodium triacetoxyborohydride was added. The mixture was heated at 50° C. for an additional 36 h. The reaction was cooled to room temperature and 0.15 g (4 mmol) of sodium borohydride was added. The reaction was heated to 80° C. for 1 h and cooled to room temperature. The mixture was diluted with dichloromethane and was washed successively with water and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude oil was purified by flash chromatography eluting with a 80% hexanes/ethyl acetate mixture to give 0.41 g (38%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 0.91 (t, J=7.4 Hz, 6H), 1.53-1.62 (m, 4H), 3.20 (t, J=7.8 Hz, 4H), 6.32 (dd, J=2.5, 6.0 Hz, 3H), 6.39 (d, J=2.5 Hz, 1H), 7.89 (d, J=6.0 Hz, 1H). N2-Diphenylmethylene-N4,N4-dipropylpyridine-2,4-diamine A mixture of 0.52 g (2.4 mmol) of 2-chloro-N4,N4-dipropylpyridin-4-amine, 0.076 g (0.12 mmol) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP), 0.33 g (3.4 mmol) of sodium tert-butoxide and 0.027 g (0.12 mmol) of palladium (II) acetate in 25 mL of toluene was treated with 0.49 mL (2.9 mmol) of benzophenone imine and heated to 85° C. for 18 h. The crude reaction mixture was diluted with ethyl acetate, filtered through a pad of celite and purified by flash chromatography eluting with a 33% hexanes/ethyl acetate mixture to give 0.65 g (75%) of the title compound as a golden oil. MS Calcd.: 357; Found: 358 (M+H). N4,N4-Dipropylpyridine-2,4-diamine To 0.235 g (0.66 mmol) of N2-diphenylmethylene-N4,N4-dipropylpyridine-2,4-diamine in 9 mL of methanol was added 0.13 g (1.6 mmol) of sodium acetate followed by 0.082 g (1.2 mmol) of hydroxylamine hydrochloride. The resulting clear golden reaction mixture was stirred at room temperature for 45 min and concentrated in vacuo. The crude solids were slurried in dichloromethane, filtered and the filtrate was concentrated. The resulting oil was purified by flash chromatography eluting with a 13% to 20% methanol/dichloromethane gradient containing 2% triethylamine to give 0.106 g (83%) of the title compound as a white solid. MS Calcd.: 193; Found: 194 (M+H). 1-[4-(Dipropylamino)pyridin-2-yl]-3-mesitylthiourea To 0.106 g (0.0.55 mmol) of N4,N4-dipropylpyridine-2,4-diamine in 10 mL of methanol was added 0.117 g (0.66 mmol) of mesitylisothiocyanate. The mixture was heated at reflux for 24 h, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and the resulting crude solid was purified by flash chromatography eluting with a 85% hexanes/ethyl acetate mixture to give 0.044 g (22%) of the title compound as a white solid. MS Calcd.: 370; Found: 371 (M+H). N2-Mesityl-N7,N7-dipropyl[1,3]thiazolo[4,5-b]pyridine-2,7-diamine To 0.040 g (0.11 mmol) of 1-[4-(Dipropylamino)pyridin-2-yl]-3-mesitylthiourea in 2 mL of glacial acetic acid was added 6.1 μL (0.12 mmol) of bromine. After 30 min at room temperature, an additional 2 μL of bromine was added. The reaction mixture was concentrated after 2 h and washed with ethyl acetate/hexanes. The organics were concentrated and the resulting oil was purified by flash chromatography eluting with a 4% methanol/dichloromethane mixture to give 0.020 g (50%) of the title compound as a light yellow powder. 1H NMR (DMSO-d6) δ 0.84 (t, J=7.2 Hz, 6H), 1.50-1.56 (m, 4H), 2.17 (s, 6H), 2.27 (s, 3H), 3.30 (s, 4H), 6.34 (d, J=5.9 Hz, 1H), 6.98 (s, 2H), 7.88 (d, J=5.9 Hz, 1H), 9.55 (br s, 1H). MS Calcd.: 368; Found: 369 (M+H). EXAMPLE 8 N2-(1-Phenylethyl)-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine 2-Chloro-7-nitro-1,3-benzothiazole (A) To 0.195 g (1.0 mmol) of 7-nitro-1,3-benzothiazol-2-amine and 0.336 g (2.5 mmol) of cupric chloride in 2 mL of N,N-dimethylformamide (DMF) was added dropwise 0.15 mL (1.25 mmol) of tert-butyl nitrite. The reaction was stirred at room temperature for 24 h, poured into water, and the resulting precipitate was collected and dried to give 0.163 g (76%) of the title compound as a tan powder. MS Calcd.: 215; Found: 214 (M−H). 7-Nitro-N2-(1-phenylethyl)-1,3-benzothiazol-2-amine (B) To 0.160 g (0.75 mmol) of 2-chloro-7-nitro-1,3-benzothiazole in 2 mL of 1-methyl-2-pyrrolidinone (NMP) was added 0.29 μL (2.2 mmol) of racemic α-methylbenzylamine. The reaction was stirred at room temperature for 18 h, diluted with water and extracted with dichloromethane. The organic layer was concentrated in vacuo and purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 0.165 g (74%) of the title compound as a light yellow solid which was used without further analysis in the subsequent step. N2-(1-Phenylethyl)-1,3-benzothiazole-2,7-diamine (C) To 0.165 g (0.55 mmol) of 7-nitro-N2-(1-phenylethyl)-1,3-benzothiazol-2-amine in 10 mL of DMF was added 0.62 g (2.8 mmol) of stannous chloride dihydrate. The reaction was heated to 80° C. for 48 h and neutralized with saturated sodium bicarbonate. The mixture was filtered through celite and extracted with ethyl acetate. The extracts were dried in vacuo and purified by flash chromatography eluting with a 50-75% ethyl acetate/hexanes gradient mixture to give 0.016 g (11%) of the title compound as a light yellow solid. MS Calcd.: 269; Found: 270 (M+H). N2-(1-Phenylethyl)-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine (D) To 0.016 g (0.059 mmol) of N2-(1-phenylethyl)-1,3-benzothiazole-2,7-diamine and 21 μL (0.30 mmol) of propionaldehyde in 2 mL of dichloroethane was added one drop of glacial acetic acid and 0.038 g (0.18 mmol) of sodium triacetoxyborohydride. The mixture was heated to 50° C. for 3 h and concentrated in vacuo. The crude solid was purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 0.008 g (38%) of the title compound as a light golden colored oil. MS Calcd.: 353; Found: 354 (M+H). EXAMPLE 9 2-Morpholin-4-yl-N,N-dipropyl-1,3-benzothiazol-7-amine b 2-Morpholin-4-yl-7-nitro-1,3-benzothiazole To 0.200 g (0.77 mmol) of 2-bromo-7-nitro-1,3-benzothiazole in 2 mL of DMF was added 0.21 g (1.5 mmol) of potassium carbonate and 81 μL (0.93 mmol) of morpholine. The mixture was stirred at room temperature for 72 h and diluted with water. The precipitate that formed was collected by filtration and purified by flash chromatography eluting with a 33% ethyl acetate/hexanes mixture to give 0.075 g (37%) of the title compound as a cream colored powder. MS Calcd.: 265; Found: 266 (M+H). 2-Morpholin-4-yl-1,3-benzothiazol-7-amine To 0.075 g (0.28 mmol) of 2-morpholin-4-yl-7-nitro-1,3-benzothiazole in 6 mL of tetrahydrofuran (THF) was added a pipet tip of Raney nickel. The reaction was kept under a hydrogen atmosphere via a balloon and stirred at room temperature for 5 h. The catalyst was removed via filtration and the filtrate was concentrated in vacuo. Purification by flash chromatography failed to provide clean B so the 0.022 g (33%) of material thus isolated was used without further purification. 2-Morpholin-4-yl-N,N-dipropyl-1,3-benzothiazol-7-amine To 0.022 g (0.094 mmol) of 2-morpholin-4-yl-1,3-benzothiazol-7-amine and 40 μL (0.56 mmol) of propionaldehyde in 2 mL of dichloroethane was added one drop of glacial acetic acid and 0.064 g (0.30 mmol) of sodium triacetoxyborohydride. The mixture was heated to 50° C. for 5 h and concentrated in vacuo. The crude solid was purified by flash chromatography eluting with a 17% ethyl acetate/hexanes mixture to give 0.009 g (30%) of the title compound as a light golden colored oil. MS Calcd.: 319; Found: 320 (M+H). EXAMPLE 10 N-(7-(Dipropylamino)-1,3-benzothiazol-2-yl)-2,4,6-trimethylbenzamide (3-Nitrophenyl)thiourea To 7.20 g (40 mmol) of 3-nitrophenylisothiocyanate in 25 mL of methanol was added 28.5 mL (200 mmol) of 7 N ammonia in methanol. After 30 min., the slurry was concentrated to give 7.9 g (100%) of the title compound as a yellow-orange powder that did not require further purification. MS Calcd.: 197; Found: 198 (M+H). 7-Nitro-1,3-benzothiazol-2-amine To 0.60 g (3.0 mmol) of (3-nitrophenyl)thiourea in 25 mL of carbon tetrachloride was added 0.17 mL (3.4 mmol) of bromine in 10 mL of carbon tetrachloride dropwise over 1 h. The mixture was heated to reflux for 18 h, cooled to room temperature and the precipitate that formed was collected by filtration. The precipitate was slurried in glacial acetic acid and the solids were collected by filtration. The solids thus obtained were slurried in water and saturated potassium carbonate was added until the pH was about 9. The free base was collected by filtration to give 0.30 g (51%) of the title compound as a light orange solid. MS Calcd.: 195; Found: 196 (M+H). 2,4,6-Trimethyl-N-(7-nitro-1,3-benzothiazol-2-yl)benzamide To 0.089 g (0.46 mmol) of 7-nitro-1,3-benzothiazol-2-amine in 1 mL of pyridine was added 0.17 g (0.91 mmol) of 2,4,6-trimethylbenzoyl chloride. The mixture was heated to 75° C. for 18 h and the volatiles were removed in vacuo. The residue was washed with water and 1 N hydrochloric acid, dissolved in ethyl acetate, dried over sodium sulfate, filtered, concentrated in vacuo and the resulting crude solid was purified by flash chromatography eluting with 25% ethyl acetate/hexanes mixture to give 0.103 g (66%) of the title compound as a tan solid. 1H NMR (DMSO-d6) δ 2.21 (s, 6H), 2.26 (s, 3H), 6.95 (s, 2H), 7.72 (t, J=8.0 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.31 (d, J=8.2 Hz, 1H), 12.98 (s, 1H). MS Calcd.: 341; Found: 342 (M+H). N-(7-Amino-1,3-benzothiazol-2-yl)-2,4,6-trimethylbenzamide To 0.200 (0.586 mmol) of 2,4,6-trimethyl-N-(7-nitro-1,3-benzothiazol-2-yl)benzamide in 5 mL of THF was added a pipet tip of Raney nickel. The reaction was kept under a hydrogen atmosphere via a balloon and stirred at room temperature for 90 min. The catalyst was removed via filtration and the filtrate was concentrated in vacuo to give a burnt orange solid. The resulting crude solid was purified by flash chromatography eluting with 25% ethyl acetate/hexanes mixture to give 0.118 g (65%) of the title compound as a light yellow powder. MS Calcd.: 311; Found: 312 (M+H). N-(7-(Dipropylamino)-1,3-benzothiazol-2-yl)-2,4,6-trimethylbenzamide To 0.118 g (0.379 mmol) of N-(7-amino-1,3-benzothiazol-2-yl)-2,4,6-trimethylbenzamide and 0.14 mL (1.9 mmol) of propionaldehyde in 5 mL of dichloroethane was added one drop of glacial acetic acid and 0.24 g (1.1 mmol) of sodium triacetoxyborohydride. The mixture was heated to 50° C. for 3 h and an additional 0.14 mL of propionaldehyde was added. The reaction was heated at 50° C. for 18 h and concentrated in vacuo. The crude solid was purified by flash chromatography eluting with a 13% ethyl acetate/hexanes mixture to give 0.080 g (53%) of the title compound as a cream colored powder. MS Calcd.: 395; Found: 396 (M+H). EXAMPLE 11 2-(2,4-Dimethylphenoxy)-N,N-dipropyl-1,3-benzothiazol-7-amine 2-Bromo-7-nitro-1,3-benzothiazole To a suspension of 7-nitro-1,3-benzothiazol-2-ylamine (1.80 g, 9.22 mmol) in acetic acid (AcOH) (20 ml) was added 48% hydrogen bromide in H2O (10 ml) with ice-cooling. Bromine (0.157 ml) was added dropwise followed by sodium nitrite (177 mg, 23.9 mmol) in H2O (1 ml). The temperature was kept at 0 to 5° C. The mixture was stirred for 2 h with ice-cooling and then was made alkaline by dropwise addition of 6N NaOH solution. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 1.91 g of the title compound. 1H-NMR (CDCl3) δ 7.68 (1H, m), 8.33 (1H, m), 8.43 (1H, m). MS Calcd: 257; Found: 258 (M−H), 260. 2-(2,4-Dimethylphenoxy)-7-nitro-1,3-benzothiazole A mixture of 2-bromo-7-nitro-1,3-benzothiazole (200 mg, 0.772 mmol), 2,4-dimethylphenol (0.093 ml, 0.772 mmol) and potassium carbonate (128 mg, 0.772 mmol) in DMF (10 ml) was stirred at 80° C. for 15 h. The mixture was diluted with water and extracted with ethyl acetate (AcOEt). The extract was washed with saturated NaHCO3 solution and brine, dried over Magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 226 mg of the title compound. 1H-NMR (CDCl3) δ 2.26 (3H, s), 2.38 (3H, s), 7.10-7.20 (3H, m), 7.55 (1H, t, J=8.0 Hz), 8.02 (1H, dd, J=0.8, 8.0 Hz), 8.24 (1H, dd, J=0.8, 8.0 Hz). MS Calcd: 300; Found: 301 (M+H). 2-(2,4-Dimethylphenoxy)-1,3-benzothiazol-7-amine A mixture of 2-(2,4-dimethylphenoxy)-7-nitro-1,3-benzothiazole (220 mg, 0.733 mmol) and tin(II) chloride dihydrate (694 mg, 3.66 mmol) in DMF (10 ml) was stirred at 80° C. for 15 h and diluted with saturated NaHCO3 solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine, dried over Magnesium sulfate, and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 226 mg of the title compound. 1H-NMR (CDCl3) δ 2.26 (3H, s), 2.36 (3H, s), 3.70 (2H, s), 6.61 (1H, dd, J=1.6, 8.0 Hz), 7.08 (1H, d, J=8.0 Hz), 7.11 (1H, m), 7.17 (1H, t, J=8.0 Hz), 7.22 (1H, d, J=8.0 Hz), 7.24 (1H, d, J=1.6 Hz). MS Calcd: 270; Found: 271 (M+H). 2-(2,4-Dimethylphenoxy)-N,N-dipropyl-1,3-benzothiazol-7-amine To a solution of 2-(2,4-dimethylphenoxy)-1,3-benzothiazol-7-amine (54 mg, 0.200 mmol) in dichloromethane (DCM) (3 ml) was added propionaldehyde (0.058 ml, 0.799 mmol) followed after 30 min by sodium triacetoxyborohydride (169 mg, 0.799 mmol) and AcOH (0.023 ml). The mixture was stirred at room temperature for 15 h. The reaction was quenched with saturated NaHCO3 solution. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 2% AcOEt in n-hexane to afford 57 mg of the title compound. 1H-NMR (CDCl3) δ 0.85 (6H, t, J=7.2 Hz), 1.40-1.55 (4H, m), 2.62 (3H, s), 3.25 (3H, s), 3.08 (4H, t, J=7.2 Hz), 6.87 (1H, d, J=8.0 Hz), 7.06 (1H, d, J=8.0 Hz), 7.10 (1H, s), 7.16 (1H, d, J=8.0 Hz), 7.27 (1H, t, J=8.0 Hz), 7.37 (1H, d, J=8.0 Hz). MS Calcd: 354; Found: 355 (M+H). EXAMPLES 12-14 EXAMPLE 12 2-[(2,4-Dimethylphenyl)thio]-N,N-dipropyl-1,3-benzothiazol-7-amine (A) EXAMPLE 13 2-[(2,4-Dimethylphenyl)sulfinyl]-N,N-dipropyl-1,3-benzothiazol-7-amine (B) EXAMPLE 14 2-[(2,4-Dimethylphenyl)sulfonyl]-N,N-dipropyl-1,3-benzothiazol-7-amine (C) 2-[(2,4-Dimethylphenyl)thio]-N,N-dipropyl-1,3-benzothiazol-7-amine (A) Compound (A) was prepared in a manner similar to that described in example 11. 1H-NMR (CDCl3) δ 0.79 (6H, t, J=7.2 Hz), 1.35-1.50 (4H, m), 2.40 (3H, s), 2.48 (3H, s), 3.05 (4H, t, J=7.2 Hz), 6.82 (1H, d, J=8.0 Hz), 7.11 (1H, d, J=8.0 Hz), 7.21 (1H, s), 7.29 (1H, t, J=8.0 Hz), 7.48 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=8.0 Hz). MS Calcd: 370; Found: 371 (M+1). 2-[(2,4-Dimethylphenyl)sulfinyl]-N,N-dipropyl-1,3-benzothiazol-7-amine (B) 3-Chloroperoxybenzoic acid (MCPBA) (20 mg, 0.0810 mmol) was added to a solution of 2-[(2,4-dimethylphenyl)thio]-N,N-dipropyl-1,3-benzothiazol-7-amine (30 mg, 0.0810 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 18 h and diluted with saturated NaHCO3. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to afford 16 mg of the title compound. 1H-NMR (CDCl3) δ 0.81 (6H, t, J=7.2 Hz), 1.20-1.30 (2H, m), 1.85-2.00 (2H, m), 2.36 (3H, s), 2.49 (3H, s), 3.40-3.60 (4H, m), 6.98 (1H, d, J=8.0 Hz), 7.06 (1H, d, J=8.0 Hz), 7.16 (1H, s), 7.39 (1H, t, J=8.0 Hz), 7.60 (1H, d, J=8.0 Hz), 7.79 (1H, d, J=8.0 Hz). MS Calcd: 386; Found: 387 (M+H). 2-[(2,4-Dimethylphenyl)sulfonyl]-N,N-dipropyl-1,3-benzothiazol-7-amine (C) MCPBA (50 mg, 0.202 mmol) was added to a solution of 2-((2,4-dimethylphenyl)thio)-N,N-dipropyl-1,3-benzothiazol-7-amine (30 mg, 0.081 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 18 h and diluted with saturated NaHCO3 solution. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to afford 6.4 mg of the title compound. 1H-NMR (CDCl3) δ 0.83 (6H, t, J=7.6 Hz), 1.10-1.20 (2H, m), 1.95-2.05 (2H, m), 2.38 (3H, s), 2.70 (3H, s), 3.45-3.70 (4H, m), 7.11 (1H, s), 7.22 (1H, d, J=8.0 Hz), 7.27 (1H, d, J=8.0 Hz), 7.58 (1H, t, J=8.0 Hz), 8.12 (1H, d, J=8.0 Hz), 8.16 (1H, d, J=8.0 Hz). MS Calcd: 402; Found: 403 (M+H). EXAMPLE 15 N2-Mesityl-4-methyl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine 4-Methyl-3-nitro)-N,N-dipropylaniline To a solution of 4-methyl-3-nitroaniline (2.00 g, 13.1 mmol) in dichloromethane (100 ml) was added propionaldehyde (3.79 ml, 52.6 mmol) followed after 30 min by sodium triacetoxyborohydride (11.1 g, 52.6 mmol) and AcOH (0.75 ml). The mixture was stirred at room temperature for 15 h. The reaction was quenched with saturated NaHCO3 solution. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 2% AcOEt in n-hexane to afford 2.50 g of the title compound. 1H-NMR (CDCl3) δ 0.93 (6H, t, J=7.6 Hz), 1.50-1.65 (4H, m), 2.44 (3H, s), 3.24 (4H, t, J=7.6 Hz), 6.74 (1H, dd, J=2.8, 8.8 Hz), 7.09 (1H, d, J=8.8 Hz), 7.18 (1H, d, J=2.8 Hz). MS Calcd: 236; Found: 237 (M+H). 4-Methyl-N1,N1-dipropyl-benzene-1,3-diamine A mixture of 4-methyl-3-nitro-N,N-dipropylaniline (2.49 g, 10.5 mmol) and 10% Pd on carbon (1.00 g) in AcOEt (50 ml) was hydrogenated for 18 h. The catalyst was removed by filtration through Celite. The filtrate was concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 689 mg of the title compound. 1H-NMR (CDCl3) δ 0.85-0.95 (6H, m), 1.45-1.60 (4H, m), 2.07 (3H, s), 3.16 (4H, t, J=7.6 Hz), 3.50 (2H, m), 6.01 (1H, d, J=2.8 Hz), 6.07 (1H, dd, J=28, 8.0 Hz), 6.85 (1H, d, J=8.0 Hz). MS Calcd: 206; Found: 207 (M+H). 1-(5-Dipropylamino-2-methylphenyl)-3-mesityl thiourea A mixture of 4-Methyl-N1,N1-dipropyl-benzene-1,3-diamine (200 mg, 0.970 mmol) and 2,4,6-trimethylphenylisothiocyanate (215 mg, 1.21 mmol) in methanol (2 ml) was refluxed for 18 h. The solvent was evaporated under vacuum. The residue was triturated with methanol. The solid was collected by filtration and washed with methanol to afford 261 mg of the title compound. 1H-NMR (CDCl3) δ 0.92 (6H, t, J=7.2 Hz), 1.56 (6H, s), 1.50-1.65 (4H, m), 2.22 (3H, s), 2.26, 2.27 (3H, s), 2.30-2.40 (4H, m), 6.57, 6.60 (1H, s), 6.80-6.90 (2H, m), 7.15, 7.26 (1H, s), 7.52 (1H, s). MS Calcd: 383; Found: 384 (M+H). N2-Mesityl-4-methyl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine To a mixture of 1-(5-dipropylamino-2-methylphenyl)-3-mesitylthiourea (100 mg, 0.261 mmol) in carbon tetrachloride (10 ml) was added dropwise bromine (0.015 ml, 0.287 mmol) in carbon tetrachloride (5 ml) over 30 min. The mixture was refluxed for 18 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 39 mg of the title compound. 1H-NMR (CDCl3) δ 0.76-0.82 (6H, m), 1.25-1.45 (4H, m), 1.58 (3H, s), 2.29 (3H, s), 2.30 (3H, s), 2.52 (3H, s), 2.90-2.99 (4H, m), 6.71 (1H, d, J=8.0 Hz), 6.95 (1H, m), 6.98 (2H, s), 7.04 (1H, d, J=8.0 Hz). MS Calcd: 381; Found: 382 (M+H). EXAMPLE 16 N2-(2,4-Dimethylphenyl)-4-methyl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine The compound of example 16 was prepared in a manner similar to that described in example 15. MS Calcd: 367; Found: 368 (M+H). EXAMPLES 17 AND 18 EXAMPLE 17 N2-Mesityl-6-methyl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine, and EXAMPLE 18 4-Ethoxy-N2-mesityl-6-methyl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine 4-Isothiocyanato-1-methyl-2-nitrobenzene To a mixture of 4-methyl-3-nitroaniline (1.00 g, 6.57 mmol) and triethylamine (2.75 ml, 19.7 mmol) in THF (150 ml, 7.23 mmol) was added dropwise thiophosgene (0.55 ml) at 0° C. After addition, the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was diluted with water and extracted with ether. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under vacuum to afford 1.04 g of the title compound. 1H-NMR (CDCl3) δ 2.60 (3H, s), 7.30-7.40 (2H, m), 7.83 (1H, m). 3-Mesityl-1-(4-methyl-3-nitrophenyl)thiourea A mixture of 4-isothiocyanato-1-methyl-2-nitrobenzene (500 mg, 2.58 mmol) and 2,4,6-trimethylaniline (0.329 ml, 2.34 mmol) in methanol (10 ml) was refluxed for 4 h. The solvent was evaporated under vacuum. The residue was triturated with ether. The resulting solid was collected by filtration to afford 550 mg of the title compound. 1H-NMR (CDCl3) δ 2.31 (6H, s), 2.33 (3H, s), 2.58 (3H, s), 7.05 (1H, s), 7.30 (1H, d, J=8.0 Hz), 7.52 (1H, s), 7.79 (1H, d, J=8.0 Hz), 7.93 (1H, s). MS Calcd: 329; Found: 330 (M+H). N-Mesityl-6-methyl-7-nitro-1,3-benzothiazol-2-amine To a mixture of 3-mesityl-1-(4-methyl-3-nitrophenyl)thiourea (500 mg, 1.52 mmol) in carbon tetrachloride (25 ml) was added dropwise bromine (0.097 ml, 1.90 mmol) in carbon tetrachloride (10 ml) over 1 h. The mixture was refluxed for 18 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and concentrated under vacuum. The residue was triturated with ether. The resulting solid was collected by filtration to afford 225 mg of the title compound. 1H-NMR (CDCl3) δ 2.30 (6H, s), 2.35 (3H, s), 2.75 (3H, s), 7.01 (2H, s), 7.17 (1H, bs), 7.28 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=8.0 Hz). MS Calcd: 327; Found: 328 (M+H). N2-Mesityl-6-methyl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine (A) and 4-Ethoxy-N2-mesityl-6-methyl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine (B) To a solution of N-mesityl-6-methyl-7-nitro-1,3-benzothiazol-2-amine (210 mg, 0.641 mmol) in ethanol was added tin(II) chloride dihydrate (608 mg, 3.21 mmol). The mixture was refluxed for 15 h. The solvent was evaporated under vacuum. The residue was diluted with saturated NaHCO3 solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine dried over magnesium sulfate and concentrated under vacuum. The residue was dissolved in dichloromethane (10 ml). To this solution was added propionaldehyde (0.087 ml, 1.21 mmol) followed after 30 min by sodium triacetoxyborohydride (257 mg, 1.21 mmol) and AcOH (0.035 ml). The mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO3 solution. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 7.1 mg of compound (A) and 11.9 mg of compound (B). Compound (A): 1H-NMR (CDCl3) δ 0.75-0.85 (6H, m), 1.25-1.40 (4H, m), 2.31 (6H, s), 2.33 (3H, s), 2.34 (3H, s), 2.90 (4H, t, J=7.6 Hz), 6.99 (2H, s), 7.06 (1H, d, J=8.0 Hz), 7.15 (1H, d, J=8.0 Hz), 7.50 (1H, m). MS Calcd: 381; Found: 382 (M+H). Compound (B): 1H-NMR (CDCl3) δ 0.75-0.85 (6H, m), 1.25-1.35 (4H, m), 1.53 (3H, t, J=7.2 Hz), 2.29 (6H, s), 2.33 (6H, s), 2.84 (4H, t, J=7.6 Hz), 4.18 (2H, q, J=7.2 Hz), 6.60 (1H, s), 6.75 (1H, m), 6.98 (2H, s). MS Calcd: 425; Found: 426 (M+H). EXAMPLE 19 N2-Mesityl-5-methyl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine Methyl 2-mesitylamino-7-nitro-1,3-benzothiazole-5-carboxylate (A) and Methyl 2-mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylate (B) To a mixture of methyl 3-[[(mesitylamino)carbonothioyl]amino]-5-nitrobenzoate (1.65 g, 4.42 mmol), which was prepared in a manner similar to that described in example 14, in carbon tetrachloride (50 ml) was added dropwise bromine (0.283 ml, 1.25 mmol) in carbon tetrachloride (20 ml) over 1 h. The mixture was refluxed for 18 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 707 mg of compound (A) and 450 mg of compound (B). Compound (A): 1H-NMR (CDCl3) δ 2.30 (6H, s), 2.36 (3H, s), 3.99 (3H, s), 7.04 (2H, s), 8.41 (1H, d, J=1.6 Hz), 8.70 (1H, d, J=1.6 Hz). MS Calcd: 371; Found: 372 (M+H). Compound (B): 1H-NMR (CDCl3) δ 2.29 (6H, s), 2.35 (3H, s), 3.98 (3H, s), 7.01 (2H, s), 8.46 (1H, d, J=2.2 Hz), 8.62 (1H, d, J=2.2 Hz). MS Calcd: 371; Found: 372 (M+H). (2-Mesitylamino-7-nitro-1,3-benzothiazol-5-yl)methanol (C) To a solution of methyl 2-mesitylamino-7-nitro-1,3-benzothiazole-5-carboxylate (350 mg, 0.942 mmol) in ethyl ether (6 ml) was added 2.0 M solution of lithium borohydride in tetrahydrofuran (THF) (1.41 ml, 2.82 mmol). The mixture was stirred at room temperature for 15 h. The reaction was quenched with saturated NH4Cl solution. The aqueous phase was extracted with ethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 189 mg of the title compound. 1H-NMR (CDCl3) δ 2.28 (6H, s), 2.38 (3H, s), 4.94 (2H, s), 7.06 (2H, s), 8.25-8.35 (3H, m). MS Calcd: 343; Found: 344 (M+H). 5-Chloromethyl-N-mesityl-7-nitro-1,3-benzothiazol-2-amine (D) Thionyl chloride (0.191 ml, 2.62 mmol) was added to a solution of (2-mesitylamino-7-nitro-1,3-benzothiazol-5-yl)methanol (180 mg, 0.524 mmol) in chloroform. The mixture was stirred at room temperature for 18 h and at 60° C. for 24 h. The mixture was poured into water and neutralized with saturated NaHCO3 solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 122 mg of the title compound. 1H-NMR (CDCl3) δ 2.29 (6H, s), 2.36 (3H, s), 4.67 (2H, s), 7.03 (2H, s), 7.80 (1H, d, J=1.6 Hz), 8.08 (1H, d, J=1.6 Hz). MS Calcd: 361; Found: 362 (M+H), 364. 5-methyl-N-mesityl-7-nitro-1,3-benzothiazol-2-amine (E) To a solution of 5-chloromethyl-N-mesityl-7-nitro-1,3-benzothiazol-2-amine (120 mg, 0.332 mmol) in dimethyl sulfoxide (DMSO) (2 ml) was added sodium borohydride (25 mg, 0.663 mmol). The mixture was stirred at room temperature for 3 h and diluted with water and neutralized with 1N HCl solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 2% AcOEt in n-hexane to afford 45 mg of the title compound. 1H-NMR (CDCl3) δ 2.28 (6H, s), 2.37 (3H, s), 2.60 (3H, s), 7.05 (2H, s), 8.01 (1H, s), 8.16 (1H, s), 8.28 (1H, s). MS Calcd: 327; Found: 328 (M+H). N2-Mesityl-5-methyl-1,3-benzothiazole-2,7-diamine (F) A mixture of 5-methyl-N-mesity-7-nitro-1,3-benzothiazol-2-amine (45 mg, 0.137 mmol) and tin(II) chloride dihydrate (124 mg, 0.550 mmol) in DMF (2 ml) was heated at 80° C. for 1 h. The mixture was poured into ice and the pH was made slightly basic (pH 7-8) by addition of 1N NaOH solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 10 mg of the title compound. MS Calcd: 297; Found: 298 (M+H). N2-Mesityl-5-methyl-N7,N7-dipropyl-1,3-benzothiazole-2,7-diamine (G) To a solution of N2-mesityl-5-methyl-1,3-benzothiazole-2,7-diamine (10 mg, 0.0336) in dichloromethane (1 ml) was added propionaldehyde (0.012 ml, 0.168 mmol) followed after 30 min by sodium triacetoxyborohydride (29 mg, 0.135 mmol) and AcOH (0.0039 ml). The mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO3 solution. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was triturated with n-hexane. The resulting solid was collected by filtration to afford 6.8 mg of the title compound. 1H-NMR (CDCl3) δ 0.80-1.00 (6H, m), 1.35-1.45 (4H, m), 2.29 (6H, s), 2.33 (3H, s), 2.37 (3H, s), 2.95-3.05 (4H, m), 6.55 (1H, s), 6.98 (2H, s), 7.02 (1H, s). MS Calcd: 381; Found: 382 (M+H). EXAMPLES 20-23 2-Mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylic acid (A) To a mixture of methyl 2-mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylate (230 mg, 0.619 mmol) (prepared in example 19) in methanol (5 ml) and THF (5 ml) was added 1 N NaOH solution (2.48 ml, 2.48 mmol). The mixture was stirred at 50° C. for 3 h. The solvent was evaporated under vacuum and the aqueous residue was neutralized with 1N HCl solution. The resulting precipitate was collected by filtration and dried under vacuum to afford 177 mg of the title compound. 1H-NMR (DMSO-d6) δ 2.15 (6H, s), 2.26 (3H, s), 7.01 (2H, s), 8.31 (2H, m), 10.00 (1H, m). EXAMPLE 20 2-(Mesitylamino)-5-nitro-N,N-dipropyl-1,3-benzothiazole-7-carboxamide (B) To a solution of 2-mesitylamino-5-nitro-1,3-benzothiazole-7-carboxylic acid (90 mg, 0.252 mmol) in DMF (2 ml) were added diethyl cyanophosphonate (0.042 ml, 0.277 mmol), dipropylamine (0.039 ml, 0.277 mmol) and triethylamine (0.74 ml, 0.277 mmol). The mixture was stirred at room temperature for 18 h and diluted with water. The aqueous solution was extracted with ether. The extract was washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 70 mg of the title compound. 1H-NMR (CDCl3) δ 0.85-1.00 (6H, m), 1.60-1.65 (4H, m), 2.27 (6H, s), 2.33 (3H, s), 3.36 (4H, m), 6.99 (2H, s), 7.12 (1H, m), 7.96 (1H, d, J=1.6 Hz), 8.35 (1H, d, J=1.6 Hz). MS Calcd: 440; Found: 441 (M+H). EXAMPLE 21 5-Amino-2-(mesitylamino)-N,N-dipropyl-1,3-benzothiazole-7-carboxamide (C) A mixture of 2-(mesitylamino)-5-nitro-N,N-dipropyl-1,3-benzothiazole-7-carboxamide (61 mg, 0.139 mmol) and 10% Pd on carbon (30 mg) in ethanol (10 ml) was hydrogenated for 4 h. The catalyst was removed by filtration through Celite. The filtrate was concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 40 mg of the title compound. 1H-NMR (CDCl3) δ 0.80-0.90 (6H, m), 1.59 (4H, m), 2.26 (6H, s), 2.31 (3H, s), 3.30 (4H, m), 3.71 (2H, m), 6.45 (1H, d, J=2.0 Hz), 6.88 (1H, d, J=2.0 Hz), 6.95 (2H, s). MS Calcd: 410; Found: 411 (M+H). EXAMPLE 22 5-(Acetylamino)-2-(mesitylamino)-N,N-dipropyl-1,3-benzothiazole-7-carboxamide (D), and EXAMPLE 23 5-(Acetylamino)-2-[acetyl(mesityl)amino]-N,N-dipropyl-1,3-benzothiazole-7-carboxamide (E) Acetyl chloride (0.0029 ml, 0.0402 mmol) was added to a mixture of 5-amino-2-(mesitylamino)-N,N-dipropyl-1,3-benzothiazole-7-carboxamide (15 mg, 0.0365 mmol) and triethylamine (0.0056 ml, 0.0402 mmol) in THF (1 ml). The mixture was stirred at room temperature for 3 h and diluted with H2O. The aqueous solution was extracted with ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 5.8 mg of compound (D) and 5.1 mg of compound (E). Compound (D): 1H-NMR (CDCl3) δ 0.80-0.95 (6H, m), 1.50-1.80 (4H, m), 2.19 (3H,s), 2.25 (6H, s), 2.30 (3H, s), 3.34 (4H, m), 6.93 (2H, s), 7.51 (2H, s), 7.70 (1H, m). MS Calcd: 452; Found: 453 (M+H). Compound (E): 1H-NMR (CDCl3) δ 0.70-1.10 (6H. m), 1.50-1.80 (4H, m), 2.05 (3H, s), 2.07 (6H, s), 2.11 (3H, s), 2.38 (3H, s), 3.20-3.55 (4H, m), 7.04 (2H, s), 7.80 (1H, s), 7.97 (1H, s). MS Calcd: 494; Found: 495 (M+H). EXAMPLE 24 7-((Dipropylamino)methyl)-N-mesityl-1,3-benzothiazol-2-amine 3-(tert-Butyldimethylsilyloxymethyl)aniline To 1.00 g (8.1 mmol) of 3-hydroxymethylaniline in 25 mL of DMF was added 0.61 g (8.9 mmol) of imidazole and 1.35 g (8.9 mmol) of tert-butyldimethylsilyl chloride. The reaction was stirred at room temperature for 18 h and poured into 12 volumes of water. The product was extracted with ether and the combined organic layers were washed successively with water and brine, dried over sodium sulfate, filtered and concentrated to a golden oil. The oil was purified by flash chromatography eluting with a 20% ethyl acetate/hexanes mixture to give 1.2 g (62%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 0.00 (s, 6H), 0.84 (s, 9H), 4.48 (s, 2H), 4.93 (s, 2H), 6.36 (d, J=7.6 Hz, 2H), 6.45 (s, 1H), 6.89 (t, J=7.6 Hz, 1H). 1-[3-(tert-Butyldimethylsilyloxymethyl)phenyl]-3-mesitylthiourea To 0.45 g (1.9 mmol) of 3-(tert-butyldimethylsilyloxymethyl)aniline in 3 mL of methanol was added 0.67 g (3.8 mmol) of mesitylisothiocyanate. The mixture was heated at reflux for 18 h. The mixture was concentrated and purified by flash chromatography eluting with a 16% ethyl acetate/hexanes mixture to give 0.56 (71%) of the title compound as a sticky white solid. MS Calcd.: 414; Found: 415 (M+H). 1-(3-Hydroxymethylphenyl)-3-mesitylthiourea To 0.56 g (0.1.4 mmol) of 1-[3-(tert-butyldimethylsilyloxymethyl)phenyl]-3-mesitylthiourea in 10 mL of ethanol was added 10 drops of concentrated hydrochloric acid. After 30 min, the reaction was diluted with water and the precipitate that formed was collected to give 0.35 g (86%) of the title compound as a white powder. MS Calcd.: 300; Found: 301 (M+H). 7-(Hydroxymethyl)-N-mesityl-1,3-benzothiazol-2-amine To 0.25 g (0.83 mmol) of 1-(3-hydroxymethylphenyl)-3-mesitylthiourea in 5 mL of glacial acetic acid was added 47 μL (0.91 mmol) of bromine. The reaction was stirred for 5 min and concentrated in vacuo to give the title compound and its regioisomer as their O-acetates. The mixture was stirred in methanol over potassium carbonate for 1 h. The mixture was concentrated in vacuo, slurried in dichloromethane and filtered. The filtrate was concentrated and purified by flash chromatography eluting with a 33-66% ethyl acetate/hexanes gradient mixture to give 0.070 g (28%) of the title compound as a white solid. MS Calcd.: 298; Found: 299 (M+H). 7-(Bromomethyl)-N-mesityl-1,3-benzothiazol-2-amine To 0.065 g (0.22 mmol) of 7-(hydroxymethyl)-N-mesityl-1,3-benzothiazol-2-amine in 2 mL of dichloromethane was added 58 μL (0.72 mmol) of pyridine and 0.24 mL (0.24 mmol) of phosphorous tribromide (1 M in dichloromethane). The reaction was stirred at room temperature for 8 h and quenched with saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.045 g (57%) of the title compound that was used without further purification in the preparation of F. MS Calcd.: 313; Found: 314 (M+H). 7-((Dipropylamino)methyl)-N-mesityl-1,3-benzothiazol-2-amine To 0.045 g (0.12 mmol) of 7-(bromomethyl)-N-mesityl-1,3-benzothiazol-2-amine in 0.5 mL of acetonitrile and 2 mL of dichloromethane was added 0.086 g (0.62 mmol) of potassium carbonate and 85 μL (0.62 mmol) of dipropylamine. The reaction was stirred for 40 min, diluted with dichloromethane and filtered. The filtrate was concentrated and purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 0.027 g (57%) of the title compound as a light yellow powder. 1H NMR (CDCl3) δ 0.76 (t, J=7.4 Hz, 6H), 1.40 (q, J=7.4 Hz, 4H), 2.30-2.34 (m, 13H), 3.58 (s, 2H), 6.95-7.01 (m, 3H), 7.18 (t, J=7.8 Hz, 1H), 7.23-7.33 (m, 1H), 8.12 (br s, 1H). MS Calcd.: 381; Found: 382 (M+H). EXAMPLE 25 N2-Mesityl-N7,N7-dipropyl-1,3-benzoxazole-2,7-diamine 2-Amino-6-nitrophenol A suspension of 2,6-dinitrophenol 5.0 g (27 mmol), ammonium hydroxide (3 ml) and ammonium chloride 14.3 g (270 mmol) in 30 ml of water was heated to 70° C. A solution of sodium sulfide nonahydrate (24.19 g, 100 mmol) in water was added and the resulting mixture stirred at 70° C. for 2 h. The reaction was cooled to room temperature, acidified (pH 3.2) with 2N HCl, and the brown precipitate separated by filtration. The filtrate was extracted with chloroform (6×75 ml), the organic extracts combined with the precipitate, and evaporated in-vacuo to yield 2.5 g (60%) of product as a dark brown solid. 1H NMR (CDCl3) δ 4.09 (s, 2H), 6.78 (t, 1H, J=8.2 Hz), 6.95 (d, 1H, J=7.8 Hz), 7.47 (d, 1H, J=8.6 Hz), 10.73 (s, 3H). 1-(2-Hydroxy-3-nitrophenyl)-3-mesitylthiourea To a mixture containing 0.10 g (0.65 mmol) of 2-amino-6-nitrophenol and 0.14 g (1.3 mmol) of sodium carbonate in ethanol was added 0.14 g (0.78 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The reaction was heated at reflux overnight. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure. Purification of the residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane gave 0.17 g (80%) of product. MS Calcd.: 331; Found: 332 (M+H). N-Mesityl-7-nitro-1,3-benzoxazol-2-amine To a solution containing 0.06 g (0.18 mmol) of 1-(2-hydroxy-3-nitrophenyl)-3-mesitylthiourea in acetonitrile was added 0.10 g (0.36 mmol) of mercury (II) chloride, and the mixture was then stirred for 1 h. The reaction mixture was diluted with ethyl acetate (2 ml) and filtered through a prepacked celite column. The filtrate was concentrated under reduced pressure and the residue purified via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane to afford 0.047 g (90%) of product. 1H NMR (CDCl3) δ 2.29 (s, 6H), 2.32 (s, 3H), 6.99 (s, 2H), 7.30 (t, 1H, J=8.2 Hz), 7.77 (d, 1H, J=8.1 Hz), 7.78 (d, 1H, J=8.6 Hz). MS Calcd.: 297; Found: 298 (M+H). N2-Mesityl-N7,N7-dipropyl-1,3-benzoxazole-2,7-diamine To a flask was added 0.10 g (0.34 mmol) of N-Mesityl-7-nitro-1,3-benzoxazol-2-amine and 40 ml of methanol. The flask was purged with nitrogen followed by the addition of 0.01 g of 10% palladium on carbon. The flask was evacuated and pressurized to 2-3 psig hydrogen and stirred for 1 h. After completion as determined by HPLC, the reaction was filtered through GF/F filter paper. The filtrate was transferred to round bottom flask and 0.1 ml (1.7 mmol) of propionaldehyde, 0.1 g (1.7 mmol) of NaBH3CN and 1 ml of acetic acid added. The mixture was stirred overnight, then diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 5% methanol/dichloromethane gave 0.11 g (90% for 2 steps) of product. 1H NMR (CDCl3) δ 0.74 (t, 6H, J=7.2 Hz), 1.47-1.53 (m, 4H), 2.27 (s, 6H), 2.29 (s, 3H), 3.18 (t, 4H, J=7.8 Hz), 6.34 (d, 1H, J=8.1 Hz), 6.70 (d, 1H, J=7.0 Hz), 6.93 (s, 2H), 6.98 (t, 1H, J=8.1 Hz). MS Calcd.: 351; Found: 352 (M+H). EXAMPLE 26 N2-Mesityl-1-methyl-N7,N7-dipropyl-1H-benzimidazole-2,7-diamine 2,6-Dinitro-N-methylaniline Methylamine (4.5 ml of 2.0 M solution in THF) was added to a stirred solution of 2-chloro-1,3-dinitrobenzene (0.90 g, 4.4 mmol) in 40 ml of THF and stirred for 30 min. The reaction was quenched by the addition of water and ether. The aqueous layer was separated and extracted twice with ether. The combined organic extracts were washed with saturated NaHCO3, brine and dried over magnesium sulfate. Filtration, removal of solvent and purification of residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane to gave 0.80 g (91%) of product. 1H NMR (CDCl3) δ 2.89 (d, 3H, J=5.6 Hz), 6.75 (t, 1H, J=8.1 Hz), 8.18 (d, 2H, J=8.3 Hz). N2-Methylbenzene-1,2,3-triamine To a flask was added 0.30 g (1.5 mmol) of 2,6-dinitro-N-methylaniline and 40 ml of methanol. The flask was purged with nitrogen followed by the addition of 0.03 g of 10% palladium on carbon. The flask was evacuated and pressurized to 2-3 psig hydrogen and stirred for 1 h. After completion as determined by HPLC, the reaction was filtered through GF/F filter paper. The filtrate was evaporated to give 0.2 g (95%) of product. MS Calcd.: 137; Found: 138 (M+H). 1-(3-Amino-2-methylaminophenyl) 3-mesitylthiourea To a mixture containing 0.25 g (1.82 mmol) of N2-methylbenzene-1,2,3-triamine and 0.40 g (3.7 mmol) of sodium carbonate in ethanol was added 0.32 g (1.86 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The reaction was heated at reflux and the solvent removed under reduced pressure. Purification of the residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane gave 0.34 g (60%) of product. 1H NMR (CDCl3) δ 2.19 (s, 6H), 2.26 (s, 3H), 3.68 (s, 3H), 3.85 (s, 4H), 6.20 (d, 2H, J=8.1 Hz), 6.87 (s, 2H), 6.95 (t, 1H, J=8.1 Hz), 7.07 (s, 1H). MS Calcd.: 314; Found: 315 (M+H). N2-Mesityl-1-methyl-1H-benzimidazole-2,7-diamine To a solution containing 0.25 g (0.79 mmol) of 1-(3-amino-2-methylaminophenyl)-3-mesitylthiourea in acetonitrile was added 0.52 g (1.6 mmol) of mercury (II) chloride, and the mixture stirred for 1 h. The reaction mixture was diluted with ethyl acetate (2 ml) and filtered through a prepacked celite column. The filtrate was concentrated under reduced pressure and the residue. purified via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane to afford 0.12 g (55%) of product. 1H NMR (CD3OD) δ 2.27 (s, 6H), 2.36 (s, 3H), 4.13 (s, 3H), 7.13 (s, 2H), 7.24-7.26 (m, 2H), 7.33 (t, 1H, J=8.1 Hz). MS Calcd.: 280; Found: 281 (M+H). N2-Mesityl-1-methyl-N7, N7-dipropyl-1H-benzimidazole-2,7-diamine To a solution containing 0.05 g (0.18 mmol) of N2-mesityl-1-methyl-1H-benzimidazole-2,7-diamine in methanol (5 ml) was added 0.03 ml (0.54 mmol) of propionaldehyde, 0.03 g (0.54 mmol) of NaBH3CN and 0.1 ml of acetic acid. The mixture was stirred overnight then diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 5% methanol/dichloromethane gave 0.04 g (70%) of product. 1H NMR (CDCl3) δ 0.85 (t, 6H, J=7.3 Hz), 1.46-1.53 (m, 4H), 2.22 (s, 6H), 2.28 (s, 3H), 2.98 (s, 4H), 3.94 (s, 3H), 6.86 (d, 1H, J=7.8 Hz), 6.92 (s, 2H), 6.99 (t, 1H, J=8.1 Hz), 7.20 (s, 1H). MS Calcd.: 364; Found: 365 (M+H). Compounds of Examples 27-30, shown in Table 2, were prepared in a manner similar to that described in Example 26. TABLE 2 Example Structure Name Physical Data 27 N2-Mesityl-N7, N4-dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 350; Found: 351 (M + H). 28 1-Isopropyl-N2- mesityl-N7, N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.86 (t, 6H, J = 7.4 Hz), 1.45-1.55 (m, 4H), 1.64 (d, 6H, J =7.0 Hz), 2.24 (s, 6H), 2.28 (s, 3H), 2.90-3.05 (m, 4H), 6.57-6.65 (m, 1H), # 6.89 (d, 1H, J =7.8 Hz), 6.93 (s, 2H), 6.98 (t, 1H, J=7.8 Hz), 7.23 (d, 1H, J =7.8 Hz); MS Calcd.: 392; Found: 393 (M + H). 29 N2-Mesityl-1- phenyl-N7, N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 426; Found: 427 (M + H). 30 1-Ethyl-N2- mesityl-N7, N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.86 (t, 6H, J = 7.2 Hz), 1.36 (t, 3H, J =7.0 Hz), 1.48-1.54 (m, 4H), 2.23 (s, 6H), 2.28 (s, 3H), 2.93-3.00 (m, 4H), 4.53-4.60 (m, 2H), 6.89 (d, # 1H, J = 7.8 Hz), 6.93 (s, 2H), 7.00 (t, 1H, J = 7.8 Hz), 7.23 (d, 1H, J = 7.5 Hz); MS Calcd.: 378; Found: 379 (M + H). EXAMPLE 31 N7-Cyclopropylmethyl-N2-mesityl-1-methyl-N7-propyl-1H-benzoimidazole-2,7-diamine 7-Amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one To 9.6 g (70 mmol) of N2-methylbenzene-1,2,3-triamine dissolved in 350 mL of THF was added 11.3 g (70 mmol) of carbonyldiimidazole. The reaction mixture was stirred for 18 h and was concentrated in vacuo. The crude solid was triturated with dichloromethane and collected by filtration to give 6.94 g (61%) of the title compound as a brown powder. 1H NMR (DMSO-d6) δ 3.51 (s, 3H), 4.85 (s, 2H), 6.30 (d, J=7.6 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 6.68 (t, J=8.0, 1H), 10.55 (s, 1H). 1-Methyl-7-(propylamino)-1,3-dihydro-2H-benzimidazol-2-one To 0.87 g (5.3 mmol) of 7-amino-1-methyl-1,3-dihydro-2H-benzoimidazol-2-one in 50 mL of methanol was added 1.94 mL (26.7 mmol) of propionaldehyde and 1.0 g (16 mmol) of sodium cyanoborohydride. The mixture was stirred at room temperature for 5 h and concentrated in vacuo. The crude solid was partitioned between water and ethyl acetate, the biphasic mixture was filtered to remove particulates and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with a 50% ethyl acetate/hexanes mixture to give 0.69 g (63%) of the title compound as a cream colored powder. MS Calcd.: 205; Found: 206 (M+H). 7-Benzyl(propyl)amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one To 0.69 g (3.4 mmol) of 1-methyl-7-(propylamino)-1,3-dihydro-2H-benzimidazol-2-one in 20 mL of methanol was added 0.68 mL (6.7 mmol) of benzaldehyde, 10 drops of glacial acetic acid and 0.63 g (10 mmol) of sodium cyanoborohydride. The mixture was stirred at 50° C. for 18 h and an additional 0.68 mL of benzaldehyde, 10 drops of glacial acetic acid and 0.63 g of sodium cyanoborohydride was added. This mixture was heated for an additional 24 h before adding an additional 0.68 mL of benzaldehyde, 10 drops of glacial acetic acid and 0.63 g of sodium cyanoborohydride. The reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude solid was partitioned between water and ethyl acetate, the organic layer was then washed with brine, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with a 33% ethyl acetate/hexanes mixture to give 0.65 g (65%) of the title compound as a colorless sticky solid. MS Calcd.: 295; Found: 296 (M+H). N7-Benzyl-2-chloro-1-methyl-N7-propyl-1H-benzimidazol-7-amine A solution of 0.65 g (2.2 mmol) of 7-benzyl(propyl)amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 10 mL of phosphorous oxychloride was heated to 100° C. After stirring for 24 h, the mixture was concentrated in vacuo and quenched with saturated sodium bicarbonate. The quenched reaction was extracted with ethyl acetate and the extracts were then washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.56 g (81%) of the title compound as a viscous yellow oil. This crude oil was used without further purification in the preparation of E. MS Calcd.: 313; Found: 314 (M+H). N7-Benzyl-N2-mesityl-1-methyl-N7-propyl-1H-benzimidazole-2,7-diamine A solution of 0.56 g (1.8 mmol) of N7-benzyl-2-chloro-1-methyl-N7-propyl-1H-benzimidazol-7-amine in 0.75 mL (5.4 mmol) of mesityl amine was heated to 130° C. After stirring for 24 h, the mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to give a tan solid. The solid thus obtained was purified by flash chromatography eluting with a 1.3% methanol/dichloromethane mixture to give 0.59 g (80%) of the title compound as a cream colored solid. MS Calcd.: 412; Found: 413 (M+H). N2-Mesityl-1-methyl-N7-propyl-1H-benzimidazole-2,7-diamine To a solution of 0.50 g (1.2 mmol) of N7-benzyl-N2-mesityl-1-methyl-N7-propyl-1H-benzimidazole-2,7-diamine in 30 mL of methanol was added 0.43 g (10 mol % Pd) of 20% Pearlman's catalyst (50% wet). The reaction was kept under a hydrogen atmosphere via a balloon and stirred at room temperature for 48 h. The catalyst was removed via filtration and the filtrate was concentrated in vacuo. Purification by flash chromatography eluting with a 7% methanol/dichloromethane mixture gave 0.23 g (58%) of the title compound as a cream colored solid. MS Calcd.: 322; Found: 323 (M+H). N7-Cyclopropylmethyl-N2-mesityl-1-methyl-N7-propyl-1H-benzimidazole-2,7-diamine To 0.041 g (0.13 mmol) of N2-mesityl-1-methyl-N7-propyl-1H-benzimidazole-2,7-diamine in 2 mL of methanol was added 95 μL (1.3 mmol) of cyclopropane carboxaldehyde, 200 μL of glacial acetic acid and 0.032 g (0.51 mmol) of sodium cyanoborohydride. The mixture was stirred at room temperature for 24 h. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The crude solid was partitioned between saturated sodium bicarbonate and dichloromethane, the organic layer was separated, dried over sodium sulfate, filtered, concentrated and purified by reverse-phase HPLC to give 0.026 g (42%) of the title compound as a colorless sticky solid. MS Calcd.: 376; Found: 377 (M+H). Compounds of Examples 32-60, shown in the Table 3, were prepared in a manner similar to that described in Example 31. Compounds 32-53 were purified by reverse phase HPLC (CH3CN containing 0.1% TFA/water containing 0.1% TFA) to obtain TFA salts. TABLE 3 Example Structure Name Physical Data 32 1-methyl-N2- phenyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 322 MS Found: 323 (M + H) 33 1-methyl-2- morpholin-4-yl- N,N-dipropyl- 1H- benzimidazol-7- amine MS Calcd.: 316 MS Found: 317 (M + H) 34 methyl 4-{[7- (dipropylamino)- 1-methyl-1H- benzimidazol-2- yl]amino}-3- methylbenzoate MS Calcd.: 394 MS Found: 395 (M + H) 35 N2-(2,6- dimethoxypyridin- 3-yl)-1- methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 383 MS Found: 384 (M + H) 36 N2-(4-tert- butyl-2,6- dimethylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 406 MS Found: 407 (M + H) 37 N2-(2,4- dimethylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 350 MS Found: 351 (M + H) 38 N2-(4-bromo-2- ethylphenyl)-1- methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 428 MS Found: 429 (M + H) 39 N2-[4- (diethylamino)- 2- methylphenyl]- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 407 MS Found: 408 (M + H) 40 1-methyl-N2-(4- methyl-5- nitropyridin-2- yl)-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 382 MS Found: 383 (M + H) 41 N2-(2,4- dichlorophenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 390 MS Found: 391 (M + H) 42 N2-(2-chloro- 4,6- dimethylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 384 MS Found: 385 (M + H) 43 N2-(2-bromo-4- isopropylphenyl)- 1-methyl- N7,N7-dipropyl- 1H- benzimidazole- 2,7-diamine MS Calcd.: 442 MS Found: 443 (M + H) 44 1-methyl-N7,N7- dipropyl-N2- (2,4,6- trichlorophenyl)- 1H-benzimidazole- 2,7-diamine MS Calcd.: 424 MS Found: 425 (M + H) 45 N2-cyclohexyl-1- methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 328 MS Found: 329 (M + H) 46 N2-(4,5- dimethoxy-2- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 396 MS Found: 397 (M + H) 47 N2-(2,6- dimethylphenyl)- 1-methyl-N7,N7- dipropyl-1H- 2,7-diamine MS Calcd.: 350 MS Found: 351 (M + H) 48 2,4-dichloro-6- {[7- (dipropylamino)- 1-methyl-1H- benzimidazol-2- yl]amino}-3- methylphenol MS Calcd.: 420 MS Found: 421 (M + H) 49 N2-(3,5- dichloropyridin- 4-yl)-1- methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 391 MS Found: 391 (M + H) 50 N2-(3-bromo-5- methylpyridin- 2-yl)-1-methyl- N7,N7-dipropyl- 1H- benzimidazole- 2,7-diamine MS Calcd.: 415 MS Found: 416 (M + H) 51 N2-(3,5- dimethoxyphenyl)- 1-methyl- N7,N7-dipropyl- 1H- benzimidazole- 2,7-diamine MS Calcd.: 382 MS Found: 383 (M + H) 52 1-methyl-N2-[2- methyl-4- (trifluoromethoxy) phenyl]- N7,N7-dipropyl- 1H- benzimidazole- 2,7-diamine MS Calcd.: 420 MS Found: 421 (M + H) 53 N2-(2,4- dimethoxyphenyl)- 1-methyl- N7,N7-dipropyl- 1H- benzimidazole- 2,7-diamine MS Calcd.: 382 MS Found: 383 (M + H) 54 N7, N7-dibutyl- N2-mesityl-1- methyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 392 MS Found: 393 (M + H) 55 N7-benzyl-N2- mesityl-1- methyl-N7- propyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 412 MS Found: 413 (M + H) 56 N7,N7- bis(cyclopropyl methyl)-N2- mesityl-1- methyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 388 MS Found: 389 (M + H) 57 N-mesityl-1- methyl-7- piperidin-1-yl- 1H- benzimidazol-2- amine MS Calcd.: 348 MS Found: 349 (M + H) 58 N7-butyl-N2- mesityl-1- methyl-N7- propyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 378 MS Found: 379 (M + H) 59 N2-mesityl-1- methyl-N7-(2- methoxyethyl)- N7-propyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 380 MS Found: 381 (M + H) 60 N7-isobutyl-N2- mesityl-1- methyl-N7- propyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 378 MS Found: 379 (M + H) EXAMPLE 61 N2-(2,4-Dimethylphenyl)-N5,N5-dipropylimidazo[1,2-a]pyridine-2,5-diamine Imidazo[1,2-a]pyridin-5-amine 2,6-diaminopyridine (5.0 g, 46 mmol) and chloroacetaldehyde (50% wt. soln in water, 6.4 mL, 50 mmol) were dissolved in absolute EtOH (120 mL). The solution was heated at 75° C. for 1 hour. The mixture was cooled and concentrated via rotavap. The residue was taken up in saturated NaHCO3 and EtOAc. The solution was extracted with EtOAc (3 times), dried over magnesium sulfate, and concentrated to give a brown solid. 4.85 g isolated (80% yield). 1H NMR (CDCl3) δ 4.48 (s, 2H), 6.10 (dd, J=7.2, 1.2 Hz, 1H), 7.10-7.20 (m, 2H), 7.42 (d, J=1.2 Hz, 1H), 7.65 (d, J=1.2 Hz, 1H). MS Calcd.: 133; Found: 134 (M+H). N,N-Dipropylimidazo[1,2-a]pyridin-5-amine Imidazo[1,2-a]pyridin-5-amine (4.85 g, 36 mmol) was dissolved in DMF (72 mL). Sodium hydride (60% in mineral oil, 5.8 g, 146 mmol) was added carefully. The mixture stirred for 0.5 hr. at room temperature. 1-Bromopropane (13.2 mL, 145 mmol) was added. After 1 hour, the solution was quenched with water and extracted with ether (4 times). The combined organic layers were dried over magnesium sulfate, and concentrated. Flash chromatography (80-100% EtOAc/hexanes) gave the title compound as a brown oil. 7.92 g obtained (83% yield). 1H NMR (CDCl3) δ 0.88 (t, J=8.4 Hz, 6H), 1.51-1.57 (m, 4H), 3.06-3.10 (m, 4H), 6.34 (d, J=6.8 Hz, 1H), 7.14-7.18 (m, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.63 (d, J=5.6 Hz, 2H). MS Calcd.: 217; Found 218 (M+H). 2-Bromo-N,N-dipropylimidazo[1,2-a]pyridin-5-amine N,N-Dipropylimidazo[1,2-a]pyridin-5-amine (1.0 g, 4.6 mmol) was diluted in DMF (25 mL). The solution was cooled to 0° C. N-bromosuccinamide (0.83 g, 4.7 mmol) was added. After 5 minutes, the reaction was quenched with water. The solution was extracted with ether, dried, and concentrated. Flash chromatography (40% EtOAc/hexanes) gave the title compound as a yellow oil which solidified upon overnight freezing at −20° C. 0.67 g obtained (49% yield). 1H NMR (CDCl3) δ 0.86 (t, J=7.6 Hz, 6H), 1.43-1.64 (m, 4H), 2.98-3.13 (m, 4H), 6.40 (d, J=8.0 Hz, 1H), 7.10-7.14 (m, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.52 (s, 1H). MS Calcd.: 296; Found: 296 (M) 298 (M+2H). N2-(2,4-Dimethylphenyl)-N5,N5-dipropylimidazo[1,2-a]pyridine-2,5-diamine 2-Bromo-N,N-dipropylimidazo[1,2-a]pyridin-5-amine (C) (0.127 g, 0.43 mmol) was diluted in 2,4-dimethylaniline (2 mL). The solution was heated to 75° C. in a sealed tube for 2 hours. The solution was flash chromatographed (20% EtOAc/hexanes) using basic alumina to give the title compound as a brown residue. 0.029 g obtained (20% yield). 1H NMR (CDCl3) δ 0.88 (t, J=6.8 Hz, 6H), 1.49-1.56 (m, 4H), 2.28 (s, 3H), 2.29 (s, 3H), 3.04-3.07 (m, 4H), 6.12 (s, 1H), 6.30-6.32 (m, 1H), 7.02-7.04 (m, 2H), 7.10-7.12 (m, 2H), 7.22 (s, 1H), 7.35 (d, J=7.6 Hz, 1H). MS Calcd.: 336; Found: 337 (M+H). Compounds of examples 62-63, shown in table 4, were prepared in a manner similar to that described in Example 61. TABLE 4 Physical Example Structure Name Data 62 2-((2,4- dimethylpheny) thio)-N,N- dipropylimidazo [1,2-a]pyridin- 5-amine MS Calcd.: 353; Found: 354 (M + H). 63 2-(2,4- dimethylphenoxy)- N,N- dipropylimidazo [1,2-a]pyridin- 5-amine MS Calcd.: 337; Found: 338 (M + H). EXAMPLE 64 (2,4-Dimethylphenyl)(5-(dipropylamino)imidazo[1,2-a]pyridin-2-yl)methanone (2,4-Dimethylphenyl)(5-(dipropylamino)imidazo[1,2-a]pyridin-2-yl)methanone 2-Bromo-N,N-dipropylimidazo[1,2-a]pyridin-5-amine (prepared in example 61) (0.136 g, 0.46 mmol) was dissolved in THF (1 mL). The solution was cooled to −78° C. t-BuLi (1.7M, 0.57 mL, 0.96 mmol) was added dropwise and the solution stirred for 1 hr. at −78° C. 2,4-Dimethylbenzoyl chloride (0.097 g, 0.57 mmol) diluted in 0.5 mL THF was added to the reaction mixture. After 0.5 hr, the solution was quenched with water and warmed to room temperature. Extraction occurred with EtOAc and the organic layer was dried over magnesium sulfate and concentrated. Flash chromatography (30-40% EtOAc/hexanes) gave the title compound. 0.039 g obtained (24% yield). 1HNMR (CDCl3) δ 0.82 (t, J=7.6 Hz, 6H), 1.32-1.65 (m, 4H), 2.40 (s, 3H), 2.48 (s, 3H), 3.13-3.19 (m, 4H), 6.55 (d, J=7.6 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.77 (s, 1H). MS Calcd.: 349; Found: 350 (M+H). EXAMPLE 65 2-(2,4-Dimethylphenyl)-N,N-dipropylimidazo[1,2-a]pyridin-5-amine 2-(2,4-Dimethylphenyl)-N,N-dipropylimidazo[1,2-a]pyridin-5-amine (2-Bromo)-N,N-dipropylimidazo[1,2-a]pyridin-5-amine (prepared in example 61) (0.17 g, 0.57 mmol) was dissolved in 1,2-dimethoxyethane (DME) (1.5 mL). Pd(PPh3)4 (0.033 g, 0.028 mmol) was added and the reaction stirred at 50° C. for 15 minutes. The solution was cooled and 2,4-dimethylphenylboronic acid (0.103 g, 0.69 mmol) in DME (1 mL) was added to the reaction mixture. KOtBu (0.128 g, 1.14 mmol) in tBuOH (1 mL) was also added to the reaction. The reaction was heated to 100° C. for 1 hr. The solution was filtered through paper and concentrated. Crude material was purified via reverse phase HPLC (acetonitrile containing 0.1% TFA/water containing 0.1% TFA) to obtain 3.1 mg of the title compound (2% yield). MS Calcd.: 321; Found: 322 (M+H). EXAMPLE 66 5-Fluoro-N2-mesityl-1-methyl-N7,N7-dipropyl-1H-benzimidazole-2,7-diamine 2-Chloro-5-fluoro-1,3-dinitrobenzene To a solution of 0.65 g (2.2 mmol) of 4-fluoro-2,6-dinitrophenol in 30 mL dimethylformamide was added 1.4 mL (15 mmol) of phosphorous oxychloride. The mixture was heated to 70° C. overnight, cooled to room temperature and quenched with ice. The mixture was diluted with water and the precipitate was collected giving 1.35 g (82%) of the title compound as a cream colored solid. 1H NMR (DMSO-d6) δ 8.55 (d, J=1.5 Hz, 1H), 8.57 (d, J=1.3 Hz, 1H). 4-Fluoro-N-methyl-2,6-dinitroaniline To 1.35 g (6.12 mmol) of 2-chloro-5-fluoro-1,3-dinitrobenzene in 20 mL of THF at 0° C. was added 6.1 mL (12 mmol) of 2N methylamine in THF. The cold bath was removed and the reaction was stirred at room temperature for 45 minutes. The solution was concentrated, diluted with ether and washed with saturated sodium bicarbonate solution. The resulting organic solution was dried over sodium sulfate, filtered and concentrated giving 1.30 g (99%) of the title compound as a bright orange powder. 1H NMR (DMSO-d6) δ 2.70 (d, J=5.5 Hz, 3H), 8.20 (br s, 1H) 8.29 (d, J=8.2 Hz, 2H) 1-[3-Amino-5-fluoro-2-(methylamino)phenyl]-3-mesitylthiourea In 75 mL of ethanol was mixed 1.30 g (6.04 mmol) of 4-fluoro-N-methyl-2,6-dinitroaniline, 3.7 mL (36 mmol) of cyclohexene and 5.1 g (2.4 mmol, 40 mol %) of 10% palladium on carbon (50% water, Degussa type). The mixture was refluxed for 2.5 h and filtered into a flask containing 0.77 g (7.3 mmol) of sodium carbonate and 1.07 g (6.04 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The resulting slurry was refluxed for 4 h, concentrated and slurried in dichloromethane. The slurry was filtered, concentrated and purified by flash chromatography eluting with a 70% hexanes/ethyl acetate mixture to give 0.65 g (32%) of the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 2.09 (s, 6H), 2.20 (s, 3H), 3.45 (s, 3H), 5.00 (br s, 4H), 5.78 (d, J=11.2 Hz, 2H), 6.79 (s, 2H), 7.93 (br s, 1H). MS Calcd.: 332; Found: 299 (M+H−H2S). 5-Fluoro-N2-mesityl-1-methyl-N7, N7-dipropyl-1H-benzimidazole-2, 7-diamine To 0.29 g (0.87 mmol) of 1-[3-amino-5-fluoro-2-(methylamino)phenyl]-3-mesitylthiourea in 15 mL of acetonitrile was added 1.09 mL (7.9 mmol) of triethylamine followed by 0.4 g (1.5 mmol) of mercuric chloride. After 2 h at room temperature an additional 0.7 g (2.6 mmol) of mercuric chloride was added. After 2 h of additional reaction time, the mixture was diluted with water and the resulting crude 5-fluoro-N2-mesityl-1-methyl-1H-benzoimidazole-2,7-diamine was collected as a brown precipitate via filtration. The crude product thus obtained was slurried in 50 mL of methanol and treated with 1.6 mL (22 mmol) of propionaldehyde, 3 mL of glacial acetic acid and 1.1 g (17 mmol) of sodium cyanoborohydride. The mixture was stirred at 50° C. for 24 h. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The crude solid was mixed with water and made basic with saturated potassium carbonate. The mixture was partioned with ethyl acetate and separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated onto silica gel and purified by flash chromatography eluting with a 75% hexanes/ethyl acetate mixture to give impure title compound. The impure material was slurried in hexanes and 0.065 g (20%) of the title compound was collected as a white solid. 1H NMR (DMSO-d6) δ 0.83 (t, J=7.2 Hz, 6H), 1.43 (q, J=7.2 Hz, 4H), 2.11 (s, 6H), 2.26 (s, 3H), 2.94 (m, 4H), 3.92 (s, 3H), 6.60 (t, J=12.3 Hz, 2H), 6.91 (s, 2H), 8.01 (s, 1H). 19F NMR (DMSO-d6) δ −117.85 (s, 1F). MS Calcd.: 382; Found: 383 (M+H). OTHER EXAMPLES TABLE 5 Example Structure Name Physical Data 67 N7,N7-dibutyl-5- fluoro-N2- mesityl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ (HCl salt) 0.86 (t, 6H, J = 7.3 Hz), 1.24-1.31 (m, 4H), 1.39-1.43 (m, 4H), 2.20 (s, 6H), 2.32 (s, 3H), 3.05 (br s, 4H), 4.06 (s, 3H), 6.80 (d, # 1H, J = 7.6 Hz), 7.04 d 1H, J = 11.9 Hz), 7.10 (s, 2H), 10.46 (s, 1H); 19F NMR (DMSO-d6) δ117.7 (s, 1F); MS Calcd.: 410; MS Found: 411 (M + H). 68 N7,N7- bis(cyclopropyl methyl)-5- fluoro-N2- mesityl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ (HCl salt) 0.08 (d, 4H, J =4.3 Hz), 0.40 (d, 4H, J =7.8 Hz), 0.84-0.92 (m, 2H), 2.20 (s, 6H), 2.32 (s, 3H), # 2.99 (br s, 4H), 4.16 (s, 3H), 6.84 (d, 1H, J = 7.8 Hz), 7.10-7.15 (m, 2H), 10.49 (s, 1H); 19F NMR (DMSO-d6) δ −117.7 (s, 1F); MS Calcd.: 406; MS Found: 407 (M + H). EXAMPLE 69 N7-butyl-N2-mesityl-N7-(4-methoxyphenyl)-1-methyl-1H-benzimidazole-2,7-diamine 7-[(4-Methoxyphenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 0.183 g (1.12 mmol) of 7-amino-1-methyl-1,3-dihydrobenzimidazol-2-one, 0.037 g (0.11 mmol) of biphenyl-2-yl-dicyclohexylphosphane, 0.237 g (2.47 mmol) of sodium tert-butoxide and 0.041 g (0.045 mmol) of tris(dibenzylidineacetone)dipalladium in 6 mL of THF was treated with 0.14 mL (1.12 mmol) of 4-bromoanisole and heated to 60° C. for 18 h. The crude reaction mixture was diluted with ethyl acetate, filtered through a pad of celite and purified by flash chromatography eluting with a 97% dichloromethane/methanol mixture to give 0.126 g (42%) of the title compound as a tan powder. 1H NMR (DMSO-d6) δ 3.29 (s, 3H), 3.66 (s, 3H), 6.62 (d, J=8.8 Hz, 2H), 6.70-6.83 (m, 4H), 6.91 (t, J=7.8 Hz, 1H), 7.30 (s, 1H), 10.85 (s, 1H). MS Calcd.: 269; Found: 270 (M+H). 7-[Butyl(4-methoxyphenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 0.100 g (0.37 mmol) of 7-[(4-methoxyphenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 0.13 mL (1.5 mmol) of butyraldehyde in 15 mL of dichloroethane was treated with four drops of glacial acetic acid and 0.31 g (1.5 mmol) of sodium triacetoxyborohydride. The mixture was heated to 70° C. for five days. The mixture was diluted with ethyl acetate and was washed successively with saturated sodium bicarbonate and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude oil was purified by flash chromatography eluting with a 97% dichloromethane/methanol mixture to give 0.70 g (45%) of the title compound as a yellow sticky semi-solid that was used without further purification in the preparation of C. N-Butyl-2-chloro-N-(methoxyphenyl)-1-methyl-1H-benzimidazol-7-amine A solution of 0.070 g (0.22 mmol) of 7-[butyl(4-methoxyphenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 2 mL of phosphorous oxychloride was heated to 100° C. After stirring for 2 h, the mixture was concentrated in vacuo and quenched with saturated sodium bicarbonate. The quenched reaction was extracted with ethyl acetate and the extracts were then washed with brine, dried over sodium sulfate, filtered and concentrated onto silica gel and purified by flash chromatography eluting with a 85% hexanes/ethyl acetate mixture to give 0.018 g (36%) of the title compound as a colorless oil. MS Calcd.: 343; Found: 310 (M+H−Cl). N7-Butyl-N2-mesityl-N7-(4-methoxyphenyl)-1-methyl-1H-benzimidazole-2,7-diamine A solution of 0.018 g (0.05 mmol) of N-butyl-2-chloro-N-(methoxyphenyl)-1-methyl-1H-benzimidazol-7-amine in 0.10 mL (0.73 mmol) of mesityl amine was heated to 130° C. After stirring for 18 h, the mixture was dissolved in dichloromethane, loaded onto silica gel and purified by flash chromatography eluting with a 96% dichloromethane/methanol mixture to give 0.015 g (65%) of the title compound as a reddish-brown solid. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.2 Hz, 3H), 1.34 (q, J=7.4 Hz, 2H), 1.62 (m, 2H), 2.10 (s, 6H), 2.26 (s, 3H), 3.45-3.55 (m, 2H), 3.52 (s, 3H), 3.65 (s, 3H), 6.48 (d, J=9.0 Hz, 2H), 6.70 (d, J=7.4 Hz, 1H), 6.77 (d, J=8.2 Hz, 2H), 6.95-7.04 (m, 2H), 7.93 (s, 1H). MS Calcd.: 442; Found: 443 (M+H). The following examples were prepared according to the procedures described in Example 26. TABLE 6 Example Structure Name Physical Data 70 N2-mesityl-N7, 1- dimethyl-N- propyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 336; MS Found: 337 (M + H) 71 N7-isopropyl-N2- mesityl-1- propyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 364; MS Found: 365 (M + H) 72 N2-mesityl-1- methyl-N7-(1- propylbutyl)- 1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.91 (t, J = 7.2 Hz, 6H), 1.37-1.56 (m, 8H), 2.19 (s, 6H), 2.33 (s, 3H), 4.06 (s, 3H), 4.88 (br s, 1H), 6.59 (dd, J =4.7, 7.8 Hz, 2H), 7.05 (t, # J = 8.0 Hz, 1H), 7.10 (s, 1H), 12.25 (s, 1H); MS Calcd.: 378; MS Found: 379 (M + H). 73 N7-benzyl-N7- (cyclopropylmethyl)- N2-mesityl- 1-methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.02 (s, 2H), 0.37 (d, J = 7.6 Hz, 2H), 0.86 (t, J = 7.0 Hz, 2H), 2.11 (s, 6H), 2.26 (s, 3H), 2.85 (d, J = 5.7 Hz, 2H), 4.02 (s, # 3H), 4.32 (s, 2H), 6.80-6.87 (m, 3H), 6.91 (s, 2H), 7.19 (t, J =7.3 Hz, 1H), 7.28 (t, J =7.6 Hz, 2H), 7.33 (d, J =7.0 Hz, 2H), 7.88 (s, 1H); MS Calcd.: 424; MS Found: 425 (M + H). 74 N7-(4- chlorobenzyl)- N7- (cyclopropylmethyl)- N2-mesityl- 1-methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ −0.01 (s, 2H), 0.38 (d, J = 7.6 Hz, 2H), 0.84-0.90 (m, 1H), 2.11 (s, 6H), 2.26 (s, 3H), 2.85 (br s, 2H), 4.90 (s, # 3H), 4.30 (s, 2H), 6.81-6.84 (m, 3H), 6.91 (s, 2H), 7.32 (s, 4H), 7.88 (s, 1H); MS Calcd.: 458; MS Found: 459 (M + H). 75 N7- (cyclopropylmethyl)- N2-mesityl- N7-(4- methoxybenzyl)- 1-methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.00 (s, 2H), 0.38 (d, J = 6.6 Hz, 2H), 0.87 (br s, 1H), 2.12 (s, 6H), 2.27 (s, 3H), 2.84 (br s, 2H), 3.72 (s, 3H), # 4.02 (s, 3H), 4.25 (br s, 2H), 6.84 (br s, 5H), 6.93 (s, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.88 (s, 1H); MS Calcd.: 454; MS Found: 455 (M + H). 76 N7- (cyclopropylmethyl)- N2-mesityl- 1-methyl-N7- (pyridin-3- ylmethyl)-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.00 (s, 2H), 0.40 (d, J = 7.4 Hz, 2H), 0.90 (br s, 1H), 2.12 (s, 6H), 2.27 (s, 3H), 2.90 (br s, 2H), 4.04 (s, 3H), # 4.36 (s, 2H), 6.87 (br s, 2H), 6.96 (br s, 3H), 7.29 (t, J = 5.1 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H); 8.39 (s, 1H), 8.50 (s, 1H); MS Calcd.: 425; MS Found: 426 (M + H). 77 N7- (cyclopropylmethyl)- N2-[2- (mesitylamino)- 1-methyl-1H- benzimidazol-7- yl]acetamide 1H NMR (DMSO- d6) δ 0.08-0.14 (m, 2H), 0.37-0.44 (m, 2H), 0.97-1.00 (m, 1H), 1.77 (s, 3H), 2.12 (s, 6H), 2.26 (s, 3H), 3.17 (dd, J = 7.7, 13.7 # Hz, 1H), 3.66 (s, 3H), 3.87 (dd, J = 6.9, 13.6 Hz, 1H), 6.83 (d, J =7.6 Hz, 1H), 6.92 (s, 2H), 6.98 (t, J =7.8 Hz, 1H), 7.11 (d, J =7.8 Hz, 1H); 8.09 (s, 1H); MS Calcd.: 376; MS Found: 377 (M + H). 78 N7-(4-tert- butylbenzyl)-N7- (cyclopropylmethyl)- N2-mesityl- 1-methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.03 (br s, 2H), 0.36 (d, J = 7.4 Hz, 2H), 0.85 (br s, 1H), 1.24 (s, 9H), 2.11 (s, 6H), 2.26 (s, 3H), 2.84 (d, J = # 6.4 Hz, 2H), 4.01 (s, 3H), 4.28 (br s, 2H), 6.81-6.85 (m, 3H), 6.91 (s, 2H), 7.25-7.32 (m, 4H), 7.88 (s, 1H); MS Calcd.: 480; MS Found: 481 (M + H). 79 N7- (cyclopropylmethyl)- N2-mesityl- 1-methyl-N7-(4- methylbenzyl)- 1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ −0.01 (br s, 2H), 0.36 (d, J = 7.8 Hz, 2H), 0.84-0.87 (m, 1H), 2.11 (s, 6H), 2.24 (s, 3H), 2.26 (s, 3H), 2.83 (d, J = # 5.4 Hz, 2H), 4.01 (s, 3H), 4.26 (br s, 2H), 6.80-6.84 (m, 3H), 6.91 (s, 2H), 7.07 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 7.86 (s, 1H); MS Calcd.: 438; MS Found: 439 (M + H). 80 N7- (cyclopropylmethyl)- N2-mesityl- 1-methyl-N7- (pyridin-4- ylmethyl)-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.00 (br s, 2H), 0.39 (d, J = 7.6 Hz, 2H), 0.86-0.88 (m, 1H), 2.12 (s, 6H), 2.26 (s, 3H), 2.88 (br s, 2H), 4.04 (s, # 3H), 4.38 (br s, 2H), 6.82 (s, 3H), 6.92 (s, 2H), 7.36 (d, J = 4.5 Hz, 2H), 7.91 (s, 1H), 8.45 (d, J = 4.3 Hz, 2H); MS Calcd.: 425; MS Found: 426 (M + H). 81 N7- (cyclopropylmethyl)- N2-mesityl- 1-methyl-N7-[4- (trifluoromethyl) benzyl]-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.00 (br s, 2H), 0.39 (d, J = 6.1 Hz, 2H), 0.88 (br s, 1H), 2.10 (s, 6H), 2.25 (s, 3H), 2.88 (br s, 2H), 4.01 (s, # 3H), 4.42 (br s, 2H), 6.82-6.86 (m, 3H), 6.91 (s, 2H(, 7.54 (d, J =7.2 Hz, 2H), 1H); 19F NMR (DMSO-d6)- 61.23 (s, 3F); MS Calcd.: 492; MS Found: 493 (M + H). 82 N7- (cyclopropylmethyl)- N7-(4- fluorobenzyl)- N2-mesityl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.00 (br s, 2H), 0.38 (d, J = 7.2 Hz, 2H), 0.87 (br s, 1H), 2.11 (s, 6H), 2.26 (s, 3H), 2.85 (br s, 2H), 4.01 (s, # 3H), 4.29 (br s, 2H), 6.83 (br s, 3H), 6.92 (s, 2H), 7.07-7.11 (m, 2H), 7.32-7.36 (m, 2H), 7.88 (br s, 1H); 19F NMR (DMSO- d6) δ −116.51 (s, 1F); MS Calcd.: 442; MS Found: 443 (M + H). 83 4- ({(cyclopropyl- methyl) [2- (mesitylamino)- 1-methyl-1H- benzimidazol-7- yl]amino}methyl) benzonitrile 1H NMR (DMSO- d6) δ 0.00 (br s, 2H), 0.39 (d, J = 6.9 Hz, 2H), 0.88 (br s, 1H), 2.11 (s, 6H), 2.26 (s, 3H), 2.88 (br s, 2H), 4.01 (s, # 3H), 4.42 (s, 2H), 6.83 (br s, 3H), 6.92 (s, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.89 (s, 1H); MS Calcd.: 449; MS Found: 450 (M + H). 84 N7- (cyclopropylmethyl)- N2-mesityl- 1-methyl-N7- (pyridin-2- ylmethyl)-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.00 (s, 2H), 0.37 (d, J = 7.6 Hz, 2H), 0.86 (br s, 1H), 2.12 (s, 6H), 2.26 (s, 3H), 2.90 (d, J = 5.8 Hz, 2H), 4.05 # (s, 3H), 4.44 (s, 2H), 6.81 (s, 3H), 6.91 (s, 2H), 7.21 (t, J = 6.2 Hz, 1H), 7.34 (d, J = 6.8 Hz, 1H); 7.69 (t, J = 7.6 Hz, 1H), 7.89 (s, 1H), 8.48 (d, J = 4.7 Hz, 1H); MS Calcd.: 425; MS Found: 426 (M + H). 85 N7-[2- (benzyloxy)ethyl]- N7- (cyclopropylmethyl)- N2-mesityl- 1-methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 0.03 (d, J = 4.3 Hz, 2H), 0.36 (d, J = 7.8 Hz, 2H), 0.85 (br s, 1H), 2.11 (s, 6H), 2.26 (s, 3H), 2.88 (br s, 2H), # 3.32 (d, J =6.6 Hz, 2H), 3.49 (br s, 2H), 3.98 (s, 3H), 4.41 (s, 2H), 6.80-6.86 (m, 3H), 6.91 (s, 2H), 7.23-7.32 (m, 5H), 7.86 (s, 1H); MS Calcd.: 468; MS Found: 469 (M + H). 86 2- {(cyclopropylmethyl) [2- (mesitylamino)- 1-methyl-1H- benzimidazol-7- yl]amino}ethanol 1H NMR (DMSO- d6) δ 0.04 (d, J = 4.7 Hz, 2H), 0.36 (d, J = 8.0 Hz, 2H), 0.84 (br s, 1H), 2.12 (s, 6H), 2.26 (s, 3H), 2.88 (br s, 2H), 3.19 (t, J = # 6.5 Hz, 2H), 3.31 (d, J =1.6 Hz, 2H), 3.46 (q, J =6.1 Hz, 2H), 4.01 (s, 3H), 4.45 (t, J =5.1. Hz, 1H), 6.85 (br s, 3H), 6.92 (s, 2H), 7.87 (s, 1H); MS Calcd.: 378; MS Found: 379 (M + H). 87 N2-(4-bromo-2,6- dimethylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 428; MS Found: 429 (M + H) 88 N2-(4-methoxy-2- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 366; MS Found: 367 (M + H) 89 N2-(2,6- dimethoxy-4- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 396; MS Found: 397 (M + H) 90 N2-(4-bromo-2- methoxy-6- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 444; MS Found: 445 (M + H) 91 N2-(2,6- dichloropyridin- 3-yl)-1- methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 391; MS Found: 392 (M + H) 92 4-{[7- (dipropylamino)- 1-methyl-1H- benzimidazol-2- yl]amino}-3- ethylbenzonitrile MS Calcd.: 375; MS Found: 376 (M + H) 93 N2-(2,4- dimethoxy-6- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CD3OD) δ (HCl salt) 0.91 (br s, 6H), 1.53 (br s, 4H), 2.32 (s, 3H), 3.12 (br s, 4H), 3.82 (s, 3H), 3.86 (s, 3H), 4.21 (s, 3H), 6.60 (br s, # 2H), 7.07 (br s, 1H), 7.24 (br s, 2H); MS Calcd.: 396; MS Found: 397 (M + H). 94 N2-(2,4- dichloro-6- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CD3OD) δ (HCl salt) 0.91 (br s, 6H), 1.53 (br s, 4H), 2.42 (s, 3H), 3.10 (br s, 4H), 4.28 (s, 3H), 7.09 (d, 1H, J =5.5 Hz), 7.27 (br s, 2H), # 7.52 (br s, 1H), 7.63 (br s, 1H); MS Calcd.: 404; MS Found: 405 (M + H). 95 N2-[2-chloro-6- (trifluoromethyl) pyridin-3- yl]-1-methyl- N7,N7-dipropyl- 1H- benzimidazole- 2,7-diamine 1H NMR (CD3OD) δ (HCl salt) 0.91 (br s, 6H), 1.54 (br s, 4H), 3.12 (br s, 4H), 4.31 (s, 3H), 7.17 (br s, 1H), 7.32 (br s, 2H), 8.03 # (br s, 1H), 8.33 (br s, 1H); MS Calcd.: 425; MS Found: 426 (M + H). 96 N2-[2-chloro-4- (trifluoromethyl) phenyl]-1- methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CD3OD) δ (HCl salt) 0.92 (br s, 6H), 1.54 (br s, 4H), 3.14 (br s, 4H), 4.29 (s, 3H), 7.17 (d, 1H, 4.7 Hz), 7.32 (br s, 2H), 7.87 (br s, # 2H), 8.06 (s, 1H); MS Calcd.: 424; MS Found: 425 (M + H). 97 N2-(2-bromo-4- methoxy-6- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CD3OD) δ (HCl salt) 0.90 (br s, 6H), 1.53 (br s, 4H), 2.39 (s, 3H), 3.10 (br s, 4H), 3.87 (s, 3H), 4.26 (s, 3H), 7.04 (s, 1H), 7.08 (d, 1H, J = # 5.2 Hz), 7.25 (br s, 3H); MS Calcd.: 444; MS Found: 445 (M + H); 98 N2-(4-chloro-2- methoxy-5- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CD3OD) δ (HCl salt) 0.91 (br s, 6H), 1.53 (br s, 4H), 2.37 (s, 3H), 3.22 (br s, 4H), 3.87 (s, 3H), 4.21 (s, 3H), 7.19 (br s, 1H), 7.28 (s, # 1H), 7.33 (br s, 2H), 7.41 (br s, 1H); MS Calcd.: 400; MS. Found: 401 (M + H). 99 N2-(4-bromo-2- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ (HCl salt) 0.83 (br s, 6H), 1.44-1.50 (m, 4H), 2.32 (s, 3H), 2.98 (br s, 4H), 4.00 (br s, 3H), 5.89 (s, 1H), 6.95 (d, 1H, J = 7.8 # Hz), 7.08 (br s, 1H), 7.33 (br s, 3H), 7.73 (br s, 1H); MS Calcd.: 414; MS Found: 415 (M + H). 100 N7- (cyclopropylmethyl)- N7-(2,4- dimethylbenzyl)- N2-mesityl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ (HCl salt) 0.04 (s, 2H), 0.43 (d, 2H, J =7.4 Hz), 0.97 (br s, 1H), 2.16 (s, 6H), 2.20 (s, 3H), 2.31 (s, 3H), # 2.32 (s, 3H), 2.97 (br s, 2H), 4.02 (br s, 3H), 4.27 (br s, 2H), 6.84 (d, 1H, J =7.8 Hz), 6.97-7.02 (m, 3H), 7.10 (s, 2H), 7.21 (t, 1H, J = 7.9 Hz), 7.38 (d, 1H, J = 8.0 Hz), 10.23 (s, 1H); MS Calcd.: 452; MS Found: 453 (M + H). 101 N2-(4-bromo-2- ethylphenyl)- N7,N7-dibutyl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ (HCl salt) 0.85-0.88 (m, 6H), 1.22-1.34 (m, 7H), 1.40-1.47 (m, 4H), 2.68 (q, 2H, J =7.5 Hz), 3.01 (br s, 4H), 3.96 (s, 3H), 6.01 (s, # 1H), 6.81 (d, 1H, J = 7.8 Hz), 7.09 (t, 1H, J = 7.0 Hz), 7.32-7.34 (m, 3H), 7.66 (s, 1H); MS Calcd.: 456; MS Found: 457 (M + H). 102 N2-(4-chloro-2- isopropyl-6- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ (HCl salt) 0.85 (t, 6H, J = 7.3 Hz), 1.07-1.14 (m, 4H), 1.19 (d, 3H, J =6.6 Hz), 1.40-1.50 (m, 4H), 2.23 (s, 3H), # 3.02 (br s, 4H), 4.15 (s, 3H), 7.01 (d, 1H, J = 7.2 Hz), 7.15-7.19 (m, 2H), 7.42 (s, 2H), 10.49 (s, 1H); MS Calcd.: 412; MS Found: 413 (M + H). 103 N7,N7-dibutyl- N2-(2,4- dimethoxy-6- methylphenyl)- 1-methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ (HCl salt) 0.80-0.87 (m, 6H), 1.21-1.30 (m, 4H), 1.34-1.41 (m, 4H), 2.25 (s, 3H), 3.04 (s, 4H), 3.76 (s, 3H), 3.83 (s, 3H), 4.07 # (s, 3H), 6.62 (s, 1H), 6.65 (s, 1H), 7.01 (d, 1H, J =7.4 Hz), 7.14-7.21 (m, 2H), 9.99 (s, 1H); MS Calcd.: 424; MS Found: 425 (M + H). 104 N2-(2-bromo-4- methoxy-6- methylphenyl)- N7,N7-dibutyl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ (HCl salt) 0.85 (t, 6H, J =7.3 Hz), 1.21-1.30 (m, 4H), 1.41 (br s, 4H), 2.34 (s, 3H), 3.05 (br s, 4H), 3.84 (s, 3H), 4.13 (s, # 3H), 7.05 (d, 1H, J = 7.4 Hz), 7.09 (s, 1H), 7.16-7.24 (m, 2H), 7.29 (s, 1H), 10.76 (s, 1H); MS Calcd.: 472; MS Found: 473 (M + H). 105 N7,N7-dipropyl- N2-(2,4,6- trimethylpyridin- 3-yl)-1,3- benzothiazole- 2,7-diamine 1H NMR (CDCl3) δ 0.81 (t, 6H, J = 7.5 Hz), 1.36-1.47 (m, 4H), 2.34 (s, 3H), 2.56 (s, 3H), 2.58 (s, 3H), 3.01 3.05 (m, 4H), 6.74 (d, 1H, J = 7.2 # Hz), 6.98 (d, 1H, J = 7.2 Hz), 7.02 (s, 1H), 7.17 (t, 1H, J = 8.0 Hz); MS Calcd.: 368; Found: 369 (M + H). 106 N2-mesityl-1-(2- methoxyethyl)- N7,N7-dipropyl- 1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.85 (t, 6H, J = 7.5 Hz), 1.43-1.55 (m, 4H), 2.19 (s, 6H), 2.27 (s, 3H), 2.90-2.96 (m, 4H), 3.43 (s, 3H), 3.83 (t, 2H, J =4.3 Hz), 4.83 (t, 2H, J = 4.3 Hz), 6.89- # 6.92 (m, 3H), 6.99 (t, 1H, J =7.8 Hz), 7.28 (d, 1H, J =8.0 Hz); MS Calcd.: 408; Found: 409 (M + H). 107 N2-mesityl- N7,N7-dipropyl- 1-(2,2,2- trifluoroethyl)- 1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.85 (t, 6H, J = 7.2 Hz), 1.42-1.55 (m, 4H), 2.18 (s, 6H), 2.28 (s, 3H), 2.85-2.98 (m, 4H), 5.36-5.45 (m, 2H), 6.92 (s, 2H), 6.99 (d, # 1H, J = 7.8 Hz), 7.07 (t, 1H, J = 7.8 Hz), 7.29 (d, 1H, J =7.5 Hz); MS Calcd.: 432; Found: 433 (M + H). 108 2-[7- (dipropylamino)- 2- (mesitylamino)- 1H- benzimidazol-1- yl]ethanol 1H NMR (CDCl3) δ 0.85 (t, 6H, J = 7.5 Hz), 1.42-1.54 (m, 4H), 2.18 (s, 6H), 2.25 (s, 3H), 2.88- 2.96 (m, 4H), 4.03 (t, 2H, J = 4.0 Hz), 4.73 (br. s, 2H), 6.86- # 6.92 (m, 3H), 6.94-7.00 (m, 1H), 7.22- 7.32 (m, 1H),; MS Calcd.: 394; Found: 395 (M + H). 109 N7,N7- bis(cyclopropyl methyl)-1- methyl-N2- (2,4,6- trimethylpyridin- 3-yl)-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.04-0.07 (m, 4H), 0.38-0.42 (m, 4H), 0.84-0.88 (m, 2H), 2.27 (s, 3H), 2.39 (s, 3H), 2.43 (s, 3H), # 2.82-3.08 (m, 4H), 3.99 (s, 3H), 6.92 (s, 1H), 6.98- 7.09 (m, 3H),; MS Calcd.: 389; Found: 390 (M + H). 110 1-acetyl-N2- mesityl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ[ 0.63 (t, J =7.5 Hz), 0.97 (t, J =7.5 Hz), 6H, rotamer], [1.44-1.53 (m), 1.58-1.64 (m), 4H, rotamer], 1.95 (s, 3H), [2.09 (s), # 2.14(s), 6H, rotamer], [2.35 (s), 2.33 (s), 3H, rotamer], [3.13-3.18 (m), 3.28-3.34 (m), 4H, rotamer], [6.26 (d, J =8.0 Hz), 6.76 (d, J = 8.0 Hz), 1H, rotamer], 6.97-7.09 (m, 3H), [6.72 (d, J =7.8 Hz), 7.22 (d, J = # 7.8 Hz), 1H, rotamer]; MS Calcd.: 392; Found: 393 (M + H). 111 N7,N7-dibutyl- N2-mesityl-1- (2,2,2- trifluoroethyl)- 1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.89 (t, 6H, J = 7.2 Hz), 1.21-1.30 (m, 4H), 1.37-1.50 (m, 4H), 2.19 (s, 6H), 2.28 (s, 3H), 2.88-2.99 (m, 4H), 5.35-5.43 (m, # 2H), 6.93 (s, 2H), 6.99 (d, 1H, J = 7.5 Hz), 7.07 (t, 1H, J = 7.8 Hz), 7.29 (d, 1H, J =7.2 Hz); MS Calcd.: 460; Found: 461 (M + H). 112 N7,N7- bis(cyclopropyl methyl)-N2- mesityl-1- (2,2,2- trifluoroethyl)- 1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.02-0.14 (m, 4H), 0.33-0.48 (m, 4H), 0.80-0.85 (m, 2H), 2.17 (s, 6H), 2.27 (s, 3H), 2.74-2.82 # (m, 2H), 3.00-3.05 (m, 2H), 5.52-5.62 (m, 2H), 6.91 (s, 2H), 7.01-7.06 (m, 2H), 7.29 (br, s, 1H); MS Calcd.: 456; Found: 457 (M + H). EXAMPLE 113 4-Bromo-N2-mesityl-1-methyl-N7,N7-dipropyl-1H-benzimidazole-2,7-diamine 4-Bromo-7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg, 0.809 mmol), N-bromosuccinimide (216 mg, 1.21 mmol) and catalytic amount of benzoylperoxide in carbon tetrachloride (20 ml) was refluxed for 60 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 30% ethyl acetate/n-hexane to afford 73 mg (28%) of the title compound. 1H-NMR (CDCl3) δ 0.84 (6H, t, J=7.2 Hz), 1.35-1.48 (4H, m), 2.85-2.95 (4H, m), 3.71 (3H, s), 6.81 (1H, d, J=8.4 Hz), 7.09 (1H, d, J=8.4 Hz), 7.82 (1H, s). MS Calcd.: 325; Found: 326 (M+H), 328. 4-Bromo-2-chloro-1-methyl-N,N-dipropyl-1H-benzimidazol-7-amine A mixture of 4-Bromo-7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (210 mg, 0.644 mmol) and phosphorus oxychloride (3.0, 32 mol) was refluxed for 18 h with stirring and concentrated to dryness under vacuum. The residue was diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated under vacuum to afford 220 (99%) of the title compound. The residue was used for the next reaction without further purification. 1H-NMR(DMSO-d6) δ 0.80 (6H, t, J=7.2 Hz), 1.35-1.45 (4H, m), 2.97 (4H, m), 4.08 (3H, s), 7.05 (1H, d, J=8.0 Hz), 7.38 (1H, d, J=8.0 Hz). MS Calcd.: 343; Found: 344 (M+H), 346. 4-Bromo-N2-mesityl-1-methyl-N7,N7-dipropyl-1H-benzimidazole-2,7-diamine (C) A mixture of 4-Bromo-2-chloro-1-methyl-N,N-dipropyl-1H-benzimidazol-7- amine (220 mg, 0.638 mmol) and mesityl amine (1.79 ml, 12.8 mmol) was heated at 120° C. for 60 h. The mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate in water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 5% n-hexane/ethyl acetate to afford the title compound. 1H-NMR (CDCl3) δ 0.80 (6H, t, J=7.2 Hz), 1.42 (4H, q, J=7.2 Hz), 2.20 (6H, s), 2.30 (3H, s), 2.91 (4H, m), 3.53 (3H, s), 6.05 (1H, s), 6.71 (1H, d, J=8.4 Hz), 6.91 (2H, s), 7.19 (1H, d, J=8.4 Hz). MS Calcd.: 442; Found: 443 (M+H), 445. Compounds of Example 114-117 shown in Table 7 were prepared in a similar manner to that described previously in Example 1. TABLE 7 Example Structure Name Physical Data 114 N7,N7-dibutyl- N2-mesityl-1,3- benzothiazole- 2,7-diamine MS Calcd.: 395; MS Found: 396 (M + H) 115 N7-isopropyl-N2- mesityl-N7- propyl-1,3- benzothiazole- 2,7-diamine MS Calcd.: 367; MS Found: 368 (M + H) 116 N-mesityl-7-(1- piperidinyl)- 1,3- benzothiazol-2- amine MS Calcd.: 351; MS Found: 352 (M + H). 117 N2-(2,4,6- trimethylpyridin- 3-yl)-1- methyl-N7, N7- di(2- methoxyethyl)- 1H- benzimidazole- 2,7-diamine hydrochloride 1H NMR (CDCl3) δ 2.27 (s, 4H), 2.61 (s, 4H), 3.13 (br s, 3H), 3.17 (br s, 3H), 3.28 (br d, J =31 Hz, 9H), # 3.60 (br s, 3H), 7.17 (br s, 3H), 7.55 (br s, 1H); MS Calcd.: 397; Found: 398 (M + H) Compounds of Examples 118-122, shown in Table 8, were prepared in a manner similar to that described in Example 1. TABLE 8 Example Structure Name Physical Data 118 N7,N7-dibutyl- N2-(2,4,6- trimethylpyridin- 3-yl)-1,3- benzothiazole- 2,7-diamine 1H-NMR (CDCl3)δ 0.82 (6H, t, J=7.24 Hz), 1.20-1.27 (4H, m), 1.34-1.42 (4H, m), 2.33 (3H, s), 2.55 (3H, s), 2.57 (3H, s), 3.04-3.08 (4H, m), 6.73 (1H, # d, J=7.78 Hz), 7.00-7.03 (2H, m), 7.18 (1H, t, J=8.05 Hz); S Calcd.: 396; Found: 397 (M + H). 119 N7,N7- diisobutyl-N2- (2,4,6- trimethylpyridin- 3-yl)-1,3- benzothiazole- 2,7-diamine 1H-NMR (CDCl3)δ 0.81 (12H, t, J=6.76 Hz), 1.69-1.77 (2H, m), 2.33 (3H, s), 2.56 (3H, s), 2.58 (3H, s), 2.88 (4H, d, J=7.24 Hz), 6.76 (1H, d, # J=7.78 Hz), 6.92-7.01 (2H, m), 7.6 (1H, t, J=7.78 Hz); MS Calcd.:396; Found: 397 (M + H). 120 N2-[6- (dimethylamino)- 4- methylpyridin- 3-yl]-N7,N7- dipropyl-1,3- benzothiazole- 2,7-diamine 1H-NMR (CDCl3)δ 0.88 (6H, t, J=7.24 Hz), 1.37-1.46 (4H, m), 2.29 (3H, s), 3.01-3.05 (4H, m), 3.13 (6H, s), 6.44 (1H, s), 6.73 (18, d, # J=8.05 Hz), 7.06 (1H, d, J=8.05 Hz), 7.17, (1H, t, J=7.78 Hz) 8.22 (1H, s); MS Calcd.: 383; Found: 384 (M + H). 121 N7,N7-bis(2- methoxyethyl)- N2-(2,4,6- trimethylpyridin- 3-yl)-1,3- benzothiazole- 2,7-diamine 1H-NMR (CDCl3)δ 2.31 (3H, s), 2.54 (6H, s), 3.24 (6H, s), 3.38 (8H, s), 6.85 (1H, d, J=7.78 Hz), 6.99 (1H, s), 7.14 (1H, d, J=8.05 Hz), # 7.23 (1H, t, J=7.78 Hz); MS Calcd.: 400; Found: 401 (M + H). 122 N7-(4-methoxy- 2,6- dimethylpyridin- 3-yl)-N7,N7- dipropyl-1,3- benzothiazole- 2,7-diamine 1H-NMR (CDCl3)δ 0.82 (6H, t, J=7.24 Hz), 1.38-1.48 (4H, m), 2.55 (3H, s), 2.56 (3H, s), 3.03 (4H, t, J=7.24 Hz), 3.81 (3H, s), 6.65 (1H, s), 6.74 (1H, # d, J=7.78 Hz), 7.13 (1H, d, J=8.05 Hz), 7.19 (1H, t, J=7.78 Hz); MS Calcd.: 384; Found: 385 (M + H). EXAMPLE 123 N2-(4-Bromo-2-methoxy-6-methylphenyl)-N7,N7-bis(2-methoxyethyl)-1-methyl-1-benzimidazole-2,7-diamine To a solution of 200 mg (1.66 mmol) of 1,1,3-trimethoxypropane in 25 mL of chloroform was added 5 g (1.66 mmol) of iron (II) chloride on silica (5% by weight) and the slurry was stirred at room temperature for several hours. The slurry was filtered, concentrated in vacuo to about 5 mL and added to a slurry of 200 mg (0.55 mmol) of N2-(4-bromo-2-methoxy-6-methylphenyl)-1-methyl-1H-benzimidazole-2,7-diamine, 1 mL of acetic acid and 2.5 g (5.08 mmol) of MP-CNBH3 in 10 mL of methanol and was stirred overnight. The above aldehyde preparation was repeated each day for 7 days and added to the reaction. The reaction was filtered and concentrated in vacuo to a residue. The residue was purified by flash chromatography eluting with a solution of 40% ethyl acetate/hexanes containing 2% ammonium hydroxide to give 47 mg (18%) of the title compound. 1H NMR (CDCl3) δ 2.19 (s, 3H), 3.28 (s, 6H), 3.33 (br s, 4H), 3.41 (br s, 4H), 3.82 (s, 3H), 4.06 (s, 3H), 5.85 (s, 1H), 6.92-6.97 (m, 2H), 7.02-7.04 (m, 2H), 7.30 (d, J=7.7 Hz, 1H); MS Calcd.: 476; Found: 477 (M+H). Compounds described below were prepared in a similar method. TABLE 9 Example Structure Name Physical Data 124 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-(2- methoxyethyl)- N7,1-dimethyl- 1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 2.18 (s, 3H), 2.80 (s, 3H), 3.23 (br s, 2H), 3.33 (s, 3H), 3.51 (t, J = 5.8 Hz, 2H), 3.82 (s, 3H), 4.05 # (s, 3H), 5.88 (s, 1H), 6.90-6.92 (m, 2H), 7.01-7.04 (m, 2H), 7.26 (br s, 1H); MS Calcd.: 432; MS Found: 433 (M + H). 125 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-isopropyl-N7- (2- methoxyethyl)- 1-methyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 460; MS Found: 461 (M + H). EXAMPLE 126 4-[[2-[(4-Bromo-2-methoxy-6-methylphenlamino)-1-methyl-1H-benzimidazol-7-yl](isopropyl)amino]butanoic acid To a solution of 100 mg (0.20 mmol) of methyl 4-[[2-(4-bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl](isopropyl)amino]butanoate in 5 mL of tetrahydrofuran and 2.5 mL of water was added 83 mg (2.0 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with water and carefully adjusted to pH 7 using 1N aqueous hydrochloric acid and the resulting slurry was filtered. The solids were washed with water, and dried under high vacuum to give 95 mg (98%) of the title compound. MS Calcd.: 488; MS Found: 489 (M+H). EXAMPLE 127 4-[[2-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl](isopropyl)amino]-N-methylbutanamide To a solution of 25 mg (0.050 mmol) of 4-[[2-[(4-Bromo-2-methoxy-6-methylphenlamino)-1-methyl-1H-benzimidazol-7-yl](isopropyl)amino]butanoic acid, 0.044 mL (0.26 mmol) of diisopropylethylamine, and 58 mg (0.15 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) was added 0.128 mL (0.26 mmol) of methylamine (2M solution in tetrahydrofuran). The reaction was stirred overnight at room temperature and concentrated in vacuo. The residue thus obtained was purified by flash chromatography eluting with a solution of 8% methanol/dichloromethane to give 42 mg (82%) of the title compound. MS Calcd.: 501; MS Found: 502 (M+H). Compounds described below were prepared in a similar method. TABLE 10 Example Structure Name Physical Data 128 4-[[2-[(4- bromo-2- methoxy-6- methylphenyl) amino]-1-methyl- 1H- benzimidazol-7- yl](isopropyl) amino]-N,N- dimethylbutanamide MS Calcd.: 515; MS Found: 516 (M + H). 129 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-isopropyl-1- methyl-N7-(4- oxo-4- pyrrolidin-1- ylbutyl)-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 1.06 (d, J =5.8 Hz, 3H), 1.17 (d, J =6.3 Hz, 3H), 1.76-1.89 (m, 6H), 2.19 (br # s, 5H), 3.06-3.10 (m, 1H), 3.18-3.21 (m, 3H), 3.31-3.37 (m, 1H), 3.41 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 4.08 (s, 3H), 5.86 (s, 1H), 6.92-6.95 (m, 2H), 6.99-7.04 (m, 2H), 7.26 (b s, 1H); MS Calcd.: 541; MS Found: 542 (M + H). 130 4-[[2-[(4- bromo-2- methoxy-6- methylphenyl) amino]-1-methyl- 1H- benzimidazol-7- yl](isopropyl) amino]-N,N- diethylbutanamide 1H NMR (CDCl3) δ 1.01-1.08 (m, 9H), 1.18 (d, J = 5.8 Hz, 3H), 1.76-1.80 (m, 2H), 2.19 (s, 3H), 2.21-2.25 (m, # 2H), 3.02-3.24 (m, 4H), 3.29-3.82 (s, 3H), 4.08 (s, 3H), 5.83 (br s, 1H), 6.92 6.94 (m, 2H), 6.99-7.04 (m, 2H), 7.26 (br s, 1H); MS Calcd.: 543; MS Found: 544 (M + H). 131 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-isopropyl-1- methyl-N7-(4- morpholin-4-yl- 4-oxobutyl)-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 1.07 (d, J =5.8 Hz, 3H), 1.18 (d, J =5.8 Hz, 3H), 1.58 (s, 3H), 1.73-1.79 (m, 2H), 2.20 (s, # 3H), 2.23-2.33 (m, 2H), 3.01-3.08 (m, 1H), 3.14-3.21 (m, 3H), 3.31-3.38 (m, 1H), 3.46-3.53 (m, 3H), 3.83 (s, 3H), 4.08 (s, 3H), 5.84 (br s, 1H),6.91-6.93 (m, 2H), 7.01 (t, J = 5.8 Hz, 1H), 7.05 (s, 1H), 7.26 (br s, 1H); MS Calcd.: 557; MS Found: 558 # (M + H). 132 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-isopropyl-1- methyl-N7-(4- oxo-4- piperidin-1- ylbutyl)-1H- benzimidazole- 2,7-diamine MS Calcd.: 555; MS Found: 556 (M + H). 133 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-isopropyl-1- methyl-N7-(4- oxo-4- thiomorpholin- 4-ylbutyl)-1H- benzimidazole- 2,7-diamine MS Calcd.: 573; MS Found: 574 (M + H) 134 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-isopropyl-1- methyl-N7-[4-(4- methylpiperazin- 1-yl)-4- oxobutyl]-1H- benzimidazole- 2,7-diamine MS Calcd.: 570 MS Found: 571 (M + H). 135 N2-[2-[(4-Bromo- 2-methoxy-6- methylphenyl) amino]-1-methyl- 1H- benzimidazol-7- yl]-N2- isopropylglycinamide MS Calcd.: 459; MS Found: 460 (M + H). EXAMPLE 136 N7-(2-Aminoethyl)-N2-(4-bromo-2-methoxy-6-methylphenyl)-N7-isopropyl-1-methyl-1H-benzimidazole-2,7-diamine Hydrochloride To a solution of 100 mg (0.25 mmol) of N2-(4-bromo-2-methoxy-6-methylphenyl)-N4-isopropyl-1-methyl-1H-benzimidazole-2,7-diamine in 2 mL of 1,2-dichloroethane containing 2 drops of acetic acid was added a solution of 79 mg (0.50 mmol) of (2-oxoethyl)carbamic acid tert-butyl ester in 1 mL of 1,2-dichloroethane. To the reaction mixture was then added 158 mg (0.74 mmol) of sodium triacetoxyborohydride. The reaction was stirred for several hours and then another two equivalents of the aldehyde were added to the reaction. The reaction was stirred overnight at room temperature and another two equivalents of the aldehyde were added and the reaction was stirred several hours. The reaction was then heated at 80° C. overnight. The reaction was cooled to room temperature and concentrated in vacuo, dissolved in dichloroethane and 1 ml (13 mmol) of trifluoroacetic acid was added. This mixture was stirred at room temperature for several hours and concentrated in vacuo. This residue thus obtained was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was dissolved in methanol. and treated with hydrochloric. acid (lN solution in diethyl ether). The solution was concentrated in vacuo to give 20 mg (18%) of the title compound as the hydrochloric salt. MS Calcd.: 445; MS Found: 446 (M+H). EXAMPLE 137 N2-(4-Bromo-2-methoxy-6-methylphenyl)-N7-[2-(dimethylamino)ethyl]-N7-isopropyl-1-methyl-1H-benzimidazole-2,7-diamine Hydrochloride To a solution of 10 mg (0.022 mmol) of N7-(2-aminoethyl)-N2-(4-bromo-2-methoxy-6-methylphenyl)-N7-isopropyl-1-methyl-1H-benzimidazole-2,7-diamine was added 0.02 mL (0.22 mmol) of formaldehyde (37% by weight aqueous solution) and 24 mg (0.11 mmol) of sodium triacetoxyborohydride. The reaction was stirred for 2 h at room temperature and diluted with dichloromethane. The organics were washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. This residue thus obtained was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was dissolved in methanol and treated with hydrochloric acid (1N solution in diethyl ether). The solution was concentrated in vacuo to give the 4 mg (38%) of the title compound as the hydrochloric salt MS Calcd.: 473; MS Found: 474 (M+H). EXAMPLE 138 N2-(4-Chloro-2-methoxy-6-methylphenyl)-N7-(4-chlorophenyl)-N7-isopropyl-1-methyl-1H-benzimidazole-2,7-diamine Hydrochloride 7-[(4-Chlorophenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 7-amino-1-methyl-1,3-dihydrobenzimidazol-2-one (5.0 g, 30.6 mmol), biphenyl-2-yl-dicyclohexylphosphine (0.537 g, 1.53 mmol), sodium tert-butoxide (7.4 g, 2.5 mmol) and tris(dibenzylidineacetone)dipalladium (0.56 g, 0.61 mmol) and dioxane (80 ml) was treated with 4-bromoanisole (6.16 g, 32.2 mmol) and refluxed for 22 h. The crude reaction mixture was cooled, poured into water (200 ml) and neutralized to pH8 by saturated aqueous ammonium chloride. The precipitate was filtered, washed with water and dried. Recrystallization from ethanol gave 3.69 g (44%) of the title compound as a tan powder. MS Calcd.: 273; Found: 274 (M+H). 7-[(4-Chlorophenyl)amino]-3-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 7-[(4-chlorophenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.27 g, 1.0 mmol), 4-methoxybenzyl chloride (0.17 ml, 1.20 mmol), potassium carbonate (0.21 g, 1.50 mmol) and N,N-dimethylformamide (1 ml) was stirred at 70° C. for 100 min. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed eluting with a 15% ethyl acetate/hexanes to give 0.39 g (quant.) of the title compound as a powder. MS Calcd.: 393; Found: 394 (M+H). 1H NMR (CDCl3) δ 3.49 (3H, s), 3.78 (3H, s), 5.02 (2H, s), 5.30 (1H, s), 6.56 (2H, d, J=8.4 Hz), 6.80-6.95 (4H, m), 6.97 (1H, t, J=8.0 Hz), 7.13 (2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.0 Hz). 7-[N-(4-Chlorophenyl)-N-isopropylamino]-3-(4-methoxy-benzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 7-[(4-chlorophenyl)amino]-3-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.118 g, 0.30 mmol), 2-bromopropane (0.056 ml, 0.60 mmol), tetrabutylammonium iodide (small amounts) and N,N-dimethylformamide (2 ml) was added sodium hydride (16 mg, 0.60 mmol, 90% dry). The mixture was stirred at 60° C. for 6 h. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (40 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed with 20-33% ethyl acetate/hexanes to give 80.6 mg (62%) of the title compound as an oil. MS Calcd.: 435; Found: 436 (M+H). 1H NMR(CDCl3) δ 0.96 (3H, d, J=6.0 Hz), 1.33 (3H, d, J=6.0 Hz), 3.30 (3H, s), 3.79 (3H, s), 4.20-4.35 (1H, m), 5.02 (2H, s), 6.40 (2H, d, J=9.2 Hz), 6.77 (1H, d, J=8.0 Hz), 6.87 (2H, d, J=8.4 Hz), 6.92 (1H, d, J=8.0 Hz), 7.05 (1H, d, J=8.0 Hz), 7.09 (2H, d, J=9.2 Hz), 7.32 (2H, d, J=8.4 Hz). 7-[N-(4-chlorophenyl)-N-isopropylamino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 7-[N-(4-chlorophenyl)-N-isopropylamino]-3-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (80 mg, 0.18 mmol). and trifluoroacetic acid (3 ml) was stirred at 65° C. for 19 h. The. mixture was concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was flash chromatographed eluting with a 33% ethyl acetate/hexanes to give 26.8 mg (34%) of the title compound as an oil. MS Calcd.: 315; Found: 316 (M+H). 1H NMR (CDCl3) δ 0.98 (3H, d, J=6.4 Hz), 1.36 (3H, d, J=6.4 Hz), 3.28 (3H, s), 4.20-4.35 (1H, m), 6.43 (2H, d, J=8.8 Hz), 6.78-6.85 (1H, m), 7.05-7.20 (4H, m), 9.09 (1H, s). 2-Chloro-N-(4-chlorophenyl)-N-isopropyl-1-methyl-1H-benzimidazol-7-amine A mixture of 7-[N-(4-chlorophenyl)-N-isopropylamino)]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (42 mg, 0.13 mmol) and phosphorous oxychloride (1.5 ml) was stirred at 80° C. for 1.5 h. The mixture was concentrated in vacuo and quenched with saturated aqueous sodium bicarbonate (10 ml) and extracted with ethyl acetate (20 ml). The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was flash chromatographed eluting with a 17% ethyl acetate/hexanes to give 31.9 mg (72%) of the title compound as an oil. MS Calcd.: 333; Found: 334 (M+H) 1H NMR (CDCl3) δ 0.95 (3H, d, J=6.0 Hz), 1.39 (3H, d, J=6.0 Hz), 3.63 (3H, s), 4.30-4.40 (1H, m), 6.40 (2H, d, J=8.8 Hz), 7.03 (1H, d, J=8.0 Hz), 7.09 (2H, d, J=8.8 Hz), 7.30 (1H, t, J=8.0 Hz), 7.70 (1H, d, J=8.0 Hz). N2-(4-Chloro-2-methoxy-6-methylphenyl)-N7-(4-chlorophenyl)-N7-isopropyl-1-methyl-1H-benzimidazole-2,7-diamine Hydrochloride A mixture of 2-chloro-N-(4-chlorophenyl)-N-isopropyl-1-methyl-1H-benzimidazol-7-amine (30 mg, 0.90 mmol) and 4-chloro-2-methyl-6-methoxyaniline (46 mg, 0.27 mmol) was stirred at 120° C. for 19 h. The mixture was dissolved in ethyl acetate (30 ml), washed with saturated aqueous sodium bicarbonate (15 ml) and water (10 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by reverse phase HPLC (acetonitrile containing 0.1 trifluoroacetic acid/water containing 0.1% trifluoroacetic acid). The fraction was concentrated to dryness, dissolved in methanol (10 ml) and treated with 2 M hydrogen chloride in diethyl ether (2 ml) and evaporated in vacuo to give 7.8 mg (19%) of the title compound as a powder. MS Calcd.: 468; Found: 469 (M+H). 1H NMR (CDCl3) δ 0.96 (3H, m), 1.35 (3H, m), 2.39 (3H, s), 3.08 (3H, s), 3.63 (3H, s), 4.20-4.35 (1H, m), 6.39 (2H, d, J=8.8 Hz), 6.74 (1H, s), 6.89 (1H, s), 7.04 (1H, d, J=8.0 Hz), 7.10 (2H, d, J=8.8 Hz), 7.40 (1H, t, J=8.0 Hz), 7.56 (1H, d, J=8.0 Hz), 10.64 (1H, brs). Compounds described below were prepared in a similar method. TABLE 11 Example Structure Name Physical Data 139 N2-(4-chloro- 2-methoxy-6- methylphenyl)- N7-(4- chlorophenyl)- 1-methyl-N7- neopentyl-1H- benzimidazole- 2,7-diamine MS Calcd: 496; Found: 497 (M + H). 1H NMR (CDCl3)δ (HCl salt) 0.93 (9H, s), 2.38 (3H, s), 3.10 (3H, s), 3.42 (1H, # d, J = 14.8 Hz), 3.62 (3H, s), 3.90 (1H, d, J = 14.8 Hz), 6.51 (2H, d, J = 8.0 Hz), 6.73 (1H, s), 6.87 (1H, 7.10 (2H, d, J =8.0 Hz), 7.20 7.40 (1H, m), 7.42 (1H, s), 10.47 (1H, s), 13.35 (1H, s). 140 N2-(4-chloro- 2-methoxy-6- methylphenyl)- N7-(2- chlorophenyl)- N7-(2- methoxyethyl)- 1-methyl-1H- benzimidazole- 2,7-diamine MS Calcd: 484; Found: 485 (M + H). 1H NMR (CDCl3)δ (HCl salt) 2.38 (3H, s), 3.07 (3H, s), 3.25 (3H, # s), 3.56 (2H, m), 3.61 (3H, s), 3.80-4.00 (2H, m), 6.49 (2H, d, J = 8.0 Hz), 6.71 (1H, s), 6.86 (1H, s), 7.12 (2H, d, J = 8.0 Hz), 7.14 (1H, d, J =8.0 Hz), 7.35 7.50 (2H, m), 10.59 (1H, s). 141 ethyl N-{2- [(4-chloro-2- methoxy-6- methylphenyl) amino]-1- methyl-1H- benzimidazol- 7-yl}-N-(4- chlorophenyl) glycinate MS Calcd: 513; Found: 514 (M + H). 1H NMR (CDCl3)δ (HCl salt) 1.23 (3H, t, J = 6.8 Hz), 2.36 (3H, s), # 3.20 (3H, s), 3.66 (3H, s), 4.23 (2H, q, J =6.8 Hz), 4.30 4.50 (1H, m), 4.50-4.70 (1H, m), 6.39 (2H, d, J = 8.0 Hz), 6.73 (1H, s), 6.87 (1H, s), 7.14 (2H, d, J = 8.0 Hz), 7.20-7.30 (1H, m), 7.30-7.60 (2H, m), 10.36 (1H, s). 142 N2-[2-[(4- chloro-2- methoxy-6- methylphenyl) amino]-1- methyl-1H- benzimidazol- 7-yl]-N2-(4- chlorophenyl)- N1,N1- dimethylglycinamide MS Calcd:.511; Found: 512 (M + H). 1H NMR (CDCl3)δ (HCl salt) 2.35 (3H, # s), 2.97 (3H, s), 3.06 (3H, s), 3.29 (3H, s), 3.63 (3H, s), 4.40-4.60 (1H, m), 4.65-4.90 (1H, m), 6.37 (2H, d, J =8.8 Hz), 6.69 (1H, s), 6.85 (1H, s), 7.11 (2H, d, J = 8.8 Hz), 7.21 (1H, d, J = 8.0 Hz), 7.35-7.50 (2H, m), 10.45 (1H, s). 143 N2-(4-chloro- 2-methoxy-6- methylphenyl)- N7-(4- chlorophenyl)- N7-(2- (dimethylamino) ethyl)-1- benzimidazole- 2,7-diamine MS Calcd: 497; Found: 498 (M + H). 1H NMR (CD3OD)δ (2HCl salt) 2.34 (3H, s), 2.97 (6H, s), 3.55-3.65 # (3H, s), 3.84 (3H, s), 4.00-4.20 (1H, m), 4.30-4.50 (1H, m), 6.74 (2H, d, J = 8.8 Hz), 7.10 (1H, s), 7.25 (1H, s), 7.25-7.35 (4H, m), 7.35 (1H, d, J = 8.0 Hz), 7.45 (1H, t, J = 8.0 Hz). 144 N2-(4-chloro- 2-methoxy-6- methylphenyl)- N7-(4- chlorophenyl)- 1-methyl-N7- (tetrahydrofuran- 3- ylmethyl)-1H- benzimidazole- 2,7-diamine MS Calcd: 510; Found: 511 (M + H). 1H NMR (CDCl3)δ1.50-1.70 (1H, m), 2.00-2.15 (1H, # m), 2.18 (3H, s), 2.65-2.80 (1H, m), 3.51 (3H, s), 3.50-3.70 (2H, m), 3.81 (3H, s), 3.65-4.00 (4H, m), 5.81 (1H, s), 6.56 (2H, d, J = 8.0 Hz), 6.79 (1H, s), 6.85-7.00 (2H, m), 7.13 (2H, d, J = 8.0 Hz), 7.10-7.20 (1H, m), 7.47 (1H d, J =6.8 Hz). 145 N2-(4-chloro- 2-methoxy-6- methylphenyl)- N7-isopropyl- N7-(4- methoxyphenyl)- 1-methyl-1H- benzimidazole- 2,7-diamine MS Calcd: 464; Found: 465 (M + H). 1H NMR (CDCl3)δ 1.00-1.45 (6H, m), 2.24 (3H, s), 3.48 (3H, s), 3.74 (6H, s), # 4.25-4.40 (1H, m), 6.50 (2H, d, J = 8.8 Hz), 6.75 (1H, s), 6.76 (2H, d, J = 8.8 Hz), 6.88 (1H, s), 6.91 (1H, d, J =8.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.45 (1H, d, J = 8.0 Hz). 146 N2-(4-chloro- 2-methoxy-6- methylphenyl)- N7-(2- methoxyethyl)- N7-(4- methoxyphenyl)- 2-methyl-1H- benzimidazole- 2,7-diamine MS Calcd: 480; Found: 481 (M + H). 1H NMR (CDCl3)δ 2.18 (3H, s), 3.31 (3H, s), 3.70 (2H, m), # 3.75 (3H, s), 3.80 (3H, s), 3.85-4.00 (2H, m), 5.80 (1H, s), 6.61 (2H, d, J = 8.0 Hz), 6.77 (2H, d, J = 8.0 Hz), 6.78 (1H, s), 6.89 (1H, s), 6.91 (1H, d, J =8.0 Hz), 7.12 (1H, t, J = 8.0 Hz), 7.42 (1H, d, J = 8.0 Hz). 147 ethyl N-{2- [(4-chloro-2- methoxy-6- methylphenyl) amino]-1- methyl-1H- benzimidazol- 7-yl}-N-(4- methoxyphenyl) glycinate MS Calcd: 508; Found: 509 (M + H). 1H NMR (CDCl3)δ 1.28 (3H, t, J = 7.2 Hz), 2.19 (3H, s), 3.69 (3H, # s), 3.75 (3H, s), 3.81 (3H, s), 4.23 (2H, q, J = 7.2 Hz), 4.4H (2H, s), 5.80 (1H, s), 6.50 (2H, d, J =8.8 Hz), 6.77 (2H, d, J = 8.8 Hz), 6.78 (1H, s), 6.89 (1H, s), 7.01 (1H, d, J = 8.0 Hz), 7.12 (1H, t, J =8.0 Hz), 7.43 (1H, d, J = 8.0 Hz). 148 N2-(4-chloro- 2-methoxy-6- methylphenyl)- N7-(4- methoxyphenyl)- 1-methyl-N7- (tetrahydro- 2H-pyran-4- ylmethyl)-1H- benzimidazole- 2,7-diamine MS Calcd: 520; Found: 521 (M + H). 1H NMR (CDCl3)δ1.30-1.50 (2H, m), 1.70-1.80 (2H, m), # 2.00-2.20 (1H, m), 2.16 (3H, s), 3.35 (2H, t, J = 7.6 Hz), 3.49 (3H, s), 3.75 (3H, s), 3.80 (3H, s), 3.70-3.90 (2H, m), 3.97 (2H, d, J = 8.8 Hz), 5.77 (1H, s), 6.57 (2H, d, J = 8.8 Hz), 6.76 (2H, d, J =8.8 Hz), 6.78 (1H, s), 6.88 (1H, s), 6.97 (1H, d, J = 8.0 # Hz), 7.13 (1H, t, J = 8.0 Hz), 7.42 (1H, d, J =8.0 Hz). 149 N2-(4-chloro- 2-methoxy-6- methylphenyl)- N7-isopropyl- 1-methyl-N7- (5- methylpyridin- 2-yl)-1H- benzimidazole- 2,7-diamine MS Calcd: 449; Found: 450 (M + H). 1H NMR (CDCl3)δ 1.00 (3H, d, J = 6.8 Hz), 1.39 (3H, d, J = 6.8 Hz), # 2.18 (6H, s), 3.53 (3H, s), 3.80 (3H, s), 5.10-5.20 (1H, m), 5.91 (1H, d, J = 8.8 Hz), 5.80 6.00 (1H, br), 6.78 (1H, s), 6.87 (1H, d, J =8.0 Hz), 6.89 (1H, s), 7.11 (1H, d, J = 8.0 Hz), 7.16 (1H, t, J = 8.0 Hz), 7.51 (1H, d, J =8.0 Hz), 8.07 (1H, s). 150 N2-(4-chloro- 2-methoxy-6- methylphenyl)- N7-(2- methoxyethyl)- 1-methyl-N7- (5- methylpyridin- 2-yl)-1H- benzimidazole- 2,7-diamine MS Calcd: 465; Found: 466 (M + H). 1H NMR (CDCl3)δ2.19 (6H, s), 3.29 (3H, s), 3.61 (3H, s), # 3.60-3.70 (1H, m), 3.70-3.80 (1H, m), 3.81 (3H, s), 4.00-4.15 (1H, m), 4.30-4.40 (1H, m), 5.83 (1H, s), 6.06 (1H, d, J =8.0 Hz), 6.78 (1H, s), 6.89 (1H, s), 6.93 (1H, d, J = 8.0 Hz), 7.05-7.20 (2H, m), 7.40-7.50 (1H, m), 8.06 (1H, s). EXAMPLE 151 N2-[2-[(4-Chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl]-N1,N1-diethyl-N2-(4-methoxyphenyl)glycinamide Hydrochloride To a solution of ethyl N-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl]-N-(4-methoxyphenyl)glycinate (20 mg, 0.039 mmol) in methanol (0.5 ml) was added 1N sodium hydroxide (0.5 ml). The mixture was stirred at room temperature for 1.5 h, then neutralized with 1N hydrochloric acid (0.5 ml) and concentrated to dryness. To a mixture of the residue, diethylamine (0.0081 ml, 0.079 mmol) and N,N-dimethylformamide (3 ml) were added triethylamine (0.011 ml, 0.079 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (22.4 mg, 0.079 mmol). The mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed eluting with a 20% acetone/hexanes) to give the crude product. The crude product was purified by reverse phase HPLC (acetonitrile containing 0.1 trifluoroacetic acid/water containing 0.1% trifluoroacetic acid). The eluent was concentrated in vacuo and the residue was dissolved in methanol (2 ml) before 2M hydrogen chloride in diethylether (2 ml) was added. The mixture was concentrated in vacuo to give 9.6 mg (46%) of the title as a powder. MS Calcd: 535; Found: 536 (M+H). 1H NMR (CDCl3) δ 1.20-1.40 (6H, m), 2.34 (3H, s), 3.25-3.40 (7H, m), 3.59 (3H, s), 3.74 (3H, s), 4.50-4.70 (2H, m), 6.41 (2H, d, J=8.8 Hz), 6.65 (1H, s), 6.73 (2H, d, J=8.8 Hz), 6.83 (1H, s), 7.15-7.45 (3H, m). EXAMPLE 152 N-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-N-(4-chlorophenyl)-1-methyl-1H-benzimidazol-7-yl]acetamide Hydrochloride A mixture of 7-[N-(4-chlorophenyl)amino]-3-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.393 g, 1.0 mmol), pyridine (0.1 ml) and acetic anhydride. (10 ml) was heated at 120° C. for 4 days. The mixture was evaporated in vacuo. The, residue was diluted with ethyl acetate (50 ml), washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed eluting with 40-50% ethyl acetate/hexanes. to give 7-[N-acetyl-N-(4-Chlorophenyl)amino]-3-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.388 g, quant.) as an oil. MS Calcd: 435; Found: 436 (M+H). 1H NMR (CDCl3) δ 2.05 (3H, s), 3.47 (3H, s), 3.79 (3H, s), 4.99 (1H, d, J=15.6 Hz), 5.05 (1H, d, J=15.6 Hz), 6.87 (2H, d, J=8.4 Hz), 6.80-6.90 (1H, m), 6.90-7.10 (2H, m), 7.31 (2H, d, J=8.4 Hz), 7.20-7.40 (4H, m). From this compound, the title compound was prepared in a similar manner as described in Example 138. MS Calcd: 468; Found: 469 (M+H). 1H NMR (CDCl3) δ 2.11 (3H, s), 2.37 (3H, s), 3.48 (3H, s), 3.65 (3H, s), 6.76 (1H, s), 6.82 (1H, s), 7.00-7.20 (1H, m), 7.20-7.30 (2H, m), 7.30-7.45 (3H, m), 7.50-7.65 (1H, m), 10.80 (1H, s). Compound described below were prepared in a similar method. TABLE 12 Example Structure Name Physical Data 153 N-{2-[(4- chloro-2- methoxy-6- methylphenyl) amino]-1- methyl-1H- benzimidazol- 7-yl}-N-(4- methoxyphenyl) acetamide MS Calcd: 464; Found: 465 (M + H). 1H NMR (CDCl3)δ 2.06 (3Hx2/3, s), 2.20 (3H, s), 2.20 (3Hx1/3, s), 3.71 # (3Hx2/3, s), 3.79 (3Hx1/3, s), 3.80 (6H, s), 5.90-6.10 (1H, brs), 6.79 (1H, s), 6.90 (1H, s), 6.80-7.00 (3H, m), 7.05-7.20 (1H, m), 7.20-7.40 (2H, m), 7.40-7.60 (1H, m). EXAMPLE 154 N2-(4-Bromo-2-methoxy-6-methylphenyl)-N7-isopropyl-1-methyl-N7-[4-(methylsulfonyl)phenyl]-1H-benzimidazole-2,7-diamine 7-[(4-Methylsulfonyl)phenylamino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 7-amino-1-methyl-1,3-dihydrobenzimidazol-2-one (0.500 g, 3.06 mmol), 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (0.0629 g, 0.153 mmol), sodium tert-butoxide (0.590 g, 6.10 mmol) and tris(dibenzylidineacetone)dipalladium (0.280 g, 0.310 mmol) and dioxane (5 ml) was treated with 4-bromophenylmethylsulfone (0.860 g, 3.70 mmol) and refluxed for 3 h. The crude reaction mixture was cooled, poured into water, and extracted with ethyl acetate (X2) and ethyla acetate-tetrahydrofuran (X2). The extract was dried over sodium sulfate and concentrted in vacuo. The residual solids were washed with ethyl acetate to give 525 mg of the title compound as crystals. 1H NMR (CDCl3) δ 3.09 (3H, s), 3.25 (3H, s), 6.70 (2H, d, J=8.6 Hz), 6.83 (1H, d, J=8.0 Hz), 6.93 (1H, d, J=8.0 Hz), 7.02 (1H, t, J=8.0 Hz), 7.64 (2H, d, J=8.6 Hz), 8.53 (1H, s), 11.01 (1H, s). From this compound, the title compound was prepared in a similar manner as described in Example 138. MS Calcd: 556, 558; Found: 557, 559 (M+H). 1H NMR (CDCl3) δ 1.04 (3H, d, J=6.4 Hz), 1.44 (3H, d, J=6.4 Hz), 2.19 (3H, s), 3.01 (3H, s), 3.49 (3H, s), 3.81 (3H, s), 4.38-4.46 (1H, m), 5.83 (1H, s), 6.61 (2H, d, J=8.8 Hz), 6.80 (1H, d, J=8.0 Hz), 6.93 (1H, s), 7.06 (1H, s), 7.17 (1H, t, J=8.0 Hz), 7.55 (1H, d, J=8.0 Hz), 7.69 (2H, d, J=8.8 Hz). Compound described below were prepared in a similar method. TABLE 13 Example Structure Name Physical Data 155 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-isopropyl-1- methyl-N7-[3- (methylsulfonyl) phenyl]-1H- benzimidazole- 2,7-diamine MS Calcd: 556, 558; Found: 557, 559 (M + H). 1H NMR (CDCl3)δ 1.03 (3H, d, J = 6.2 Hz), 1.42 (3H, # d, J = 6.2 Hz), 2.18 (3H, s), 3.05 (3H, s), 3.53 (3H, s), 3.81 (3H, s), 4.39-4.45 (1H, m), 5.83 (1H, s), 6.58 (1H, d, J = 7.8 Hz), 6.80 (1H, d, J =7.8 Hz), 6.81 (1H, d, J = 7.8 Hz), 6.92 (1H, s), 7.05 (1H, s), 7.16 (1H, t, J = 7.8 Hz), 7.22-7.29 (3H, # m), 7.53 (1H, d, J = 7.8 Hz). Compounds of Examples 156-182, shown in the Table 14, were prepared in a manner similar to that described in Example 31. TABLE 14 Example Structure Name Physical Data 156 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-ethyl-N7- isopropyl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ (HCl salt) 0.92 (t, 3H, J = 7.0 Hz), 1.03 (br s, 3H); 1.13 (br s, 3H); 2.29 (s, 3H); 3.10-3.14 (m, 2H); 3.32-3.39 # (m, 1H); 3.80 (s, 3H); 4.12 (s, 3H); 7.06 1H, J =7.2. Hz); 7.18-7.25 (m, 2H); 7.29 (s, 1H); 7.33 (s, 1H); 10.21 (s, 1H); 12.61 (s, 1H); MS Calcd.: 430; MS Found: 431 (M + H). 157 N2-(4-bromo-2,6- diethylphenyl)- 1-methyl-N71N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 457; MS Found: 458 (M + H). 158 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7,N7-dibutyl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.88 (t, J =7.2 Hz, 6H), 1.27 (q, J =7.4 Hz, 4H), 1.45 (t, J =7.2 Hz, 4H), 2.19 (3H, s), 3.01 (br s, 4H), 3.83 (s, # 3H), 4.04 (s, 3H), 6.89-6.92 (m, 2H), 7.00 7.05 (m, 2H), 7.26 (br, s, 1H); MS Calcd.: 472; MS Found: 473 (M + H). 159 N2-(4-chloro- 2,6- diethylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.86 (t, J =7.2 Hz, 6H), 1.18 (t, J =7.2 Hz, 6H), 1.50 (q, J =7.2 Hz, 4H), 2.61 (d, J =7.1 Hz, 4H), 2.98 (br s, # 4H), 4.01 (s, 3H), 6.88 (d, J = 7.3 Hz, 1H), 7.01 (br s, 1H), 7.15 (s, 2H), 7.22 (d, J = 6.7 Hz, 1H); MS Calcd.: 413; MS Found: 414 (M + H). 160 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-ethyl-N7- isopropyl-1- methyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 430; MS Found: 431 (M + H). 161 methyl 4- [(cyclopropylmethyl) [2- (mesitylamino)- 1-methyl-1H- benzimidazol-7- yl]amino]butanoate MS Calcd.: 434; MS Found: 435 (M + H). 162 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7,N7-diethyl-1- methyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 416; MS Found: 417 (M + H). 163 N2-(4-chloro-2- methoxy-6- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 400; MS Found: 401 (M + H). 164 methyl 4-[[2- [(4-bromo-2- methoxy-6- methylphenyl) amino]-1-methyl- 1H- benzimidazol-7- yl](isopropyl) amino]butanoate 1H NMR (CDCl3) δ 1.02 (d, J =5.9 Hz, 3H), 1.19 (d, J =5.9 Hz, 3H), 1.73-1.79 (m, 2H), 2.19 (s, 3H), 2.28-2.32 # (m, 2H), 2.97-3.02 (m, 1H), 3.18-3.22 (m, 1H), 3.29-3.35 (m, 1H), 3.64 (s, 3H), 3.82 (s, 3H), 4.05 (s, 3H), 6.90-6.92 (m, 2H), 6.96-7.06 (m, 2H), 7.25-7.28 (m, 1H); MS Calcd.: 502; MS Found: 503 (M + H). 165 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7,N7-diethyl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ0.95 (t, J = 7.0 Hz, 6H), 2.09 (s, 3H), 3.00-3.08 (m, 4H), 3.74 (s, 3H), 3.95 (s, 3H), 6.77-6.80 (m, 1H), 6.86-6.89 (m, # 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.84 (s, 1H); MS Calcd.: 416; MS Found: 417 (M + H). 166 N2-(3,4- dichloro-2- methoxy-6- methylphenyl)- 1-methyl-N7,N7- dipropyl-1H- 2,7-diamine MS Calcd.: 434; MS Found: 435 (M + H). 167 N2-(4-bromo-2- methoxy-6- methylphenyl)- N7-isopropyl- N7,1-dimethyl- 1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 1.11 (d, J =5.5 Hz, 6H), 2.17 (s, 3H), 2.71 (s, 3H), 3.33-3.41 (m, 1H), 3.81 (s, 3H), 4.03 (s, 3H), 6.87-6.93 # (m, 2H), 6.99 7.04 (m, 2H), 7.23-7.24 (m, 1H); MS Calcd.: 416; MS Found: 417 (M + H). 168 N7-ethyl-N7- isopropyl-1- ethyl-N2- (2,4,6- trimethoxyphenyl)- 1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.95 (t, J =7.0 Hz, 3H), 1.09 (d, J =5.5 Hz, 6H), 3.07-3.12 (m, 2H), 3.28-3.33 (m, 1H), 3.78 (s, 6H), 3.82 # (s, 3H), 4.02 (s, 3H), 6.21 (s, 2H), 6.88 (d, J = 7.8 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 7.26-7.27 (m, 1H); MS Calcd.: 398; MS Found: 399 (M + H). 169 N2-(4-chloro-2- methoxy-6- methylphenyl)- N7-ethyl-N7- isopropyl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.97 (t, J =7.0 Hz, 3H), 1.10 (br s, 6H), 2.20 (s, 3H), 3.02-3.16 (m, 2H), 3.31-3.36 (m, 1H), 3.82 (s, 3H), # 4.07 (s, 3H), 6.78 (s, 1H), 6.89-6.94 (m, 2H), 7.01 (t, J = 7.8 Hz, 1H), 7.26-7.29 (m, 1H); MS Calcd.: 386; MS Found: 387 (M + H). 170 N2-(4-chloro-2- methoxy-6- methylphenyl)- N7,N7-diethyl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 1.02 (t, J =7.0 Hz, 6H), 2.19 (s, 3H), 3.06-3.11 (m, 4H), 3.81 (s, 3H), 4.06 (s, 3H), 6.78 (s, 1H), 6.87-6.90 (m, 2H), 7.02 # (t, J = 7.8 Hz, 1H), 7.23-7.26 (m, 1H); MS Calcd.: 372; MS Found: 373 (M + H). 171 N2-(4-chloro- 2,6- diethylphenyl)- N7,N7-diethyl-1- methyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 484; MS Found: 485 (M + H). 172 N2-(4-chloro- 2,6- diethylphenyl)- N7-ethyl-N7- isopropyl-1- methyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 398; MS Found: 399 (M + H). 173 5-chloro-2-[[7- (dipropylamino)- 1-methyl-1H- benzimidazol-2- yl]amino]phenol 1H NMR (CDCl3) δ 0.84 (t, J =7.4 Hz, 6H) 1.41-1.48 (m, 4H), 2.97 (br s, 4H), 4.10 (s, 3H), 6.81-6.84 (m, 1H), 6.90 (d, J =8.6 Hz, 1H), 6.96 (d, J =7.8 Hz, 1H), # 7.06-7.09 (m, 2H), 7.21 (d, J = 7.8 Hz, 1H); MS Calcd.: 372; MS Found: 373 (M + H). 174 [5-chloro-2- [[7- (dipropylamino)- 1-methyl-1H- benzimidazol-2- yl]amino]phenyl]methanol MS Calcd.: 386; MS Found: 387 (M + H). 175 N2-(4-chloro-2- methoxyphenyl)- 1-methy1-N7,N7- benzimidazole- 2,7-diamine MS Calcd.: 386; MS Found: 387 (M + H). 176 N2-(2-bromo-4- chlorophenyl)- dipropyl-1H- 1-methyl-N7,N7- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.84 (t, J =7.2 Hz, 6H), 1.47 (q, J =7.5 Hz, 4H), 2.99 (br s, 4H), 4.12 (s, 3H), 6.87 (br s, 1H), 6.98 Hz, 1H), 7.10 (d, J = 7.8 # (t, J = 7.8 Hz, 1H), 7.33-7.37 (m, 2H), 7.5 (d, J =2.4 Hz, 1H), 8.58 (d, J =8.2 Hz, 1H); MS Calcd.: 434; MS Found: 435 (M + H). 177 N2-(3-tert- butyl-1-methyl- 1H-pyrazol-5- yl)-N7-ethyl-N7- isopropyl-1- methyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.95 (t, J =7.1 Hz, 3H), 1.09 (d, J =6.5 Hz, 6H), 1.33 (s, 9H), 3.80 (q, J =7.0 Hz, 2H), 3.25-3.30 (m, # 1H), 3.48 (s, 1H), 3.74 (s, 3H), 3.86 (s, 3H), 4.71 (s, 1H), 6.83 (s, 1H), 6.95 (s, 2H); MS Calcd.: 368; MS Found: 369 (M + H). 178 5-chloro-2-[[7- (dipropylamino)- 1-methyl-1H- benzimidazol-2- yl]amino]benzonitrile MS Calcd.: 382; MS Found: 383 (M + H). 179 N2-[4-chloro-2- (methoxymethyl)- phenyl]-1- methyl-N71N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 400; MS Found: 401 (M + H). 180 N7,N7-bis[2- (benzyloxy)ethyl]- 1-methyl-N2- (2,4,6- trimethylpyridin- 3-yl)-1H- benzimidazole- 2,7-diamine 1H NMR (DMSO- d6) δ 2.20 (s, 3H); 2.45 (s, 6H); 3.39 (s, 4H); 3.55-3.62 (m, 4H); 3.93 (s, 3H); 4.43 (s, 4H); 6.91 (s, 2H); 7.00 # (br s, 1H); 7.24-7.35 (m, 12H); MS Calcd.: 549; MS Found: 550 (M + H). 181 N2-(4-chloro-2- methoxyphenyl)- 3-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 400; MS Found: 401 (M + H). 182 1-methyl-N2- (pentamethylphenyl)- N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine 1H NMR (CDCl3) δ 0.84 (t, 6H, J = 7.5 Hz), 1.38-1.48 (m, 4H), 2.03 (s, 6H), 2.18 (s, 6H), 2.19 (s, 3H), 2.90-2.95 (t, 4H, J =7.5 Hz), 3.90 (s, 3H), 6.89 # (d, 1H, J =7.8 Hz), 6.92 (s, 1H), 6.98 (t, 1H, J =7.8 Hz) 7.23 (d, 1H, J =7.8 Hz) MS Calcd.: 392 MS Found: 393 (M + H) EXAMPLE 183 N-(4-Bromo-2-methoxy-6-methylphenyl)-7-(2-ethyl-1-piperidinyl)-1-methyl-1H-benzimidazol-2-amine 7-(2-Ethyl-1-piperidinyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 1-ethylcyclopentene (1.0 g, 10.4 mmol) and sodium bicarbonate (0.1 g, 1.19 mmol) in methanol (150 ml) was ozonized at −78° C. until TLC analysis indicated complete consumption of 1-ethylcyclopentene. The crude ozonide was transferred directly to a mixture of 7-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.5 g, 3.07 mmol) and 10% palladium on carbon (0.05 g, Degussa type; 50% wet). The flask was fitted with a balloon of hydrogen and allowed to stir for 12 h. The reaction was filtered through GF/F paper and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography eluting with a 10% acetone/hexanes mixture to afford 597 mg (75%) of the title compound. 1H-NMR (CDCl3) δ 0.73 (3H, t, J=7.5 Hz), 1.15-1.21 (1H, m), 1.29-1.44 (3H, m), 1.62-1.68 (2H, m), 1.86-1.91 (2H, m), 2.63-2.69 (1H, m), 2.77-2.82 (1H, m), 3.01-3.04 (1H, m), 3.77 (3H, s), 6.89-7.01 (3H, m), 10.08 (1H, s); MS Calcd.: 259; Found: 260 (M+H). 2-Chloro-7-(2-ethyl-1-piperidinyl)-1-methyl-1H-benzimidazole A mixture of 7-(2-ethyl-1-piperidinyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg, 0.77 mmol) and phosphorus oxychloride (3.55 g, 23.1 mol) was refluxed for 12 h with stirring and concentrated to dryness under vacuum. The residue was purified by column chromatography eluting with a 10% acetone/hexanes mixture to afford 192 mg (90%) of the title compound. 1H-NMR (CD3OD) δ 0.77 (3H, t, J=7.5 Hz), 1.21-1.57 (4H, m), 1.67-1.81 (2H, m), 1.83-2.02 (2H, m), 2.74 (1H, t, J=11.27 Hz), 3.03 (1H, t, J=6.4 Hz), 3.15 (1H, d, J=12.1 Hz), 4.41 (3H, s), 7.51-7.61 (3H, m); MS Calcd.: 277; Found: 278 (M+H). N-(4-Bromo-2-methoxy-6-methylphenyl)-7-(2-ethyl-1-piperidinyl)-1-methyl-1H-benzimidazol-2-amine A mixture of 2-chloro-7-(2-ethyl-1-piperidinyl) -1-methyl-1H-benzimidazole (100 mg, 0.36 mmol) and 4-bromo-2-methoxy-6-methylaniline (390 mg, 1.8 mmol) was heated at 110° C. for 12 h. The mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate in water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with a 15% acetone/hexanes mixture to afford 49.3 mg (30%) of the title compound. 1H-NMR (CDCl3) δ 0.73 (3H, t, J=7.5 Hz), 1.16-1.26 (2H, m), 1.34-1.48 (2H, m), 1.62-1.65 (2H, m), 1.87-1.95 (2H, m), 2.18 (3H, s), 2.67-2.74 (1H, m), 2.83-2.87 (1H, m), 3.09-3.12 (1H, m), 3.81 (3H, s), 4.10 (3H, s), 6.91 (1H, s), 6.95-7.04 (3H, m), 7.29 (1H, d, J=7.5 Hz); MS Calcd.: 456; Found: 457 (M+H), 459. Compounds described below were prepared in a similar method. TABLE 15 Example Structure Name Physical Data +TC,,1 184 N-(4-bromo-2- methoxy-6- methylphenyl)- 1-methyl-7-(2- methylpiperidin- 1-yl)-1H- benzimidazol-2- amine 1H-NMR (CDCl3) δ 0.90 (3H, d, J=6.17 Hz), 1.38-1.48 (2H, m), 1.67-1.73(2H, m), 1.81-1.82(2H, m), 2.18(3H, s), 2.69-2.76 (1H, m), 2.96-3.08(1H, m), 3.02-3.15(1H, m), 3.81(3H, s), 4.11(3H, s), 6.91(1H, s), 6.95-7.04 (3H, m), 7.26-7.29(1H, m); MS Calcd.: 442; #Found: 443(M+H), 445. 185 N-(4-bromo-2- methoxy-6- methylphenyl)- 7-(2-ethyl-1- pyrolidinyl)- 1-methyl-1H- benzimidazol-2- amine 1H-NMR (CDCl3) δ 0.85 (3H, t, J=7.25 Hz), 1.29-1.38(1H, m), 1.56-1.67(2H, m), 1.81-1.97 (2H, m), 2.10-2.16(1H, m), 2.19(3H, s), 2.78-2.85(1H, m), 3.32-3.41 (2H, m), 3.81 (3H, s), 4.01 (3H, s), 6.91-6.98(2H, m), 7.01-7.05(2H, m), 7.25(1H, m); MS Calcd.: #442; Found: 443(M+H), 445. 186 N-(4-bromo-2- methoxy-6- methylphenyl)- 1-methyl-7-(2- methyl-1- pyrolidin-1- yl)-1H- benzimidazol-2- amine 1H-NMR (CDCl3) δ 1.07 (3H, d, J=5.9 Hz), 1.54-1.63 (2H, m), 1.83-1.99(2H, m), 2.19(3H, s), 2.77-2.85(1H, m), 3.39-3.49 (2H, m), 3.81 (3H, s), 4.02 (3H, s), 6.88-6.92(2H, m), 7.00-7.05 (2H, m), 7.25(1H, m); MS Calcd.: 428; Found: 429(M+H), 431. 187 N-(4-bromo-2- methoxy-6- methylphenyl)- 7-(3-ethyl-4- morpholinyl)-1- methyl-1H- benzimidazol-2- amine 1H-NMR (CDCl3) δ 0.77 (3H, t, J=7.5 Hz), 1.13-1.20 (1H, m), 1.33-1.49(1H, m), 1.54-1.63(1H, m), 2.18(3H, s), 2.92-3.16 (3H, m), 3.40-3.46(1H, m), 3.77-3.81(1H, m), 3.82(3H, s), 3.91-3.94 (1H, m), 4.09 (3H, s), 6.92 (1H, s), 6.98-7.08(3H, m), 7.31-7.34(1H, #m); MS Calcd.: 458; Found: 459(M + H), 461. 188 N-(4-bromo-2- mthoxy-6- methylphenyl)- 1-methyl-7-(2- propyl-1- piperidinyl)- 1H- benzimidazol-2- amine 1H-NMR (CDCl3) δ 0.73 (3H, t, J=6.9 Hz), 1.10-1.68 (8H, m), 1.83-1.88(1H, m), 1.95-1.98(1H, m), 2.19(3H, s), 2.66∫2.72 (1H, m), 2.88-2.92(1H, m), 23.08-3.12(1H, m), 3.81(3H, s), 4.08(3H, s), 6.92-7.04 (4H, m), 7.28-7.30(1H, m); MS Calcd.: 470; Found: #471(M+H), 473. 189 N-(4-bromo-2- methoxy-6- methylphenyl)- 1-methyl-7-(2- methoxymethyl- 1-piperidinyl)- 1H- benzimidazol-2- amine 1H-NMR (CDCl3) δ 1.24-1.28(1H, m), 1.46-1.57(3H, m), 1.67-1.71 (2H, m), 1.84-1.91(1H, m), 22.02-2.05(1H, m), 2.21(3H, s), 2.73-2.80 (1H, m), 3.09 (3H, s), 3.23-3.25(1H, m), 3.65-3.73(1H, m), 3.80(3H, s), 4.03(3H, s), 6.92(1H, s), 6.98-7.12 (3H, m), #7.25-7.31(1H, m); MS Calcd.: 472; Found: 473(M+H), 475. 190 N5-(7-(2-ethyl- 1-piperidinyl)- 1-methyl-1H- benzimidazol-2- yl)-N2,N2,4- trimethyl-2,5- pyridiamine 1H NMR (CDCl3) δ. 0.74(t, J=7.4 Hz, 3H), 1.18-1.23(m, 1H), 1.32-1.45 (m, 4H), 1.68 (br s, 1H), 1.91(m, 2H), 2.23(s, 3H), 2.70-2.73(m, 1H), 2.82-2.86 (m, 1H), 3.07 (br s, 6H), 4.03(s, 3H), 4.69(s, 2H), 6.42(s, 1H), 6.93-6.94(m, 1H), 7.02(t, J=7.7 Hz, #1H), 7.24-7.26 (m, 1H(), 8.10 (s, 1H); MS Calcd.: 392; MS Found: 393 (M+H). 191 methyl 1-[2- [(4-bromo-2- methoxy-6- methylphenyl)amino]- -1-methyl- 1H- benzimidazole- 7- yl]piperidine- 2-carboxylate 1H-NMR (CDCl3) δ1.56-1.85(4H, m), 1.94-1.98 (1H, m), 2.05-22.08(1H, m), 2.18(3H, s), 2.65-2.71(1H, m), 3.17-3.20(1H, m), 3.45(3H, s), 3.81(3H, s), 3.86-3.89(1H, m), 4.15(3H, s), 6.88-6.91(2H, m), 6.98(1H, t, J=8.05 Hz), 7.03(1H, s), 7.25-7.31(1H, m); MS Calcd.: 486; Found: 487(M+H); 489. EXAMPLE 192 N2-(4-Bromo-2-methoxy-6-methylphenyl)-3-methyl-N4,N4-dipropyl-3H-imidazo[4,5-c]pyridine-2,4-diamine N3-Methyl-1-oxypyridine-3,4-diamine To a slurry of 5.00 g (22.8 mmol) of 3-bromo-4-nitropyridine-1-oxide in 50 mL of tetrahydrofuran (THF) was slowly added 68.5 mL (137 mmol) of methylamine (2.0 M solution in THF). The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The thus obtained residue was dissolved in 250 mL of dichloromethane and washed with 100 mL of saturated aqueous sodium bicarbonate and 100 ml of water. The combined aqueous layers were extracted with 100 mL of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 3.78 g (98%) of the title compound. 1H NMR (CDCl3) δ 3.03 (d, J=5.3 Hz, 3H), 7.48 (d, J=7.2 Hz, 1H), 7.94 (s, 1H), 8.02 (d, J=7.2 Hz, 1H); MS Calcd.: 169; Found: 170 (M+H). N3-Methylpyridine-3,4-diamine To a nitrogen inerted slurry of 3.78 g (22.3 mmol) of N3-methyl-1-oxypyridine-3,4-diamine in 150 mL of methanol was added 2 mL of Raney nickel (50% slurry in water). The reaction mixture was purged with hydrogen and then stirred under balloon pressure hydrogen overnight. The catalyst was removed by filtration through GFF paper and the filtrate was concentrated in vacuo to a pink residue that solidified under high vacuum to give 2.90 g (100%) of the title compound. 1H NMR (CDCl3) δ 2.89 (s, 3H), 3.48 (s, 1H), 3.99 (br s, 2H), 6.55 (d, J=5.1 Hz, 1H), 7.87 (s, 1H), 7.89 (d, J=5.3 Hz, 1H); MS Calcd.: 123; Found: 124 (M+H). 3-Methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one To a solution of 2.80 g (22.7 mmol) of N3-methylpyridine-3,4-diamine in 125 mL of THF was added 4.42 g (27.3 mmol) of 1,1′-carbonyldiimidazole and the reaction was stirred overnight at room temperature. The reaction slurry was concentrated in vacuo to a volume of about 65 mL and cooled in a −10° C. bath, filtered, and the solids washed with 25 mL of THF. The solids were dried under high vacuum to give 2.35 g (69%) of the title compound. 1H NMR (DMSO-d6) δ 3.29 (d, J=1.2 Hz, 3H), 6.99 (d, J=5.1 Hz, 1H), 8.12 (d, J=5.1 Hz, 1H), 8.28 (s, 1H), 11.27 (br s, 1H); MS Calcd.: 149; Found: 150 (M+H). 3-Methyl-4-nitro-1,3-dihydroimidazo[4,5-c]pyridin-2-one To a solution of 1.73 g (11.6 mmol) of 3-methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one in 6.3 ML of concentrated sulfuric acid, cooled in an 0° C. ice bath, was slowly added a solution of 1.50 mL (36.0 mmol) of fuming nitric acid in 1.5 mL of concentrated sulfuric acid. The reaction was removed from the ice bath and stirred for 0.5 h at room temperature and then heated at 100° C. for 2 h. The reaction was quenched over 300 mL of ice and solid ammonium carbonate was added to adjust the pH to 9. The resulting slurry was filtered and the collected solids washed with water and dried under high vacuum to give 1.94 g (86%) of the title compound. 1H NMR (DMSO-d6) δ 2.47 (s, 3H), 7.33-7.37 (m, 1H), 8.07 (d, J=5.1 Hz, 1H), 11.27 (br s, 1H); MS Calcd.: 194; Found: 195 (M+H). 4-Amino-3-methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one To a nitrogen inerted slurry of 2.24 g (11.5 mmol) of 3-methyl-4-nitro-1,3-dihydroimidazo[4,5-c]pyridin-2-one in 25 mL of methanol was added 0.5 mL of Raney nickel (50% slurry in water). The reaction slurry was purged with hydrogen and then stirred under balloon pressure hydrogen for 1 h. To the reaction slurry was added 20 mL of methanol and the reaction slurry was purged with hydrogen and then stirred under balloon pressure hydrogen for 2 h. The catalyst was removed by filtration through GFF paper and the filtrate was concentrated in vacuo. The residue thus obtained (1.54 g, 81%) was used in the next reaction without further purification. MS Calcd.: 164; Found: 165 (M+H). 4-Dipropylamino-3-methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one To a slurry of 750 mg (4.57 mmol) of 4-amino-3-methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one in 15 mL of dichloroethane was added 3.30 mL (45.7 mmol) of propionaldehyde, 1.0 mL of acetic acid, and 2.90 g (13.7 mmol) of sodium triacetoxyborohydride and the reaction was heated at 45° C. for 7.5 h. The reaction was diluted with 15 mL of dichloromethane and 15 mL of water and the aqueous layer was extracted with 15 mL of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue thus obtained (0.91 g, 80%) was used in the next reaction without further purification. MS Calcd.: 248; Found: 249 (M+H). (2-Chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)-dipropylamine A solution of 0.91 g (3.66 mmol) of 4-dipropylamino-3-methyl-1,3-dihydroimidazo[4,5-c]pyridin-2-one in 30 mL of phosphorous oxychloride was heated at 100° C. overnight and concentrated in vacuo. The thus obtained residue was quenched with water, adjusted with aqueous sodium bicarbonate to pH 5, and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The thus obtained residue was triturated with acetonitrile, filtered, and the filtrate, which contained the desired product, was concentrated in vacuo. The residue thus obtained (0.18 g, 18%) was used in the next reaction without further purification. MS Calcd.: 266; Found: 267 (M+H). N2-(4-Bromo-2-methoxy-6-methylphenyl)-3-methyl-N4,N4-dipropyl-3H-imidazo[4,5-c]pyridine-2,4-diamine A neat mixture of 180 mg (0.67 mmol) of (2-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)-dipropylamine and 157 mg (0.73 mmol) of 4-bromo-2-methoxy-6-methylaniline was heated at 100° C. for 1 h. The reaction was cooled to room temperature and the residue was dissolved in 10 mL of dichloromethane, washed with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. This residue thus obtained was purified by preparative HPLC to give 4.5 mg (2% for 3 steps) of the title compound as the trifluoroacetic acid salt. 1H NMR (CDCl3) δ 0.87 (t, J=7.4 Hz, 6H), 1.47-1.56 (m, 4H), 2.22 (s, 3H), 3.17 (t, J=7.6 Hz, 4H), 3.83 (s, 3H), 3.99 (s, 3H), 4.72 (br s, 1H), 6.94 (s, 1H), 7.07 (s, 1H), 7.12 (d, J=5.4 Hz, 1H), 8.00 (d, J=5.4 Hz, 1H); MS Calcd.: 445; Found: 446 (M+H). EXAMPLE 193 N2-[2-(3-Bromopropoxy)-4-chlorophenyl]-1-methyl-N7, N7-dipropyl-1H-benzimidazole-2,7-diamine To a solution of 100 mg (0.27 mmol) of 5-chloro-2-(7-dipropylamino-1-methyl-1H-benzimidazol-2-ylamino)phenol in 4 mL of tetrahydrofuran was added 77 mg (0.30 mmol) of triphenylphosphine and 51 mg (0.30 mmol) of diethylazodicarboxylate and the reaction mixture was stirred for 90 minutes at room temperature. To the reaction mixture was added 41 mg (0.30 mmol) of 3-bromopropan-1-ol and the reaction was stirred overnight. The reaction was concentrated in vacuo and the resulting residue was purified by flash chromatography eluting with 20% ethyl acetate/hexanes to give 100 mg (76%) of the title compound. 1H NMR (CDCl3) δ 0.84 (t, J=7.2 Hz, 6H), 1.47 (q, J=7.2 Hz, 4H), 2.40-2.47 (m, 2H), 2.98 (br s, 4H), 3.61 (t, J=6.3 Hz, 2H), 4.07 (s, 3H), 4.28 (t, J=6.0 Hz, 2H), 6.85 (s, 1H), 6.91 (s, 1H), 6.95 (d, J=7.0 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.08 (t, J=7.8, 1H), 7.36 (d, J=7.8 Hz, 1H), 8.47 (d, J=8.8 Hz, 1H); MS Calcd.: 492; MS Found: 493 (M+H). EXAMPLE 194 4-[5-Chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy)butanenitrile To a solution of 80 mg (0.16 mmol) of N2-[2-(3-bromopropoxy)-4-chlorophenyl]-1-methyl-N7, N7-dipropyl-1H-benzimidazole-2,7-diamine in. 2 mL of dimethylsulfoxide was added 13 mg (0.19 mmol) of potassium cyanide. The reaction was stirred at room temperature for several hours, diluted with 10 mL water, and extracted twice with 10 mL ethyl acetate. The organics were washed with water, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography eluting with a solution of 20% acetone/hexanes to give 75 mg (100%) of the title compound. 1H NMR (CDCl3) δ 0.84 (t, J=7.3 Hz, 6H), 1.42-1.51 (m, 4H), 2.22-2.28 (m, 2H), 2.59 (t, J=6.8 Hz, 2H), 2.98 (br s, 4H), 4.07 (s, 3H), 4.23 (t, J=5.5 Hz, 2H), 6.86 (d, J=8.6 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 7.02-7.09 (m, 2H), 7.34 (d, J=7.8 Hz, 1H), 8.40 (d, J=8.6 Hz, 1H); MS Calcd.: 439; MS Found: 440 (M+H). A compound described below was prepared in a similar method. TABLE 16 Example Structure Name Physical Data 195 N2-[2-(2- bromoethoxy)-4- chlorophenyl]- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 478; MS Found: 479 (M+H). EXAMPLE 196 [5-Chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy]acetonitrile To a solution of 48 mg (0.40 mmol) of 5-chloro-2-(7-dipropylamino-1-methyl-1H-benzimidazol-2-ylamino)phenol in 5 mL of tetrahydrofuran was added 114 mg (0.59 mmol) of cesium bicarbonate and 50 mg (0.41 mmol) of bromoacetonitrile and the reaction was stirred overnight at room temperature. Bromoacetonitrile, 200 mg (1.64 mmol), was added to the reaction and the mixture was stirred several hours at room temperature. Then 50 mg (0.36 mmol) of potassium carbonate was added to the reaction and it was stirred at room temperature overnight. The reaction was concentrated in vacuo to a residue that was dissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with a solution of 20% ethyl acetate/hexanes to give 64 mg (58%) of the title compound. 1H NMR (CDCl3) δ 0.84 (t, J=7.3 Hz, 6H), 1.42-1.52 (m, 4H), 2.99 (br s, 4H), 4.09 (s, 3H), 4.88 (s, 2H), 6.68 (s, 1H), 6.93-6.98 (m, 2H), 7.09 (t, J=7.8 Hz, 1H), 7.12-7.15 (m, 1H), 7.35 (d, J=7.8 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H); MS Calcd.: 411; MS Found: 412 (M+H). A compound of Example 197, shown in the Table 17, was prepared in a manner similar to that described in Example 193. TABLE 17 Example Structure Name Physical Data 197 N2-[2-(4- bromobutoxy)-4- chlorophenyl]- 1-methyl-N7,N7- dipropyl-1H- benzimidazole- 2,7-diamine MS Calcd.: 506; MS Found: 507 (M+H). A compound of Example 198, shown in the Table 18, was prepared in a manner similar to that described in Example 194. TABLE 18 Example Structure Name Physical Data 198 5-(5-cchloro- 2-[[7- (dipropylamino)- 1-methyl- 1H- benzimidazol- 2- yl]amino]phenoxxy)- pentanenitrile 1H NMR (CDCl3) δ 0.84(t, J=7.2 Hz, 6H), 1.42-1.51(m, 4H), 1.88-1.95(m, 2H), 2.06-2.13(m, 2H), 2.49(t, J=6.8 Hz, 2H), 2.98(br s, 4H), 4.08(s, 3H), 4.15(t, J=6.0 Hz, 2H), 4.72(s, 1H), 6.87(s, 1H), 6.95(d, J=7.8 Hz, 1H), 7.03(d, J=9.6 Hz, 1H), 7.08 #(t, J=8.0 Hz, 1H), 7.35(d, J=7.8 Hz, 1H), 8.44(d, J=8.8 Hz, 1H). MS Calcd.: 453; MS Found: 454 (M+H). EXAMPLE 199 4-[5-Chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy]butyric acid To a solution of 63 mg (0.14 mmol) of 4-[5-chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy)butanenitrile in 3 mL of EtOH and 1 mL of water was added 29 mg (0.72 mmol) of sodium hydroxide pellets and the reaction was stirred at 75° C. for 48 h. To the reaction mixture was. added 75 mg (1.87 mmol) of sodium hydroxide pellets and the reaction heated at 75° C. for 24 h and concentrated in vacuo to a residue. The thus obtained residue was dissolved in 5 mL of water and the pH was adjusted to 4-5 using hydrochloric acid (1N aqueous solution). The resulting slurry was filtered, and the solids were washed with water and dried under high vacuum to give 46 mg (70%) of the title compound as white solids. MS Calcd.: 458; MS Found: 459 (M+H). EXAMPLE 200 4-[5-Chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy]-N-methylbutanamide Hydrochloride To a slurry of 20 mg (0.044 mmol) of 4-[5-chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy]butyric acid in 2 mL of tetrahydrofuran was added 25 mg (0.065 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 19 μL (0.11 mmol) of diisopropylethylamine, and 54 μL (0.11 mmol) of methylamine (2M solution in tetrahydrofuran). The reaction was stirred at room temperature for 3 h, diluted with water and extracted with dichloromethane. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The thus obtained residue was purified via preparative TLC eluting with a 75% ethyl acetate/hexanes solution. The isolated product was washed off the silica with 100% ethyl acetate and concentrated in vacuo. The thus obtained residue was dissolved in methanol and hydrochloric acid (1N solution in diethyl ether) was added. The resulting slurry was concentrated in vacuo to give 9.0 mg (44%) of the title compound as the hydrochloric salt. 1H NMR (CDCl3) δ(free form) 0.84 (t, J=7.2 Hz, 6H), 1.43-1.52 (m, 4H), 2.23-2.28 (m, 2H), 2.31-2.34 (m, 2H), 2.66 (d, J=4.9 Hz, 3H), 2.99 (br s, 4H), 4.08 (t, J=5.6 Hz, 2H), 4.16 (s, 3H), 5.54 (br s, 1H), 6.82 (s, 1H), 6.95 (t, J=8.0 Hz, 2H), 7.07 (t, J=7.8 Hz, 2H), 7.29 (d, J=7.4 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H). MS Calcd.: 471; MS Found: 472 (M+H). A compound described below was prepared in a similar method. TABLE 19 Example Structure Name Physical Data 201 4-[5-chloro-2- [[7- (dipropylamino)- 1-methyl-1H- benzimidazol-2- yl]amino]phenoxy]- N,N- dimthylbutan- amide 1H NMR (CDCl3) δ 0.84(t, J=7.2 Hz, 6H), 1.42-1.51(m, 4H), 2.24-2.30(m, 2H), 2.52(t, J=6.6 Hz, 2H), 2.89(s, 3H), 2.97(br s, 7H), 4.12-4.15(m, 5H), 6.86(s, 1H), 6.93(d, J=7.8 Hz, 1H), 6.98-7.00(m, 1H), 7.05-7.09(m, 2H), 7.34(d, J=7.8 Hz, #1H), 8.41(d, J=8.8 Hz, 1H). MS Calcd.: 485; MS Found: 486 (M+H). EXAMPLE 202 2-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-N,N-diethyl-1-methyl-1H-benzimidazole-7-carboxamide Hydrochloride Methyl 2-chloro-1-methyl-1H-benzimidazole-7-carboxylate A solution of 2.00 g (9.70 mmol) of methyl 1-methyl-2-oxo-1,3-dihydro-2H-benzimidazole-7-carboxylate in 20 mL of phosphorous oxychloride was heated at 100° C. for 6 h. The reaction was concentrated in vacuo and the thus obtained residue was quenched with water and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The thus obtained residue was purified via flash chromatography eluting with a solution of 20% ethyl acetate/hexanes to give 1.77 g (81%) of the title compound as white solids. 1H NMR (CDCl3) δ 3.98 (s, 3H), 4.00 (s, 3H), 7.26-7.31 (m, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H). MS Calcd.: 224; MS Found: 225 (M+H). Methyl 2-[(4-bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate A mixture of 1.50 g (6.68 mmol) of methyl 2-chloro-1-methyl-1H-benzimidazole-7-carboxylate and 2.89 g (13.4 mmol) of 4-bromo-2-methoxy-6-methylphenylamine was heated at 100° C. for five days. The cooled reaction was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate, water and brine. The organics were dried over sodium sulfate,. filtered, and concentrated in vacuo. The. thus obtained residue was purified via flash chromatography eluting with 100% dichloromethane to elute the residual 4-bromo-2-methoxy-6-methylphenylamine and 30% ethyl. acetate/hexanes to give 356 mg (13%) of the title compound. 1H NMR (CDCl3) δ 2.17 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H), 3.97 (s, 3H), 5.96 (s, 1H), 6.94 (s, 1H), 7.05 (s, 1H), 7.12 (t, J=7.8 Hz, 1H), 7.61-7.67 (m, 2H). MS Calcd.: 403; MS Found: 404 (M+H). 2-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylic acid To a solution of 150 mg (0.371 mmol) of methyl 2-[(4-bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate in 5 mL of tetrahydrofuran and 2.5 mL of water was added 156 mg (3.71 mmol) of lithium hydroxide monohydrate and the reaction was stirred at room temperature overnight and concentrated in vacuo. The thus obtained residue was diluted with water and carefully adjusted to pH 4-5 using 1 N aqueous hydrochloric acid. The resulting solids were filtered, washed with water and dried under high vacuum to give 112 mg (77%) of the title compound as white solids. MS Calcd.: 389; MS Found: 390 (M+H). 2-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-N,N-diethyl-1-methyl-1H-benzimidazole-7-carboxamide Hydrochloride To a slurry of 22 mg (0.056 mmol) of 2-[(4-bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylic acid in 4 mL of tetrahydrofuran was added 32 mg (0.085 mmol) of HATU, 25 μL (0.14 mmol) of diisopropylethylamine, and 15 μL (0.14 mmol) of diethylamine and the reaction was stirred at room temperature for 4 h and concentrated in vacuo. The thus obtained residue was diluted with water and extracted with dichloromethane containing 5% methanol. The organics were dried over sodium sulfate, filtered, concentrated in vacuo and the thus obtained residue was purified via preparative TLC eluting with 10% methanol/dichloromethane. The isolated product was washed off the silica with 5% methanol/ethyl acetate and concentrated in vacuo. To a solution of the purified title compound in methanol was added hydrochloric acid (1N solution in diethyl ether) and the thus obtained slurry was concentrated in vacuo to give 14 mg (58%) of the title compound as the hydrochloric salt. 1H NMR (CDCl3) δ (free form) 1H NMR (CDCl3) δ 1.11 (t, J=7.0 Hz, 3H), 1.32 (t, J=7.0 Hz, 3H), 2.17 (s, 3H), 3.31 (q, J=7.0 Hz, 2H), 3.55 (br s, 2H), 3.67 (s, 3H), 3.82 (s, 3H), 4.72 (s, 1H), 6.93-6.96 (m, 2H), 7.05 (s, 1H), 7.10 (t, J=7.7 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H). MS Calcd.: 444; MS Found: 445 (M+H). Compounds described below were prepared in a similar method. TABLE 20 Example Structure Name Physical Data 203 2-[[4-bromo-2- methoxy-6- methylphenyl)- amino]-N,N- dipropyl-1- methyl-1H- benzimidazole- 7-carboxamide MS Calcd.: 472; MS Found: 473 (M+H). 204 N-(4-bromo-2- methoxy-6- methylphenyl)- 1-methyl-7- (pyrolidin-1- ylcarbonyl)-1H- benzimidazol-2- amine 1H NMR (CDCl3) δ 1.90-1.95 (m, 2H), 1.99-2.04(m, 2H), 2.18(s, 3H), 3.35(t, J=6.7 Hz, 2H), 3.68(s, 3H), 3.73(t, J=6.7 Hz, 2H), 3.82(s, 3H), 4.72(s, 1H), 6.93(s, 1H), 7.01-7.05(m, 2H), 7.10(t, J=7.6 Hz, 1H), 7.51(d, J=8.0 Hz, 1H). MS Calcd.: 442; MS Found: #443 (M+H). 205 N-(4-bromo-2- methoxy-6- methylphenyl)- 1-methyl-7- (morpholin-4- ylcarbonyl)-1H- benzimidazol-2- amine 1H NMR (CDCl3) δ 2.19(s, 3H), 3.44-3.49(m, 2H), 3.61(br s, 1H), 3.70(br s, 4H), 3.82 (br s, 5H), 3.91(br s, 2H), 4.72(s, 1H), 6.94(br s, 2H), 7.06 (s, 1H), 7.11 (t, J=7.7 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H). MS Calcd.: 458; MS Found: 459 (M+H). EXAMPLE 206 N2-(4-Bromo-2-methoxy-6-methylphenyl)-N7-propyl-1-methyl-N7-[2-(methylsulfonyl)phenyl]-1H-benzimidazole-2,7-diamine 7-[N-[(2-Methylsulfonyl)phenyl]-N-propylamino]-3-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one A mixture of 7-[N-[(2-methylthio)phenyl]-N-propylamino]-3-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (630 mg, 1.41 mmol), prepared in a similar manner as described in Example 138, m-chloroperbenzoic acid (730 mg, 4.22 mmol) and acetonitrile (5 ml) was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated. in vacuo. The residue was chromatographed on silica gel eluting with a solution of 50% hexane/ethyl acetate to give 500 mg (74%) of the title compound as an oil. MS Calcd: 479; Found: 480 (M+H). 1H NMR (CDCl3) δ 0.91 (3H, t, J=7.4 Hz), 1.68-1.74 (2H, m), 2.35 (3H, s), 3.50-3.54 (2H, m), 3.77 (3H, s), 3.89 (3H, s), 5.02 (2H, s), 6.20 (1H, d, J=8.0 Hz), 6.67 (1H, t, J=8.0 Hz), 6.74 (1H, d, J=8.0 Hz), 6.84 (2H, d, J=8.8 Hz), 7.26-7.31 (3H, m), 7.48 (1H, d, J=8.0 Hz), 7.64-7.69 (1H, m), 8.07 (1H, dd, J=8.0, 1.6 Hz). From this compound, the title compound was prepared in a similar manner as described in Example 138. MS Calcd: 556, 558; Found: 557, 559 (M+H). 1H NMR (CDCl3) δ 0.95 (3H, t, J=7.4 Hz), 1.73-1.79 (2H, m), 2.04 (3H, s), 2.22 (3H, s), 3.58 (2H, t, J=8.0 Hz), 3.85 (3H, s), 4.13 (3H, s), 5.95 (1H, s), 6.24 (1H, d, J=7.8 Hz), 6.83 (1H, t, J=7.8 Hz), 6.94 (1H, s), 7.06 (1H, s), 7.21-7.32 (2H, m), 7.49 (1H, d, J=7.8 Hz), 7.67 (1H, t, J=7.8 Hz), 8.07 (1H, d, J=7.8 Hz). EXAMPLE 207 4-[[2-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl](isopropyl)amino]benzonitrile 4-[(2-Chloro-1-methyl-1H-benzimidazol-7-ylamino]benzonitrile A mixture of 4-[(1-methyl-2-oxo-1,3-dihydro-2H-benzimidazol-7-yl)amino]benzonitrile (137 mg, 0.518 mmol), prepared in a similar manner as described in Example 138, and phosphorous oxychloride (1.5 ml) was refluxed for 3 h. The mixture was concentrated in vacuo and quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was flash chromatographed eluting with a solution of 25% ethyl acetate/hexane to give 66 mg (45%) of the title compound. MS Calcd.: 282; Found: 283 (M+H) 1H NMR (CDCl3) δ 3.79 (3H, s), 5.97 (1H, s), 6.62 (2H, d, J=8.6 Hz), 7.09 (1H, d, J=7.8 Hz), 7.28 (1H, t, J=7.8 Hz), 7.46 (2H, d, J=8.6 Hz), 7.66 (1H, d, J=7.8 Hz). 4-[(2-Chloro-1-methyl-1H-benzimidazol-7-yl)(isopropyl)amino]benzonitrile To a suspension of 4-[(2-chloro-1-methyl-1H-benzimidazol-7-yl)amino]benzonitrile (64 mg, 0.226 mmol), tetrabutylammonium iodide (8.4 mg, 0.023 mmol) and sodium hydride (18.1 mg, 0.679 mmol, 90% dry) was added 2-bromopropane (0.07231 ml, 0.679 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with a solution of 50% hexane/ethyl acetate to give 64 mg (84%) of the title compound. MS Calcd.: 324; Found: 325 (M+H) 1H NMR (CDCl3) δ 0.96 (3H, d, J=6.6 Hz), 1.43 (3H, d, J=6.6 Hz), 3.58 (3H, s), 4.30-4.43 (1H, m), 6.49 (2H, d, J=8.2 Hz), 7.02 (1H, d,. J=8.0 Hz), 7.34 (1H, t, J=8.0 Hz), 7.42 (2H, d, J=8.2 Hz), 7.75 (1H, d, J=8.0 Hz). 4-[[2-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl](isopropyl)amino]benzonitrile A mixture of 4-[(2-chloro-1-methyl-1H-benzimidazol-7-yl)(isopropyl)amino]benzonitrile (50 mg, 0.154 mmol) and 4-bromo-2-methyl-6-methoxyaniline (100 mg, 0.46 mmol) was stirred at 120° C. for 3 days. The mixture was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a solution of 33% ethyl acetate/hexane. The desired fractions were concentrated in vacuo, and the residual solids were washed with diethyl ether-hexane to give 7.4 mg (9.5%) of the title compound. MS Calcd.: 503, 505; Found: 504, 506 (M+H). 1H NMR (CDCl3) δ 1.03 (3H, d, J=6.6 Hz), 1.42 (3H, d, J=6.6 Hz), 2.18 (3H, s), 3.49 (3H, s), 3.81 (3H, s), 4.34-4.40 (1H, m), 5.82 (1H, s), 6.55 (2H, d, J=8.6 Hz), 6.80 (1H, d, J=7.8 Hz), 6.93 (1H, s), 7.06 (1H, s), 7.16 (1H, t, J=7.8 Hz), 7.42 (2H, d, J=8.6 Hz), 7.55 (1H, d, J=7.8 Hz). A compounds described below was prepared in a similar method. TABLE 21 208 4-[[2-[(4- bromo-2- methoxy-6- methylphenyl)- amino]-1-methyl- 1H- benzimidazol-7- yl](isopropyl)- amino]-2- methoxybenzo- nitrile 1H NMR (CDCl3) δ1.03(3H, d, J=4.8 Hz), 1.37 (3H, d, J=4.8 Hz), 2.20(3H, s), 3.57(3H, s), 3.82(3H, s), 3.84(3H, s), 4.22-4.29 (1H, m), 5.84 (1H, s), 6.66-6.68(1H, m), 6.78-6.80(3H, m), 6.93(1H, s), 7.06(1H, s), 7.14(1H, d, J=7.8 Hz), 7.51(1H, d, J=7.8 Hz). MS Calcd.: 533, 535; Found: 534, 536(M+H). EXPERIMENT 1 Measurement of Corticotropin-Releasing Factor (CRF) binding inhibitory rate A receptor binding experiment was carried out using a human CRF receptor expressing CHO cellular membrane fraction and sheep CRF, [125I]-tyr0(125I-CRF). 100 nM of a test compound was incubated with 1 μg of human CRF receptor expressing CHO cellular membrane fraction and 50 pM of 125I-CRF in a binding assay buffer (50 mM Tris-HCl, 5 mM EDTA, 10 mM MgCl2, 0.05% CHAPS, 0.1% BSA, 0.5 mM PMSF, 0.1 g/ml pepstatin, 20 μg/ml leupeptin, pH 7.5). In addition, for measuring nonspecific binding (NSB), 0.1 μM unlabelled human Urocortin was incubated with 1 μg of human CRF receptor expressing CHO cellular membrane fraction and 50 pM of 125I-CRF in a binding assay buffer. After a binding reaction was carried out at room temperature for 1 hour, the membrane was entrapped on a glass filter (UniFilter plate GF-C/Perkin Elmer) by suction filtration using a cell harvester (Perkin Elmer), and washed with ice-cooled 50 mM Tris-HCl (pH 7.5). After drying the glass filter, a liquid scintillation cocktail (Microscinti 0, Perkin Elmer) was added, and the radioactivity of 125I-CRF remaining on a glass filter was measured using Topcount (Perkin Elmer). (TB−SB)/(TB−NSB)×100 (SB: radioactivity when a compound is added, TB: maximum binding radioactivity, NSB: nonspecific binding radioactivity) was calculated to obtain a binding inhibitory rate under the presence of 1,000 nM or 100 nM of each test substances. Binding inhibitory rates of respective compounds measured by the aforementioned method are shown in Table 22. TABLE 22 Example No. Binding inhibitory rate (%) 1000 nM 26 >80 42 >80 46 >80 145 >80 183 >80 EXPERIMENT 2 CRF Antagonistic Activity The CRF antagonistic activity was obtained by measuring inhibition of Adenylate Cyclase activity induced by CRF. Measurement of intracellular cyclic AMP (cAMP) concentration was carried out using Alpha Screen Reagent (Perkin Elmer) according to the method described in the protocol attached to the reagent. Specifically, a human CRF receptor expressing CHO cell was inoculated on a 96-well plate at 40000 cells/well, cultured for 24 hours, the culture medium was sucked, and 1 μM of test compound and 100 μl of assay buffer (20 mM HEPES, Hanks' Balanced Salt Solution, 0.1% BSA, 100 μM IBMX, pH 7.2) containing 1 nM of human CRF were added. In addition, in order to measure the intracellular cAMP concentration at stationary state, a compound and a buffer containing no CRF were added. After reacting at room temperature for 30 minutes, a buffer containing 1.5 μg of Anti-cAMP acceptor beads was added thereto, 2 μg of Biotin-cAMP/streptoavidin beads and a buffer containing 0.15% Tween 20 were added, the mixture were reacted at room temperature for 3 hours, and light emission was measured with Fusion (Perkin Elmer). INDUSTRIAL APPLICABILITY Compound (I) or (Ia) of the present invention has an excellent CRF antagonistic activity, and therefore useful as drugs for treating or preventing affective disorder, depression, anxiety, and the like.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to novel nitrogen-containing fused heterocyclic compounds having CRF (corticotropin releasing factor) antagonistic activity and pharmaceutical compositions containing them. 2. Background Art Corticotropin-releasing factor (hereinafter, abbreviated as “CRF”) is a neuropeptide composed of 41 amino acids, and was isolated and purified as a peptide promoting release of adrenocorticotropic hormone (ACTH) from pituitary gland. First, the structure thereof was determined from sheep hypothalamus and, thereafter, the presence thereof was confirmed also in a rat or a human, and the structure thereof was determined [Science, 213, 1394(1981); Proc. Natl. Acad. Sci USA, 80, 4851(1983); EMBO J. 5, 775(1983)]. An amino acid sequence is the same in a human and a rat, but differed in 7 amino acids in ovine. CRF is synthesized as a carboxy-terminal of prepro CRF, cut and secreted. The CRF peptide and a mRNA thereof are present at the largest amount in hypothalamus and pituitary gland, and are widely distributed in a brain such as cerebral cortex, cerebellum, hippocampus and corpus amygdaloideum. In addition, in peripheral tissues, the existence has been confirmed in placenta, adrenal gland, lung, liver, pancreas, skin and digestive tract [J. Clin. Endocrinol. Metab., 65, 176(1987); J. Clin. Endocrinol. Metab., 67, 768(1988); Regul. Pept., 18, 173(1987), Peptides, 5 (Suppl. 1), 71(1984)]. A CRF receptor is a 7-transmembrane G protein-coupled receptor, and two subtypes of CRF1 and CRF2 are present. It is reported that CRF1 is present mainly in cerebral cortex, cerebellum, olfactory bulb, pituitary gland and tonsil nucleus. On the other hand, the CRF2 receptor has two subtypes of CRF2α and CRF2β. It was made clear that the CRF2α receptor is distributed much in hypothalamus, septal area and choroids plexus, and the CRF2α receptor is present mainly in peripheral tissues such as skeletal muscle and is distributed in a blood vessel in a brain [J. Neurosci. 15, 6340(1995); Endocrinology, 137, 72(1996); Biochim. Biophys. Acta, 1352, 129(1997)]. Since each receptor differs in distribution in a living body, it is suggested that a role thereof is also different [Trends. Pharmacol. Sci. 23, 71(2002)]. As a physiological action of CRF, the action on the endocrine system is known in which CRF is produced and secreted in response to stress in hypothalamus and acts on pituitary gland to promote the release of ACTH [Recent Prog. Horm. Res., 39, 245(1983)]. In addition to the action on the endocrine system, CRF acts as a neurotransmitter or a neuroregulating factor in a brain, and integrates electrophysiology, autonomic nerve and conducts to stress [Brain Res. Rev., 15, 71(1990); Pharmacol. Rev., 43, 425(1991)]. When CRF is administered in a cerebral ventricle of experimental animal such as a rat, anxiety conduct is observed, and much more anxiety conduct is observed in a CRF-overexpressing mouse as compared with a normal animal [Brain Res., 574, 70(1992); J. Neurosci., 10, 176(1992); J. Neurosci., 14, 2579(1994)]. In addition, α-helical CRF(9-41) of a peptidergic CRF receptor antagonist exerts an anti-anxiety action in an animal model [Brain Res., 509, 80(1990); J. Neurosci., 14, 2579(1994)]. A blood pressure, a heart rate and a body temperature of a rat are increased by stress or CRF administration, but the α-helical CRF(9-41) of a peptidergic CRF antagonist inhibits the increase in a blood pressure, a heart rate and a body temperature due to stress [J. Physiol., 460, 221(1993)]. The α-helical CRF(9-41) of a peptidergic CRF receptor antagonist inhibits abnormal conducts due to withdrawal of a dependent drug such as an alcohol and a cocaine [Psychopharmacology, 103, 227(1991); Pharmacol. Rev.53, 209(2001)]. In addition, it has been reported that learning and memory are promoted by CRF administration in a rat [Nature, 375, 284(1995); Neuroendocrinology, 57, 1071(1993); Eur. J. Pharmacol., 405, 225(2000)]. Since CRF is associated with stress response in a living body, there are clinical reports regarding stress-associated depression or anxiety. The CRF concentration in a cerebrospinal fluid of a depression patient is higher as compared with that of a normal person [Am. J. Psychiatry, 144, 873(1987)], and the mRNA level of CRF in hypothalamus of a depression patient is increased as compared with that of a normal person [Am. J. Psychiatry, 152, 1372(1995)]. A CRF binding site of cerebral cortex of a patient who suicide by depression is decreased [Arch. Gen. Psychiatry, 45, 577(1988)]. The increase in the plasma ACTH concentration due to CRF administration is small in a depression patient [N. Engl. J. Med., 314, 1329(1986)]. In a patient with panic disorder, the increase of plasma ACTH concentration due to CRF administration is small [Am. J. Psychiatry, 143, 896(1986)]. The CRF concentration in a cerebrospinal fluid of a patient with anxiety induced by stress such as obsessive-compulsive neurosis, post-psychic trauma stress disorder, Tourette's syndrome and the like is higher as compared with that of a normal person [Arch. Gen. Psychiatry, 51, 794(1994); Am. J. Psychiatry, 154, 624(1997); Biol. Psychiatry, 39, 776(1996)]. The CRF concentration in a cerebrospinal fluid of schizophrenics is higher as compared with that of a normal person [Brain Res., 437, 355(1987); Neurology, 37, 905(1987)]. Thus, it has been reported that there is abnormality in the living body response system via CRF in stress-associated mental disease. The action of CRF on the endocrine system can be presumed by the characteristics of CRF gene-introduced animal and actions in an experimental animal. In a CRF-overexpressing mouse, excessive secretions of ACTH and adrenal cortex steroid occur, and abnormalities analogous to Cushing's syndrome such as atrophy of muscle, alopecia, infertility and the like are observed [Endorcrinology, 130, 3378(1992)]. CRF inhibits ingestion in an experimental animal such as a rat [Life Sci., 31, 363 (1982); Neurophamacology, 22, 337(1983)]. In addition, α-helical CRF(9-41) of a peptidergic CRF antagonist inhibited decrease of ingestion due to stress loading in an experimental model [Brain Res. Bull., 17, 285(1986)]. CRF inhibited weight gain in a hereditary obesity animal [Physiol. Behav., 45, 565(1989)]. In a nervous orexia inactivity patient, the increase of ACTH in plasma upon CRF administration is small [J. Clin. Endocrinol. Metab., 62, 319(1986)]. It has been suggested that a low CRF value is associated with obesity syndrome [Endocrinology, 130, 1931(1992)]. There has been suggested a possibility that ingestion inhibition and weight loss action of a serotonin reuptake inhibiting agent are exerted via release of CRF [Pharmacol. Rev., 43, 425(1991)]. CRF is centrally or peripherally associated with the digestive tract movement involved in stress or inflammation [Am. J. Physiol. Gastrointest. Liver Physiol. 280, G315(2001)]. CRF acts centrally or peripherally, weakens the shrinkablity of stomach, and decreases the gastric excreting ability [Regulatory Peptides, 21, 173(1988); Am. J. Physiol., 253, G241(1987)]. In addition, α-helical CRF (9-41) of a peptidergic CRF antagonist has a restoring action for hypofunction of stomach by abdominal operation [Am. J. Physiol., 258, G152(1990)]. CRF inhibits secretion of a bicarbonate ion in stomach, decreases gastric acid secretion and inhibits ulcer due to cold restriction stress [Am. J. Physiol., 258, G152(1990)]. Furthermore, α-helical CRF (9-41) of a peptidergic CRF antagonist shows the inhibitory action on gastric acid secretion decrease, gastric excretion decrease, small intestinal transport decrease and large intestinal transport enhancement due to restriction stress [Gastroenterology, 95, 1510(1988)]. In a healthy person, mental stress increases a gas and abdominal pain due to anxiety and intestine dilation, and CRF decreases a threshold of discomfort [Gastroenterology, 109, 1772(1995); Neurogastroenterol. Mot., 8, 9 [1996]. In a irritable bowel syndrome patient, large intestinal movement is excessively enhanced by CRF administration as compared with a healthy person [Gut, 42, 845(1998)]. It has been reported from studies on experimental animals and clinical studies that CRF is induced by inflammation and is involved in a inflammatory reaction. In an inflammatory site of an experimental animal and in a joint fluid of a rheumatoid arthritis patient, production of CRF is topically increased [Science, 254, 421(1991); J. Clin. Invest., 90, 2555(1992); J. Immunol., 151, 1587(1993)]. CRF induces degranulation of a mast cell and enhances the blood vessel permeability [Endocrinology, 139, 403(1998); J.Pharmacol. Exp. Ther., 288, 1349(1999)]. CRF can be detected also in a thyroid gland of autoimmune thyroiditis-patient [Am. J. Pathol. 145, 1159(1994)]. When CRF is administered to an experimental autoimmune cerebrospinal meningitis rat, the progression of symptom such as paralysis was remarkably inhibited [J. Immunil., 158, 5751(1997)]. In a rat, the immune response activity such as T-lymphocyte proliferation and the natural killer cell activity is reduced by CRF administration or stress loading [Endocrinology, 128, 1329(1991)]. From the above-mentioned reports, it is expected that the CRF receptor antagonistic compound would exert an excellent effect for treating or preventing various diseases in which CRF is involved. As a CRF antagonist, for example, peptide CRF receptor antagonists are reported in which a part of an amino acid sequence of CRF or associated peptides of a human or other mammals is altered or deleted, and they are reported to show a pharmacological action such as ACTH release-inhibiting action and anti-anxiety action [Science, 224, 889(1984); J. Pharmacol. Exp. Ther., 269, 564(1994); Brain Res. Rev., 15, 71(1990)]. However, from a pharmacokinetic point of view such as chemical stability and absorbability for oral administration in a living body, bioavailability and intracerebral transferability, peptide derivatives have a low utility value as a medicine.

<SOH> SUMMARY OF THE INVENTION <EOH>According to the present invention, there is provided: (1) A compound represented by the formula (I): wherein, ring A is a 5-membered ring represented by the formula (A′): wherein X is a carbon and X 1 is an oxygen, a sulfur or —NR 5 — (wherein R 5 is a hydrogen, an optionally substituted hydrocarbyl or an acyl), or formula (A″): wherein X is a nitrogen and R 6 is a hydrogen, an optionally substituted hydrocarbyl or an acyl; R 1 is (1) an amino substituted by two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, or (2) an optionally substituted cyclic amino, provided that the amino nitrogen of said cyclic amino has no carbonyl adjacent to the nitrogen; R 2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocyclic; Y 1 , Y 2 and Y 3 are each an optionally substituted methyne or a nitrogen, provided that one or less of Y 1 , Y 2 and Y 3 is. nitrogen; W is a bond, — (CH 2 ) n — or —(CH 2 )m—CO— (wherein n is an integer of 1 to 4 and m is an integer of 0 to 4); Z is a bond, —CO—, an oxygen, a sulfur, —SO—, —SO 2 —, —NR 4 —, —NR 4 —alk—, —CONR 4 — or —NR 4 CO— (wherein alk is an optionally substituted C 1-4 alkylene and R 4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl); provided that (i) the compound wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X 1 is a sulfur), W is a bond, Z is —NHCO— or —CONH—, and y 1 is CR 3a (wherein R 3a is a hydrogen, a halogen, or an alkoxy) and (ii) the compound wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X 1 is an oxygen, a sulfur, or —NH—), R 1 is an optionally substituted 1-piperazinyl, W is a bond, Z is a bond and R 2 is an optionally substituted aryl, are excluded; or a salt thereof; (2) A prodrug of the compound according to the above-mentioned (1); (3) The compound according to the above-mentioned (1) wherein R 1 is an amino substituted by two optionally substituted C 1-4 alkyl groups; (4) The compound according to the above-mentioned (1) wherein R 1 is an amino substituted by an optionally substituted C 1-4 alkyl and an optionally substituted phenyl or optionally substituted heterocyclic; (5) The compound according to the above-mentioned (1) wherein R 1 is a 5- or 6-membered cyclic amino which may be substituted with one or more substituents; (6) The compound according to claim 1 wherein Y 1 is CR 3a , Y 2 is CR 3b , and Y 3 is CR 3c (wherein R 3a , R 3b and R 3c are independently a hydrogen, a halogen, a nitro, an optionally substituted C 1-4 hydrocarbyl, an optionally substituted C 1-4 hydrocarbyloxy, an optionally substituted C 1-4 hydrocarbylthio, an optionally substituted amino or an acyl containing up to 4 carbon atoms); (7) The compound according to above-mentioned (1) wherein one of Y 1 , Y 2 and Y 3 is nitrogen; (8) The compound according to the above-mentioned (1) wherein W is a bond; (9) The compound according to the above-mentioned (1) wherein R 2 is an optionally substituted C 6-10 aryl or an optionally substituted 5- or 10-membered heterocyclic; (10) The compound according to the above-mentioned (1) wherein R 2 is an optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclic; (11) The compound according to the above-mentioned (1) wherein Z is -NR 4 - (wherein R 4 is as defined in the above-mentioned (1)); (12) The compound according to the above-mentioned (1) wherein ring A is a thiazole ring or an imidazole ring represented by the formula (Aa): wherein R 5a is a hydrogen, an optionally substituted C 1-4 alkyl or an acyl containing up to 4 carbon atoms; (13) The compound according to the above-mentioned (1) wherein Y 1 is CR 3a , Y 2 is CR 3b and Y 3 is CR 3c , (wherein R 3a , R 3b and R 3c is independently a hydrogen, a halogen or an optionally substituted hydrocarbyl); W is a bond; R 2 is an optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclic; and Z is —NR 4 — (wherein R 4 is a hydrogen or an optionally substituted hydrocarbyl); (14) The compound according to the above-mentioned (1) wherein Y 1 is CR 3a , Y 2 is CR 3b and Y 3 is CR 3 c (wherein R 3a , R 3b and R 3c are independently a hydrogen, a halogen, a nitro,. an optionally substituted C 1-4 hydrocarbyl, an optionally substituted C 1-4 hydrocarbyloxy, an optionally substituted C 1-4 hydrocarbylthio, an optionally substituted amino or an acyl containing up to 4 carbon atoms); W is a bond; R 2 is an optionally substituted C 6-10 aryl or an optionally substituted 5- or 10-membered heterocyclic; and Z is —NR 4 — (wherein R 4 is a hydrogen or an optionally substituted hydrocarbyl); and ring A is a thiazole ring or an imidazole ring represented by the formula (Aa) wherein R 5a is a hydrogen, an optionally substituted C 1-4 alkyl, or an acyl containing up to 4 carbon atoms; (15) A method for treating or preventing a disease wherein a CRF receptor is implicated, which comprises administering to a subject in need thereof an effective amount of a compound represented by the formula (Ia): wherein ring A is a 5-membered ring represented by the formula (A′): wherein X is a carbon and X 1 is an oxygen, a sulfur or —NR 5 —(wherein R 5 is a hydrogen, an optionally substituted hydrocarbyl or an acyl), or formula (A″): wherein X is a nitrogen and R 6 is a hydrogen, an optionally substituted hydrocarbyl or an acyl; R 1a is (1) an amino substituted by two substituents selected from an optionally substituted hydrocarbyl group and an optionally substituted heterocyclic group, or (2) an optionally substituted cyclic amino; R 2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heterocyclic; Y 1 , Y 2 and Y 3 are each an optionally substituted methyne or a nitrogen, provided that one or less of Y 1 , Y 2 and Y 3 is nitrogen; W is a bond, —(CH 2 ) n — or —(CH 2 ) m —CO—, wherein n is an integer of 1 to 4 and m is an integer of 0 to 4; Z is a bond, —CO—, an oxygen, a sulfur, —SO—, —SO 2 —, —NR 4 —, —NR 4 —alk—, —CONR 4 — or —NR 4 CO— (wherein alk is an optionally substituted C 1-4 alkylene and R 4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl); provided that the compound wherein ring A is the 5-membered ring of the formula A′ (wherein X is a carbon and X 1 is a sulfur), W is a bond, Z is —NHCO—or —CONH—, and Y 1 is CR 3a (wherein R 3a is a halogen, or an alkoxy) is excluded; or a salt thereof; (16) The method according to the above-mentioned (15) wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety; (17) Use of the compound (Ia) according to the above-mentioned (15), or a salt thereof for manufacturing a medicament for preventing or treating a disease wherein a CRF receptor is implicated; (18) Use of the compound (Ia) according. to the above-mentioned (15), or a salt thereof for manufacturing a, medicament for preventing or treating affective disorder, depression or anxiety; (19) An agent for preventing or treating a disease wherein a CRF receptor is implicated, which comprises the compound (Ia) according to the above-mentioned (15) or a salt thereof; and (20) An agent for preventing or treating affective disorder, depression or anxiety which comprises the compound (Ia) according to the above-mentioned (15) or a salt thereof. detailed-description description="Detailed Description" end="lead"?

20060428

20100511

20070614

59052.0

A61K31519

OTTON, ALICIA L

NITROGEN-CONTAINING FUSED HETEROCYCLIC COMPOUNDS

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Method for storing and/or changing state-information of a memory as well as integrated circuit and data carrier

In a method for storing and/or changing state information in a memory (2) containing a plurality of memory cells (3), wherein the memory cells (3) assume an irreversible memory state as a result of a programming step, wherein the state information is represented by a number and/or position of memory cells (3) that are in an irreversible memory state or are programmed, the state information (S3, S13) is determined by checking the memory state of the memory, and then, after selecting (S4, S14) an unprogrammed memory cell (3) the selected memory cell is programmed during or for changing the state information (2).

1. A method for storing and/or changing a state information item of a memory containing a plurality of memory cells, wherein the memory cells assume an irreversible memory state as a result of a programming step, wherein the state information is represented by a number and/or position of memory cells existing or programmed in an irreversible memory state, said method comprising the steps presented in the following; determining the state information by checking the memory state of the memory and selecting an unprogrammed memory cell and programming the selected memory cell during and/or for changing the state information of the memory. 2. A method according to claim 1, wherein, prior to determination of the state information, an encryption of data and/or a verification of an access authorization to the memory is carried out. 3. A method according to claim 1, wherein, for determining the state information of the memory, a serial output of the memory is fed to a counter or a toggle flip-flop, whereby the number of memory cells programmed or in an irreversible memory state and/or the position of an unprogrammed memory cell is determined. 4. A method according to claim 3, wherein timing pulses are applied to memory and by verifying the timing pulses at the serial output of the memory a position of an unprogrammed memory cell is determined. 5. An integrated circuit for storing and/or changing state information of a memory containing a plurality of memory cells wherein the memory cells assume an irreversible memory state as a result of a programming step, said integrated circuit containing a programming unit for programming the memory cells and a feed-logic circuit said feed-logic circuit being provided for picking up and emitting data for programming and determining the state information of memory. 6. An integrated circuit according to claim 5, wherein a serial output of the feed-logic circuit interacts with an evaluation unit for determining the state information and for selecting an unprogrammed memory cell. 7. An integrated circuit according to claim 6, wherein the serial output of the feed-logic circuit interacts with a counter or a toggle flip-flop in order to determine the number of memory cells programmed or being in an irreversible memory state and/or the position of an unprogrammed memory cell. 8. An integrated circuit according to claim 6 wherein additionally a circuit is provided for the verification and/or encryption of data. 9. An integrated circuit according to claims 5, wherein additionally a memory is provided for additional storage of preset data and/or data that can be entered via an input device. 10. A data carrier containing an integrated circuit according to claim 5. 11. A data carrier according to claim 10, wherein the data carrier is designed for contactless communication with a communication station. 12. A data carrier according to claim 10, wherein the data carrier is in the form of a tag or label.

The invention relates to a method for storing and/or changing at least one state information item in a memory. The invention further relates to an integrated circuit, which contains a memory of said kind, and to a data carrier, which contains an integrated circuit of said kind. In connection with the marking of objects or products, application of a tag or label to such products is known. Serial numbers and/or manufacturing details relating to the production of the product and/or possibly sale-specific details, such as data relating to the seller and/or buyer are, for example, stored on the tag. It is desirable that a tag of this kind should not be readable by unauthorized persons after purchase of said product and for example after leaving a store. One possible way of preventing said reading is physical destruction of the tag or deactivation by sending a blocking command to the tag, so that following reception and evaluation of the blocking command the tag can no longer be read. A disadvantage with said deactivation is that, for example, if there are subsequent complaints, it is no longer possible to read or activate the tag again, so consideration was given to putting said tag in a special state, in which reading of the tag by unauthorized persons is impossible, but reading becomes possible again as a result of special activation by authorized agencies and/or persons. In this connection, it is known for example for a memory that contains said data relating to the product and/or its manufacture and/or possibly additional data relating to a sale and/or buyer, to be combined with a non-volatile memory, for example an EEPROM, it being possible for the non-volatile memory to be put into an appropriate state in which for example after leaving a store it is no longer possible to read the tag, but an authorized agency, for example a manufacturer, in the case of servicing or a complaint, can return the non-volatile memory to a state in which it is possible to read the data contained on the tag. A method of this kind is known for example from patent document WO 99/65168. In this known method or in this known device it has proved to be a disadvantage that provision of said non-volatile memory, for example an EEPROM, is associated with comparatively high costs. In contrast, memory cells exist which, in an OTP (one time programmable) process, can only be programmed once and can no longer be changed, and are much less expensive than non-volatile memories, for example an EEPROM, though when using OTP memory cells of this kind the aforementioned disadvantages arise, that once a tag or label has been canceled it can no longer be read or reactivated. The object to be achieved by the invention is to remedy the aforementioned disadvantages and provide an improved method and an improved integrated circuit and an improved data carrier. To achieve the aforementioned object, a method for storing and/or changing a state information item in a memory containing a plurality of memory cells, wherein the memory cells assume an irreversible memory state as a result of a programming step, wherein the state information is represented by a number and/or position of memory cells existing or programmed in an irreversible memory state, said method comprising the steps presented in the following, namely determining the state information by checking the memory state of the memory and selecting an unprogrammed memory cell and programming the selected memory cell during and/or for changing the state information of the memory. To achieve the aforementioned object, an integrated circuit contains for storing and/or changing status information of a memory containing a plurality of memory cells, wherein the memory cells assume an irreversible memory state as a result of a programming step, a programming unit for programming the memory cells and a feed-logic circuit, said feed-logic circuit being provided for pick-up and delivery of data for programming and for determining the state information of the memory. To achieve the aforementioned object, a data carrier contains an integrated circuit having the form defined in the preceding paragraph. As a result of the features according to the invention, a data carrier, for example tag or label, that is located on a product or object, enters a state in a simple and cost-effective way, which state prevents unauthorized reading of data, wherein by programming a selected memory cell for changing the state information of the memory by an authorized agency the data carrier can be returned to a state in which access to the data present on the data carrier is possible. By using a plurality of memory cells, which assume an irreversible state through a programming step employing an OTP process, a cost saving is made relative to use of a non-volatile memory, for example an EEPROM, on account of memory cells of simple structure, which assume an irreversible memory state through a programming step, wherein as a result of the plurality of memory cells, which are programmable only once and can no longer be changed, not only the same security requirements are made as when a non-volatile memory is used, but also a multiple change of information of the memory is possible. According to the measures of claims 2 and 8 the advantage is obtained that for additionally increasing security before determining the state information of the memory and subsequent programming of a selected, unprogrammed memory cell, verification regarding the authorization of access to the memory and hence change of the state information is made possible. With this verification of access authorization, at the same time verification or adjustment can be undertaken, so that, if necessary, differently authorized agencies have access to different data areas of a data carrier according to the invention. According to the features of claims 3 and 7, a simple possibility is provided for determining the state information of the memory as well as the position of an unprogrammed memory cell for a subsequent change of the state information of the memory. The memory state of the plurality of memory cells, which assume an irreversible memory state as a result of a programming step, can be changed in, such a way that during programming of each selected memory cell a respective bit is changed from a “0” state to a “1” state, so that when the serial output of the memory is applied to a counter or a toggle flip-flop, it is a simple matter to determine the number of memory cells that are in a “1” state, so that the state information of the memory can be determined or derived directly from the result found for the number of memory cells that are in the “1” state. Similarly, with said counter or toggle flip-flop, the position of a next unprogrammed memory cell can also be found directly. The memory state of the memory is then determined in a particularly simple manner by using a toggle flip-flop, which toggles at the output whenever there is a “1” state at the input. A memory state of the plurality of memory cells that assume an irreversible memory state as a result of a programming step can, however, also be changed by transposing an appropriate bit from a “1” state to a “0” state during programming of each selected memory cell. According to the features of claim 4, it is a simple matter to determine the timing pulse at which the first memory cell with the “0” state appears or has appeared, so that this bit or this unprogrammed memory cell that has been determined represents directly the selected memory cell for changing the state information. According to the features of claim 6, an integrated circuit is provided that is particularly simple and can be manufactured in a cost-effective way. According to the features of claim 9, in addition to the proposed change, according to the invention, of the state information or of the memory state of a memory, it becomes possible to include a large number of further data in an integrated circuit according to the invention, as has already been presented several times above in connection with tags or labels of a product or object. According to the features of claim 11, a simple use of a data carrier according to the invention is provided, employing known devices in connection with the marking or coding of objects or products by applying a tag or label. The invention is described below on the basis of an embodiment illustrated in the drawings, but the invention is not limited to this. FIG. 1 shows flow charts in connection with determination of the state information of a memory and programming of a memory cell according to a method according to the invention, where FIG. 1a shows a flow chart of a sequence for resetting a chip or memory from a “quiet” state according to the inventive method and FIG. 1b shows a flow chart of a sequence of setting a memory into a quiet state. FIG. 2 shows, schematically, a memory-with a plurality of memory cells for carrying out the method according to the invention. FIG. 3 shows a schematic representation of a once-programmable memory cell for use in a memory according to FIG. 2. FIG. 4 shows schematically, in the form of a block diagram, a portion of an integrated circuit with which it is possible to set or program a memory cell after the state information of the memory according to FIG. 2 has been determined. FIG. 1 shows schematically flow charts in connection with determination of the state information of a memory and the programming of a selected memory cell of the memory for changing the state information of the memory, the construction of said memory being explained below, with reference to FIGS. 2 and 3. As shown in FIG. 2, in a memory 2 for reversible setting or establishing of a quiet state, a plurality of memory cells 3 is provided, each of said memory cells 3 representing one bit. In the present case the quiet state is represented by ten (10) memory cells 3, i.e. ten (10) bits. Said memory cell 3 is shown in FIG. 3. Each memory cell 3 is thus constructed as a so-called OTP (one time programmable) cell, and thus assumes, after a programming step, an irreversible memory state. Starting from a memory state in which all memory cells 3 or bits representing the quiet state are in a “0” state, on first setting a quiet state, a first bit is set, so that in the present case of ten (10) bits the following bit pattern is obtained for the state information of the quiet state of memory 2 or chip: “1000000000”. Said memory 2 is, as explained in more detail below, contained in a data carrier. In order to return such a data carrier with such a memory 2 or chip to a state in which other data contained in the data carrier can be read, it is necessary to reset the quiet state, determining a memory cell 3 that is to be programmed subsequently, as is explained in detail with reference to FIG. 4. After a programming of a selected unprogrammed memory cell 3, the following bit pattern is obtained for the state information of the quiet state of memory 2: “1100000000”, so that the memory 2 or the associated chip or data carrier is no longer in the quiet state, but in a non-quiet state, namely active state, and consequently a replying or reading can be performed again. After said replying or reading, deactivation must be provided to prevent unauthorized access. For this purpose, after a further determining of the state information and a further selecting of a next unprogrammed memory cell 3, a further programming to the quiet state is carried out, so that the following bit pattern is obtained as recent state information of the quiet state: “1110000000”. When two different states are provided as in the present case—namely the quiet state and the non-quiet state, in accordance with the above example an odd number of “1” states thus signifies that the memory 2 or chip is in the quiet state, and an even number of “1” states signifies that the memory 2 or chip is in the non-quiet state, i.e. is in an active mode. The establishing or determining of the quiet state or of the active mode and a programming of a selected memory cell 3 for changing the state information is shown in detail in the flow charts according to FIG. 1. The flow chart according to FIG. 1a shows a sequence for resetting a quiet state or assuming the active mode, said sequence starting at a block S1. At a next block S2 the state information of the memory state of memory 2 is read or determined, i.e. in the present case reading of the ten (10) bits that are provided for the quiet state. At a next block S3, verification is carried out as to whether there is an odd number of “1” states of the read bit. If the verification at block S3 is positive, corresponding, in accordance with the foregoing, to the quiet state of the memory 2 or of the chip containing memory 2, a selecting of a next unprogrammed memory cell 3 takes place at a next block S4, and then a programming of the selected memory cell 3 for changing the state information of memory 2 takes place at a next block S5. Thus, memory 2 or the data carrier containing memory 2 is in an active state at a next block S6. If the verification at block S3 proves negative, the sequence is continued immediately after block S5, because in such a case memory 2 is already in the active mode. Similarly, FIG. 1bshows a flow chart for a sequence for setting or establishing a quiet state, said sequence starting at a block S11. At a next block S12 reading of the memory state or determining of the state information again takes place, and according to a next block S13 the number of “1” states in the bit pattern of the ten (10) bits of the quiet state is verified, i.e. as to whether there is an even number of “1” states. If the verification at block S13 proves positive, i.e. there is an even number of “1” states in the bit pattern, and therefore the chip of memory 2 is in the active mode, the sequence is continued at a block S 14, where a next unprogrammed memory cell 3 or a next unprogrammed bit is established, which in a next block S15 is put or brought into a “1” state, so that memory 2 is in the quiet,state or an inactive state at a subsequent block S16. If the verification at block S13 proves negative, the sequence is continued at block S16, because when there is an odd number of “1” states in the bit pattern, the quiet state or inactive state is already present. FIG. 2 shows a portion of an integrated circuit 1, wherein the integrated circuit 1 comprises a memory 2 with a plurality of memory cells 3 that are programmable in an OTP process (see FIG. 3). Each memory cell 3 has a fuse 4 in addition to a resistance R, said fuse 4 burning through for a programming of the memory cell 3. A bit, i.e. a “1” state or a “0” state, can be determined or picked up at an output 5 of memory cell 3. As well as memory 2, the integrated circuit 1 according to FIG. 2 contains an address decoder 6, in said address decoder 6 a logical memory address being assigned to a physical memory cell 3, a circuit 7 for the verification and encryption of data, which contains an encryption logic stage, and a programming device 8 for programming the plurality of memory cells 3 that are provided in memory 2, and which can be brought into an irreversible memory state by means of a programming step. Furthermore it contains a feed-logic circuit 9, into which at least one address can be entered in accordance with the indicated connection 10. A line 11 is also provided, for feeding a command for programming a memory cell 3. A serial output 12 is provided as a data output. A clock input 13 is also provided, for feeding a command for a relocation operation. The data required for programming the memory cell 3 can be supplied to the feed-logic circuit 9 via a line 14. Data required for a programming can be fed along line 15 from the feed-logic circuit 9 to the memory 2, verification of the memory address and allocation of the logical memory address to the physical memory cell 3 taking place over a line 16. The block diagram according to FIG. 4 shows a portion of an integrated circuit 1a, explaining a determining of the state information of the memory state of memory 2 and a programming of a selected memory cell 3. The integrated circuit 1a contains the integrated circuit 1 according to FIG. 2 and accordingly the memory 2, which memory 2 contains a plurality (n) of memory cells 3. The serial output 12 of the feed-logic circuit is connected to a toggle flip-flop 17, which toggle flip-flop 17 serves for determining the number of programmed memory cells 3 that are in an irreversible memory state, i.e. the “1” state, and hence for determining the state information of memory 2. A result obtained from the toggle flip-flop 17 is fed via line 18 to a sequencing circuit 19 of integrated circuit Ia. A counting stage 20 is also provided, to which a clock signal can be fed from a clock generator (not shown) and to which, via a line 21, a start-counting command and a stop-counting command can be fed from the sequencing circuit 19 and which delivers, via a line 22, a pulse-shaped shift signal (clock signal) to the clock input 13 of integrated circuit 1. The counting stage 20 serves for determining the position of a next unprogrammed memory cell 3, by counting the clock signals fed to it and—if a “0” state, i.e. a next unprogrammed memory cell 3 is determined-with the aid of the sequencing circuit 19, to which sequencing circuit 19 the data available at the serial output 12 of integrated circuit 1 are fed via line 25—is stopped by means of a counting stop command emitted by the sequencing circuit 19, and then the count contained in counting stage 20 represents the position of the next unprogrammed memory cell 3. For storing this count and hence the determined position of the next unprogrammed memory cell 3, a position memory 23 is provided, to which position memory 23 the count is fed over a line from the counting stage 20 and which is connected via a line 24 to the sequencing circuit 19, so that the sequencing circuit 19 can interrogate the stored count. An address is fed to the integrated circuit 1 via connection 10 with the aid of the sequencing circuit 19, and additionally a command for programming a memory cell 3 is transferred via line 14. As has already been mentioned several times above, apart from the elements shown in particular in FIG. 2, the integrated circuit 1 has at least one additional memory for storing preset data and/or data that can be entered via an input device (not shown), in order for example to make available a label or tag as data carrier for a product that is to be marked. Said storing of data for a product that is to be marked and a corresponding data carrier are described in the international patent application having application number IB03/01434“Method of protecting from deactivation of an RFID-Transponder associated with a product”, the disclosure of which is hereby incorporated by reference. By providing the plurality of memory cells 3 or bits, each programmable once, according to the number of said memory cells 3 provided, a data carrier provided with the integrated circuit 1a can be shifted repeatedly into an inactive state or quiet state, in which quiet state the data carrier does not reply and cannot be read, and repeatedly into an active state or non-quiet state. Provision of circuit 7 for the verification and encryption of data not only ensures verification of access authorization for changing the state information of memory 2, but it therefore additionally permits, if required, restricted access to the additional memory of integrated circuit 1a or of the data carrier for the storage of preset and/or enterable data. Such restriction of access to data or reading of data contained in a data carrier is provided for example for the case where, following purchase, during servicing or complaint for example all data are made available, whereas during disposal of a product or object provided with a data carrier,.only details relating to the manufacture and/or specific constituents are permitted to be read, whereas further details in connection-with an acquisition of the product are not to be made known. It may be mentioned that instead of the provision of two different states, as is provided in the case described above, in other cases for example three or more different states can be defined, and the reversible state information of the memory is determined by appropriately modified verification criteria similarly to blocks S3 or S13 in FIG. 1 just as in the case described above, and after the state information has been determined or established, there is again a selecting of an unprogrammed memory cell and a subsequent programming for changing the state information to a desired state. It may further be mentioned that instead of a quiet state of a tag or label, the method according to the invention can for example also be used for a write-protect mode for a Smart Card. As in the embodiment described above in connection with a tag or label, in this case the state information of the memory is verified, and the state information of the memory can only be changed if there is an appropriate access authorization. It may further be mentioned that in addition, the method according to the invention can for example be used for changing a regional code for a DVD player, with change of said regional code being limited to a small number, for example five (5) changes. These changes correspond in each case to changing the state information of a corresponding memory. Furthermore, it may be mentioned that the method according to the invention for storing and/or changing state information of a memory containing a plurality of memory cells can be used as write protection for video cassettes.

20060426

20090901

20070719

59698.0

G06F1300

DUDEK JR, EDWARD J

METHOD FOR STORING AND/OR CHANGING STATE-INFORMATION OF A MEMORY AS WELL AS INTEGRATED CIRCUIT AND DATA CARRIER

UNDISCOUNTED

ACCEPTED

G06F

ACCEPTED

Adjustable reclining chair

One aspect of the invention concerns a lift-recliner chair comprising a base portion (12), a seat portion (14) pivotally connected to the base portion, a back portion (16) pivotally connected to the seat portion and a first actuator (62) for moving the seat portion with respect to the base portion and a second actuator (64) for moving the back portion with respect to the seat portion so as to alter the configuration of the chair. The actuators are substantially enclosed within the base portion of the chair between a pair of opposed structural base portion side panels (18) in all configurations of the chair. The seat portion is pivotally connected to the side panels (18) and is movable between a retracted and nested position within the base portion to an raised position in which it is telescopically extended from the base. The nested configuration can reduce the risk of entrapment between moving parts of the chair.

1. A lift-recliner chair comprising a base portion, a seat portion pivotally connected to the base portion, a back portion pivotally connected to the seat portion and actuator means for moving the seat portion with respect to the base portion and the back portion with respect to the seat portion to alter the configuration of the chair, wherein the said actuator means is substantially enclosed within the base portion in all configurations of the chair. 2. A lift-recliner chair as claimed in claim 1 wherein the seat portion is movable between a substantially horizontal position in which at least part of the seat portion is nested with the base portion and an inclined position in which the seat is telescopically extended from the base. 3. A lift recliner chair as claimed in claim 1 wherein the seat portion is nested within and extendable from the base portion. 4. A lift-recliner chair as claimed in claim 1 wherein the base portion comprises a front and a back panel and a pair of substantially vertical side panels between the front and back panels, and the said seat portion comprises a seat frame including a pair of substantially vertical side panels arranged substantially parallel with and adjacent to the respective base portion side panels. 5. A lift-recliner chair as claimed in claim 4 wherein the seat portion is pivoted with respect to the base portion about a pivot axis positioned towards the front of the base portion. 6. A lift recliner chair as claimed in claim 4 wherein the seat portion is pivotally connected to the said side panels. 7. A lift-recliner chair as claimed claim 5 wherein the back portion comprises a generally rectangular frame and a pair of pivot arms which extend from the frame and pivotally connect the frame to the seat portion. 8. A lift recliner chair as claimed in claim 7 wherein the pivot arms pivotally connect the back portion to the side panels of the seat portion. 9. A lift-recliner chair as claimed in claim 7 wherein the pivot arms comprise part of a bell-crank arrangement for moving the back portion about a pivot axis spaced from the said rectangular frame. 10. A lift-recliner chair as claimed in claim 7 wherein the pivot arms extend parallel with and adjacent to respective vertical side panels of the seat portion on an interior side thereof. 11. A lift-recliner chair as claimed in claim 1 wherein the said back portion pivots away from the seat portion when the seat portion is moved towards an inclined position. 12. A lift recliner chair as claimed in claim 11 wherein the said back portion pivots away from the seat portion when the seat portion is moved to a pre-determined position between the lowered and inclined position of the seat portion. 13. A lift-recliner chair as claimed in claim 1 wherein the said actuator means comprises a first actuator for moving the said seat portion and a second actuator for moving the back portion. 14. A lift-recliner chair as claimed in claim 1 wherein the said first and second actuators are mounted in fixed relation to the base portion. 15. A lift-recliner chair as claimed in claim 1 wherein the said first actuator is fixed in relation to the base portion and the said second actuator is fixed in relation to the seat portion. 16. A lift-recliner chair as claimed in claim 4 wherein the front panel of the base is pivotally movable with respect to the side and rear panels of the base for movement from a generally vertical position to a generally horizontal position. 17. A lift-recliner chair as claimed in claim 16 wherein the said actuator means comprises a third actuator fixed in relation to the fixed side panels of base for moving the said front panel about its pivot axis. 18. A lift-recliner chair as claimed in claim 16 wherein the said front panel is pivotally moveable with respect to the base portion about a pivot axis corresponding substantially to the position of the seated user's knee joint. 19. A lift recliner chair as claimed in claim 16 wherein the pivot axis of the said front panel is coincident with the pivot axis connecting the seat portion to the base portion. 20. A recliner chair comprising a base portion, a seat portion, and a back portion pivotally mounted with respect to the seat portion, and actuator means for moving the back portion about its pivot axis between a generally upright position and a reclined position, wherein the said actuator means is enclosed within the base portion on the underside of the seat. 21. A recliner chair as claimed in claim 20 wherein the base portion comprises a front panel pivotally mounted with respect to the seat portion and wherein the said actuator means comprises a first actuator for moving the back portion about its pivot axis and a second actuator for moving the front panel about its pivot axis from a generally vertical orientation to a generally horizontal orientation. 22. A recliner chair comprising a base portion, a seat portion, and a back portion pivotally mounted with respect to the base portion, the base portion having a pair of lateral side panels and a front panel pivotally mounted with respect to the said side panels, and a common actuator for moving both the back portion about its pivot axis and the front panel about its pivot axis to alter the configuration of the chair form a generally up-right configuration to a generally reclined configuration, wherein the back portion moves from a generally vertical to an inclined orientation and the front panel moves from a generally vertical to a generally horizontal orientation. 23. A recliner chair as claimed in claim 22 further comprising a first cam means for determining the movement path of the back portion with respect to the base portion. 24. A recliner chair as claimed in claim 22 further comprising a second cam means for determining the movement path of the front panel with respect to the side panels. 25. A recliner chair as claimed in claim 24 wherein the said first and second cam means are engaged by a cam engagement means connected to the said actuator. 26. A recliner chair as claimed in claim 25 wherein the said cam engagement means is pivotally mounted with respect to the sides of the said base portion for pivotal movement by the said actuator. 27. A recliner chair as claimed in claim 26 wherein the said first, and second cam means are pivotally mounted with respect to the said sides of the base portion. 28. A recliner chair as claimed in claim 27 wherein the said first and second cam means are pivotally mounted about a common pivot axis. 29. A recliner chair as claimed in any claim 25 wherein the cam engagement means comprises at least one engagement pin, and the said first and second cam means comprise first and second pin engagement slots engaged by the said pin. 30. A recliner chair as claimed in claim 29 wherein the said first and second slots are provided in respective first and second cam plates pivotally mounted in the interior of the base portion of the chair on both lateral sides thereof, each pair of first and second cam slots being engaged by a respective engagement pin. 31. A recliner chair as claimed in claim 22 wherein the actuator comprises a linear actuator. 32. A recliner chair as claimed in claim 22 wherein the said actuator means is enclosed within the said base portion on the underside of the seat.

This invention relates to powered furniture and in particular concerns powered recliner chairs and lift-recliner chairs. A typical recliner chair comprises a base that sits on the floor, a seat portion that supports a generally horizontal seat cushion and a back portion that may be fixed to the seat or pivotally connected to it. Recliner chairs are also usually provided with a footrest at the front of the chair which is movable between a vertical orientation when the chair is in a generally upright configuration for sitting, and a generally horizontal orientation when the chair is reconfigured for reclining. Recliner chairs are known where the seat portion moves during the reclining operation to tilt the seat slightly downwards at the rear edge and raise the front edge of the seat. Other types of recliner seat are known where the seat is fixed with respect to the base and only the back and footrest are moved when the seat is reclined. Various types of lift-recliner chairs have been developed, principally for the elderly and less physically able people, to provide assistance when moving out of the chair to a standing position. Typical lift recliner chairs are described in U.S. Pat. No. 4,852,939, U.S. Pat. No. 4,993,777 and U.S. Pat. No. 5,265,935 which describe various arrangements of levers, links and motors for raising the chair from a seated to a standing position. The actuating arrangements of known recliner and lift-recliner chairs are generally mechanically complex adding significantly to the cost, weight and complexity of the chair. In addition, in known lift-recliner chairs the seat and back portion of the chair are typically lifted off of the base support structure (typically a metal frame) when the chair is raised towards the standing position creating entrapment points between the underside of the seat and the base, and in particular in between the levers and links of the actuating arrangement that are exposed between the seat and the base support structure when the chair is raised. There is a requirement to provide a simple actuating arrangement for recliner and lift-recliner chairs which requires fewer moving components than hitherto known designs, and also an actuating arrangement that is relatively simple to construct and to integrate within the structure of a recliner or lift recliner chair. According to a first aspect of the invention there is provided a lift-recliner chair comprising a base portion, a seat portion pivotally connected to the base portion, a back portion pivotally connected to the seat portion and actuator means for moving the seat portion with respect to the base portion and the back portion with respect to the seat portion whereby to alter the configuration of the chair, wherein the said actuator means is substantially enclosed within the base portion in all configurations of the chair. The lift-recliner chair according to the above aspect of the invention has the advantage that the actuator means is enclosed within the base portion of the chair, thereby providing a chair in which the actuator means is wholly integrated within the structure of the chair. This can substantially eliminate the risk of entrapment when ihe chair is moved from one configuration to another, for example when raised or lowered. The lift-recliner chair according to this aspect of the invention also enables all moving parts of the actuating mechanism to be enclosed within the base portion of an upholstered chair. The seat portion of the chair may be moved between a substantially horizontal position in which at least part of the seat portion is nested with the base portion and an inclined position in which the seat is extended telescopically from the base. The nested arrangement of the seat portion and the base readily enables the actuator means to be enclosed within the base on the underside of the seat cushion part of the seat portion so that the actuator means is guarded by the base and seat structure and also hidden from view so that the aesthetic appearance of the chair is also significantly improved. It will be readily apparent to the skilled person that by carefully selecting the clearance dimensions between the nested parts of the chair entrapment points can be substantially eliminated. This is a significant advantage when considered in relation to known types of lift recliner chair where a significant risk of entrapment exists between the moving parts on the underside of the seat portion of the chair between the seat and the base and between the seat and the base parts when the seat is moved. In preferred embodiments the seat portion is nested within and extendable from the base portion. Preferably, the base portion comprises a front and a back panel and a pair of substantially vertical side panels between the front and back panels, and the said seat portion comprises a seat panel and pair of substantially vertical side panels arranged substantially parallel with and adjacent to the respective base portion side panels. Preferably, the base portion has a rectangular shape with the side and back panels comprise part of the structural framework of the chair with the front panel being movable with respect to the other panels of the base to a horizontal orientation to provide a foot rest. Preferably, the seat portion is pivoted to the base portion about a pivot axis positioned towards the front of the base portion, that is to say towards the front panel of the base. In this way it is possible to raise and lower the seat portion of the chair by tilting the seat portion about its pivot axis to provide the lifting function of the chair. By positioning the pivot axis towards the front of the chair the person seated in the chair can be gently raised towards the standing position with substantially no effort since the movement of the seat gently straightens the legs of the person seated since the knee joints of the user's legs are substantially coincident with the pivot axis as the seat is pivoted and raised. In preferred embodiments the back portion comprises a generally rectangular frame and a pair of pivot arms which extend from the frame and pivotally connect the frame to the seat portion. In this way the pivot arms may comprise part of a bell-crank arrangement for moving the back portion about a pivot axis spaced from the rectangular frame of the seat back. The extended pivot arms readiy enable the back portion to be moved by actuator means enclosed within the enclosed region on the underside of the seat or at the rear of the seat cushion. This is possible in embodiments where the pivot arms extend into the region on the underside of the seat panel, or into the region at the rear of the seat cushion, where they can be connected to an actuator without interfering with other parts of the seat. In preferred embodiments the pivot arms extend parallel with and adjacent to the respective vertical side panels of the seat, and preferably the pivot arms are positioned on the interior side of the vertical side panels of the seat. Preferably the back portion pivots away from the seat portion when the seat is moved to an inclined position, that is to say the angle between the seat panel and the seat back is increased. Preferably, the back portion pivots away from the seat portion when the seat is moved to a half raised position. In preferred embodiments the seat and back portions of the chair are moved independently of each other by dedicated first and second actuators, including a first actuator for moving the seat portion and a second actuator for moving the back portion. The first and second actuators are preferably controlled by a microprocessor or the like so that the movements of the seat and back portions of the chair are co-ordinated. Preferably, the first and second actuators are mounted in fixed relation to the base portion of the chair. In preferred embodiments the actuators ate fixed to a structural, preferably metal, frame on which the side and rear panels of the base are mounted. In other embodiments the first actuator for moving the seat portion is fixed to the base and the second actuator for moving the back portion is fixed relative to the seat portion. The front panel of the base portion is preferably pivotally mounted with respect to the side and rear panels of the base so that it may be moved from a generally vertical orientation in the normal seated configuration of the chair to a generally horizontal orientation in a reclined configuration of the chair. In this embodiment a third actuator is provided for moving the front panel about its pivot axis. It is preferred that the third actuator is fixed in relation to the side panels of the base and preferably mounted to the same metal frame as the first and second actuators. According to a second aspect of the invention there is provided a recliner chair comprising a base portion, a seat portion, and a back portion pivotally mounted with respect to the seat portion, and actuator means for moving the back portion about its pivot axis between a generally upright position and a reclined position, wherein the said actuator means is enclosed within the base portion on the underside of the seat. The recliner chair according to the second aspect of the invention comprises many but not all the features of the lift-recliner chair according to the first aspect of the invention including the enclosure of the actuator means within the base portion of the chair on the underside of the seat. The advantages discussed in relation to the recliner chair relating to the enclosure and integration of the actuator means in the base portion of the chair are therefore equally relevant and applicable to the recliner chair according to the second aspect of the invention. Preferably, the base portion of the recliner chair comprises a front panel pivotally mounted with respect to the seat portion, and the actuator means comprises a first actuator for moving the back portion about its pivot axis and a second actuator for moving the front panel about its pivot axis from a generally vertical orientation to a generally horizontal orientation. According to a third aspect of the present invention there is provided a recliner chair comprising a base portion, a seat portion, and a back portion pivotally mounted with respect to the base portion, the base portion having a pair of lateral side panels and a front panel pivotally mounted with respect to the said side panels, and a comnmon actuator for moving both the back portion about its pivot axis and the front panel about its pivot axis to alter the configuration of the chair form a generally up-right configuration to a generally reclined configuration, wherein the back portion moves from a generally vertical to an inclined orientation and the front panel moves from a generally vertical to a generally horizontal orientation. The recliner chair according to the third aspect of the invention shares many of the advantages of the chairs of the aforementioned first and second aspects of the invention but has the further advantage that the chair has a single common actuator for moving both the back portion of the chair and the front panel, so that the configuration of the chair may be changed by the activation ofa single actuator acting on both ofthe backrest and front panel. The third aspect of the invention therefore provides a relatively simple and compact actuator arrangement that is readily integrated into the interior of the base on the underside of the seat panel of the chair. Preferably, the recliner chair according to the third aspect of the invention farther comprises a first cam means for determining the movement path of the back portion with respect to the base portion and a second cam means for determining the movement path of the front panel with respective side panels. The first and second cam means readily and reliably ensure the movement of the front panel and back portion of the chair are coordinated when the chair is moved from its upright position to its fully reclined position and the intermediate positions therebetween. In preferred embodiments the first and second cam means are engaged by a cam engagement means connected to the actuator. Preferably the cam engagement means is pivotally mounted with respect to the sides of the base portion for movement by the actuator. It is also preferred that the first and second cam means are pivotally mounted with respect to the sides of the base and that they are pivotally mounted about a common axis. In preferred embodiments the cam engagement means comprises at least one engagement pin and that the first and second cam means comprise first and second pin engagement slots engaged by the pin. In preferred embodiments the first and second slots are provided in first and second cam plates pivotally mounted in the interior of the base portion on both sides of the base with each pair of the first and second cam slots being engaged by a respective engagement pin. This arrangement readily enables the actuator load to be transferred evenly to the back portion of the chair and the front panel on both sides of the chair. In preferred embodiments the common actuator comprises a linear actuator. Various embodiments of the present invention will now be more particular described, by way of example only, with reference to the accompanying drawings, in which: FIG. 1 is a perspective view from the front of the frame of the lift-recliner chair according to an embodiment of the present invention; FIG. 2 is the perspective view of the frame of the chair shown in FIG. 1 viewed from the underside of the chair frame; FIG. 3 is a perspective view of a chair of FIG. 1 from above; FIG. 4 is a perspective view of the frame of the chair of FIG. 1 viewed from the side showing the rear of the chair with the frame in a partly raised configuration; FIG. 5 is a perspective view similar to that of FIG. 1 of the frame of the chair shown in a fully raised configuration; FIG. 6 is a cross-section view through the base of a lift-recliner chair according to another embodiment of the invention; FIG. 7 is a side view of a lift-recliner chair according to a further embodiment of the invention; FIG. 8 is a side view of the chair of FIG. 7 shown with a seat portion in a raised configuration; FIG. 9 is a perspective view of the rear of the chair of FIG. 8; FIG. 10 is a side view of the chair of FIG. 7 shown with a back portion in a reclined configuration and a foot panel in a raised configuration; FIG. 11 is a diagrammatic view of the back section of the chair of FIGS. 7 to 10; FIG. 12 is a diagrammatic perspective view showing the underneath of the chair of FIGS. 7 to 11; and FIG. 13 is a diagrammatic side view showing the working mechanisms of the chair of FIGS. 7 to 12. FIG. 1 shows the structural frame of a lift-recliner chair 10 according to an embodiment of the present invention. The frame, and hence the chair, comprises three main sections including a base portion 12 a seat portion 14 and a back portion 16. The base portion includes a pair of lateral side panels 18 and a rear panel 20 secured to the respective sides of the rectangular metal frame 22 on the underside of the chair. The panels 18 and 20 and the other panels of the frame of the chair shown in FIGS. 1 to 5 are preferably of MDF type board material but the invention also contemplates other board material such as wood, plywood or plastic etc. as is typically used in the furniture industry for upholstered and non-upholstered furniture The metal frame 22, best seen in the view of FIG. 2, comprises a pair of lateral side members 24, a front cross member 26 extending between the side members 24 at the front of the chair and a pair of intermediate cross members 28 and 30 which extend between the side members 24 at a point midway along the length of the side member and towards the rear of the chair respectively. The side panels 18 are secured to the side members 24 of the frame with the rear panel 20 secured to the ends of the respective side panels at the rear of the chair to provide a box-type structure for supporting the other parts of the chair. The base portion 12 further comprises a front panel 32 which is pivotally mounted to the lateral side panels 18 of the base by a linkage arrangement 34 at both ends of the panel 32 adjacent to the respective side panels 18. The linkage arrangement 34 is of a known arrangement and enables the front panel 32 to be moved from the position shown in FIG. 1, where it has a generally vertical orientation, to the position shown in FIG. 2, where it has a substantially horizontal configuration. The seat portion 14 comprises a similar box-type panel frame secured to a further metal rectangular frame 36, as can best be seen in the view of FIG. 3. The metal frame 36 includes a pair of lateral side members 38 to which the lateral side panels 40 of the seat are attached, a front cross member 42 at the front of the seat portion, a rear cross member 44 at the rear of the seat and an intermediate cross member 46 approximately midway between the front member 42 and rear member 44. The cross members extend between the side members 38. The rectangular frame section between the cross members 44 and 46 at the rear of the seat has a slightly reduced width dimension to that of the rectangular frame section between the front cross member 36 and intermediate member 46. For reasons that will become apparent later in this description this reduced width dimension provides a clearance between the side members 38 of the frame and the respective side panels 40 of the seat towards the rear of the chair. The clearance dimension is approximately equal to the width dimension of the metal tubes that constitute the metal frame. The seat portion 14 is nested within the base portion 12 and pivotally connected to the base portion about a pivot axis perpendicular to the lateral sides 40 at the front of the chair. The seat portion is pivotally mounted to the base portion by pivot pins (not shown) which extend from pivot plates 48 through corresponding apertures in the side panels 40 and 18 towards the front of the chair. The rear most ends of the side panels 40 are arcuate having a centre of curvature defined by the pivot axis of the mounting pins so that the rear part of the seat portion can move freely with respect to the base end panel 20 when the seat portion is pivoted about its axis in use. Similarly, an end panel 50, as seen in FIG. 4 which extends between the side panels 40 at the rear of the chair also has a curvature which follows the curvature of the arcuate end faces 49, that is to say it has the pivot axis of the seat portion as its centre of curvature. The width dimension of the seat portion between the side panels 40 is slightly less than the width dimension between the base side panels 18 so that the seat portion nests between the side panels 18 when in the sitting configuration shown in FIG. 1 and is extendable telescopically there from when pivoted about its pivot axis to the lift position shown in FIG. 5. The back portion of the chair fiame also comprises a rectangular frame in which a pair of a pair of elongate pivot arms 52 on the lateral sides of the back portion 16. The arms 52 are joined together by a pair of cross members 54 and 55 towards the top and the bottom part of the back portion 16. The back portion 16 is pivotally connected to the seat portion 14 in the same way that the seat portion is pivotally connected to the base 12, that is to say by means of a pair of pivot pins 56 secured to pivot pin plates 58 on the respective side panels 40. The pins 56 pass through corresponding apertures in the respective panels 40 and pivot arms 52. As can best be seen in the view of FIG. 2 the pivot arms 52 extends beyond the pivot pins 56 into the interior region of the base portion 12. The lower part of the pivot arms 52 pass through the gaps created between the undersize frame part towards the rear of the frame 36 and the side panels 40 on the seat. The ends of the pivot arms extend beyond the metal seat frame 36 into the region on the underside of the frame 36 and are joined together at their remote ends by a metal cross bar member 60. The pivot arms 52 are free to rotate with respect to the seat portion, and hence the base portion, in a manner that enables the back portion to be reclined with respect to the seat portion either for altering the configuration of the chair from an upright configuration to a reclined configuration or to a raised configuration as shown in FIG. 5. Three linear actuators 62, 64 and 66 are mounted on the metal frame 22 in the interior of the base portion 12 on the underside of the seat frame 36. A first of the actuators 62 is mounted on the intermediate cross member 28 with the end of the actuator ram 63 fixed to the rear face of the front panel 32 adjacent to the upper edge 70 of the front panel. Extension of the actuator arm 63 moves the front panel from its generally vertical orientation as shown in FIG. 1 to the horizontal orientation shown in FIG. 2 to provide a footrest support. Actuator 64 is mounted to the front cross member 26 of the frame 22. The actuator arm 65 of the actuator 64 is connected at its extendable end to the cross member 46 ofthe metal seat frame 36 so that extension of the actuator arm 65 moves the seat portion 14 about its pivot access to tilt the seat portion between the positions shown in FIGS. 1 and 5. The third actuator 66 is also mounted to the cross member 26 of the metal frame 22 with the extendable end of its actuator arm 67 connected to the cross member 60 extending between the pivot arms 52. Extension of the actuator arm 67 by the actuator 66 moves the back portion 16 about its pivot access to alter the tilt angle of the back portion 16 with respect to the seat portion 14. Retraction of the actuator arm 67 causes the angle between the back portion and seat portion to increase, for example when the chair is reclined or when the seat portion 14 is raised to the standing position. Extension of the actuator arm 67 reverses this operation and when fully retracted the back portion is moved to its upright position with respect to the seat portion. Actuators 62, 64 and 66 are of a known type, for example Dewart type 34931 linear actuators, that comprise electrical motors controlled by control electronics which may be in the form of a microprocessor suitably programmed to provide co-ordinated control of the actuators for co-ordinated movement of the moveable sections of the chair, both for reclining and lifting movements. It will be understood that the configuration of the chair shown in FIGS. 1 to 5 may be changed from the upright configuration shown in FIG. 1 to a reclined configuration where the back portion 16 is reclined with respect to the remainder of the chair and the front panel 32 is raised to provide a foot rest with or without movement of the seat portion 14, and that the configuration may be changed from the upright configuration to the raised configuration shown in FIG. 5 for assisting the seated user out of the chair. If the seat portion 14 is tilted to the raised configuration shown in FIG. 5 with the back portion 16 remaining in its upright configuration this could cause problems by dictating or even forcing an individual to move out of the chair directly from a seated position. Adjusting from a seated position to a standing position as the seat portion tilts forward may not be possible or desirable for all users. If the back portion 16 is moved to its reclined position prior to or during movement of the seat portion 16 then a user can be placed into a standing position by the chair by the time the seat portion 16 has tilted to the point at which the user leaves the chair. The chair may therefore have the facility to provide co-ordinated pivotal movement of the seat portion 14 and the back portion 16 in which the back portion 16 reclines as the seat portion 14 lifts. In this way an individual is moved from a seated to a standing position by the chair to avoid the possibility of them being pushed out of the chair whilst still in a seated position. In a preferred embodiment of the invention the back portion begins to tilt rearwards when the seat portion is pivoted, or raised, at a point half way between its lowered and raised positions, preferably the movement of the seat and back rest portion is co-ordinated by control signals generated by software implemented in the microprocessor controller. A recliner chair according to another aspect of the present invention comprises an operating mechanism as shown in the drawing of FIG. 6. FIG. 6 is a cross section view through the base portion of a recliner chair with an operating mechanism 71 housed substantially within the interior of the base of the chair. The base of the chair shown in FIG. 6 is similar to the base of the chair described with reference to FIGS. 1 to 5 in that it comprises a generally rectangular box-type structural framework including a metal base frame 72, of a tubular metal construction, and a pair of lateral side panels 74, preferably but not necessarily of MDF board material, bolted to the side members of the frame 72 on respective sides of the chair. A front panel 76 is pivotally mounted to the side panels 74 by respective link assemblies 78 mounted on the interior side of the side panels 74 on both sides of the chair. The link assembly 78 and front panel 76 are substantially identical to the linkage system 34 and front panel 32 of the chair described with reference to FIGS. 1 to 5. The link assembly 78 on each side of the chair includes four link elements that are pivotally connected together, including a first link element 80 which is pivoted at one end to the side panel 74 and at its other end to one end of a second link element 82. The other end of the link element 82 is pivotally connected to a bracket 83 secured to the interior facing surface of the front panel 76 towards the top edge of the panel when configured in its vertical orientation as shown in FIG. 6. A third link element 84 is pivotally connected at one end thereof to the side panel 74 between the link element 80 and the front panel 76 and at the other end thereof to one end of a fourth link element 86, the other end of which is also pivotally connected to the bracket 83 at a position spaced from the link 82 and approximately one third along the depth of the front panel 76. The second and third link elements 82 and 84 are also pivotally connected together at the point of their mutual intersection (not shown). The front panel 76 is deployed from its vertical orientation shown in FIG. 6 to a generally horizontal orientation to provide a foot rest by activation of a linear actuator 88 located within the interior of the base of the chair. The linear actuator 88 may be a Dewart type 34931 linear actuator comprising an electric motor 90 at one end thereof and a piston arm 92 at the other end thereof which is extendable from a housing 94. The end of the actuator 88 nearest the motor section 90 is pivotally connected to a bracket 96 integral with and upstanding from the base frame 72 at the front of the frame 72. At the other end of the actuator the extendable arm 92 is pivotally connected at its end to a bracket 98 extending on one side of a square cross section metal tube member 100 to which extends along the width of the chair and is welded to respective metal bell-crank plates 102 at opposite sides ofthe chair, only one of which is shown in the cross-section view of FIG. 6. The bell-crank plates 102 are substantially parallel with the respective side panels 74 and perpendicular to the metal tube which connects the bell-crank plates 102 on either side of the chair together. Each bell-crank plate 102 is pivotally connected to its respective side panel 74 by a pin type mounting 104 positioned towards the top edge 106 of the side panel 74. Each bell-crank plate 102 is provided with an upstanding engagement pin 108 extending perpendicular to the plane of the plate. The pin 108 constitutes a cam engagement means and is engaged within respective first and second cam slots 110 and 112 provided in the respective cam plates 114 and 116 pivotally mounted to the respective sidepanels 74 towards the rear of the chair on both sides thereof. The first and second cam plates 114 and 116 are pivotally mounted on a common pivot pin 118 which extends into the interior of the base portion from the side panel 74. The cam plates 114 and 116 are generally planar and parallel with the bell-crank 102 and the side panel 74. The first cam plate 114 constitutes a seat back cam for determining the movement path of the back portion of the chair (not shown) with respect to the base. The second cam plate 116 constitutes a footrest cam for determining the movement path of the front panel 76 with respect to the side panels of the base. The seat back cam 114 has a shallow V-shape with the mounting pin 118 positioned at the apex of the V. The upper arm of the V, i.e. the arm shown towards the top of the drawing in FIG. 6, constitutes a lever for connecting the seat back cam plate to the back portion of the chair, while the cam slot 110 is formed in the lower arm of the V. The cam slot 110 includes a linear portion 120 and an arcuate portion 122 with the linear portion 120 extending towards the extremity of the V and the arcuate portion disposed towards the middle part of the V in the lower arm. The curvature of the arcuate portion 122 is such that the side of the slot facing the front of the chair in the view of FIG. 6 is concave. The cam plate 116 is generally arcuate and is pivotally connected at one end ofthe arc to the mounting pin 118 and at its other end to a linear push rod link element 124. The cam slot 112 in the cam plate 116 also comprises a linear section 126 and a longer arcuate section 128. The arcuate section 128 of the slot extends along the majority of the arcuate length of the cam plate from the lower end of the plate that is connected to the push rod 124 along approximately 75% of the arc of the plate where the remainder of the slot is linear. The linear push rod 124 connects the link assembly 78 to the cam plate 116. One end of the push rod 124 is pivotally connected to the first link 80 at a point substantially midway along its length, and the other end is pivotally connected to the cam plate 116. The operating mechanism described with reference to FIG. 6 provides for simultaneous coordinated pivotal movement of the back of the chair and the foot rest front panel 76. In the drawing of FIG. 6 the operating mechanism is shown configured for a chair in an upright configuration with the front panel foot rest 76 retracted to the vertical position at the front of the chair and the back portion of the chair substantially upright with respect to the base and seat. By activating the actuator 88 to retract the armn 92 into the housing 94 the bell crank 102 is caused to rotate about the pin 104. This movement causes the cam engagement pin 108 to follow a circular path about the centre of the pin 104, in a clockwise direction when viewed in the plane of the drawing of FIG. 6. This then causes the cam plate 114 to follow the pin 108 so that the cam plate rotates about the mounting pin 118 in a clockwise direction, as viewed in the plane of the drawing of FIG. 6, thereby causing the back of the chair to rotate towards a reclined position with respect to the seat. Simultaneously, the slot 112 in the cam plate 116 is constrained to follow the movement of the cam pin 108 so that the plate 116 also rotates in a clockwise direction about the mounting pin 118. The fixed relationship between the position of the pin 118 and the end of the push rod 124 connected to the plate 116 causes the push rod link 124 to move in a general direction towards the front panel of the chair pivoting the links 80 and 84 of the link assembly also in a clockwise direction so that the front panel 76 is moved from the vertical position shown in FIG. 6 towards its deployed horizontal position to provide a foot rest. FIGS. 7 to 13 show a lift-recliner chair 210 according to an alternative embodiment of the present invention. The chair 210 is similar to the chair 10 shown in FIGS. 1 to 5. The chair 210 comprises a base portion 212, a seat portion 214 and a back portion 216. The seat portion 214 is pivoted with respect to the base portion 212 and is movable between the lowered position shown in FIG. 7 and the raised position shown in FIG. 8 and 9. The back portion 216 is pivoted with respect to the seat portion 214 and is movable between the raised position shown in FIG. 7 and the reclined position shown in FIG. 10; in addition a front panel 232 is pivoted with respect to the base portion 212 and can be moved from the vertical position of FIG. 7, and best shown in FIG. 13, to the horizontal position shown in FIG. 10. The base portion 212 includes a pair of lateral side panels 218 and a rear panel 220 is secured to the rear of the side panels 218. Together with the front panel 232 the base portion 212 comprises a box-type structure. As shown in FIGS. 12 and 13 the side panels 218 are joined at their lower edges to a metal base frame 222 comprising a pair of lateral side members 224, a front cross member 226 extending between the side members 224 at the front ofthe chair and an intermediate cross member 230 which extends between the side members 224 towards the rear of the chair. The seat portion 214 comprises a pair of lateral side panels 240 joined by a central, mainly wooden, rectangular frame 236. The frame 236 comprises a pair of side members 238 and front and rear cross members 242,244 extending between the front and rear side members 238. At the front of the seat section frame 236 the side members 238 are attached to the side panels 240 by a pair of metal reinforcement brackets 241. At the rear of the seat section frame 236 a metal cross member 237 is attached to and extends between the panels 240 and is also attached to the frame side members 238. A further cross member 219 is attached to and extends between the side panels 240 directly below the cross member 237 at the lower rear corners of the panels 240. The seat portion 214 is nested within the base portion 212 and is pivotally connected to the base portion 212 about a pivot axis perpendicular to the side panels 240 by pivot pins 247. The pins 247 extend from pivot pin mounting plates 248 positioned at the respective upper front corners ofthe side panels 240 and extend through the panels 240 and through the side panels 218 of the base portion 212. The rear ends of the side panels 240 are arcuate and an end panel 250 extending between the side panels 240 is correspondingly curved. As is the case for the chair 10 of FIGS. 1 to 5, the centre of curvature of the rear ends of the side panels 240 and the end panel 250 is determined by the pivot axis 247 of the seat portion so that the seat portion 214 can extend and retract telescopically, with minimum clearance, within the base portion 212 between the lowered position shown in FIG. 7 and the raised position shown in FIGS. 8 and 9. As shown best in FIG. 11, the back portion 216 comprises a pair of elongate pivot arms 252 joined by a top cross member 254, an intermediate cross member 257 and a bottom cross member 255. Two outer arms 259 lie outwardly spaced from and parallel to the pivot arms 252. The arms 259 are connected by the top cross member 254 and the intermediate cross member 257, and terminate slightly below the bottom of the pivot arms 252. The three cross members 254, 255, 257 aid in the attachment of webbing (not shown) in the upholstering of the chair 210. As can be seen in FIG. 7 and 8 the pivot arms 252 are provided with metal brackets 203 for mounting the back portion 216 on corresponding interlocking bracket parts 201a of L-shape bell crank members 201. A metal cross member 260 extends between and is fixed to the L-shape members 201. The pivot arms 252 thereby slot into the respective leg 201a portions of the L-shape member 201. The other leg portions 201b of the L-shaped brackets 201 connect the brackets to respective pivot pins 256 extending through the panels 240. The back portion 216 is thereby pivotally connected to the seat portion 214. As shown best in FIGS. 12 and 13, three linear actuators 262, 264, 266 are provided within the base portion for movement of the front panel 232, the seat portion 214 and the back portion 216 respectively. The actuator 262 is mounted centrally on the rear cross member 230 with the actuator ram 263 fixed to the rear face of the front panel 232 via a bracket 235. The actuator 263 is of the ‘push only’ type in which the piston is not attached to the screw jack (not shown). Accordingly the actuator 262 can move the panel 232 from the vertical position shown in FIG. 7 to the horizontal position shown in FIG. 10. The return action is provided not by the actuator 262, but by the weight of the panel 232 and by a lightly tensioned elastic cord 234 strung between bolts 234a, 234b which extend from the points of connection of the two ends of the actuator 262 to the panel 232 and the cross member 228 respectively. Because the actuator 262 is not involved in the return movement of the panel, if an object, such as a leg or arm, becomes trapped by the panel 232 as it moves towards the vertical position then the object is held only by the weight of the panel 232 and the tension ofthe cord 234. Accordingly the force applied to the object by the panel 232 is minimised and can easily be overcome compared to a system using an actuator to effect the return action. The panel 232 is connected to the base portion 212 via two hinges 233, one at either side of the panel 232. Each hinge 233 comprises an arcuate quarter circle plate 233a connected at one of its circumferential ends to the panel 232 and at its other circumferential end to a linear radially extending plate 233b. The linear plate 233b is pivotally connected to the base side panels of the chair by the pivot pins 247 extending from the base portion side panels 218 through the linear plates and through the side panels 240 of the seat section to the mounting plates 248. The main pivot point provided by pivot pins 247 thereby defines the pivot axis for both the panel 232 and the seat portion 214. This arrangement also means that the hinges 233 slide between the side panels 240 of the seat portion 214 and the side panels 218 of the base portion 212 when extended and retracted. The positioning of the combined main pivot points of the foot rest 232 and the seat portion provided by the pivot pins 247 approximately at the upper front corners of the base portion 212 and seat portion 214, coincides with the natural position of the seated user's Imee joint which brings ergonomic advantages. The same advantage could, of course, be achieved if the pivot points for the front panel and the seat portion were slightly spaced apart but still in the same general area so that they are roughly coincident with the seated user's knee joint. Because the panel 232 is connected to the base portion 212 via hinges 233 the panel 232 can undergo only a rotation movement with no radial extension. As a result the position of the panel 232 may not extend away from the chair sufficiently to suit all users. Accordingly, in other embodiments (not shown) the chair may have some means of increasing the distance the panel extends away from the seat portion 214. For example, the panel 232 or a part thereof may be telescopic so that it moves to a position further away from the seat portion 214 during or following the pivoting movement. Alternatively a ‘flipper board’ arrangement could be used, in which a further panel is pivotally attached to the main foot panel 232 and can be flipped over from a position in which it rests on the panel 232 to a position in which it is co-extensive with the panel 232 to increase the length of the panel. The actuator 264 is mounted centrally on the front cross member 226. The actuator ram 265 is fixed centrally to a cross member 237 which spans between and is attached to the side panels 240 and supports the rear of the seat section frame 236. The front of the seat section frame 236 is carried on a pair of brackets 241 attached to the frame members 238 and to the inner faces of the side panels 240. As discussed above, the side panels 240 are pivotally connected to the main pivot points so that the seat portion 214 pivots about the pivot points under the control of the actuator 264 as shown in FIGS. 8 and 9. The actuator 266 is mounted centrally on a cross member 21 which extends between and is fixed to the side panels 240 of the seat portion. The actuator ram 267 of actuator 266 is connected centrally to the cross member 260 at a point offset from the pivot axis 256 to provide a bell crank type lever. The bell crank arrangement means that the back portion 216 can be lowered to the position shown in FIG. 10 by retracting the ram 267, or raised to the position shown in FIG. 7 by extending the ram 267. The back portion 216 can be moved at the same time as movement of the seat portion 214 and/or the footrest panel 232 or independently thereof as previously described with reference to the embodiment of FIGS. 1 to 5. Although aspects of the invention have been described with reference to the embodiments shown in the accompanying drawings, it is to be understood that the invention is not so limited to those precise embodiments and that various changes and modifications may be effected without further inventive skill and effort. For example, the lift recliner chair described with reference to FIGS. 1 to 5 may be modified to provide a reclining function only in the sense that the base portion of the chair is provided with only two actuators, one for reclining the back portion of the chair with respect to the base and a fixed seat, and another for deploying the front panel from its vertical position to its horizontal position to provide a foot rest for the chair. It will be appreciated that various changes and modifications may be made to the chairs described herein with any of the integers described in one embodiment being interchangeable with integers in another embodiment, and that the embodiments maybe modified by deletion or addition of any of the integers described with reference to any of the embodiments described herein.

20060621

20090818

20070614

66081.0

A47C100

BROWN, PETER R

ADJUSTABLE RECLINING CHAIR

UNDISCOUNTED

ACCEPTED

A47C

ACCEPTED

Adhesive Compounds of Butyl-Type Rubber

The present invention relates to a substantially gel-free sealant or adhesive compound comprising butyl-type polymer without any conjugated aliphatic diene in its composition having an average molecular weight Mn of more than 20,000 g/mol and containing less than 15 wt. % of solid matter insoluble in boiling cyclohexane under reflux for 60 min. In another of its aspects, the present invention relates to a self-supporting shaped article comprising said compound optionally layered on or interposed between one or more supporting means. In still another of its aspects, the present invention relates to a tape comprising said substantially gel-free compound optionally layered on or interposed between one or more supporting means. In still another of its aspects, the present invention relates to an adhesive composition comprising said substantially gel-free compound. In still another of its aspects, the present invention relates to a sealant composition comprising said substantially gel-free compound.

1. A substantially gel-free compound comprising: a. at least one elastomeric polymer without any conjugated aliphatic diene in its composition having an average molecular weight Mn of more than 20,000 g/mol comprising repeating units derived from at least one C4 to C7 isomonoolefin monomer, at least one multiolefin cross-linking agent and at least one chain transfer agent, said polymer containing less than 15 wt. % of solid matter insoluble in boiling cyclohexane under reflux for 60 min, b. at least one filler and c. optionally at least one diluent. 2. The compound of claim 1, wherein at least one of said elastomeric polymers comprising repeating units derived from at least one C4 to C7 isomonoolefin monomer, at least one multiolefin cross-linking agent and at least one chain transfer agent, said polymer containing less than 15 wt. % of solid matter insoluble in boiling cyclohexane under reflux for 60 min, is partially vulcanized. 3. The compound of any of the claims 1-2, wherein the compound further comprises a diluent. 4. A self-supporting shaped article comprising a substantially gel-free compound comprising: a. at least one elastomeric polymer without any conjugated aliphatic diene in its composition having an average molecular weight Mn of more than 20,000 g/mol comprising repeating units derived from at least one C4 to C7 isomonoolefin monomer, at least one multiolefin cross-linking agent and at least one chain transfer agent, said polymer containing less than 15 wt. % of solid matter insoluble in boiling cyclohexane under reflux for 60 min, b. at least one filler. 5. An article according to claim 4, wherein the C4 to C7 isomonoolefin monomer(s) are selected from the group consisting of isobutylene, 2-methyl-1-butene, 3-methyl-1-butene, 2-methyl-2-butene, 4-methyl-1-pentene and mixtures thereof. 6. An article according to any of claims 4-5, wherein the article further comprises at least one supporting means on which the compound is layered. 7. A tape comprising the compound of any of the claims 1-3 and optionally one or more supporting means. 8. A sealant or adhesive composition comprising the compound of any of the claims 1-3.

FIELD OF THE INVENTION The present invention relates to a substantially gel-free sealant or adhesive compound comprising butyl-type polymer having an average molecular weight Mn of more than 20,000 g/mol and containing less than 15 wt. % of solid matter insoluble in boiling cyclohexane under reflux for 60 min. In another of its aspects, the present invention relates to a self-supporting shaped article comprising said compound optionally layered on or interposed between one or more supporting means. In still another of its aspects, the present invention relates to a tape comprising said substantially gel-free compound optionally layered on or interposed between one or more supporting means. In still another of its aspects, the present invention relates to an adhesive composition comprising said substantially gel-free compound. In still another of its aspects, the present invention relates to a sealant composition comprising said substantially gel-free compound. BACKGROUND OF THE INVENTION Butyl rubber is known for its excellent insulating and gas barrier properties. Generally, commercial butyl polymer is prepared in a low temperature cationic polymerization process using Lewis acid-type catalysts, of which a typical example is aluminum trichloride. The process used most extensively employs methyl chloride as the diluent for the reaction mixture and the polymerization is conducted at temperatures on the order of less than −90° C., resulting in production of a polymer in a slurry of the diluent. Alternatively, it is possible to produce the polymer in a diluent which acts as a solvent for the polymer (e.g., hydrocarbons such as pentane, hexane, heptane and the like). The product polymer may be recovered using conventional techniques in the rubber manufacturing industry. Adhesives (glues) are substances capable of forming and maintaining a bond between two surfaces, and sealants (caulks) are substances used to fill gaps or joints between two materials to prevent the passage of liquids, solids or gases. These two classes of materials are often considered together because quite frequently a given formulation performs the both functions. Butyl sealants are available as one-component solvent evaporation curing products and as thermoplastic hot melts. There is no curing process, the compound gets its functionality through solvent loss and/or a decrease in temperature. When a sealant is applied, the solvent evaporates or migrates into porous substrates and the tough, rubbery compound is left in place. This is in contrast to other sealant types that cure chemically. It is known to use a commercial pre-cross-linked butyl rubber such as commercially available Bayer® XL-10000 (or, formerly XL20 and XL-50) that will add additional strength to the sealant/adhesive. XL-10000 is partially cross-linked with divinylbenzene already in the polymerization stage. While said commercial pre-cross-linked polymers exhibit excellent properties in many applications, they have a gel content of at least 50 wt. % which sometimes makes the even dispersion of fillers and additives normally used during compounding difficult. This increases the likelihood of inhomogeneous areas within the rubbery article, rendering its physical properties inferior and unpredictable. Also, the Mooney viscosity of this rubber is high, usually 60-70 units (1′+8′@125° C.) which may cause significant processing difficulties, especially in a mixing stage. Processability-improving polymers are often added to the pre-cross-linked butyl rubber to overcome some of these problems. Such polymers are particularly useful for improving the mixing or kneading property of a rubber composition. They include natural rubbers, synthetic rubbers (for example, IR, BR, SBR, CR, NBR, IIR, EPM, EPDM, acrylic rubber, EVA, urethane rubber, silicone rubber, and fluororubber) and thermoplastic elastomers (for example, of styrene, olefin, vinyl chloride, ester, amide, and urethane series). These processability-improving polymers may be used in the amount of up to 100 parts by weight, preferably up to 50 parts by weight, and most preferably up to 30 parts by weight, per 100 parts by weight of a partially cross-linked butyl rubber. However, the presence of other rubbers dilutes desirable properties of butyl rubber. RU 2,130,948 discloses the copolymerization of isobutylene with DVB in an aromatic or aliphatic hydrocarbon solvent initiated with a system comprising TiCl4 and triisobutylaluminum. The content of DVB in the monomer feed was 0.1 to 5.0 wt. %, based on isobutylene. The process was carried out in the temperature range −40 to +40° C. The products had low molecular weights (Mv<15,000 g/mol) and were useful as a source for preparing glues. In one example, the process was carried out at +40° C. and the viscosity average molecular weight of the polymer was about 5400 g/mol. This is different from the process described in the present invention, where a typical polymerization temperature was −95° C. and the viscosity average molecular weight of the product was above 200,000 g/mol. The above application did not involve the presence of a chain-transfer agent in the monomer feed during polymerizations. Co-Pending Canadian Application CA-2,316,741 discloses terpolymers of isobutylene, isoprene, divinyl benzene (DVB) prepared in the presence of a chain-transfer agent, such as diisobutylene, which are substantially gel-free and have an improved processability. However, the above application is silent about applications for sealants and adhesives. Co-Pending Canadian Application CA 2,386,628 discloses peroxide curable compounds comprising terpolymers of isobutylene, isoprene, divinyl benzene (DVB) prepared in the presence of a chain-transfer agent, such as diisobutylene, which are substantially gel-free and have an improved processability but is also silent about compounds for sealants/adhesives. In the above two applications, an aliphatic conjugated diene, like isoprene, was an integral part of the compounds. SUMMARY OF THE INVENTION The present invention provides a substantially-gel free compound comprising: a. at least one elastomeric polymer without any conjugated aliphatic diene in its composition having an average molecular weight Mn of more than 20,000 g/mol and comprising repeating units derived from at least one C4 to C7 isomonoolefin monomer and at least one multiolefin cross-linking agent and at least one chain transfer agent, said polymer containing less than 15 wt. % of solid matter insoluble in boiling cyclohexane under reflux for 60 min, b. at least one filler and c. optionally at least one diluent especially useful for the manufacture of shaped articles for sealants and/or adhesives. Another aspect of the invention is a self-supporting shaped article comprising said compound optionally layered on or interposed between one or more supporting means. Yet another aspect of the invention is a tape comprising said substantially gel-free compound optionally layered on or interposed between one or more supporting means. Yet another aspect of the invention is an adhesive composition comprising said substantially gel-free compound. Yet another aspect of the invention is a sealant composition comprising said substantially gel-free compound. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to butyl-type polymers. The terms “butyl rubber”, “butyl polymer” and “butyl rubber polymer” are used throughout this specification interchangeably. While the prior art in using butyl rubber refers to polymers prepared by reacting a monomer mixture comprising a C4 to C7 isomonoolefin monomer and a C4 to C14 multiolefin monomer or β-pinene, this invention specifically relates to elastomeric polymers comprising repeating units derived from at least one C4 to C7 isomonoolefin monomer, optionally further copolymerizable monomers, at least one multiolefin cross-linking agent and at least one chain transfer agent, which due to the lack of multiolefin monomer/conjugated aliphatic diene or β-pinene in the monomer mixture have no double bonds in the polymer chains. In connection with this invention the term “substantially gel-free” is understood to denote a polymer containing less than 15 wt. % of solid matter insoluble in cyclohexane (under reflux for 60 min), preferably less than 10 wt. %, in particular less than 5 wt %. The present invention is not restricted to any particular C4 to C7 isomonoolefin monomers. Preferred C4 to C7 monoolefins are isobutylene, 2-methyl-1-butene, 3-methyl-1-butene, 2-methyl-2-butene, 4-methyl-1-pentene and mixtures thereof. The most preferred C4 to C7 isomonoolefin monomer is isobutylene. Even more, the present invention is not restricted to any particular multiolefin cross-linking agent. Preferably, the multiolefin cross-linking agent is a multiolefinic hydrocarbon compound. Examples of these are norbornadiene, 2-isopropenylnorbornene, 5-vinyl-2-norbornene, 1,3,5-hexatriene, 2-phenyl-1,3-butadiene, divinylbenzene, diisopropenylbenzene, divinyltoluene, divinylxylene or C1 to C20 alkyl-substituted derivatives of the above compounds. More preferably, the multiolefin crosslinking agent is divinylbenzene, diisopropenylbenzene, divinyltoluene, divinylxylene or C1 to C20 alkyl substituted derivatives of said compounds. Most preferably the multiolefin cross-linking agent is divinylbenzene or diisopropenylbenzene. Even more, the present invention is not restricted to any particular chain transfer agent. However, the chain transfer agent should preferably be a strong chain transfer agent—i.e., it should be capable of reacting with the growing polymer chain, terminate its further growth and subsequently initiate a new polymer chain. The type and amount of chain transfer agent is dependent upon the amount of multiolefin cross-linking agent. At low concentrations of multiolefin cross-linking agent low amounts of chain transfer agent and/or a weak chain transfer agent can be employed. As the concentration of the multiolefin crosslinking agent is increased, however, the chain transfer agent concentration should be increased and/or a stronger chain transfer agent should be selected. Use of a weak chain transfer agent should be avoided because too much can decrease the polarity of the solvent mixture and also would make the process uneconomical. The strength of the chain transfer agent may be determined conventionally—see, for example, J. Macromol. Sci.-Chem., A1(6) pp. 995-1004 (1967). A number called the transfer constant expresses its strength. According to the values published in this paper, the transfer constant of 1-butene is 0. Preferably, the chain transfer agent has a transfer coefficient of at least 10, more preferably at least 50. Non-limiting examples of useful chain transfer agents are piperylene, 1-methylcycloheptene, 1-methyl-1-cyclopentene, 2-ethyl-1-hexene, 2,4,4-trimethyl-1-pentene, indene and mixtures thereof. The most preferred chain transfer agent is 2,4,4-trimethyl-1-pentene. Preferably the monomer mixture to be polymerized comprises in the range of from 75% to 99.98% by weight of at least one C4 to C7 isomonoolefin monomer, in the range of from 0.01% to 15% by weight of a multifunctional cross-linking agent, and in the range of from 0.01% to 10% by weight of a chain-transfer agent. More preferably, the monomer mixture comprises in the range of from 82% to 99.9% by weight of a C4 to C7 isomonoolefin monomer, in the range of from 0.05% to 10% by weight of a multifunctional cross-linking agent, and in the range of from 0.05% to 8% by weight of a chain-transfer agent. Most preferably, the monomer mixture comprises in the range of from 90% to 99.85% by weight of a C4 to C7 isomonoolefin monomer, in the range of from 0.1% to 5% by weight of a multifunctional cross-linking agent, and in the range of from 0.05% to 5% by weight of a chain-transfer agent. It will be apparent to the skilled in the art that the total of all monomers will result in 100% by weight. The monomer mixture may contain one or more additional polymerizable co-monomers, provided, of course, that they are copolymerizable with the other monomers in the monomer mixture. For example, the monomer mixture may contain a small amount of a styrenic monomer like p-methylstyrene, styrene, α-methylstyrene, p-chlorostyrene, p-methoxystyrene, indene (including indene derivatives) and mixtures thereof. If present, it is preferred to use the styrenic monomer in an amount of up to 5.0% by weight of the monomer mixture. The values of the C4 to C7 isomonoolefin monomer(s), and/or crosslinking agent, and/or chain-transfer agent will have to be adjusted accordingly to result again in a total of 100% by weight. The present invention is not restricted to a special process for preparing/polymerizing the monomer mixture. This type of polymerization is well known to the skilled in the art and usually comprises contacting the reaction mixture described above with a catalyst system. Preferably, the polymerization is conducted at a temperature conventional in the production of butyl polymers—e.g., in the range of from −100° C. to +50° C., more preferably at temperatures below −40° C., most preferable at temperatures below −50° C. The polymer may be produced by polymerization in solution or by a slurry polymerization method. Polymerization is preferably conducted in suspension (the slurry method)—see, for example, Ullmann's Encyclopedia of Industrial Chemistry (Fifth, Completely Revised Edition, Volume A23; Editors Elvers et al., 290-292). The inventive polymer preferably has a Mooney viscosity ML (1+8@125° C.) in the range of from 2 to 40 units, more preferably in the range of from 4 to 35 units. As an example, in one embodiment the polymerization is conducted in the presence of an inert aliphatic hydrocarbon diluent (such as n-hexane) and a catalyst mixture comprising a major amount (in the range of from 80 to 99 mole percent) of a dialcylaluminum halide (for example diethylaluminum chloride), a minor amount (in the range of from 1 to 20 mole percent) of a monoalkylaluminum dihalide (for example isobutylaluminum dichloride), and a minor amount (in the range of from 0.01 to 10 ppm) of at least one of a member selected from the group comprising water, aluminoxane (for example methylalurninoxane) and mixtures thereof. Of course, other catalyst systems conventionally used to produce butyl polymers can be used to produce a butyl polymer which is useful herein—see, for example, “Cationic Polymerization of Olefins: A Critical Inventory” by Joseph P. Kennedy (John Wiley & Sons, Inc. © 1975, 10-12). Polymerization may be performed both continuously and discontinuously. In the case of continuous operation, the process is preferably performed with the following three feed streams: I) solvent/diluent+isomonoolefin(s) (preferably isobutene) and optionally additional co-monomers, II) multifunctional cross-linking. agent(s) and chain-transfer agent(s), III) catalyst. In the case of discontinuous operation, the process may, for example, be performed as follows: The reactor, precooled to the reaction temperature, is charged with solvent or diluent and the monomers. The initiator is then pumped in the form of a dilute solution in such a manner that the heat of polymerization may be dissipated without problem. The course of the reaction may be monitored by means of the evolution of heat. The compound further comprises at least one active or inactive filler. The filler may be in particular: highly dispersed silicas, prepared e.g. by the precipitation of silicate solutions or the flame hydrolysis of silicon halides, with specific surface areas of in the range of from 5 to 1000 m2/g, and with primary particle sizes of in the range of from 10 to 400 nm; the silicas can optionally also be present as mixed oxides with other metal oxides such as those of Al, Mg, Ca, Ba, Zn, Zr and Ti; synthetic silicates, such as aluminum silicate and alkaline earth metal silicate like magnesium silicate or calcium silicate, with BET specific surface areas in the range of from 20 to 400 m2/g and primary particle diameters in the range of from 10 to 400 nm; natural silicates, such as kaolin and other naturally occurring silica; glass fibers and glass fiber products (matting, extrudates) or glass microspheres; metal oxides, such as zinc oxide, calcium oxide, magnesium oxide and aluminum oxide; metal carbonates, such as magnesium carbonate, calcium carbonate and zinc carbonate; metal hydroxides, e.g., aluminum hydroxide and magnesium hydroxide; carbon blacks; the carbon blacks to be used here are prepared by the lamp black, furnace black or gas black process and have preferably BET (DIN 66 131) specific surface areas in the range of from 20 to 200 m2/g, e.g., SAF, ISAF, HAF, EF or GPF carbon blacks; rubber gels, especially those based on polybutadiene, butadiene/styrene copolymers, butadiene/acrylonitrile copolymers and polychloroprene; or mixtures thereof. Examples of preferred mineral fillers include silica, silicates, clay such as bentonite, gypsum, alumina, titanium dioxide, talc, mixtures of these, and the like. These mineral particles have hydroxyl groups on their surface, rendering them hydrophilic and oleophobic. This exacerbates the difficulty of achieving good interaction between the filler particles and the tetrapolymer. For many purposes, the preferred mineral is silica, especially silica made by carbon dioxide precipitation of sodium silicate. Dried amorphous silica particles suitable for use in accordance with the invention may have a mean agglomerate particle size in the range of from 1 to 100 microns, preferably between 10 and 50 microns and most preferably between 10 and 25 microns. It is preferred that less than 10 percent by volume of the agglomerate particles are below 5 microns or over 50 microns in size. A suitable amorphous dried silica moreover usually has a BET surface area, measured in accordance with DIN (Deutsche Industrie Norm) 66131, of in the range of from 50 and 450 square meters per gram and a DBP absorption, as measured in accordance with DIN 53601, of in the range of from 150 and 400 grams per 100 grams of silica, and a drying loss, as measured according to DIN ISO 787/11, of in the range of from 0 to 10 percent by weight. Suitable silica fillers are available under the trademarks HiSil® 210, HiSil® 233 and HiSil® 243 from PPG Industries Inc. Also suitable are Vulkasil® S and Vulkasil® N, from Bayer AG. It might be advantageous to use a combination of carbon black and mineral filler in the inventive compound. In this combination the ratio of mineral fillers to carbon black is usually in the range of from 0.05 to 20, preferably 0.1 to 10. For the rubber composition of the present invention it is usually advantageous to contain carbon black in an amount of in the range of from 20 to 200 parts by weight, preferably 30 to 150 parts by weight, more preferably 40 to 100 parts by weight. The compound optionally further comprises at least one diluent. The diluent is intended to reduce the viscosity of the compound and preferably evaporates after the compound is in its final position. The term “diluent” expressly includes solvents of the polymer component or the whole compound. The invention is not limited to a special diluent. For example, aromatic or cyclic hydrocarbons such as toluene and cyclohexane or aliphatic hydrocarbons such as hexane are suitable. Preferred diluents for the polymer component are aliphatic and cyclic hydrocarbons. Usually the amount of diluent in the compound is in the range of from 0 to 200 phr (=per hundred rubber), preferably from 0 to 150 phr. In cases where the compound is intended for application as a hot-melt, there is little or preferably no diluent present in the compound. Even if it is not preferred, the compound may further comprise other natural or synthetic rubbers such as BR (polybutadiene), ABR (butadiene/acrylic acid-C1-C4-alkylester-copolymers), CR (polychloroprene), IR (polyisoprene), SBR (styrene/butadiene-copolymers) with styrene contents in the range of 1 to 60 wt %, NBR (butadiene/acrylonitrile-copolymers with acrylonitrile contents of 5 to 60 wt %, HNBR (partially or totally hydrogenated NBR-rubber), EPDM (ethylene/propylene/diene-copolymers), FKM (fluoropolymers or fluororubbers), and mixtures of the given polymers. The rubber composition according to the invention can contain further auxiliary products for rubbers, such as reaction accelerators, antioxidants, foaming agents, anti-aging agents, heat stabilizers, light stabilizers, ozone stabilizers, processing aids, plasticizers, tackifiers, blowing agents, dyestuffs, pigments, waxes, extenders, organic acids, inhibitors, metal oxides, and activators such as triethanolamine, polyethylene glycol, hexanetriol, etc., which are known to the rubber industry. The rubber aids are used in conventional amounts, which depend inter alia on the intended use. Conventional amounts are e.g. from 0.1 to 50 wt. %, based on rubber. Generally, the self-adhesive rubber composition according to the present invention does not contain tackifying agents. However, it may be advantageous for certain applications to use such tackifying agents. Petroleum resins are often used for this purpose. These resins are frequently produced by polymerization of a mixture of a distillate obtained by petroleum cracking that normally boils in the range from 25° C. to 80° C., and a monovinyl aromatic monomer with 8 to 9 carbon atoms in proportions such as to form a resin that contains 5 to 15 wt. % of the monovinyl aromatic compound measured by means of nuclear resonance analysis (NMR). The distillate obtained from the petroleum cracking comprises a mixture of saturated and unsaturated monomers, the unsaturated monomers being monoolefins and diolefins, and some higher and lower materials such as C6 olefins and diolefins may be present, although the unsaturated materials are predominantly C5 olefins. The distillate may also contain saturated or aromatic materials that may act as polymerization solvents. Further tackifying resins include terpene resins as well as those resins that are formed in the polymerization of unsaturated C5-C9 hydrocarbon monomers. Examples of commercially available resins based on a C5 olefin fraction of this type are the tackifying resins Wingtack™ 95 and 115 (Goodyear Tire and Rubber Co., Akron, Ohio). Other hydrocarbon resins include Regalrez™ 1078 and 1126 (Hercules Chemical Co. Inc., Wilmington, Del.), Arkon™ resins such as Arkon™ P115 (Arakawa Forest Chemical Industries, Chicago, Ill.) and Escorez™ resins (Exxon Chemical Co., Houston, Tex.). Suitable terpene resins include terpene polymers such as polymeric resin-containing materials that are obtained by the polymerization and/or copolymerization of terpene hydrocarbons such as alicyclic, monocyclic and bicyclic monoterpenes and their mixtures. Commercially available terpene resins include the Zonarezm terpene resins of the B Series and 7000 Series (Arizona Chemical Corp., Wayne, N.J.). The tackifying resin may be ethylenically unsaturated, although saturated tackifying resins are preferred for those applications in which resistance to oxidation is important. Also suitable are the coumarone-indene resins marketed by Rhein Chemie, Germany, under the trade name Rhenosin® (Rhenosin® types: C 10, C 30, C 90, C 100, C 110, C 120, C 150), hydrocarbon resins (Rhenosine types: TP 100, TT 10, TT 30, TT 90, TT 100, TD 90, TD 100, TD 110), phenolic resins (Rhenosin® types: P 9447 K, P 7443 K, P 6204 K) as well as bitumen resins (Rhenosin® types: 145 and 260). These resins are normally used in an amount in the range from 0.1 to 150 parts by weight per 100 parts of butyl polymer. The ingredients of the final compound are mixed together, suitably at an elevated temperature that may range from 25° C. to 200° C. Normally the mixing time does not exceed one hour and a time in the range from 2 to 30 minutes is usually adequate. The mixing is suitably carried out in a suitable mixing means, preferably an internal mixer such as a Banbury mixer, or a Haake or Brabender miniature internal mixer. A two roll mill mixer also provides a good dispersion of the additives within the elastomer. An extruder also provides good mixing, and permits shorter mixing times. It is possible to carry out the mixing in two or more stages, and the mixing can be done in different apparatus, for example one stage in an internal mixer and one stage in an extruder. However, it should be taken care that no unwanted pre-crosslinking (=scorch) occurs during the mixing stage. For compounding and vulcanization see also: Encyclopedia of Polymer Science and Engineering, Vol. 4, p. 66 et seq. (Compounding) and Vol. 17, p. 666 et seq. (Vulcanization). Furthermore, the invention provides a self-supporting shaped article comprising said compound optionally layered on or interposed between one or more supporting means. Self-supporting shaped articles without supporting means are 3-dimensional articles such as sheets, pellets, sticks, films or beads. Yet another aspect of the invention is a tape comprising said substantially gel-free compound optionally layered on or interposed between one or more supporting means. For this application, the inventive self-adhesive rubber composition is applied to the preferably primed surface of a suitable supporting means (i.e. substrate). As a rule the layer thickness of the rubber composition is in the range from 6 to 250 μm, in particular 10 to 100 μm. Preferred substrates are polyolefins such as LDPE, HDPE, PP, BOPP, polyurethanes, polyethylene terephthalates, PVC, ABS, polycarbonates, polyamides and polyesters. The priming material is, for example, a neutralized hydrogenated colophony. By priming the substrate with this composition, the adhesive remains firmly adherent to the latter, even after the substrate composite has been applied to a surface. The primer composition according to the present invention produces a highly polar surface to which the self-adhesive composition can adhere. Types of colophony that are suitable for the primer composition include polar colophony that contains acidic groups. Colophony that is at least partially hydrogenated is preferred. Commercially available colophony includes Foral™ AX hydrogenated colophony, Dresinol™ 205 colophony and Staybeliterm hydrogenated colophony (all from Hercules Chemical Co.), as well as Hypale™ colophony (Arakawa). Acid-containing colophony is highly polar and may be used in the present self-adhesive composition also as a surface-active agent and/or tackifying agent. However, this type of colophony is used as a primer in order to improve the adherence of the rubber composition to the substrate. In order to neutralize the acid-containing colophony, the latter is, for example, reacted with a solution of a basic compound that can form a metal salt on reaction with the colophony. Suitable bases include alkali metal hydroxides (e.g. LiOH, NaOH, KOH) and alkaline earth metal hydroxides (e.g. Ca(OH)2, Mg(OH)2). On account of their solubility properties, alkali metal hydroxides, in particular KOH and NaOH, are preferred. Such hydroxides may be dissolved in a polar solvent such as water. In order to react the colophony and the basic compound, both substances are as a rule dissolved in a solvent, preferably a polar solvent (because these compounds tend to exhibit polarity), most preferably water. The substances are then allowed to undergo an acid-base reaction. Since such reactions normally occur spontaneously, no special measures (for example elevated temperature or elevated pressure) are necessary, although they may be employed if desired. Normally stoichiometric amounts of colophony and base (or a slight excess of base) are used. The neutralized colophony may optionally be mixed with an elastomeric compound before being applied to the substrate. Preferably, the elastomeric compound is highly compatible with the organic part of the colophony and with a saturating agent used in the tape substrate. Also, the elastomer is preferably dispersible in water. Since many substrates that are available contain crepe paper saturated with an acrylate polymer or with a styrene-butadiene rubber (styrene-butadiene rubber=SBR) and since acrylates and SBRs are compatible with the organic part of most types of hydrogenated colophony, they are preferred types of elastomers. SBRs are known in the art and can be obtained from various suppliers. Common examples include Butofan™ NS209, NS222, NS 155 and NS248 rubber (BASF Corp., Parsippany, N.J. and Perbunan™ latices from Polymer Latex GmbH & Co. KG, Germany). Other suitable polymers include nitrile rubber such as the Hycar™ polymer series (B.F. Goodrich Co., Akron, Ohio) and (meth)acrylate polymers. Also suitable as elastomers are carboxylated NBR, HNBR and liquid NBR types, for example Therban® VBKA 8889, Krynac® K.X. 7.40, K.X. 7.50, K.X. 90 and K.E. 34.38 from Bayer AG. A mixture of a rubber-based emulsion polymer, a colophony-based surface-active agent and a colophony-based tackifying agent is described in U.S. Pat. No. 5,385,965 (Bernard, et al.). The list of suitable rubber-based polymers includes carboxylated statistical styrene-butadiene copolymers. Foral™ AX colophony compounds are included in the list of suitable tackifying resins. If an elastomeric component together with a neutralized colophony is used in the primer, the two components may be mixed in any ratio in the range from 0.01:99.99 to 75:25, though a ratio of 50:50 (by weight) is preferred. (Other ranges are also suitable depending on the coating process that is employed.) The mixing is effected simply by adding the elastomer to the neutralized aqueous colophony mixture. The mixture can then be diluted to a desired concentration for coating. Preferred concentrations are in the range from 5 to 25 wt. %, more preferably in the range from 10 to 20 wt. %. A preferred primer composition for a tape substrate saturated with SBR may be produced by neutralizing Foral™ AX colophony with an approximately stoichiometric amount of a strong base (for example an aqueous solution of KOH) in water at elevated temperature (e.g. 88° C.). After the neutralized colophony mixture has been removed from the heat source, it is combined with an approximately equal amount (by weight) of Butofan™ NS209 SBR and the resulting mixture is diluted in water to a solids content of about 15%. Also preferred are priming compositions with a minor amount of double bonds, such as ethylene-vinyl acetate copolymers with vinyl acetate contents below 40 wt. %, ethylene-α-olefin copolymers or ethylene-α-olefin-diene terpolymers. The priming composition and/or the self-adhesive composition can be applied to a substrate (for example a tape substrate) by many different methods, including solvent coating, solvent spraying, emulsion coating, low pressure coating or other processes known to the person skilled in the art. Suitable substrates include polyolefin films (e.g. polyethylene and polypropylene films), in particular corona-treated polyolefin films, and paper saturated with elastomer. The suitable coating weight is in the range from 0.1 to 5 mg/cm2, preferably from 0.2 to 1.0 mg/cm2, and more preferably from 0.3 to 0.5 mg/cm2. When the priming layer has been applied to a substrate, it is then preferably dried. This drying preferably takes place at elevated temperature, under reduced pressure, or both. A further preferred method for the production of coated substrates is co-extrusion coating, which is normally carried out in a coating device with a melt film of the self-adhesive composition that is melted in an extruder and is applied via a flat-sheeting die to a substrate that may consist of one or more polymer layers. The composite that is thereby formed is then cooled in a cooling/press roll unit and smoothed. The composite strip material is then coiled in a corresponding coiling machine. In the furthermore preferred lamination process the procedures of application of the coating composition to the carrier strip, smoothing and cooling, and stripping and coiling are carried out in a similar manner to the coating process. In the actual extrusion lamination, a prefabricated carrier strip is fed into a calender roll frame with 4 rollers. In this case, the carrier strip is coated before the first roller gap with a melt film that is melted in an extruder and applied via a flat-sheeting die. A second prefabricated strip is fed in before the second roller gap. The composite material that is, thereby formed, is smoothed on passing through the second roller gap, then cooled, stripped, and coiled in a coiling unit. These so-called cast films may be pretreated to improve the range of the composite bonding (carrier film/self-adhesive composition). The PO carrier film is typically either subjected to a corona oxidation or is coated with a silicone layer. According to the furthermore preferred blowing/flat-sheeting die extrusion process, the inventive composition in dry form and various polymers are generally first of all melted in different extruders under suitable conditions and are then combined in the form of melt streams with the formation of a multilayer melt stream in the extrusion apparatus. This is followed by the discharge, stripping and cooling of the multilayer molten strip containing the self-adhesive composition and the coiling of the composite material. A composite film is obtained in this way. The flat-sheeting die extrusion process is preferably employed in this connection. Suitable polymers for these processes include, in particular, thermoplastics such as, for example, polyamides, polystyrene, polyesters, polycarbonates or polyolefins. Polyolefins are preferably used, for example ethylene homopolymers, propylene homopolymers or statistical propylene-ethylene copolymers. The production of such polyolefins may be carried out by conventional types of polymerization known to the person skilled in the art, for example by Ziegler-Natta polymerization, by polymerization with the aid of Phillips catalysts, by high pressure polymerization or by polymerization with the aid of metallocene-containing catalysts. The coating/extrusion processes are as a rule carried out at temperatures in the range from 170° C. to 300° C., pressures of 250 to 400 bar, and mean transit times of 5 to 20 minutes. Since the copolymers in the melt and in the film have a high tendency to stick to all contact surfaces, it may be advantageous to coat the rollers used for the production of the composites as well as the stripping rollers with a material that is anti-adhesive with respect to the copolymers, for example with polytetrafluoroethylene. In this way appropriate strip tensions for the satisfactory coiling of the composite materials can, for example, be maintained. The films coated with self-adhesive composition that are obtained in this way can advantageously be used in the coating of glass, wood, ceramics, production of floor coverings or all types of lacquered articles, such as metal, alloys, as well as plastics such as polycarbonate, polyamide, polyester and ABS. Generally such applications are those in which high quality surfaces have to be protected for a certain time. Yet another aspect of the invention is an adhesive composition comprising said substantially gel-free compound, in particular a hot-melt system. Yet another aspect of the invention is a sealant composition comprising said substantially gel-free compound in particular a hot-melt system. The hot melt system is preferably a 100% solids system, where the composition is usually provided in small particles, such as pellets or another shaped article, such as a stick. The shaped article is heated to the softening temperature, preferably 200-215° C., by a suitable means and applied on or between the materials to seal or glue. It might be advantageous to cover the shaped articles with a powdering substance such as a polyolefin powder in order to reduce the tackiness of the shaped article and to ensure that the articles won't stick together after transport to the customer. Self-supporting shaped articles, such as tapes are especially useful in architectural work and for insulating glass sealing. Hot melt systems comprising the inventive compound are especially useful as insulation sealants for glass windows and doors. Further areas of application include: building/construction, bridges, roads, transport, woodworking and wood bonding, bookbinding, graphic industry, packaging industry, disposable articles, laminates, shoe manufacture, end customer adhesive applications, and in the sealant and insulating industry. The compound of the invention is permanently tacky, remains flexible, and is especially recommended for internal or non-exposed applications. The present invention will be further illustrated by the following examples. EXAMPLES Methyl chloride (Dow Chemical) serving as a diluent for polymerization and isobutylene monomer (Matheson, 99%) were transferred into a reactor by condensing a vapor phase. Aluminum chloride (99.99%), isoprene (99%) and 2,4,4-trimethyl-1-pentene (99%) were from Aldrich. The inhibitor was removed from isoprene by using an inhibitor removing disposable column from Aldrich. Commercial divinylbenzene (ca. 64%) was from Dow Chemical. The Mooney viscosity test was carried out according to ASTM standard D-1646 on a Monsanto MV 2000 Mooney Viscometer. The solubility of a polymer was determined after the sample refluxed in cylohexane over 60-minute period. The stickness (adhesion) of the polymer was measured using a Tel-Tak apparatus (Monsanto Company, Model TT-1). The test measured a force to separate a specimen from the metal surface (a polished stainless steel). The specimens were cut into ¼″×2″ strips reinforced with fabric backing. They were placed in the instrument at a right angle to the metal strip thus defining the area of contact. The contact time was 30 sees and the contact pressure was 16 ounces. A small gear motor provided 1 inch/minute movement of the lower platen automatically when the dwell time interval was completed. The force to separate the two surfaces was measured by a force gauge with a built-in stop that left the pointer at the maximum reading. Example 1 Comparative A sample of commercial XL-10000 terpolymer was tested. The Mooney viscosity of the rubber was 61.2 units (ML 1′+8′@ 125° C.) and the content of a soluble fraction was 24.7 wt. %. The force to separate a rubber specimen from stainless steel in a Tel-Tak test was 3 lb/in2. Example 2 Comparative A sample of commercial butyl rubber Bayer® Butyl 301 was tested. The Mooney viscosity of the rubber was 51.0 units (ML 1′+8′@ 125° C.) and the rubber was totally soluble in cyclohexane. The force to separate a rubber specimen from stainless steel in a Tel-Tak test was 11 lb/in2. Example 3 To a 50 mL Erlenmeyer flask, 0.45 g of AlCl3 was added, followed by 100 mL of methyl chloride at −30° C. The resulting solution was stirred for 30 min at −30° C. and then cooled down to −95° C., thus forming the catalyst solution. To a 2000 mL glass reactor equipped with an overhead stirrer, 900 mL of methyl chloride at −95° C. were added, followed by 120.0 mL isobutylene at −95° C. and 2.0 mL of commercial DVB at room temperature. Also, 2.25 mL of 2,4,4-trimethyl-1-pentene was added to the reaction feed. The reaction mixture was cooled down to −95° C. and 10.0 mL of the catalyst solution was used to start the reaction. The reaction was carried out in MBRAUN® dry box under the atmosphere of dry nitrogen. The reaction was terminated after 10 minutes by adding into the reaction mixture 10 mL of ethanol containing some sodium hydroxide. The obtained polymer was steam coagulated and dried on a 6″×12″ mill at ca. 105° C. followed by drying in a vacuum oven at 50° C. to a constant weight. The yield of the reaction was 87.4%. The Mooney viscosity of the rubber was 4.5 units (ML 1′+8′@ 125° C.) and the content of a soluble fraction was 99.0 wt. %. The force to separate a rubber specimen from stainless steel in a Tel-Tak test was 24 lb/in2.

<SOH> BACKGROUND OF THE INVENTION <EOH>Butyl rubber is known for its excellent insulating and gas barrier properties. Generally, commercial butyl polymer is prepared in a low temperature cationic polymerization process using Lewis acid-type catalysts, of which a typical example is aluminum trichloride. The process used most extensively employs methyl chloride as the diluent for the reaction mixture and the polymerization is conducted at temperatures on the order of less than −90° C., resulting in production of a polymer in a slurry of the diluent. Alternatively, it is possible to produce the polymer in a diluent which acts as a solvent for the polymer (e.g., hydrocarbons such as pentane, hexane, heptane and the like). The product polymer may be recovered using conventional techniques in the rubber manufacturing industry. Adhesives (glues) are substances capable of forming and maintaining a bond between two surfaces, and sealants (caulks) are substances used to fill gaps or joints between two materials to prevent the passage of liquids, solids or gases. These two classes of materials are often considered together because quite frequently a given formulation performs the both functions. Butyl sealants are available as one-component solvent evaporation curing products and as thermoplastic hot melts. There is no curing process, the compound gets its functionality through solvent loss and/or a decrease in temperature. When a sealant is applied, the solvent evaporates or migrates into porous substrates and the tough, rubbery compound is left in place. This is in contrast to other sealant types that cure chemically. It is known to use a commercial pre-cross-linked butyl rubber such as commercially available Bayer® XL-10000 (or, formerly XL20 and XL-50) that will add additional strength to the sealant/adhesive. XL-10000 is partially cross-linked with divinylbenzene already in the polymerization stage. While said commercial pre-cross-linked polymers exhibit excellent properties in many applications, they have a gel content of at least 50 wt. % which sometimes makes the even dispersion of fillers and additives normally used during compounding difficult. This increases the likelihood of inhomogeneous areas within the rubbery article, rendering its physical properties inferior and unpredictable. Also, the Mooney viscosity of this rubber is high, usually 60-70 units (1′+8′@125° C.) which may cause significant processing difficulties, especially in a mixing stage. Processability-improving polymers are often added to the pre-cross-linked butyl rubber to overcome some of these problems. Such polymers are particularly useful for improving the mixing or kneading property of a rubber composition. They include natural rubbers, synthetic rubbers (for example, IR, BR, SBR, CR, NBR, IIR, EPM, EPDM, acrylic rubber, EVA, urethane rubber, silicone rubber, and fluororubber) and thermoplastic elastomers (for example, of styrene, olefin, vinyl chloride, ester, amide, and urethane series). These processability-improving polymers may be used in the amount of up to 100 parts by weight, preferably up to 50 parts by weight, and most preferably up to 30 parts by weight, per 100 parts by weight of a partially cross-linked butyl rubber. However, the presence of other rubbers dilutes desirable properties of butyl rubber. RU 2,130,948 discloses the copolymerization of isobutylene with DVB in an aromatic or aliphatic hydrocarbon solvent initiated with a system comprising TiCl 4 and triisobutylaluminum. The content of DVB in the monomer feed was 0.1 to 5.0 wt. %, based on isobutylene. The process was carried out in the temperature range −40 to +40° C. The products had low molecular weights (M v <15,000 g/mol) and were useful as a source for preparing glues. In one example, the process was carried out at +40° C. and the viscosity average molecular weight of the polymer was about 5400 g/mol. This is different from the process described in the present invention, where a typical polymerization temperature was −95° C. and the viscosity average molecular weight of the product was above 200,000 g/mol. The above application did not involve the presence of a chain-transfer agent in the monomer feed during polymerizations. Co-Pending Canadian Application CA-2,316,741 discloses terpolymers of isobutylene, isoprene, divinyl benzene (DVB) prepared in the presence of a chain-transfer agent, such as diisobutylene, which are substantially gel-free and have an improved processability. However, the above application is silent about applications for sealants and adhesives. Co-Pending Canadian Application CA 2,386,628 discloses peroxide curable compounds comprising terpolymers of isobutylene, isoprene, divinyl benzene (DVB) prepared in the presence of a chain-transfer agent, such as diisobutylene, which are substantially gel-free and have an improved processability but is also silent about compounds for sealants/adhesives. In the above two applications, an aliphatic conjugated diene, like isoprene, was an integral part of the compounds.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a substantially-gel free compound comprising: a. at least one elastomeric polymer without any conjugated aliphatic diene in its composition having an average molecular weight M n of more than 20,000 g/mol and comprising repeating units derived from at least one C 4 to C 7 isomonoolefin monomer and at least one multiolefin cross-linking agent and at least one chain transfer agent, said polymer containing less than 15 wt. % of solid matter insoluble in boiling cyclohexane under reflux for 60 min, b. at least one filler and c. optionally at least one diluent especially useful for the manufacture of shaped articles for sealants and/or adhesives. Another aspect of the invention is a self-supporting shaped article comprising said compound optionally layered on or interposed between one or more supporting means. Yet another aspect of the invention is a tape comprising said substantially gel-free compound optionally layered on or interposed between one or more supporting means. Yet another aspect of the invention is an adhesive composition comprising said substantially gel-free compound. Yet another aspect of the invention is a sealant composition comprising said substantially gel-free compound. detailed-description description="Detailed Description" end="lead"?

20070323

20081118

20071129

69801.0

C08K300

SCOTT, ANGELA C

ADHESIVE COMPOUNDS OF BUTYL-TYPE RUBBER

UNDISCOUNTED

ACCEPTED

C08K

ACCEPTED

Pixel circuit, display device, and method of driving pixel circuit

A pixel circuit, a display device, and a method of driving a pixel circuit able to obtain a source-follower output without luminance deterioration even when the current-voltage characteristic of a light emitting element changes due to aging, making a source-follower circuit of n-channel transistors possible, and in addition able to display uniform and high quality images not without regard to variations of threshold values and mobilities of the active elements inside pixels, wherein a capacitor C111 is connected between a gate and a source of a TFT 111, the source side of the TFT 111 is connected to a fixed potential (GND) through a TFT 114, a predetermined reference current Iref is supplied to the source of the TFT 111 with a predetermined timing, a voltage corresponding to the reference current Iref is held, and an input signal voltage centered about the voltage is coupled, whereby an EL light emitting element 19 is driven centered about the center value of variation of the mobilities.

1. A pixel circuit for driving an electro-optical element changing in luminance according to a flowing current, comprising: a data line to which a data signal in accordance with a luminance information is supplied; first, second, third, and fourth nodes; first and second reference potentials; a reference current supplying means for supplying a predetermined reference current; an electric connecting means connected to the second node; a pixel capacitor element connected between the first node and the second node; a coupling capacitor element connected between the electric connecting means and the fourth node; a drive transistor forming a current supply line between a first terminal and a second terminal and controlling a current flowing in the current supply line in accordance with the potential of the control terminal connected to the second node; a first switch connected between the first node and the third node; a second switch connected between the third node and the fourth node; a third switch connected between the first node and a fixed potential; a fourth switch connected between the second node and a predetermined potential line; a fifth switch connected between the data line and the fourth switch; and a sixth switch connected between the third node and the reference current supplying means, wherein, between the first reference potential and the second reference potential, the current supply line of the drive transistor, the first node, the third node, the first switch, and the electro-optical element are connected in series. 2. A pixel circuit as set forth in claim 1, wherein the electric connecting means includes an interconnect for directly connecting the second node and the coupling capacitor element. 3. A pixel circuit as set forth in claim 1, wherein the electric connecting means includes a seventh switch selectively connecting the second node and the coupling capacitor element. 4. A pixel circuit as set forth in claim 1, further including: a seventh switch connected between the first node and the electro-optical element and an eighth switch connected between the first node and the data line. 5. A pixel circuit as set forth in claim 1, further including: a seventh switch connected between the first node and the electro-optical element and an eighth switch connected between the first node and the fourth node. 6. A pixel circuit as set forth in claim 3, further including: a seventh switch connected between the first node and the electro-optical element and an eighth switch connected between the first node and the data line. 7. A pixel circuit as set forth in claim 3, further including: a seventh switch connected between the first node and the electro-optical element and an eighth switch connected between the first node and the fourth node. 8. A pixel circuit as set forth in claim 1, wherein the predetermined potential line is shared together with the data line. 9. A pixel circuit as set forth in claim 1, wherein the drive transistor is a field effect transistor, a source is connected to the third node, and a drain is connected to the first reference potential. 10. A pixel circuit as set forth in claim 2, wherein, when the electro-optical element is driven, as a first stage, in a state where the first, second, fourth, fifth, and sixth switches are held in a non-conductive state, the third switch is held in the conductive state and the first node is connected to a fixed potential; as a second stage, the second, fourth, and sixth switches are held in the conductive state, a predetermined potential is input to the second node, the reference current flows in the third node, and the predetermined potential is charged in the pixel capacitor element; as a third stage, the second and sixth switches are held in the non-conductive state, further the fourth switch is held in the non-conductive state, the fifth switch is held in the conductive state, the data propagated through the data line is input to the second node, then the fifth switch is held in the non-conductive state; and as a fourth stage, the first switch is held in the conductive state, and the third switch is held in the non-conductive state. 11. A pixel circuit as set forth in claim 3, wherein, when the electro-optical element is driven, as a first stage, in a state where the first, second, fourth, fifth, sixth, and seventh switches are held in the non-conductive state, the third switch is held in the conductive state, and the first node is connected to the fixed potential; as a second stage, the second, fourth, sixth, and seventh switches are held in the conductive state, the data potential propagated through the data line is input to the second node, the reference current flows in the third node, and a predetermined potential is charged in the pixel capacitor element; as a third stage, the second and sixth switches are held in the non-conductive state, further the fourth switch is held in the non-conductive state, the fifth switch is held in the conductive state, the data propagated through the data line is input to the second node via the fourth node, then the fifth and seventh switches are held in the non-conductive state; and as a fourth stage, the first switch is held in the conductive state, and the third switch is held in the non-conductive state. 12. A display device comprising: a plurality of pixel circuits arranged in a matrix; data lines interconnected for each column of a matrix array of the pixel circuits and supplied with a data signal in accordance with the luminance information; first and second reference potentials; and a reference current supplying means for supplying a predetermined reference current, wherein the pixel circuit has: an electro-optical element changing in luminance according to a flowing current; first, second, third, and fourth nodes; an electric connecting means connected to the second node; a pixel capacitor element connected between the first node and the second node; a coupling capacitor element connected between the electric connecting means and the fourth node; a drive transistor forming a current supply line between a first terminal and a second terminal and controlling a current flowing in the current supply line in accordance with the potential of the control terminal connected to the second node; a first switch connected between the first node and the third node; a second switch connected between the third node and the fourth node; a third switch connected between the first node and a fixed potential; a fourth switch connected between the second node and a predetermined potential line; a fifth switch connected between the data line and the fourth switch; and a sixth switch connected between the third node and the reference current supplying means, and, between the first reference potential and the second reference potential, the current supply line of the drive transistor, the first node, the third node, the first switch, and the electro-optical element are connected in series. 13. A method for driving a pixel circuit having an electro-optical element changing in luminance according to a flowing current; a data line to which a data signal in accordance with luminance information is supplied; first, second, third, and fourth nodes; first and second reference potentials; a reference current supplying means for supplying a predetermined reference current; an electric connecting means connected to the second node; a pixel capacitor element connected between the first node and the second node; a coupling capacitor element connected between the electric connecting means and the fourth node; a drive transistor forming a current supply line between a first terminal and a second terminal and controlling a current flowing in the current supply line in accordance with the potential of the control terminal connected to the second node; a first switch connected between the first node and the third node; a second switch connected between the third node and the fourth node; a third switch connected between the first node and a fixed potential; a fourth switch connected between the second node and a predetermined potential line; a fifth switch connected between the data line and the fourth switch; and a sixth switch connected between the third node and the reference current supplying means, wherein the current supply line of the drive transistor, the first node, the third node, the first switch, and the electro-optical element are connected in series between the first reference potential and the second reference potential, comprising steps of holding the third switch in the conductive state and connecting the first node to a fixed potential in the state where the first, second, fourth, fifth, and sixth switches are held in the non-conductive state; holding the second, fourth, and the sixth switches in the conductive state and inputting the predetermined potential to the second node, sending the reference current in the third node, and charging the predetermined potential in the pixel capacitor element; holding the second and sixth switches in the non-conductive state, and further holding the fourth switch in the non-conductive state, holding the fifth switch in the conductive state and inputting the data propagated through the data line to the second node, then holding the fifth switch in the non-conductive state; and holding the first switch in the conductive state and holding the third switch in the non-conductive state.

TECHNICAL FIELD The present invention relates to a pixel circuit having an electro-optical element controlled in luminance by a current value in an organic EL (electroluminescence) display etc., more particularly, among image display devices in which these pixel circuits are arranged in a matrix, a so-called active matrix type image display device in which the value of the current flowing in each electro-optical element is controlled by an insulating gate type field effect transistor provided inside each pixel circuit, and a method of driving the pixel circuit. BACKGROUND ART In an image display device, for example, a liquid crystal display etc., the image is displayed by arranging a large number of pixels in a matrix and controlling the intensity of light for each pixel in accordance with image information to be displayed. The same is also true for an organic EL display etc., but an organic EL display is a so-called self light emission type display having a light emitting element in each pixel circuit and has the advantages that the viewability of the image is high in comparison with a liquid crystal display, no backlight is necessary, the response speed is fast, and so on. Further, this is very different from a liquid crystal display in the point that the luminance of each light emitting element can be controlled by the value of the current flowing through it so as to obtain scales of color, that is, each light emitting element is a current controlled type. In an organic EL display, in the same way as a liquid crystal display, the simple matrix system and the active matrix system are possible as the method for driving the same. The former is simple in structure, but has the problems that realization of a large sized and high definition display is difficult and so on, therefore there has been much development work on the active matrix system for controlling the current flowing in the light emitting element inside each pixel circuit by an active element provided inside the pixel circuit, generally a TFT (thin film transistor). FIG. 1 is a block diagram showing the configuration of a general organic EL display device. This display device, as shown in FIG. 1, has a pixel array 2 comprised of pixel circuits (PXLC) 2a arranged in an m×n matrix, a horizontal selector (HSEL) 3, a write scanner (WSCN) 4, data lines DTL1 to DTLn selected by the horizontal selector 3 and supplied with data signals in accordance with the luminance information, and scanning lines WSL1 to WSLm selected and driven by the write scanner 4. Note that the horizontal selector 3 and the write scanner 4 are sometimes formed on polycrystalline silicon or formed on the periphery of the pixels by MOSIC etc. FIG. 2 is a circuit diagram showing an example of the configuration of the pixel circuit 2a of FIG. 1 (see for example Patent Documents 1 and 2). The pixel circuit of FIG. 2 has the simplest circuit configuration among the large number of circuits proposed and is a circuit of the so-called two-transistor drive system. The pixel circuit 2a of FIG. 2 has a p-channel thin film field effect transistor (hereinafter referred to as an TFT) 11 and TFT 12, a capacitor C11, and a light emitting element constituted by an organic EL element (OLED) 13. Further, in FIG. 42, DTL indicates the data line, and WSL indicates the scanning line. The organic EL element has a rectification property in many cases, so sometimes is called an OLED (organic light emitting diode). The symbol of a diode is used as the light emitting element in FIG. 2 and other figures, but a rectification property is not always required for the OLED in the following explanation. In FIG. 2, a source of the TFT 11 is connected to a power supply potential VCC, and a cathode of the light emitting element 13 is connected to a ground potential GND. The operation of the pixel circuit 2a of FIG. 2 is as follows. Step ST1: When the scanning line WSL is in a selected state (low level here) and a write potential Vdata is supplied to the data line DTL, the TFT 12 becomes conductive and the capacitor C11 is charged or discharged, and a gate potential of the TFT 11 becomes Vdata. Step ST2: When the scanning line WSL is in a non-selected state (high level here), the data line DTL and the TFT 11 are electrically disconnected, but the gate potential of the TFT 11 is held stably by the capacitor C11. Step ST3: The current flowing in the TFT 11 and the light emitting element 13 becomes a value in accordance with a voltage Vgs between the gate and source of the TFT 11, and the light emitting element 13 continuously emits light with a luminance in accordance with the current value. As in above step ST1, the operation of selecting the scanning line WSL and transferring the luminance information given to the data line to the inside of the pixel will be called “writing” below. As explained above, in the pixel circuit 2a of FIG. 2, when once writing the Vdata, during the period up to when next rewriting the data, the light emitting element 13 continues emitting light with a constant luminance. As explained above, in the pixel circuit 2a, by changing the gate voltage of the drive transistor constituted by the TFT 11, the value of the current flowing in the EL light emitting element 13 is controlled. At this time, the source of the p-channel drive transistor of is connected to a power supply potential VCC, so this TFT 11 is constantly operating in the saturated region. Accordingly, it becomes a constant current source having a value shown in the following equation 1. (Equation 1) Ids=½·μ(W/L)Cox(Vgs−|Vth|)2 (1) Here, μ indicates the mobility of a carrier, Cox indicates a gate capacitance per unit area, W indicates a gate width, L indicates a gate length, Vgs indicates a gate-source voltage of the TFT 11, and Vth indicates a threshold value of the TFT 11. In a simple matrix type image display device, each light emitting element emits light only at an instant when it is selected, but in contrast, in an active matrix, as explained above, the light emitting element continues emitting light even after the end of writing, therefore this becomes advantageous especially in a large sized and high definition display in the point that a peak luminance and a peak current of the light emitting element can be lowered in comparison with the simple matrix. FIG. 3 is a diagram showing aging of the 10 current-voltage (I-V) characteristic of an organic EL element. In FIG. 3, the curve indicated by a solid line indicates the characteristic at the time of an initial state, and the curve indicated by a broken line indicates the characteristic after the aging. In general, the I-V characteristic of the organic EL element deteriorates when time passes as shown in FIG. 3. However, the two-transistor drive of FIG. 2 is a constant current drive, therefore a constant current continuously flows in the organic EL element as explained above. Even when the I-V characteristic of the organic EL element deteriorates, the light emission luminance thereof will not deteriorate by aging. The pixel circuit 2a of FIG. 2 is configured by a p-channel TFT, but if it could be configured by an n-channel TFT, it would become possible to use a usual amorphous silicon (a-Si) process in TFT fabrication. By this, a reduction of the cost of the TFT substrate would become possible. Next, a pixel circuit replacing the transistor by an n-channel TFT will be considered. FIG. 4 is a circuit diagram showing a pixel circuit replacing the p-channel TFT of the circuit of FIG. 2 by an n-channel TFT. A pixel circuit 2b of FIG. 4 has an n-channel TFT 21 and TFT 22, a capacitor C21, and a light emitting element constituted by an organic EL element (OLED) 23. Further, in FIG. 4, DTL indicates the data line, and WSL indicates the scanning line. In this pixel circuit 2b, a drain side of the drive transistor constituted by the TFT 21 is connected to the power supply potential VCC, and the source is connected to an anode of the EL element 23 to thereby form a source-follower circuit. FIG. 5 is a diagram showing operation points of the drive transistor constituted by the TFT 21 and the EL element 23 in the initial state. In FIG. 5, an abscissa indicates a drain/source voltage Vds of the TFT 21, and an ordinate indicates a drain/source current Ids. As shown in FIG. 5, the source voltage is determined by the operation points of the drive transistor constituted by the TFT 21 and the EL element 23. The voltage thereof has a different value according to the gate voltage. This TFT 21 is driven in a saturated region, therefore a current Ids having a current value shown in the above equation 1 flows concerning Vgs with respect to the source voltage of the operation point. Patent Document 1: U.S. Pat. No. 5,684,365 Patent Document 1: Japanese Patent Publication (A) No. 8-234683 DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention However, here as well, the I-V characteristic of the El element deteriorates in the same way by aging. As shown in FIG. 6, the operation point fluctuates by this aging deterioration, therefore, even when the same gate voltage is applied, the source voltage fluctuates. Due to this, the gate/source voltage Vgs of the drive transistor constituted by the TFT 21 changes, and the value of flowing current fluctuates. Simultaneously, the value of the current flowing in the EL element 23 changes, therefore, when the I-V characteristic of the EL element 23 deteriorates, in the source-follower circuit of FIG. 4, the light emission luminance changes by aging. Further, as shown in FIG. 7, a circuit configuration connecting the source of the drive transistor constituted by the n-channel TFT 31 to the ground potential GND, connecting the drain to the cathode of the EL element 33, and connecting the anode of the EL element 33 to the power supply potential VCC can be considered. With this system, in the same way as a drive operation by the p-channel TFT of FIG. 2, the potential of the source is fixed. Therefore, the drive transistor constituted by the n-channel TFT 31 operates as the constant current source and can prevent a change in luminance due to the deterioration of the I-V characteristic of the EL element 33. With this system, however, it is necessary to connect the drive transistor to the cathode side of the EL element. This cathode connection requires new development of the anode/cathode electrodes. This is considered to be very difficult by the current art. From the above, in the usual, an organic EL element using an n-channel transistor not changing in luminance has not yet been developed. Further, even developing an organic EL element using an n-channel transistor not changing in luminance, the TFT transistor is generally characterized in that the variations of mobility g and threshold values Vth are large, therefore even when a voltage having the same value is supplied to the gate of the drive transistor, the current value varies for each pixel according to the mobility μ and threshold value Vth of the drive transistor, so a uniform image quality cannot be obtained. An object of the present invention is to provide a pixel circuit in which a source-follower output free from luminance deterioration can be obtained even when the current-voltage characteristic of a light emitting element changes by aging, a source-follower circuit of an n-channel transistor becomes possible, an n-channel transistor can be used as the drive element of the optical element by using current anode/cathode electrodes as they are, and uniform, high quality images can be displayed without regard as to variations of threshold values and mobilities of the active elements inside the pixel, a display device, and a method of driving a pixel circuit. Means for Solving the Problem To achieve the above object, according to a first aspect of the present invention, there is provided a pixel circuit for driving an electro-optical element changing in luminance according to a flowing current, comprising a data line to which a data signal in accordance with a luminance information is supplied; first, second, third, and fourth nodes; first and second reference potentials; a reference current supplying means for supplying a predetermined reference current; an electric connecting means connected to the second node; a pixel capacitor element connected between the first node and the second node; a coupling capacitor element connected between the electric connecting means and the fourth node; a drive transistor forming a current supply line between a first terminal and a second terminal and controlling a current flowing in the current supply line in accordance with the potential of the control terminal connected to the second node; a first switch connected between the first node and the third node; a second switch connected between the third node and the fourth node; a third switch connected between the first node and a fixed potential; a fourth switch connected between the second node and a predetermined potential line; a fifth switch connected between the data line and the fourth switch; and a sixth switch connected between the third node and the reference current supplying means, wherein, between the first reference potential and the second reference potential, the current supply line of the drive transistor, the first node, the third node, the first switch, and the electro-optical element are connected in series. Preferably, the electric connecting means includes an interconnect for directly connecting the second node and the coupling capacitor element. Preferably, the electric connecting means includes a seventh switch selectively connecting the second node and the coupling capacitor element. Preferably, it includes a seventh switch connected between the first node and the electro-optical element and an eighth switch connected between the first node and the data line. Alternatively, it includes a seventh switch connected between the first node and the electro-optical element and an eighth switch connected between the first node and the fourth node. Preferably, the predetermined potential line is shared together with the data line. Further, the drive transistor is a field effect transistor, a source is connected to the third node, and a drain is connected to the first reference potential. Preferably, when the electro-optical element is driven, as a first stage, in a state where the first, second, fourth, fifth, and sixth switches are held in a non-conductive state, the third switch is held in the conductive state and the first node is connected to a fixed potential; as a second stage, the second, fourth, and sixth switches are held in the conductive state, a predetermined potential is input to the second node, the reference current flows in the third node, and the predetermined potential is charged in the pixel capacitor element; as a third stage, the second and sixth switches are held in the non-conductive state, further the fourth switch is held in the non-conductive state, the fifth switch is held in the conductive state, the data propagated through the data line is input to the second node, then the fifth switch is held in the non-conductive state; and as a fourth stage, the first switch is held in the conductive state, and the third switch is held in the non-conductive state. Alternatively, preferably, when driving the electro-optical element, as a first stage, in a state where the first, second, fourth, fifth, sixth, and seventh switches are held in the non-conductive state, the third switch is held in the conductive state, and the first node is connected to the fixed potential; as a second stage, the second, fourth, sixth, and seventh switches are held in the conductive state, the data potential propagated through the data line is input to the second node, the reference current flows in the third node, and a predetermined potential is charged in the pixel capacitor element; as a third stage, the second and sixth switches are held in the non-conductive state, further the fourth switch is held in the non-conductive state, the fifth switch is held in the conductive state, the data propagated through the data line is input to the second node via the fourth node, then the fifth and seventh switches are held in the non-conductive state; and as a fourth stage, the first switch is held in the conductive state, and the third switch is held in the non-conductive state. According to a second aspect of the present invention, there is provided a display device comprising a plurality of pixel circuits arranged in a matrix; data lines interconnected for each column of a matrix array of the pixel circuits and supplied with a data signal in accordance with the luminance information; first and second reference potentials; and a reference current supplying means for supplying a predetermined reference current, wherein the pixel circuit has an electro-optical element changing in luminance according to a flowing current; first, second, third, and fourth nodes; an electric connecting means connected to the second node; a pixel capacitor element connected between the first node and the second node; a coupling capacitor element connected between the electric connecting means and the fourth node; a drive transistor forming a current supply line between a first terminal and a second terminal and controlling a current flowing in the current supply line in accordance with the potential of the control terminal connected to the second node; a first switch connected between the first node and the third node; a second switch connected between the third node and the fourth node; a third switch connected between the first node and a fixed potential; a fourth switch connected between the second node and a predetermined potential line; a fifth switch connected between the data line and the fourth switch; and a sixth switch connected between the third node and the reference current supplying means, and, between the first reference potential and the second reference potential, the current supply line of the drive transistor, the first node, the third node, the first switch, and the electro-optical element are connected in series. According to a third aspect of the present invention, there is provided a method for driving a pixel circuit having an electro-optical element changing in luminance according to a flowing current, a data line to which a data signal in accordance with luminance information is supplied; first, second, third, and fourth nodes; first and second reference potentials; a reference current supplying means for supplying a predetermined reference current; an electric connecting means connected to the second node; a pixel capacitor element connected between the first node and the second node; a coupling capacitor element connected between the electric connecting means and the fourth node; a drive transistor forming a current supply line between a first terminal and a second terminal and controlling a current flowing in the current supply line in accordance with the potential of the control terminal connected to the second node; a first switch connected between the first node and the third node; a second switch connected between the third node and the fourth node; a third switch connected between the first node and a fixed potential; a fourth switch connected between the second node and a predetermined potential line; a fifth switch connected between the data line and the fourth switch; and a sixth switch connected between the third node and the reference current supplying means, wherein the current supply line of the drive transistor, the first node, the third node, the first switch, and the electro-optical element are connected in series between the first reference potential and the second reference potential, comprising steps of holding the third switch in the conductive state and connecting the first node to a fixed potential in the state where the first, second, fourth, fifth, and sixth switches are held in the non-conductive state; holding the second, fourth, and the sixth switches' in the conductive state and inputting the predetermined potential to the second node, sending the reference current in the third node, and charging the predetermined potential in the pixel capacitor element; holding the second and sixth switches in the non-conductive state, and further holding the fourth switch in the non-conductive state, holding the fifth switch in the conductive state and inputting the data propagated through the data line to the second node, then holding the fifth switch in the non-conductive state; and holding the first switch in the conductive state and holding the third switch in the non-conductive state. According to the present invention, at the time of for example the light emission state of the electro-optical element, the first switch is held in an ON state (conductive state), and the second to seventh switches are held in an OFF state (non-conductive state). The drive transistor is designed so as to operate in the saturated region, and the current Ids flowing in the electro-optical element takes a value shown by the above equation 1. Next, the first switch becomes OFF, and the third switch becomes ON in the state where the second and the fourth to seventh switches are held in the OFF state as they are. At this time, the current flows via the third switch, and the potential of the first node falls to a ground potential GND. For this reason, a voltage supplied to the electro-optical element becomes 0V, and the electro-optical element no longer emits light. Next, in the state where the third switch is held in the ON state and the first and fifth switches are held in the OFF state as they are, the second, fourth, sixth, and seventh switches become ON. Due to this, for example the predetermined potential 0V or an input potential Vin propagated through the data line is input to the second node, and the reference current flows in the third node by the reference current supplying means parallel to this. As a result, a gate/source voltage Vgs of the drive transistor is charged in the coupling capacitor element. At this time, the drive transistor operates in the saturated region, therefore the gate/source voltage Vgs of the drive transistor becomes a term including a mobility μ and a threshold value Vth. Further, V0 or Vin is charged in the pixel capacitor element at this time. Next, the second and sixth switches become OFF. Due to this, the source potential of the drive transistor (potential of the third node) rises up to for example (V0 or Vin−Vth). Then, further, in the state where the third and seventh switches are held in the ON state, and the first, second, and sixth switches are held in the OFF state as they are, the fifth switch becomes ON, and the fourth switch becomes OFF. By the turning on of the fifth switch, the input voltage Vin propagated through the data line via the fifth switch couples a voltage ΔV with the gate of the drive transistor through the coupling capacitor element. This coupling amount ΔV is determined according to a voltage change amount (Vgs of the drive transistor) between the first node and the second node, a pixel capacitor element, a coupling capacitor element, and a parasitic capacitance of the drive transistor, almost all of the change amount is coupled with the gate of the drive transistor if the capacitance of the coupling capacitor element is made large in comparison with the pixel capacitor element and the parasitic capacitance, and the gate potential of the drive transistor becomes (V0 or Vin+Vgs). After the end of the writing, the fifth and seventh switches become OFF, and further the first switch becomes ON and the third switch becomes OFF. Due to this, the source potential of the drive transistor once falls to the ground potential GND, then rises, and the current starts to flow also in the electro-optical element. Irrespective of the fact that the source potential of the drive transistor fluctuates, there is a pixel capacitor element between the gate and the source thereof. By making the capacitance of the pixel capacitor element larger than the parasitic capacitance of the drive transistor, the gate/source potential is always held at a constant value such as (Vin+Vgs). At this time, the drive transistor is driven in the saturated region, therefore the value of the current Ids flowing in the drive transistor becomes the value shown by Equation 1. That is determined by the gate/source voltage. This Ids flows also in the electro-optical element in the same way, whereby the electro-optical element emits light. EFFECT OF THE INVENTION According to the present invention, even when the I-V characteristic of the EL light emitting element changes by aging, a source-follower output without luminance deterioration can be achieved. A source-follower circuit of an n-channel transistor becomes possible, and an n-channel transistor can be used as a drive element of an EL light emitting element by using current anode/cathode electrodes as they are. Further, not only the variation of threshold values of drive transistors, but also the variation of mobilities can be greatly suppressed, and image quality having good uniformity can be obtained. Further, variation of the threshold values of drive transistors is cancelled out by the reference current, therefore it is not necessary to cancel the threshold value by setting the ON/OFF timing of the switch for each panel, therefore an increase of the number of steps for setting the timing can be suppressed. Further, the capacitance inside the pixel can be easily designed, and the capacitance can be made smaller, therefore the pixel area can be reduced, and it becomes possible to make the definition of the panel higher. Further, almost all of the voltage change can be coupled with the gate of the drive transistor when inputting the input voltage, therefore variation of the current value for each pixel can be reduced, and a uniform image quality can be obtained. Further, the time during which the input voltage from the signal line is input into the pixel can be shortened by inputting the fixed potential to the gate of the drive transistor and sending the reference current Iref, the data can be written into the pixel at a high speed, and it becomes possible to cope with a drive system dividing that 1 H into several parts and writing that data into the pixel as in three-part write system. Further, the transistors of the pixel circuits can be configured by only n-channel transistors, and it becomes able to use the a-Si process in TFT fabrication. Due to this, a reduction of the cost of the TFT substrate becomes possible. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a block diagram showing the configuration of a general organic EL display device. FIG. 2 is a circuit diagram showing an example of the configuration of the pixel circuit of FIG. 1. FIG. 3 is a diagram showing aging of the current-voltage (I-V) characteristic of the organic EL element. FIG. 4 is a circuit diagram showing a pixel circuit obtained by replacing a p-channel TFT of the circuit of FIG. 2 by an n-channel TFT. FIG. 5 is a diagram showing operation points of a drive transistor constituted by a TFT and an EL element in an initial state. FIG. 6 is a diagram showing operation points of a drive transistor constituted by a TFT and an El element after aging. FIG. 7 is a circuit diagram showing a pixel circuit in which a source of the drive transistor constituted by an n-channel TFT is connected to a ground potential. FIG. 8 is a block diagram showing the configuration of an organic EL display device employing a pixel circuit according to a first embodiment. FIG. 9 is a circuit diagram showing a specific configuration of a pixel circuit according to the first embodiment in the organic EL display device of FIG. 8. FIGS. 10A to 10I are timing charts for explaining a method of driving the circuit of FIG. 9. FIGS. 11A and 11B are diagrams for explaining an operation according to the method of driving the circuit of FIG. 9. FIGS. 12A and 12B are diagrams for explaining the operation according to the method of driving the circuit of FIG. 9. FIG. 13 is a diagram for explaining the operation according to the method of driving the circuit of FIG. 9. FIG. 14 is a diagram for explaining the operation according to the method of driving the circuit of FIG. 9. FIG. 15 is a diagram for explaining a reason why a reference current is supplied to the source of the drive transistor. FIG. 16 is a diagram for explaining the reason why a reference current is supplied to the source of the drive transistor. FIG. 17 is a diagram for explaining the reason why a reference current is supplied to the source of the drive transistor. FIG. 18 is a diagram for explaining the reason why a reference current is supplied to the source of the drive transistor. FIG. 19 is a circuit diagram showing a specific configuration of a pixel circuit according to a second embodiment. FIGS. 20A to 20I are timing charts for explaining the method of driving the circuit of FIG. 19. FIG. 21 is a block diagram showing the configuration of an organic EL display device employing a pixel circuit according to a third embodiment. FIG. 22 is a circuit diagram showing a specific configuration of a pixel circuit according to a third embodiment in the organic EL display device of FIG. 21. FIGS. 23A to 23H are timing charts for explaining the method of driving the circuit of FIG. 22. FIG. 24 is a circuit diagram showing a specific configuration of the pixel circuit according to a fourth embodiment. FIGS. 25A to 25H are timing charts for explaining the method of driving the circuit of FIG. 24. FIG. 26 is a circuit diagram showing a specific configuration of the pixel circuit according to a fifth embodiment. FIG. 27 is a circuit diagram showing a specific configuration of the pixel circuit according to a sixth embodiment. FIGS. 28A to 28K are timing charts for explaining the operation of the circuit of FIG. 26. FIGS. 29A to 29K are timing charts of the circuit of FIG. 27. FIGS. 30A and 30B are diagrams for explaining the operation of the circuit of FIG. 26. FIGS. 31A and 31B are diagrams for explaining the operation of the circuit of FIG. 26. FIGS. 32A and 32B are diagrams for explaining the operation of the circuit of FIG. 26. FIGS. 33A and 33B are diagrams for explaining the operation of the circuit of FIG. 26. FIG. 34 is a diagram for explaining the reason why the reference current is supplied to the source of the drive transistor in the circuit of FIG. 26. FIG. 35 is a diagram for explaining the reason why the reference current is supplied to the source of the drive transistor in the circuit of FIG. 26. FIG. 36 is a circuit diagram showing a specific configuration of the pixel circuit according to a seventh embodiment. FIG. 37 is a circuit diagram showing a specific configuration of the pixel circuit according to an eighth embodiment. FIGS. 38A to 38K are timing charts for explaining the operation of the circuit of FIG. 36. FIGS. 39A to 39K are timing charts for explaining the operation of the circuit of FIG. 37. FIG. 40 is a circuit diagram showing a specific configuration of the pixel circuit according to a ninth embodiment. FIG. 41 is a circuit diagram showing a specific configuration of the pixel circuit according to a 10th embodiment. FIGS. 42A to 42J are timing charts for explaining the operation of the circuit of FIG. 40. FIGS. 43A to 43J are timing charts for explaining the operation of the circuit of FIG. 41. FIG. 44 is a circuit diagram showing a specific configuration of the pixel circuit according to an 11th embodiment. FIG. 45 is a circuit diagram showing a specific configuration of the pixel circuit according to a 12th embodiment. FIGS. 46A to 46J are timing charts for explaining the operation of the circuit of FIG. 44. FIGS. 47A to 47J are timing charts for explaining the operation of the circuit of FIG. 45. 100, 100A to 100J . . . display device, 101 . . . pixel circuit (PXLC), 102 . . . pixel array, 103 . . . horizontal selector (HSEL), 104 . . . write scanner (WSCN), 105 . . . first drive scanner (DSCN1), 106 . . . second drive scanner (DSCN2), 107 . . . third drive scanner (DSCN3), 108 . . . fourth drive scanner (DSCN4), 109 . . . fifth drive scanner (DSCN5), 110 . . . sixth drive scanner (DSCN6), DTL101 to DTL10n . . . data line, WSL101 to WSL10m . . . scanning lines, DSL101 to DSL10m, DSL111 to DSL11m, DSL121 to DSL12m, DSL131 to DSL13m, DSL141 to DSL14m, DSL151 to DSL15m, DSL161 to DSL16m . . . drive lines, 111 . . . drive transistor constituted by TFT, 112 . . . first switch constituted by TFT, 113 . . . second switch constituted by TFT, 114 . . . third switch constituted by TFT, 115 . . . fourth switch constituted by TFT, 116 . . . fifth switch constituted by TFT, 117 . . . sixth switch constituted by TFT, 118 . . . seventh switch constituted by TFT, 119 . . . light emitting element, 120 . . . seventh or eighth switch constituted by TFT, 121 . . . eighth or ninth switch constituted by TFT, ND111 . . . first node, ND112 . . . second node, ND113 . . . third node, ND114 . . . fourth node. BEST MODE FOR WORKING THE INVENTION Below, embodiments of the present invention will be explained with reference to the attached drawings. First Embodiment FIG. 8 is a block diagram showing the configuration of an organic EL display device employing a pixel circuit according to the first embodiment. FIG. 9 is a circuit diagram showing a specific configuration of a pixel circuit according to the first embodiment in the organic EL display device of FIG. 8. This display device 100, as shown in FIG. 8 and FIG. 9, has a pixel array 102 comprised of pixel circuits (PXLC) 101 arranged in an m×n matrix, horizontal selector (HSEL) 103, write scanner (WSCN) 104, first drive scanner (DSCN1) 105, second drive scanner (DSCN2) 106, third drive scanner (DSCN3) 107, fourth drive scanner (DSCN4) 108, fifth drive scanner (DSCN5) 109, sixth drive scanner (DSCN6) 110, reference constant current source (RCIS) 111, data lines DTL101 to DTL10n selected by the horizontal selector 103 and supplied with data signals in accordance with the luminance information, scanning lines WSL101 to WSL10m selected and driven by the write scanner 104, drive lines DSL101 to DSL10m selected and driven by the first drive scanner 105, drive lines DSL111 to DSL11m selected and driven by the second drive scanner 106, drive lines DSL121 to DSL12m selected and driven by the third drive scanner 107, drive lines DSL131 to DSL13m selected and driven by the fourth drive scanner 108, drive lines DSL141 to DSL14m selected and driven by the fifth drive scanner 109, drive lines DSL151 to DSL15m selected and driven by the sixth drive scanner 110, and reference current supply lines ISL101 to ISL10n supplied with the reference current Iref by the constant current source 111. Note that, in the pixel array 102, the pixel circuits 101 are arranged in an m×n matrix, but in FIG. 8, for simplification of the drawing, an example in which they are arranged in a 2(=m)×3(=n) matrix is shown. Further, in FIG. 9 as well, for simplification of the drawing, the specific configuration of one pixel circuit is shown. The pixel circuit 101 according to the first embodiment, as shown in FIG. 9, has n-channel TFT 111 to TFT 118, capacitors C111 and C112, a light emitting element 119 made of an organic EL element (OLED: electro-optical element), a first node ND111, a second node ND112, a third node ND113, and a fourth node ND114. Further, in FIG. 9, DTL101 indicates the data line, WSL101 indicates the scanning line, and DSL101, DSL111, DSL121, DSL131, DSL141, and DSL151 indicate drive lines. Among these components, the TFT 111 configures the field effect transistor (drive transistor) according to the present invention, the TFT 112 configures the first switch, the TFT 113 configures the second switch, the TFT 114 configures the third switch, the TFT 115 configures the fourth switch, the TFT 116 configures the fifth switch, the TFT 117 configures the sixth switch, the TFT 118 configures the seventh switch as the electric connecting means, the capacitor C111 configures the pixel capacitor element according to the present invention, and the capacitor C112 configures the coupling capacitor element according to the present invention. The supply line (power supply potential) of the power supply voltage VCC corresponds to the first reference potential, and the ground potential GND corresponds to the second reference potential. Further, in the first embodiment, the data line and the predetermined potential line are shared. In the pixel circuit 101, between the first reference potential (the power supply potential VCC in the present embodiment) and the second reference potential (the ground potential GND in the present embodiment), the drive transistor constituted by the TFT 111, the third node ND113, the first switch constituted by the TFT 112, the first node ND111, and the light emitting element (OLED) 119 are connected in series. Specifically, a cathode of the light emitting element 119 is connected to the ground potential GND, an anode is connected to the first node ND111, the source of the TFT 112 is connected to the first node ND111, source and drain of the TFT 112 are connected between the first node ND111 and the third node ND113, a source of the TFT 111 is connected to the third node ND113, and a drain of the TFT 111 is connected to the power supply potential VCC. A gate of the TFT 111 is connected to the second node ND112, and a gate of the TFT 112 is connected to the drive line DSL111 driven by the second drive scanner 106. Source and drain of the second switch constituted by the TFT 113 are connected between the third node ND113 and the fourth node ND114, and a gate of the TFT 113 is connected to the drive line DSL141 driven by the fifth drive scanner 109. A drain of the third switch constituted by the TFT 114 is connected to the first node ND111 and a first electrode of the capacitor C111, a source is connected to the fixed potential (the ground potential GND in the present embodiment), and a gate of the TFT 114 is connected to the drive line DSL151 driven by the sixth drive scanner. Further, a second electrode of the capacitor C111 is connected to the second node ND112. Source and drain of the seventh switch constituted by the TFT 118 are connected to the second node ND112 and a first electrode of the capacitor C112, and a gate driven by the third drive scanner of the TFT 118 is connected to the drive line DSL121. Source and drain of the fourth switch constituted by the TFT 115 are connected to the data line (predetermined potential line) DTL101 and the second node ND112, and a gate of the TFT 115 is connected to the drive line DSL131 driven by the fourth drive scanner 108. Source and drain of the fifth switch constituted by the TFT 116 are connected to the data line DTL101 and the fourth node ND114. A gate of the TFT 116 is connected to the scanning line WSL101 driven by the write scanner 104. Further, the source and drain of the sixth switch constituted by the TFT 117 are connected between the third node ND113 and the reference current supply source line ISL101. A gate of the TFT 117 is connected to the drive line DSL101 driven by the first drive scanner 105. In this way, the pixel circuit 101 according to the present embodiment is configured so that the pixel capacitance constituted by the capacitor C111 is connected between the gate and source of the drive transistor constituted by the TFT 111, a source side potential of the TFT 111 is connected to the fixed potential via the switch transistor constituted by the TFT 114 in a non-light emission period, the predetermined reference current (for example 2 μA) is supplied to the source of the TFT 111 (third node ND13) at a predetermined timing, a voltage corresponding to the reference current Iref is held, and the input signal voltage is coupled centered on the voltage, whereby the EL light emitting element 119 is driven centered about the center value of variations of the mobilities, and an image quality suppressing the variation of the uniformity due to variation of the mobilities of the drive transistor constituted by the TFT 111 is obtained. Next, the operation of the above configuration will be explained focusing on the operation of the pixel circuit with reference to FIGS. 10A to 10I and FIG. 11, FIGS. 12A and 12B, and FIG. 13 and FIG. 14. Note that FIG. 10A shows a drive signal ds[4] applied to the drive line DSL131 of the first row in the pixel alignment, FIG. 10B shows a scanning signal ws[1] applied to the scanning line WSL101 of the first row in the pixel alignment, FIG. 10C shows a drive signal ds[3] applied to the drive line DSL121 of the first row in the pixel alignment, FIG. 10D shows a drive signal ds[5] applied to the drive line DSL141 of the first row in the pixel alignment, FIG. 10E shows a drive signal ds[6] applied to the drive line DSL151 of the first row in the pixel alignment, FIG. 10F shows a drive signal ds[2] applied to the drive line DSL111 of the first row in the pixel alignment, FIG. 10G shows a drive signal ds[1] applied to the drive line DSL101 of the first row in the pixel alignment, FIG. 10H shows a gate potential Vg111 of the drive transistor constituted by the TFT 111, and FIG. 10I shows a potential VND111 of the first node ND111. First, at the time of the light emission state of the ordinary EL light emitting element 119, as shown in FIGS. 10A to 10G, the scanning signal ws[1] to the scanning line WSL101 is set at the low level by the write scanner 104, the drive signal ds[1] to the drive line DSL101 is set at the low level by the drive scanner 105, the drive signal ds[3] to the drive line DSL121 is set at the low level by the drive scanner 107, the drive signal ds[4] to the drive line DSL131 is set at the low level by the drive scanner 108, the drive signal ds[5] to the drive line DSL141 is set at the low level by the drive scanner 109, the drive signal ds[6] to the drive line DSL151 is set at the low level by the drive scanner 110, and only the drive signal ds[2] to the drive line DSL111 is selectively set at a high level by the drive scanner 106. As a result, in the pixel circuit 101, as shown in FIG. 11A, the TFT 112 is held in the ON state (conductive state), and the TFT 113 to TFT 118 are held in the OFF state (non-conductive state). The drive transistor 111 is designed so as to operate in the saturated region, and the current Ids flowing in the EL light emitting element 119 takes a value shown by the above Equation 1. Next, in the non-light emission period of the EL light emitting element 119, as shown in FIGS. 10A to 10G, the scanning signal ws[1] to the scanning line WSL101 is held at the low level by the write scanner 104, the drive signal ds[1] to the drive line DSL101 is held at the low level by the drive scanner 105, the drive signal ds[2] to the drive line DSL111 is switched to the low level by the drive scanner 106, the drive signal ds[3] to the drive line DSL121 is held at the low level by the drive scanner 107, the drive signal ds[4] to the drive line DSL131 is held at the low level by the drive scanner 108, the drive signal ds[5] to the drive line DSL141 is held at the low level by the drive scanner 109, and the drive signal ds[6] to the drive line DSL151 is selectively set at the high level by the drive scanner 110. As a result, in the pixel circuit 101, as shown in FIG. 11B, the TFT 112 becomes OFF, and the TFT 114 becomes ON in the state where the TFT 113, and TFT 115 to TFT 118 are held in the OFF state as they are. At this time, the current flows via the TFT 114, and the potential VND111 of the first node ND111 falls to the ground potential GND as shown in FIGS. 10H and 10I. For this reason, the voltage applied to the EL light emitting element 119 becomes 0V, and the EL light emitting element 119 no longer emits light. Next, as shown in FIGS. 10A to 10G, in the state where the scanning signal ws[1] to the scanning line WSL101 is held at the low level by the write scanner 104, the drive signal ds[2] to the drive line DSL111 is held at the low level by the drive scanner 106, and the drive signal ds[6] to the drive line DSL151 is held at the high level by the drive scanner 110, the drive signal ds[1] to the drive line DSL101 from the drive scanner 105, the drive signal ds[3] to the drive line DSL121 by the drive scanner 107, the drive signal ds[4] to the drive line DSL131 by the drive scanner 108, and the drive signal ds[5] to the drive line DSL141 are selectively set at the high level by the drive scanner 109. As a result, in the pixel circuit 101, as shown in FIG. 12A, the TFT 113, TFT 115, TFT 117, and TFT 118 become ON in the state where the TFT 114 is held in the ON state and the TFT 112 and 116 are held in the OFF state as they are. Due to this, the input voltage Vin propagated through the data line DTL101 via the TFT 115 is input to the second node ND112, and the reference current Iref (for example 2 μA) supplied to the reference current supply line ISL101 by the constant current source 111 flows in the third node ND113 parallel to this. As a result, the voltage Vgs between the gate and source of the drive transistor constituted by the TFT 111 is charged in the capacitor C112. At this time, the TFT 111 operates in the saturated region, therefore, as shown in the following Equation (2), the gate/source voltage Vgs of the TFT 111 becomes a term including the mobility g and the threshold value Vth. Further, at this time, Vin is charged in the capacitor C111. (Equation 2) Vgs=Vth+{2Ids/(μ(W/L)Cox)}2 (2) Next, after Vin is charged in the capacitor C111, as shown in FIGS. 10A to 10G, in the state where the scanning signal ws[1] to the scanning line WSL101 is held at the low level by the write scanner 104, the drive signal ds[2] to the drive line DSL111 is held at the low level by the drive scanner 106, the drive signal ds[3] to the drive line DSL121 is held at the high level by the drive scanner 107, the drive signal ds[4] to the drive line DSL131 is held at the high level by the drive scanner 108, and the drive signal ds[6] to the drive line DSL151 is held at the high level by the drive scanner 110, the drive signal ds[1] to the drive line DSL101 is selectively set at the low level by the drive scanner 105, and the drive signal ds[4] to the drive line DSL141 is selectively set at the low level by the drive scanner 109. As a result, in the pixel circuit 101, from the state of FIG. 12A, the TFT 113 and the TFT 117 become OFF. Due to this, the source potential of the TFT 111 (potential of the third node ND113) rises up to (Vin−Vth). Then, further, the scanning signal ws[1] to the scanning line WSL101 is switched to the high level by the write scanner 104, and the drive signal ds[4] to the drive line DSL131 is switched to the low level by the drive scanner 108. As a result, in the pixel circuit 101, as shown in FIG. 12B, in the state where the TFT 114 and the TFT 118 are held in the ON state, and the TFT 112, the TFT 113, and the TFT 117 are held in the OFF state as they are, the TFT 116 becomes ON, and the TFT 115 becomes OFF. By the turning on of the TFT 116, the input voltage Vin propagated through the data line DTL101 via the TFT 116 couples the voltage ΔV with the gate of the TFT 111 through the capacitor C112. This coupling amount ΔV is determined according to the voltage change between the first node ND111 and the second node ND112 (Vgs of the TFT 111), capacitances of capacitors C111 and C112, and the parasitic capacitance 113 of the TFT 111. When the capacitance of the capacitor C112 is made large in comparison with the capacitance of the capacitor C111 and the parasitic capacitance C113, almost all of the change is coupled with the gate of the TFT 111, and the gate potential of the TFT 111 becomes (Vin+Vgs). After the end of the writing, as shown in FIGS. 10A to 10G, the scanning signal ws[1] to the scanning line WSL101 is switched to the low level by the write scanner 104, the drive signal ds[3] to the drive line DSL121 is switched to the low level by the drive scanner 107, further the drive signal ds[2] to the drive line DSL111 is switched to the high level by the drive scanner 106, and the drive signal ds[6] to the drive line DSL151 is switched to the low level by the drive scanner 110. Due to this, in the pixel circuit 101, as shown in FIG. 13, the TFT 116 and the TFT 118 become OFF, and further the TFT 112 becomes ON, and the TFT 114 becomes OFF. Due to this, the source potential of the TFT 111 once falls to the ground potential GND then rises, and current starts to flow also in the EL light emitting element 119. Irrespective of the fluctuation of the source potential of the TFT 111, the capacitor C111 exists between the gate and source thereof. By making the capacitance of the capacitor C111 larger than the parasitic capacitance C113 of the TFT 111, the gate/source potential is constantly held at the constant value such as (Vin+Vgs). At this time, the TFT 111 is driven in the saturated region, therefore the value of the current Ids flowing in the TFT 111 becomes the value shown by Equation 1 and is determined by the gate/source voltage. This Ids flows also in the EL light emitting element 119 in the same way, and the EL light emitting element 119 emits light. An equivalent circuit of the pixel circuit 101 including this EL light emitting element 119 becomes as shown in FIG. 14, therefore the source potential of the TFT 111 rises up to the gate potential for running the current Ids through the EL light emitting element 119. Along with this potential rise, the gate potential of the TFT 111 rises in the same way via the capacitor C111. Due to this, the gate/source potential of the TFT 111 is held constant as previously explained. Here, the reference current Iref will be considered. As explained above, by running the reference current Iref, the gate/source voltage of the TFT 111 is given the value represented by Equation 2. However, the gate/source voltage does not become Vth when Iref=0. This is because even when the gate/source voltage becomes Vth, a leakage current slightly flows in the TFT 111, therefore, as shown in FIG. 15, the source voltage of the TFT 111 rises up to Vcc. In order to make the gate/source voltage of the TFT 111 Vth, it is necessary to adjust the period for turning on the TFT 113 and turn off the TFT 113 when the gate/source voltage becomes Vth. This timing must be adjusted for each panel in a real device. As in the present embodiment, when the reference current Iref is not flowing, even if the gate/source voltage can be set at Vth by adjusting the timing of the TFT 113, even when the same input voltage Vin is applied in for example the pixels A and B having different mobilities, according to Equation 1, variation of the current Ids occurs according to the mobility μ as shown in FIG. 16, and the luminance of the pixel becomes different. That is, as a larger value of current flows and it becomes brighter, the current value is affected by the variation of mobilities, the uniformity varies, and the image quality is degraded. However, as in the present embodiment, by running a constant amount of reference current Iref, as shown in FIG. 17, not according to the ON/OFF timing of the TFT 113, the gate/source voltage of the TFT 111 can be set to a constant value shown in Equation 2. Even in the pixels A and B having different mobilities, as shown in FIG. 18, the variation of the current Ids can be kept small, therefore variation of the uniformity can be suppressed. Further, the circuit of the present embodiment will be considered based on problems of the usual source-follower. Also in the present circuit, as the light emission time of the EL light emitting element 119 becomes longer, the I-V characteristic thereof deteriorates. For this reason, even when the TFT 111 passes the same value of current, the potential applied to the EL light emitting element 119 changes, and the potential VND111 of the first node ND111 falls. However, in the present circuit, the potential VND111 of the first node ND111 falls in the state where the gate/source potential of the TFT 111 is held constant as it is, therefore the current flowing in the TFT 111 does not change. Accordingly, even when the current flowing in the EL light emitting element 119 does not change, and the I-V characteristic of the EL light emitting element 119 deteriorates, a current corresponding to the gate/source voltage constantly continuously flows, so the past problems can be solved. As explained above, according to the first embodiment, the voltage drive type TFT active matrix organic EL display device is configured so that the capacitor C111 is connected between the gate and source of the drive transistor constituted by the TFT 111, the source side of the TFT 111 (the first node ND111) is connected through the TFT 114 to the fixed potential (GND in the present embodiment), the predetermined reference current (for example 2 μA) Iref is supplied to the source of the TFT 111 (the third node ND13) at a predetermined timing, the voltage corresponding to the reference current Iref is held, and the input signal voltage is coupled centered about the voltage, to thereby drive the EL light emitting element 119 centered about the center value of variations of mobilities, therefore the following effects can be obtained. Namely, even when the I-V characteristic of the EL light emitting element changes by aging, a source-follower output without luminance deterioration can be obtained. A source-follower circuit of an n-channel transistor becomes possible, and the n-channel transistor can be used as the drive element of the EL light emitting element by using current anode/cathode electrodes as they are. Further, not only variation of threshold values of drive transistors, but also variation of mobilities can be greatly suppressed, and an image quality having good uniformity can be obtained. Further, variation of the threshold values of drive transistors is cancelled out by the reference current, therefore it is not necessary to cancel the threshold value by setting the ON/OFF timing of the switch for each panel, therefore an increase of the number of steps for setting the timing can be suppressed. Further, the transistors of the pixel circuits can be configured by only n-channel transistors, and it becomes able to use the a-Si process in TFT fabrication. Due to this, a reduction of the cost of the TFT substrate becomes possible. Second Embodiment FIG. 19 is a circuit diagram showing the specific configuration of a pixel circuit according to a second embodiment. Further, FIG. 20 is a timing chart of the circuit of FIG. 19. The difference of the second embodiment from the first embodiment explained above resides in that the fourth switch constituted by the TFT 115 does not share the predetermined potential line to which the TFT 115 is connected together with the data line DTL, but is separately provided. The rest of the configuration is the same as that of the first embodiment, so a detailed explanation concerning the configuration and function is omitted here. In the second embodiment, when running the reference current Iref to the source of the driver transistor constituted by the TFT 111, the input voltage Vin is not input to the gate voltage of the TFT 111, but the fixed potential V0 is input. By inputting the fixed potential V0 and running the reference current Iref, the time during which the Vin is input into the pixel can be shortened, and the data can be written into the pixel at a high speed. For this reason, it becomes possible to cope with a drive system dividing that 1 H into several parts and writing that data into the pixel as in three-part write system. Third Embodiment FIG. 21 is a block diagram showing the configuration of an organic EL display device employing a pixel circuit according to a third embodiment. FIG. 22 is a circuit diagram showing the specific configuration of a pixel circuit according to the third embodiment in the organic EL display device of FIG. 21. Further, FIGS. 23A to 23H are timing charts of the circuit of FIG. 22. The difference of the third embodiment from the first embodiment resides in that, in place of the configuration in which the electric connecting means for connecting the first electrode of the capacitor C112 and the second node ND112 is configured by the switch 118 for selectively connecting the two, they are directly connected by an electric interconnect. As a result, the third drive scanner 107 and the drive line DSL121 become unnecessary. The rest of the configuration is the same as that of the second embodiment explained above. According to the third embodiment, in addition to the effects of the first embodiment explained above, there are the advantages that the number of elements in the pixel circuit can be decreased, and the circuit configuration can be simplified. Fourth Embodiment FIG. 24 is a circuit diagram showing a specific configuration of the pixel circuit according to the fourth embodiment. Further, FIGS. 25A to 25H are timing charts of the circuit of FIG. 24. The difference of the fourth embodiment from the third embodiment explained above resides in that the predetermined potential line to which the TFT 115 as the fourth switch is connected is not shared together with the data line DTL, but is separately provided. The rest of the configuration is the same as that of the first embodiment, so a detailed explanation concerning the configuration and function is omitted here. In the fourth embodiment, when running the reference current Iref to the source of the driver transistor constituted by the TFT 111, the input voltage Vin is not input to the gate voltage of the TFT 111, but the fixed potential V0 is input. By inputting the fixed potential V0 and running the reference current Iref, the time during which the Vin is input into the pixel can be shortened, and the data can be written into the pixel at a high speed. For this reason, it becomes possible to cope with a drive system dividing that 1 H into several parts and writing that data into the pixel as in three-part write system. Fifth Embodiment and Sixth Embodiment FIG. 26 is a circuit diagram showing the specific configuration of a pixel circuit according to a fifth embodiment. Further, FIG. 27 is a circuit diagram showing a specific configuration of the pixel circuit according to a sixth embodiment. The difference of the fifth embodiment from the first embodiment explained above resides in that an eighth switch constituted by a TFT 120 is inserted between the first node ND111 and the anode of the light emitting element 119, the first node ND111 and the data line DTL101 are connected by a ninth switch constituted by a TFT 121, and the source of the TFT 114 is connected to the fixed potential V0. A gate of the TFT 120 is connected to drive lines DSL161 (to 16m) driven by a seventh drive scanner (DSCN7) 122, and a gate of the TFT 121 is connected to drive lines DSL171 (to 17m) driven by an eighth drive scanner (DSCN8) 123. Further, the difference of the sixth embodiment from the fifth embodiment resides in that the first node ND111 is selectively connected to the fourth node ND114 in place of selectively connecting the first node ND111 to the data line DTL101 by the TFT 121. Basically, the same operation is carried out in the fifth and sixth embodiments. FIGS. 28A to 28K and FIGS. 29A to 29K show timing charts of examples of those operations. Note that FIG. 28A and FIG. 29A show the drive signal ds[4 ] applied to the drive line DSL131 of the first row in the pixel alignment, FIG. 28B and FIG. 29B show the scanning signal ws[1] applied to the scanning line WSL101 of the first row in the pixel alignment, FIG. 28C and FIG. 29C show the drive signal ds[3] applied to the drive line DSL121 of the first row in the pixel alignment, FIG. 28D and FIG. 29D show the drive signal ds[5] applied to the drive line DSL141 of the first row in the pixel alignment, FIG. 28E and FIG. 29E show the drive signal ds[2] applied to the drive line DSL111 of the first row in the pixel alignment, FIG. 28F and FIG. 29F show the drive signal ds[1] applied to the drive line DSL101 of the first row in the pixel alignment, FIG. 28G and FIG. 29G show the drive signal ds[7] applied to the drive line DSL161 of the first row in the pixel alignment, FIG. 28H and FIG. 29H show the drive signal ds[6] applied to the drive line DSL141 of the first row in the pixel alignment, FIG. 28I and FIG. 29I show the drive signal ds[8] applied to the drive line DSL171 of the first row in the pixel alignment, FIG. 28J and FIG. 29J show the gate potential Vg111 of the TFT 111 as the drive transistor, and FIG. 28K and FIG. 29K show the potential VND111 of the first node ND111. Below, the operation of the circuit of FIG. 26 will be explained with reference to FIGS. 30A and 30B, FIGS. 31A and 31B, FIGS. 32A and 32B, and FIGS. 33A and 33B. First, the light emission state of the ordinary EL light emitting element 119 is the state where the TFT 112 and the TFT 120 become ON as shown in FIG. 30A. Next, in the non-light emission period of the EL light emitting element 119, as shown in FIG. 30B, the TFT 120 is turned off while turning on the TFT 112 as it is. At this time, a current is no longer supplied to the EL light emitting element 119, so it no longer emits the light. Next, as shown in FIG. 31A, the TFT 115, TFT 118, TFT 113 and TFT 117 are turned on and the input voltage (Vin) is input to the gate of the drive transistor constituted by the TFT 111. By running the current Iref from the current source, the gate/source voltage Vgs of the drive transistor is charged in the capacitors C111 and C112. At this time, the TFT 114 operates in the saturated region, therefore Vgs becomes a term including μ and Vth as shown in Equation 3. (Equation 3) Vgs=Vth+[2I/(μ(W/L)Cox]1/2 (3) After Vgs is charged in the capacitors C111 and C112, the TFT 113 and TFT 112 are turned off. Due to this, the voltages charged in the capacitors C111 and C112 are set to Vgs. Thereafter, as shown in FIG. 31B, by turning off the TFT 117 and suspending the supply of the current, the source potential of the TFT 111 rises up to Vin−Vth. Further, as shown in FIG. 32A, the TFT 115 is turned off and the TFT 116 and TFT 121 are turned on. By turning on the TFT 116 and TFT 121, Vin is passed through the capacitors C111 and C112 and the voltage ΔV is coupled with the gate of the drive transistor constituted by the TFT 111. This coupling amount ΔV is determined according to the voltage change (Vgs) of a point A and a point B in the figure and a ratio of a sum of capacitances C1 and C2 of the capacitors C111 and C112 and the parasitic capacitance C3 of the TFT 111 (Equation 4). When the sum of C1 and C2 is made larger than C3, almost all of the change is coupled with the gate of the TFT 111, and the gate potential of the TFT 111 becomes Vin+Vgs. (Equation 4) ΔV=ΔV1+ΔV2={(C1+C2)/(C1+C2+C3)}·Vgs (4) After the writing ends, as shown in FIG. 32B, the TFT 121 is turned off and the TFT 114 is turned on. The TFT 114 is connected to a fixed potential such as V0. By turning on it, the voltage change (V0−Vin) of the node ND112 is coupled with the gate of the TFT 111 through the capacitor C111 again. This coupling amount ΔV3 is determined according to voltage change of the node ND112 and the ratio of the sum of C1 and C3 and C2 (Equation 5). When defining this ratio as α, the gate potential of the TFT 111 becomes (1−α)Vin+Vgs+αV0, and the voltage held in the capacitor C111 rises from Vgs by exactly (1−α) (Vin−V0). (Equation 5) ΔV={C1/(C1+C2+C3)}·(V0−Vin)=α (5) Thereafter, as shown in FIG. 33A, the TFT 116 and TFT 118 are turned off, the TFT 112 and TFT 120 are turned on, and the TFT 114 is turned off. Due to this, the source potential of the TFT 111 once becomes the V0 level, then current starts to flow in the EL light emitting element 119. Irrespective of the fact that the source potential of the TFT 111 fluctuates, the capacitor C111 exists between the gate and the source. By making the capacitance C1 of the capacitor C111 larger than the parasitic capacitance C3, the gate/source potential is constantly held at a constant value. At this time, the TFT 111 is driven in the saturated region, therefore the value of current Ids flowing in the TFT 111 becomes the value indicated by Equation 1 and is determined by the gate/source voltage. This Ids flows also in the EL light emitting element 119 in the same way, and the EL light emitting element 119 emits light. The equivalent circuit of the element becomes as shown in FIG. 33B, therefore the source voltage of the TFT 111 rises up to the gate potential for running the current Ids through the EL light emitting element 119. Along with this potential rise, the gate potential of the TFT 111 rises in the same way via the capacitor C111. Due to this, the gate/source voltage is held constant as previously explained, the EL light emitting element 119 is deteriorated by aging, therefore even when the source potential of the TFT 111 changes, the gate/source voltage is constant as it is, and the value of current flowing in the EL light emitting element 119 will not change. Here, the capacitances C1 and C2 of the capacitors C111 and C112 will be considered. First, the sum of C1 and C2 must be set to C1+C2>>C3. By making the sum much larger than C3, all of the potential change of the nodes ND111 and ND112 can be coupled with the gate of the TFT 111. At this time, the value of current flowing through the TFT 111 becomes the value shown by Equation 1, the gate/source voltage of the TFT 111 becomes larger than the voltage flowing through the Iref by exactly a constant value such as α(V0−Vin) as in FIG. 34, and even in pixels A and B having different mobilities, the variation of Ids can be suppressed to small, therefore the variation of the uniformity can be suppressed. However, when C1+C2 is made small, all of the voltage change of the nodes ND111 and ND112 is not coupled, but a gain ends up occurring. When this gain is defined as the amount of current flowing in the TFT 111 is represented by Equation 6, and the gate/source voltage of T10 becomes larger than the voltage for sending Iref by exactly a value such as Vin+(β−1)Vgs, but Vgs has a different value for each pixel, therefore it becomes unable to keep variation of the Ids small (FIG. 35). Due to this, C1+C2 must be made larger than C3. (Equation 6) ΔV={C1/(C1+C2+C3)}·Vgs (6) Next, the magnitude of C1 will be considered. C1 must be much larger than the parasitic capacitance C3. If C1 is at the same level as C3, the fluctuation of the source potential of the TFT 114 is coupled with the gate of the TFT 114 through the capacitor C111, and the voltage held in the capacitor C111 fluctuates. For this reason, the TFT 111 becomes unable to carry a constant amount of current, and variation occurs for each pixel. Due to this, C1 must be made very large in comparison with the parasitic capacitance C3 of the TFT 111. Further, C2 will be considered. Assuming that C2 >>C1, when turning on the TFT 114 and coupling the voltage change such as V0−Vin with the gate of the TFT 111 through the capacitor C111, the potential difference held in the capacitor C111 increases from the potential such as Vgs held by running Iref through the TFT 111 by exactly a constant value such as Vin−V0, therefore, even in the pixels A and B having different mobilities, the variation of Ids can be kept small, and variation of the uniformity can be suppressed. However, assuming that C2>>C1, the variation of Ids cannot be kept small, and also variation of the uniformity cannot be suppressed. Next, if C2<<C1, when turning on the TFT 114, the voltage change such as V0−Vin is completely coupled with the gate of the TFT 111 through the capacitor C111, therefore the voltage held in the capacitor C111 does not change at all from Vgs. Due to this, the EL light emitting element 119, irrespective of the input voltage, can only carry a constant current such as Iref, therefore the pixel can only perform raster display. Due to the above, it is necessary to set the magnitudes of C1 and C2 at the same level and impart a constant gain in the coupling by turning on the TFT 114. Here, as previously explained, C3 is the parasitic capacitance of the TFT 114, and the magnitude thereof is an order of several tens to several hundreds of fF, but the relationships of C1, C2, and C3 are C2>>C3 and C1>>C3, and C1 and C2 must be the same level, therefore C1 and C2 may have magnitudes of from several hundreds fF to several pF. Due to this, the capacitance can be easily set in a limited magnitude inside the pixel, and also the conventional problems of the current value varying for each pixel and unevenness of pixels occurring can be overcome. Seventh Embodiment and Eighth Embodiment FIG. 36 is a circuit diagram showing the specific configuration of a pixel circuit according to a seventh embodiment. FIG. 37 is a circuit diagram showing the specific configuration of a pixel circuit according to an eighth embodiment. The difference of the seventh embodiment from the fifth embodiment explained above resides in that the predetermined potential line to which the fourth switch constituted by the TFT 115 is connected is not shared together with the data line DTL, but is separately provided. In the same way, the difference of the eighth embodiment from the sixth embodiment explained above resides in that the predetermined potential line to which the fourth switch constituted by the TFT 115 is connected is not shared together with the data line DTL, but is separately provided. The rests of the configurations are the same as those of the fifth and sixth embodiments, so a detailed explanation concerning the configurations and functions is omitted here. The seventh and eighth embodiments basically operate in the same way. FIGS. 38A to 38K and FIGS. 39A to 39K show timing charts of examples of those operations. In the seventh and eighth embodiments, when running the reference current Iref to the source of the driver transistor constituted by the TFT 111, the input voltage Vin is not input to the gate voltage of the TFT 111, but the fixed potential V0 is input. By inputting the fixed potential V0 and running the reference current Iref, the time during which the Vin is input into the pixel can be shortened, and the data can be written into the pixel at a high speed. For this reason, it becomes possible to cope with a drive system dividing that 1 H into several parts and writing that data into the pixel as in three-part write system. Ninth Embodiment and 10th Embodiment FIG. 40 is a circuit diagram showing the specific configuration of a pixel circuit according to a ninth embodiment. FIG. 41 is a circuit diagram showing the specific configuration of a pixel circuit according to a 10th embodiment. The difference of the ninth embodiment from the fifth embodiment resides in that, in place of the configuration in which the electric connecting means for connecting the first electrode of the capacitor C112 and the second node ND112 is configured by the switch 118 for selectively connecting the two, they are directly connected by an electric interconnect. The difference of the 10th embodiment from the sixth embodiment resides in that, in place of the configuration in which the electric connecting means for connecting the first electrode of the capacitor C112 and the second node ND112 is configured by the switch 118 for selectively connecting the two, they are directly connected by an electric interconnect. As a result, the third drive scanner 107 and the drive line DSL121 become unnecessary. The rests of the configurations are the same as those of the fifth and sixth embodiments explained above. The ninth and 10th embodiments basically operate in the same way. FIGS. 42A to 42J and FIGS. 43A to 43J show timing charts of examples of those operations. According to the ninth and 10th embodiments, in addition to the effects of the fifth and sixth embodiments explained above, there are the advantages that the number of elements in the pixel circuit can be decreased, and the circuit configuration can be simplified. 11th Embodiment and 12th Embodiment FIG. 44 is a circuit diagram showing the specific configuration of a pixel circuit according to an 11th embodiment. FIG. 45 is a circuit diagram showing the specific configuration of a pixel circuit according to a 12th embodiment. The difference of the 11th embodiment from the seventh embodiment resides in that, in place of the configuration in which the electric connecting means for connecting the first electrode of the capacitor C112 and the second node ND112 is configured by the switch 118 for selectively connecting the two, they are directly connected by an electric interconnect. The difference of the 12th embodiment from the eighth embodiment resides in that, in place of the configuration in which the electric connecting means for connecting the first electrode of the capacitor C112 and the second node ND112 is configured by the switch 118 for selectively connecting the two, they are directly connected by an electric interconnect. As a result, the third drive scanner 107 and the drive line DSL121 become unnecessary. The rests of the configurations are the same as those of the seventh and eighth embodiments explained above. The 11th and 12th embodiments basically operate in the same way. FIGS. 46A to 46J and FIGS. 47A to 47J show timing charts of examples of those operations. According to the 11th and 12th embodiments, in addition to the effects of the seventh and eighth embodiments explained above, there are the advantages that the number of elements in the pixel circuit can be decreased, and the circuit configuration can be simplified. INDUSTRIAL CAPABILITY According to the pixel circuit, display device, and method of driving a pixel circuit of the present invention, even when the current-voltage characteristic of a light emitting element changes due to aging, source-follower output without a luminance deterioration can be obtained, the source-follower circuit of the n-channel transistor becomes possible. In addition, it is possible to display uniform and high quality images without regard to variations of the threshold values and mobilities of the active elements inside the pixels. Therefore, the present invention can be applied to electronic devices such as display devices for personal digital assistants, personal computers, and car navigation systems, mobile phones, digital cameras, and video cameras.

<SOH> BACKGROUND ART <EOH>In an image display device, for example, a liquid crystal display etc., the image is displayed by arranging a large number of pixels in a matrix and controlling the intensity of light for each pixel in accordance with image information to be displayed. The same is also true for an organic EL display etc., but an organic EL display is a so-called self light emission type display having a light emitting element in each pixel circuit and has the advantages that the viewability of the image is high in comparison with a liquid crystal display, no backlight is necessary, the response speed is fast, and so on. Further, this is very different from a liquid crystal display in the point that the luminance of each light emitting element can be controlled by the value of the current flowing through it so as to obtain scales of color, that is, each light emitting element is a current controlled type. In an organic EL display, in the same way as a liquid crystal display, the simple matrix system and the active matrix system are possible as the method for driving the same. The former is simple in structure, but has the problems that realization of a large sized and high definition display is difficult and so on, therefore there has been much development work on the active matrix system for controlling the current flowing in the light emitting element inside each pixel circuit by an active element provided inside the pixel circuit, generally a TFT (thin film transistor). FIG. 1 is a block diagram showing the configuration of a general organic EL display device. This display device, as shown in FIG. 1 , has a pixel array 2 comprised of pixel circuits (PXLC) 2 a arranged in an m×n matrix, a horizontal selector (HSEL) 3 , a write scanner (WSCN) 4 , data lines DTL 1 to DTLn selected by the horizontal selector 3 and supplied with data signals in accordance with the luminance information, and scanning lines WSL 1 to WSLm selected and driven by the write scanner 4 . Note that the horizontal selector 3 and the write scanner 4 are sometimes formed on polycrystalline silicon or formed on the periphery of the pixels by MOSIC etc. FIG. 2 is a circuit diagram showing an example of the configuration of the pixel circuit 2 a of FIG. 1 (see for example Patent Documents 1 and 2). The pixel circuit of FIG. 2 has the simplest circuit configuration among the large number of circuits proposed and is a circuit of the so-called two-transistor drive system. The pixel circuit 2 a of FIG. 2 has a p-channel thin film field effect transistor (hereinafter referred to as an TFT) 11 and TFT 12 , a capacitor C 11 , and a light emitting element constituted by an organic EL element (OLED) 13 . Further, in FIG. 42 , DTL indicates the data line, and WSL indicates the scanning line. The organic EL element has a rectification property in many cases, so sometimes is called an OLED (organic light emitting diode). The symbol of a diode is used as the light emitting element in FIG. 2 and other figures, but a rectification property is not always required for the OLED in the following explanation. In FIG. 2 , a source of the TFT 11 is connected to a power supply potential VCC, and a cathode of the light emitting element 13 is connected to a ground potential GND. The operation of the pixel circuit 2 a of FIG. 2 is as follows. Step ST1: When the scanning line WSL is in a selected state (low level here) and a write potential Vdata is supplied to the data line DTL, the TFT 12 becomes conductive and the capacitor C 11 is charged or discharged, and a gate potential of the TFT 11 becomes Vdata. Step ST2: When the scanning line WSL is in a non-selected state (high level here), the data line DTL and the TFT 11 are electrically disconnected, but the gate potential of the TFT 11 is held stably by the capacitor C 11 . Step ST3: The current flowing in the TFT 11 and the light emitting element 13 becomes a value in accordance with a voltage Vgs between the gate and source of the TFT 11 , and the light emitting element 13 continuously emits light with a luminance in accordance with the current value. As in above step ST1, the operation of selecting the scanning line WSL and transferring the luminance information given to the data line to the inside of the pixel will be called “writing” below. As explained above, in the pixel circuit 2 a of FIG. 2 , when once writing the Vdata, during the period up to when next rewriting the data, the light emitting element 13 continues emitting light with a constant luminance. As explained above, in the pixel circuit 2 a , by changing the gate voltage of the drive transistor constituted by the TFT 11 , the value of the current flowing in the EL light emitting element 13 is controlled. At this time, the source of the p-channel drive transistor of is connected to a power supply potential VCC, so this TFT 11 is constantly operating in the saturated region. Accordingly, it becomes a constant current source having a value shown in the following equation 1. (Equation 1) in-line-formulae description="In-line Formulae" end="lead"? Ids =½·μ( W/L ) Cox ( Vgs−|Vth |) 2 (1) in-line-formulae description="In-line Formulae" end="tail"? Here, μ indicates the mobility of a carrier, Cox indicates a gate capacitance per unit area, W indicates a gate width, L indicates a gate length, Vgs indicates a gate-source voltage of the TFT 11 , and Vth indicates a threshold value of the TFT 11 . In a simple matrix type image display device, each light emitting element emits light only at an instant when it is selected, but in contrast, in an active matrix, as explained above, the light emitting element continues emitting light even after the end of writing, therefore this becomes advantageous especially in a large sized and high definition display in the point that a peak luminance and a peak current of the light emitting element can be lowered in comparison with the simple matrix. FIG. 3 is a diagram showing aging of the 10 current-voltage (I-V) characteristic of an organic EL element. In FIG. 3 , the curve indicated by a solid line indicates the characteristic at the time of an initial state, and the curve indicated by a broken line indicates the characteristic after the aging. In general, the I-V characteristic of the organic EL element deteriorates when time passes as shown in FIG. 3 . However, the two-transistor drive of FIG. 2 is a constant current drive, therefore a constant current continuously flows in the organic EL element as explained above. Even when the I-V characteristic of the organic EL element deteriorates, the light emission luminance thereof will not deteriorate by aging. The pixel circuit 2 a of FIG. 2 is configured by a p-channel TFT, but if it could be configured by an n-channel TFT, it would become possible to use a usual amorphous silicon (a-Si) process in TFT fabrication. By this, a reduction of the cost of the TFT substrate would become possible. Next, a pixel circuit replacing the transistor by an n-channel TFT will be considered. FIG. 4 is a circuit diagram showing a pixel circuit replacing the p-channel TFT of the circuit of FIG. 2 by an n-channel TFT. A pixel circuit 2 b of FIG. 4 has an n-channel TFT 21 and TFT 22 , a capacitor C 21 , and a light emitting element constituted by an organic EL element (OLED) 23 . Further, in FIG. 4 , DTL indicates the data line, and WSL indicates the scanning line. In this pixel circuit 2 b , a drain side of the drive transistor constituted by the TFT 21 is connected to the power supply potential VCC, and the source is connected to an anode of the EL element 23 to thereby form a source-follower circuit. FIG. 5 is a diagram showing operation points of the drive transistor constituted by the TFT 21 and the EL element 23 in the initial state. In FIG. 5 , an abscissa indicates a drain/source voltage Vds of the TFT 21 , and an ordinate indicates a drain/source current Ids. As shown in FIG. 5 , the source voltage is determined by the operation points of the drive transistor constituted by the TFT 21 and the EL element 23 . The voltage thereof has a different value according to the gate voltage. This TFT 21 is driven in a saturated region, therefore a current Ids having a current value shown in the above equation 1 flows concerning Vgs with respect to the source voltage of the operation point. Patent Document 1: U.S. Pat. No. 5,684,365 Patent Document 1: Japanese Patent Publication (A) No. 8-234683

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a block diagram showing the configuration of a general organic EL display device. FIG. 2 is a circuit diagram showing an example of the configuration of the pixel circuit of FIG. 1 . FIG. 3 is a diagram showing aging of the current-voltage (I-V) characteristic of the organic EL element. FIG. 4 is a circuit diagram showing a pixel circuit obtained by replacing a p-channel TFT of the circuit of FIG. 2 by an n-channel TFT. FIG. 5 is a diagram showing operation points of a drive transistor constituted by a TFT and an EL element in an initial state. FIG. 6 is a diagram showing operation points of a drive transistor constituted by a TFT and an El element after aging. FIG. 7 is a circuit diagram showing a pixel circuit in which a source of the drive transistor constituted by an n-channel TFT is connected to a ground potential. FIG. 8 is a block diagram showing the configuration of an organic EL display device employing a pixel circuit according to a first embodiment. FIG. 9 is a circuit diagram showing a specific configuration of a pixel circuit according to the first embodiment in the organic EL display device of FIG. 8 . FIGS. 10A to 10 I are timing charts for explaining a method of driving the circuit of FIG. 9 . FIGS. 11A and 11B are diagrams for explaining an operation according to the method of driving the circuit of FIG. 9 . FIGS. 12A and 12B are diagrams for explaining the operation according to the method of driving the circuit of FIG. 9 . FIG. 13 is a diagram for explaining the operation according to the method of driving the circuit of FIG. 9 . FIG. 14 is a diagram for explaining the operation according to the method of driving the circuit of FIG. 9 . FIG. 15 is a diagram for explaining a reason why a reference current is supplied to the source of the drive transistor. FIG. 16 is a diagram for explaining the reason why a reference current is supplied to the source of the drive transistor. FIG. 17 is a diagram for explaining the reason why a reference current is supplied to the source of the drive transistor. FIG. 18 is a diagram for explaining the reason why a reference current is supplied to the source of the drive transistor. FIG. 19 is a circuit diagram showing a specific configuration of a pixel circuit according to a second embodiment. FIGS. 20A to 20 I are timing charts for explaining the method of driving the circuit of FIG. 19 . FIG. 21 is a block diagram showing the configuration of an organic EL display device employing a pixel circuit according to a third embodiment. FIG. 22 is a circuit diagram showing a specific configuration of a pixel circuit according to a third embodiment in the organic EL display device of FIG. 21 . FIGS. 23A to 23 H are timing charts for explaining the method of driving the circuit of FIG. 22 . FIG. 24 is a circuit diagram showing a specific configuration of the pixel circuit according to a fourth embodiment. FIGS. 25A to 25 H are timing charts for explaining the method of driving the circuit of FIG. 24 . FIG. 26 is a circuit diagram showing a specific configuration of the pixel circuit according to a fifth embodiment. FIG. 27 is a circuit diagram showing a specific configuration of the pixel circuit according to a sixth embodiment. FIGS. 28A to 28 K are timing charts for explaining the operation of the circuit of FIG. 26 . FIGS. 29A to 29 K are timing charts of the circuit of FIG. 27 . FIGS. 30A and 30B are diagrams for explaining the operation of the circuit of FIG. 26 . FIGS. 31A and 31B are diagrams for explaining the operation of the circuit of FIG. 26 . FIGS. 32A and 32B are diagrams for explaining the operation of the circuit of FIG. 26 . FIGS. 33A and 33B are diagrams for explaining the operation of the circuit of FIG. 26 . FIG. 34 is a diagram for explaining the reason why the reference current is supplied to the source of the drive transistor in the circuit of FIG. 26 . FIG. 35 is a diagram for explaining the reason why the reference current is supplied to the source of the drive transistor in the circuit of FIG. 26 . FIG. 36 is a circuit diagram showing a specific configuration of the pixel circuit according to a seventh embodiment. FIG. 37 is a circuit diagram showing a specific configuration of the pixel circuit according to an eighth embodiment. FIGS. 38A to 38 K are timing charts for explaining the operation of the circuit of FIG. 36 . FIGS. 39A to 39 K are timing charts for explaining the operation of the circuit of FIG. 37 . FIG. 40 is a circuit diagram showing a specific configuration of the pixel circuit according to a ninth embodiment. FIG. 41 is a circuit diagram showing a specific configuration of the pixel circuit according to a 10th embodiment. FIGS. 42A to 42 J are timing charts for explaining the operation of the circuit of FIG. 40 . FIGS. 43A to 43 J are timing charts for explaining the operation of the circuit of FIG. 41 . FIG. 44 is a circuit diagram showing a specific configuration of the pixel circuit according to an 11th embodiment. FIG. 45 is a circuit diagram showing a specific configuration of the pixel circuit according to a 12th embodiment. FIGS. 46A to 46 J are timing charts for explaining the operation of the circuit of FIG. 44 . FIGS. 47A to 47 J are timing charts for explaining the operation of the circuit of FIG. 45 . detailed-description description="Detailed Description" end="lead"? 100 , 100 A to 100 J . . . display device, 101 . . . pixel circuit (PXLC), 102 . . . pixel array, 103 . . . horizontal selector (HSEL), 104 . . . write scanner (WSCN), 105 . . . first drive scanner (DSCN 1 ), 106 . . . second drive scanner (DSCN 2 ), 107 . . . third drive scanner (DSCN 3 ), 108 . . . fourth drive scanner (DSCN 4 ), 109 . . . fifth drive scanner (DSCN 5 ), 110 . . . sixth drive scanner (DSCN 6 ), DTL 101 to DTL 10 n . . . data line, WSL 101 to WSL 10 m . . . scanning lines, DSL 101 to DSL 10 m, DSL 111 to DSL 11 m, DSL 121 to DSL 12 m, DSL 131 to DSL 13 m, DSL 141 to DSL 14 m, DSL 151 to DSL 15 m, DSL 161 to DSL 16 m . . . drive lines, 111 . . . drive transistor constituted by TFT, 112 . . . first switch constituted by TFT, 113 . . . second switch constituted by TFT, 114 . . . third switch constituted by TFT, 115 . . . fourth switch constituted by TFT, 116 . . . fifth switch constituted by TFT, 117 . . . sixth switch constituted by TFT, 118 . . . seventh switch constituted by TFT, 119 . . . light emitting element, 120 . . . seventh or eighth switch constituted by TFT, 121 . . . eighth or ninth switch constituted by TFT, ND 111 . . . first node, ND 112 . . . second node, ND 113 . . . third node, ND 114 . . . fourth node.

20060503

20080408

20070308

57220.0

G09G336

LE, TUNG X

PIXEL CIRCUIT, DISPLAY DEVICE, AND METHOD OF DRIVING PIXEL CIRCUIT

UNDISCOUNTED

ACCEPTED

G09G

ACCEPTED

Transmission power range setting during channel assignment for interference balancing in a cellular wireless communication system

The present invention relates to a method for balancing the distribution of interference between radio cells in a wireless communication system comprising cells in which subcarrier blocks are used for communication. A number of adjacent cells build a cell cluster. Moreover, the present invention relates to a corresponding method adapted for use in a system in which multi beam antennas or multiple antennas are used. Furthermore, the present invention relates to base stations performing the above method as well as a communication system comprising the base stations. To reduce the large average SIR variations without causing additional SIR estimation, measurement and calculation problem as introduced with power control the invention suggests to group subcarrier blocks into a plurality of subcarrier block sets in each cell of a cell cluster, to determine transmission power ranges for each of the cells of said cell cluster, and to assign transmission power ranges to the subcarrier block sets to perform TPC within the ranges.

1-44. (canceled) 45. A method for balancing the distribution of interference between radio cells in a wireless communication system, the system comprising a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, wherein a number of adjacent radio cells build a cell cluster, the method comprising the steps of: grouping said subcarrier blocks into a plurality of subcarrier block sets in each radio cell of the cell cluster, determining a plurality of transmission power ranges for each of the radio cell of said cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, assigning the plurality of transmission power ranges to the subcarrier block sets of radio cells of the cell cluster. 46. The method according to claim 45, wherein the radio cells of the cell cluster each comprise corresponding subcarrier block sets having the same subcarriers. 47. The method according to claim 46, wherein said plurality transmission power ranges is assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single radio cell, there is a mapping of each of said plurality of transmission power ranges to a subcarrier block set of said single radio cell, and there is a mapping of each of said plurality of transmission power ranges to one of said corresponding subcarrier block sets in the radio cells of said cell cluster. 48. The method according to claim 46, wherein said plurality transmission power ranges is assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single radio cell, there is a mapping of each of said plurality of subcarrier block sets of said single radio cell to a transmission power range, and there is a mapping of each of said corresponding subcarrier block sets in the radio cells of said cell cluster to one of said plurality of transmission power ranges. 49. The method according to claim 47, wherein the mapping is a unique or one-to-one mapping. 50. A method for balancing the distribution of interference between radio cells in a wireless communication system, the system comprising a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, wherein N adjacent radio cells build a cell cluster, N being an integer number of 2 or more, the method comprising the steps of: grouping said subcarrier blocks into N subcarrier block sets in each radio cell of the cell cluster, wherein the radio cells of the cell cluster each comprise corresponding subcarrier block sets having the same subcarriers, determining N transmission power ranges for each of the radio cell of said cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, assigning N transmission power ranges to the N subcarrier block sets of radio cells of the cell cluster, such that each of the N transmission power ranges in a radio cell is assigned to one of the N subcarrier block sets of said radio cell, and each of the N transmission power ranges is assigned to one subcarrier block set of corresponding subcarrier block sets. 51. A method for balancing the distribution of interference between radio cells in a wireless communication system, the system comprising a plurality of radio cells each of them comprising at least two sectors, wherein in each sector a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, wherein a number of adjacent radio cells build a cell cluster, the method comprising the steps of: grouping said subcarrier blocks into a plurality of subcarrier block sets in each of the sectors of each radio cell of said cluster, determining a plurality of transmission power ranges for each sector of each radio cell of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, assigning the plurality of transmission power ranges to the plurality of subcarrier block sets of a sector of a radio cell and its adjacent sectors of said other radio cells. 52. The method according to claim 51, wherein each sector of a radio cell has adjacent sectors in the other radio cells of the cell cluster, and wherein a sector of a radio cell and its adjacent sectors in said other radio cells build a sector cluster and each comprise corresponding subcarrier block set having the same subcarriers. 53. The method according to claim 52, wherein said plurality of transmission power ranges is assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single sector of a radio cell, there is a mapping of each of said plurality of transmission power ranges to a subcarrier block set of said sector, and there is a mapping of each of said plurality of transmission power ranges to one of said corresponding subcarrier block sets in said sector cluster. 54. The method according to claim 51, wherein said plurality of transmission power ranges is assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single sector of a radio cell, there is a mapping of each of said plurality of subcarrier block sets of said sector to a transmission power range, and there is a mapping of each of said plurality of said corresponding subcarrier block sets in said sector cluster to one transmission power range. 55. The method according to claim 53, wherein the mapping is a unique or one-to-one mapping. 56. The method according to claim 45, wherein the communication system comprises a plurality of communication terminals communicating with base stations associated to said plurality of radio cells/sectors, the method further comprising the steps of: measuring the path loss of a communication signal of a communication terminal and the path loss of interference from adjacent radio cells/sectors for said communication signal, and assigning the communication terminal to a subcarrier block of a subcarrier block set in a radio cell/sector based on said measurement. 57. The method according to claim 56, further comprising the step of determining a transmission power range for said communication terminal based on said measurement, and wherein the communication terminal is assigned to a block set based on the determined transmission power range. 58. The method according to claim 45, wherein the transmission power ranges in different radio cells/sectors vary. 59. The method according to claim 45, wherein the subcarrier block set size of corresponding subcarrier block sets is equal. 60. The method according to claim 45, further comprising the step of reconfiguring the subcarrier block sets in a radio cell/sector of radio cell. 61. The method according to claim 45, further comprising the step of reconfiguring the transmission power ranges in a radio cell/sector of a radio cell. 62. The method according to claim 60, wherein the reconfiguration of the power ranges and/or the subcarrier block sets in the radio cell is performed in accordance with the other radio cells of its cell cluster. 63. The method according to claim 60, wherein the reconfiguration of the power ranges and/or the subcarrier block sets in the sector is performed in accordance with the other sectors of its sector cluster. 64. The method according to claim 60, wherein the reconfiguration is based on channel quality measurements. 65. The method according to claim 45, further comprising the step of signaling information related to a reconfiguration of the subcarrier block sets in a radio cell/sector from the/its radio cell to at least one adjacent radio cell/sector. 66. The method according to claim 61, further comprising the step of signaling information related to channel qualities in a radio cell/sector from the/its radio cell to at least one adjacent radio cell/sector. 67. The method according to claim 65, further comprising the step of signaling the information to a control unit in the communication system. 68. The method according to claim 56, further comprising the step of signaling information related to a subcarrier block assignment and/or a subcarrier block set assignment to a communication terminal. 69. A base station in a wireless communication system, the system comprising a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, wherein a number of adjacent radio cells build a cell cluster, the base station comprising: processing unit operable to group said subcarrier blocks into a plurality of subcarrier block sets in each radio cell of the cell cluster, determination unit operable to determine a plurality of transmission power ranges for each of the radio cell of said cell cluster, power control unit operable to perform power control within a range of transmission power levels defined by one of said plurality of transmission power ranges, assigning unit operable to assign the plurality transmission power ranges to the subcarrier block sets of radio cells of the cell cluster. 70. The base station according to claim 69, wherein the radio cells of the cell cluster each comprise corresponding subcarrier block sets having the same subcarriers. 71. The base station according to claim 69, wherein said assigning unit is operable to assign said plurality transmission power ranges to the subcarrier block sets of radio cells of the cell cluster, such that in a single radio cell, there is a mapping of each of said plurality of transmission power ranges to a subcarrier block set of said single radio cell, and there is a mapping of each of said plurality of transmission power ranges to one of said corresponding subcarrier block sets in the radio cells of said cell cluster. 72. The base station according to claim 69, wherein said assigning unit is operable to assign said plurality transmission power ranges to the subcarrier block sets of radio cells of the cell cluster, such that in a single radio cell, there is a mapping of each of said plurality of subcarrier block sets of said single radio cell to a transmission power range, and there is a mapping of each of said corresponding subcarrier block sets in the radio cells of said cell cluster to one of said plurality of transmission power ranges. 73. A base station in a wireless communication system, the system comprising a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, wherein N adjacent radio cells build a cell cluster, N being an integer number of 2 or more, the base station comprising: processing unit operable to group said subcarrier blocks into x·N subcarrier block sets in each radio cell of the cell cluster, wherein the radio cells of the cell cluster each comprise corresponding subcarrier block sets having the same subcarriers, x being an integer number of 1 ore more, determination unit operable to determine y·N transmission power ranges for each of the radio cell of said cell cluster, y being an integer number of 1 ore more, power control unit operable to perform power control within a range of transmission power levels defined by one of said plurality of transmission power ranges, assigning unit operable to assign y·N transmission power ranges to the x·N subcarrier block sets of radio cells of the cell cluster, such that each of the y·N transmission power ranges in a radio cell is assigned to one of the x·N subcarrier block sets of said radio cell, and y/x transmission power ranges on average are assigned to one subcarrier block set of corresponding subcarrier block sets. 74. A base station in a wireless communication system, the system comprising a plurality of radio cells each of them comprising at least two sectors, wherein in each sector a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, and wherein a number of adjacent radio cells builds a cell cluster, the base station comprising: processing unit operable to group said subcarrier blocks into N subcarrier block sets in each of the sectors of each radio cell of said cluster, wherein each sector of a radio cell has N−1 adjacent sectors in the other radio cells of the cell cluster, and wherein a sector of a radio cell and its adjacent sectors in said other radio cells each comprise corresponding subcarrier block set having the same subcarriers, N being an integer number of 2 or more, determination unit operable to determine N transmission power ranges for each sector of each radio cell of the cell cluster, power control unit operable to perform power control within a range of transmission power levels defined by one of said plurality of transmission power ranges, assigning unit operable to assign the N transmission power ranges to the N subcarrier block sets of a sector of a radio cell and its adjacent sectors of said other radio cells, such that in a sector, each of the N transmission power ranges in a sector of a radio cell is assigned to one of the N subcarrier block sets of said sector, and each of the N transmission power ranges is assigned to one subcarrier block set of corresponding sectors. 75. A base station in a wireless communication system, the system comprising a plurality of radio cells each of them comprising at least two sectors, wherein in each sector a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, and wherein N adjacent radio cells builds a cell cluster, the base station comprising: processing unit operable to group said subcarrier blocks into x·N subcarrier block sets in each of the sectors of each radio cell of said cluster, wherein each sector of a radio cell has N−1 adjacent sectors in the other radio cells of the cell cluster, and wherein a sector of a radio cell and its adjacent sectors in said other radio cells each comprise corresponding subcarrier block set having the same subcarriers, x being an integer number of 1 ore more and N being an integer number of 2 or more, determination unit operable to determine y·N transmission power ranges for each sector of each radio cell of the cell cluster, y being an integer number of 1 ore more, power control unit operable to perform power control within a range of transmission power levels defined by one of said plurality of transmission power ranges, assigning unit operable to assign the y·N transmission power ranges to the x·N subcarrier block sets of a sector of a radio cell and its adjacent sectors of said other radio cells, such that in a sector, each of the y·N transmission power ranges in a sector of a radio cell is assigned to one of the x·N subcarrier block sets of said sector, and y/x transmission power ranges on average are assigned to one subcarrier block set of corresponding sectors. 76. The base station according claim 69, wherein the base station is adapted to perform a method for balancing the distribution of interference between radio cells in a wireless communication system, the system comprising a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, wherein a number of adjacent radio cells build a cell cluster, the method comprising the steps of: grouping said subcarrier blocks into a plurality of subcarrier block sets in each radio cell of the cell cluster, determining a plurality of transmission power ranges for each of the radio cell of said cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, assigning the plurality of transmission power ranges to the subcarrier block sets of radio cells of the cell cluster. 77. The base station according to claims 73, further comprising: measuring unit operable to measure the path loss of a communication signal of a communication terminal and the path loss due to interference among adjacent sectors for said communication signal, and the assigning unit is operable to assign the communication terminal to one of said subcarrier block sets based on said measurements. 78. A communication terminal in a wireless communication system, the system comprising a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, the communication terminal comprising power control unit operable to perform power control between a base station of a radio cell communicating with the communication terminal, wherein the power control unit is operable to perform power control in a transmission power control range in an interval defined by a transmission power level of 0 and a maximum transmission power level. 79. The communication terminal according to claim 42, further comprising receiving unit operable to receive information indicating a subcarrier block assignment and/or a subcarrier block set assignment, and selection unit operable to select the signaled assigned subcarrier block and/or signaled assigned subcarrier block set for data transmission. 80. A radio communication system comprising a base station according to claim 69 and a communication terminal in a wireless communication system, the system comprising a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers, the communication terminal comprising power control unit operable to perform power control between a base station of a radio cell communicating with the communication terminal, wherein the power control unit is operable to perform power control in a transmission power control range in an interval defined by a transmission power level of 0 and a maximum transmission power level.

FIELD OF THE INVENTION The present invention relates to a method for balancing the distribution of interference between radio cells in a wireless communication system. The system comprises a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers. Further, a number of adjacent radio cells build a cell cluster. Moreover, the present invention relates to a corresponding method adapted for use in a system in which sectorized base stations are used. Furthermore, the present invention relates to base stations performing the above method as well as a communication system comprising the base stations. BACKGROUND ART In modern packet-based cellular mobile communication systems, Dynamic Channel Assignment (DCA) schemes are popular, since they are an efficient tool to increase the (air interface) system throughput. DCA schemes utilize the short term fluctuations (fast fading) of the channel quality of the links between base stations (BS) and mobile stations (MS). In such a system a so-called scheduler (usually part of the base station) tries to assign system resources preferably to mobile stations in favorable channel conditions. In time domain DCA works on a frame-by-frame basis, where a frame duration is typically in the (sub-)millisecond region. Furthermore—depending on the multiple access scheme—the air interface resources are divided in e.g. code and/or frequency domain. The following description concentrates on downlink scenarios (BS transmits to MS), however without loss of generality, DCA can also be applied to the uplink (MS transmits to BS). In any case, the scheduler performing the DCA needs to have detailed channel knowledge of the BS-MS links, which is gathered by channel estimation. If the scheduler is located in the network and the measurement is performed in the MS, the channel information is signaled from MS to BS. It is important, that the channel quality is measured on a instantaneous basis in order to reflect the instantaneous received signal power and the instantaneous interference. In Frequency Division Multiple Access (FDMA) systems, DCA is performed in time-frequency domain, since physical layer channels are defined in frequency domain. Typically, the channel quality varies significantly in frequency domain (frequency selective fading). Hence, depending on the conditions of the channels over all available frequencies and all active mobile stations, the scheduler can assign the channels dynamically at each scheduling instant to specific BS-MS links. In an OFDMA (Orthogonal Frequency Division Multiple Access) system, the frequency resource is partitioned into narrowband subcarriers, which typically experience flat fading. Here, generally the scheduler dynamically assigns subcarrier blocks (containing M adjacent or separated subcarriers) to a specific MS in order to utilize favorable channel conditions on a link. Example of such a system is known from Rohling et al., “Performance of an OFDM-TDMA mobile communication system”, IEEE Proceedings on the Conference on Vehicular Technology (VTC 1996), Atlanta, 1996. In case of a CDMA (Code Division Multiple Access) the system resources are defined in code domain and, therefore, the scheduler dynamically assigns codes to specific BS-MS links. Note, that in contrast to FDMA, for a given link the channel quality is similar for all resources/codes (fading is not code selective) and, hence, in code domain the DCA is performed with respect to the number of codes to assign to a specific MS and not which codes to assign. The DCA is focused on the time domain scheduling utilizing the fast fading characteristics. HSDPA (High Speed Downlink Packet Access) within the 3GPP (3rd Generation Partnership Project) standard is such a CDMA system employing DCA. A MC-CDMA (Multi-Carrier CDMA) system can be considered as a combination of CDMA and (O)FDMA. Hence, DCA can be performed as well in code as in frequency domain. Generally, the DCA throughput efficiency increases with the number of active mobile stations in a cell, since this increases the number of links in good channel conditions and, therefore, increases the probability that a channel in favorable conditions is scheduled (multi-user diversity). Typically, DCA is combined with link adaptation techniques such as Adaptive Modulation and Coding (AMC) and hybrid Automatic Repeat reQuest (ARQ). Furthermore, DCA can be combined with power control schemes, where the power assigned to a specific channel (in code, frequency domain) is controlled in order to compensate the channel power variations and/or to support the AMC operation. Properties of Non-Power Controlled Systems As described in the previous section, for efficient DCA operation the scheduler in the BS when assuming a non-power controlled system needs detailed knowledge on the instantaneous quality of all channels over all available subcarrier blocks and all involved BS-MS links. Considering a DCA OFDMA multi-cell scenario and a frequency re-use factor of 1, the system is typically interference limited. I.e. the channel quality per subcarrier block is primarily defined by the signal (S) to interference (I) ratio (SIR), where the interference is dominated by the intercell-interference (co-channel interference) caused by the transmissions on the respective channel (subcarrier block) in adjacent cells (C denotes the set of adjacent cells): ChannelQuality ≈ SIR = S I ≈ S ∑ c ⁢ I c ( 1 ) In case of an OFDMA system with DCA and frequency selective fading, the instantaneous SIR(t) for a given link to a mobile station m varies over the subcarrier blocks b, since both the signal and the interference experience fading: SIR b m ⁡ ( t ) = S b m ⁡ ( t ) I b m ⁡ ( t ) ≈ S b m ⁡ ( t ) ∑ c ⁢ ( I b m ⁡ ( t ) ) c ( 2 ) As mentioned earlier, the performance of a system employing DCA and AMC greatly depends on the accuracy of the SIR estimation. Therefore, according to equation (2) the following problems occur. All values in equation (2) experience fast fading and will change between the point in time of the measurement and the point in time of the actual transmission (after performing DCA and AMC selection). This delay causes inaccurate DCA and AMC operation. The delay even increases, if the measurement is performed at the MS and needs to be fed back by signaling to the BS. The number of interferers in the denominator depends on the actual usage (allocation) of the subcarrier block in the adjacent cells. I.e. depending on the actual load in the adjacent cells some subcarrier blocks might not be used. Generally, at the point in time of the measurement, the usage of subcarrier block at the point in time of the transmission is unknown in adjacent cells due to the following reasons: The channel quality measurement is performed based on an outdated interference caused by the subcarrier block allocation (scheduling) in the adjacent cells (measurement for the n-th frame is performed at the (n-k)-th frame, where the subcarrier allocation is most likely different). Further, there exists the so-called chicken-and-egg allocation problem: In cell A, the subcarrier block allocation and AMC can only be performed after the SIR measurement/calculation in cell A has been performed, which requires knowledge of the subcarrier block allocation in cell B (adjacent cells). However, before the subcarrier block allocation in cell B can be performed the SIR measurement/calculation in cell B needs to be performed, which requires the knowledge of the subcarrier block allocation in cell A. In case the chicken-and-egg problem may be avoided/solved by e.g. an iterative process, signaling of e.g. the allocation status between base stations would be required. However, since the scheduling frames are in the millisecond region, the signaling would introduce additional significant delay. Additionally, without any power control, the average SIR (neglecting fast fading influences) for a BS-MS link strongly depends on the geometry (e.g. distance to BS) of the MS causing the following effects: With increasing distance between BS and MS, the SIR for the respective links decreases, since the average received signal power decreases and the average received interference power increases. This translates in a significantly lower achievable data rate per subcarrier-block for links to mobile stations in low geometry. The difference in average SIR can be on the order of tens of dB, which requires a large dynamic range for the AMC scheme definition. This leads to an increased amount of signaling, since the required number of combinations of modulation schemes and code rates increases when keeping the AMC granularity with respect to smaller dynamic ranges Compared to power controlled systems, for non-power controlled systems it is more likely that multilevel modulation schemes (e.g. 8-PSK, 16-QAM, 64-QAM, etc) are chosen for links to mobile stations in high geometry. Although, this increases the available throughput for those mobile stations, it can decrease the overall system throughput compared to a system, where the available power is distributed such that only non-multilevel modulation schemes (e.g. QPSK) are used. This is caused by the reduced power efficiency of multilevel modulation schemes. Compared to power controlled systems, for non-power controlled systems it is more likely that mobile stations in low geometry cannot receive any data with single transmission attempts, but would need several retransmissions. Therefore, the average number of transmissions (ARQ retransmissions) increases, which in turn increases the transmission delay and feedback signaling, as well as decreasing the bandwidth efficiency. Data transmission to mobile stations in high geometry is burstier in the time domain, since on average higher modulation and coding schemes can be selected. This results in a burstier subcarrier block allocation. This will make the SIR estimation according to equation (2) more difficult, since the subcarrier block allocation changes more often. Properties of Power Controlled Systems DCA and AMC can also be combined with Power Control (PC) schemes. Employing PC the system tries to compensate fluctuations of the received signal power due to the signal path loss, shadowing effects (slow fading) and or fast fading effects. Generally, PC schemes can be classified into two categories: Fast PC and slow PC. In contrast to systems without PC, for slow PC systems the average SIR does not depend on the geometry of the mobile stations, assuming only slow fading effects and unlimited minimum and maximum transmit power. Hence, the achievable data rates per subcarrier block do not depend on the MS position. Note however, the slow PC can only operate within certain limits (dynamic range of the control commands), i.e. the power compensation might not be sufficient or fast enough for any link Fast power control is usually performed jointly with the AMC in order to adapt the transmission rate to short term fluctuations and in order to optimize the overall power usage. With slow/fast PC the instantaneous SIR estimation/measurement/calculation problem as outlined in the previous sections above, is more severe compared to the non-PC case. That is, the unknown number of interference components of the sum in the denominator equation (2) do not only experience fast fading, but significantly vary in amplitude due to the PC in adjacent cells. I.e. the intercell-interference on a given subcarrier block from a given adjacent cell can vary from frame to frame in tens of dB depending on which MS is scheduled on the respective subcarrier block, since the transmitted power might vary significantly depending primarily on the MS location. This is especially critical, if the interference is dominated by few interferers, since there is no interference averaging effect. SUMMARY OF THE INVENTION One object of the present invention is to reduce the large intercell interference fluctuations caused by power control schemes. The object is solved by the subject matter of the independent claims. The different embodiments of the present invention are subject matters of the dependent claims. In more detail, the present invention provides a method for balancing the distribution of interference between radio cells in a wireless communication system. The system may comprise a plurality of radio cells in which a plurality of subcarrier blocks is used for communication. Each subcarrier block may comprise a plurality of subcarriers and a number of adjacent radio cells may build a cell cluster. Further, it should be noted that the term “subcarrier block” may also be understood as a (physical layer) channel in a FDM (Frequency Division Multiplex) based communication system, e.g. in case the number of subcarriers of a subcarrier block is equal to one. According to the method the subcarrier blocks may be grouped into a plurality of subcarrier block sets (SBSs) in each radio cell of the cell cluster. Further, a plurality of transmission power ranges may be determined for each of the radio cells of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, and the plurality of transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster. It is noted that according to this embodiment, the number of transmission power ranges and subcarrier block sets are independent of one another, i.e. same do not necessarily have to be of same number. According to a further embodiment, the radio cells of the cell cluster may each comprise corresponding subcarrier block sets having the same subcarriers. More specifically, a transmission power range as mentioned above may define a range of transmission power levels used to power control of a communication channel (subcarrier block) to a mobile communication terminal, i.e. when choosing a subcarrier block for communication, only a predetermined transmission power level range of the subcarrier block set to which the respective subcarrier block belongs to may be used for power control. The plurality transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single radio cell, there is a mapping of each of the plurality of transmission power ranges to a subcarrier block set of the single radio cell, and there is a mapping of each of the plurality of transmission power ranges to one of the corresponding subcarrier block sets in the radio cells of the cell cluster. This rule for the distribution of power ranges may be especially applicable in situations in which the number of available transmission power ranges is chosen to be large or equal to the number of subcarrier block sets. Further, the plurality transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single radio cell, there is a mapping of each of the plurality of subcarrier block sets of the single radio cell to a transmission power range, and there is a mapping of each of the corresponding subcarrier block sets in the radio cells of the cell cluster to one of the plurality of transmission power ranges. In contrast to the distribution rule exemplary mentioned above, this rule for the distribution of power ranges may be especially applicable in situations in which the number of available subcarrier block sets is chosen to be larger or equal to the number of transmission power ranges. According to another embodiment, the mapping used in the two above mentioned assignment rules is a unique or one-to-one mapping. This means that e.g. when mapping the transmission power ranges to subcarrier block sets, each of the transmission power ranges is mapped to a corresponding single subcarrier block set. If the subcarrier block sets are mapped to the transmission power ranges, each subcarrier block set is mapped to a corresponding single transmission power range. To simplify the distribution of transmission power ranges and subcarrier block sets, their number may be determined based on the number of radio cells forming a cell cluster. Hence, in a further embodiment, the present invention provides a method for balancing the distribution of interference between radio cells in a wireless communication system, comprising a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers. Further, N adjacent radio cells may build a cell cluster, wherein N is an integer number of 2 or more. According to this embodiment of the present invention the subcarrier blocks may be grouped into N subcarrier block sets in each radio cell of the cell cluster, wherein the radio cells of the cell cluster each comprise corresponding subcarrier block sets having the same subcarriers. Hence, the number of subcarrier block sets corresponds to the number of radio cells in a cluster in this embodiment. Further, N transmission power ranges may be determined for each of the radio cells of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, and the N transmission power ranges may be assigned to the N subcarrier block sets of radio cells of the cell cluster, such that each of the N transmission power ranges in a radio cell is assigned to one of the N subcarrier block sets of the radio cell, and each of the N transmission power ranges is assigned to one subcarrier block set of corresponding subcarrier block sets. When choosing the number of cells in a cell cluster, the number of subcarrier block sets and the number of transmission power ranges as proposed in this embodiment the general distribution rules as defined above may be significantly simplified. Another embodiment of the present invention relates to a system in which the number of transmission power ranges and subcarrier block sets are each integer multiples of the number of radio cells in a cell cluster. This embodiment also provides a method for balancing the distribution of interference between radio cells in a wireless communication system. Again the system may comprise a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block may comprise a plurality of subcarriers. N adjacent radio cells may build a cell cluster, wherein N may be an integer number of 2 or more. According to the method, the subcarrier blocks may be grouped into x·N subcarrier block sets in each radio cell of the cell cluster, wherein the radio cells of the cell cluster each comprise corresponding subcarrier block sets having the same subcarriers. x represents an integer number of 1 or more. Further, y·N transmission power ranges may be determined for each of the radio cells of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, and wherein y is an integer number of 1 ore more. Next, the y·N transmission power ranges may be assigned to the x·N subcarrier block sets of radio cells of the cell cluster, such that each of the y·N transmission power ranges in a radio cell is assigned to one of the x·N subcarrier block sets of the radio cell, and y/x transmission power ranges on average are assigned to one subcarrier block set of corresponding subcarrier block sets. It is noted that the ratio y/x may also result in an non-integer number depending on the choice of the parameters x and y. Obviously, it is not possible to assign half of a transmission power range to a subcarrier block set. However, it is possible to distribute an integer number of power ranges to subcarrier block sets in that different quantities of power ranges are assigned to each of the subcarrier block sets such that on average the ratio of y/x power ranges is assigned. It is further noted that the different embodiments of the method for balancing the interference in a wireless communication system outlined above should not be understood as restricting the power ranges in the different cells of a cell cluster to identical power ranges. The individual power ranges in each radio cell of a cell cluster may be identical or may be different from each other. This is of advantage to be able to adapt to e.g. the respective channel conditions and/or cell-sizes in the different cells. In all embodiments above, the method may further comprise the steps of measuring the path loss of a communication signal of a communication terminal and the path loss of the interference from adjacent cells. The embodiments above may further comprise the assignment of the communication terminal to at least one subcarrier block of one of the subcarrier block sets based on the measurement. A transmission power range for the communication terminal may be determined based on the above mentioned measurement, and the communication terminal may be assigned to at least one subcarrier block set based on the determined transmission power range. It should be noted that the actual channel assignment may be carried out onto a subcarrier block. In this context, the assignment to a subcarrier block set may be regarded as a pre-selection. In an alternative embodiment, it may also be considered to assign a block set to a communication terminal first and to choose the respective transmission power level based on the assignment. Hence, the transmission power range may be determined based on the assigned block set. The transmission power range of the assigned subcarrier block set may be chosen based on the ratio of the measured signal path loss and the measured interference path loss. Consequently, for a communication terminal that is located close to a base station of a radio cell the measurement results may indicate that a transmission power range comprising low transmission power levels may be sufficient for a communication between the communication terminal and the base station. In contrast, for a communication terminal that is located near to the cell boundaries of a radio cell the measurement results may indicate an accordingly transmission power range comprising large transmission power levels may be required for a communication between the communication terminal and the base station. Further, it should be noted the channel quality fluctuations may be countered by changing the transmission power level within the allowed power range for the respective subcarrier block set, by changing the transmit power range (i.e. changing the subcarrier block set), or by performing link adaptation by changing the modulation and coding scheme. It is of further advantage, if the transmission power ranges in different radio cells of a cell cluster vary, such that same may be adapted to the respective channel conditions in each of the radio cells of the cell cluster. Further, the transmission power ranges in a radio cell may vary between the radio cells. As explained above, this allows individual control of the transmission power ranges in each of the cells to adapt same to changing channel quality conditions in the respective cell. To be able to adapt to changing channel quality conditions also the subcarrier block sets in a radio cell may be reconfigured. For the same reason as above also the transmission power ranges in a radio cell may be reconfigured. The reconfiguration of the power ranges and/or the subcarrier block sets in the radio cell may be performed in accordance with the other radio cells of its cell cluster. The reconfiguration may be based on channel quality measurements in the radio cell and/or the other radio cells of its cell cluster. Further, information related to a reconfiguration of the subcarrier block sets in a radio cell may be signaled from the radio cell to the other radio cells of its cell cluster or may be signaled from a control unit (e.g. radio network controller) to the radio cells forming a cell cluster. According to a further embodiment of the present invention also information related to channel qualities in a radio cell may be signaled from the radio cell to the other radio cells of its cell cluster. By signaling the channel qualities in a radio cell to adjacent radio cells, same may include the information when reconfiguring the transmission power ranges or subcarrier block sets in the respective radio cell. The main idea underlying the present invention may also be applicable to systems in which radio cells are divided into sectors, i.e. to systems using multi-beam antennas or multiple antennas. Employing this layout, a single cell may be divided in a plurality of sectors each covered by an antenna beam. According to another embodiment, the present invention therefore provides a method for balancing the distribution of interference between radio cells in a wireless communication system. The system may comprise a plurality of radio cells each of them comprising at least two sectors, wherein in each sector a plurality of subcarrier blocks is used for communication. Each subcarrier block may comprise a plurality of subcarriers, and a number of adjacent radio cells build a cell cluster. The subcarrier blocks may be grouped into a plurality of subcarrier block sets in each of the sectors of each radio cell of the cluster. A plurality of transmission power ranges may be determined for each sector of each radio cell of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control. Next, the plurality of transmission power ranges may be assigned to the plurality of subcarrier block sets of a sector of a radio cell and its adjacent sectors of the other radio cells. In another embodiment, each sector of a radio cell may have adjacent sectors in the other radio cells of the cell cluster. Further, a sector of a radio cell and its adjacent sectors belonging to other radio cells may build a sector cluster and each may comprise corresponding subcarrier block set having the same subcarriers. The plurality of transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single sector of a radio cell, there is a mapping of each of the plurality of transmission power ranges to a subcarrier block set of the sector, and there is a mapping of each of the plurality of transmission power ranges to one of the corresponding subcarrier block sets in the sector cluster. Alternatively, the plurality of transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single sector of a radio cell, there is a mapping of each of the plurality of subcarrier block sets of the sector to a transmission power range, and there is a mapping of each of the plurality of the corresponding subcarrier block sets in the sector cluster to one transmission power range. As outlined above, the mapping may be a unique or one-to-one mapping. To simplify the distribution of transmission power ranges and subcarrier block sets, their number may be determined in relation to the number of radio cells forming a cell cluster. Hence, in a further embodiment, the present invention provides a method for balancing the distribution of interference between radio cells in a wireless communication system. The system may comprise a plurality of radio cells each of them comprising at least two sectors, wherein in each sector a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers. A number of adjacent radio cells may build a cell cluster. The subcarrier blocks may be grouped into N subcarrier block sets in each of the sectors of each radio cell of the cluster, wherein each sector of a radio cell has N−1 adjacent sectors in the other radio cells of the cell cluster, and wherein a sector of a radio cell and its adjacent sectors in the other radio cells each comprise corresponding subcarrier block set having the same subcarriers and wherein N may be an integer number of 2 or more. Further, N transmission power ranges may be determined for each sector of each radio cell of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control. The N transmission power ranges may be assigned to the N subcarrier block sets of a sector of a radio cell and its adjacent sectors of the other radio cells, such that in a sector, each of the N transmission power ranges In a sector of a radio cell is assigned to one of the N subcarrier block sets of the sector, and each of the N transmission power ranges is assigned to one subcarrier block set of corresponding sectors. Another embodiment of the present invention relates to a system in which the number of transmission power ranges and subcarrier block sets are each integer multiples of the number of radio cells in a cell cluster. This embodiment also provides a method for balancing the distribution of interference between radio cells in a wireless communication system. Again, the system may comprise a plurality of radio cells each of them comprising at least two sectors, wherein in each sector a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers. A number of adjacent radio cells may build a cell cluster. In this embodiment, the subcarrier blocks may be grouped into x·N subcarrier block sets in each of the sectors of each radio cell of the cluster, wherein each sector of a radio cell has N−1 adjacent sectors in the other radio cells of the cell cluster, and wherein a sector of a radio cell and its adjacent sectors in the other radio cells each comprise corresponding subcarrier block set having the same subcarriers. x may be an integer number of 1 ore more and N may be an integer number of 2 or more. Further, y·N transmission power ranges may be determined for each sector of each radio cell of the cell cluster, wherein y may be an integer number of 1 ore more. The y·N transmission power ranges may be assigned to the x·N subcarrier block sets of a sector of a radio cell and its adjacent sectors of the other radio cells, such that in a sector, each of the y·N transmission power ranges in a sector of a radio cell is assigned to one of the x·N subcarrier block sets of the sector, and y/x transmission power ranges on average are assigned to one subcarrier block set of corresponding sectors. The communication system may further comprise a plurality of communication terminals communicating with base stations associated to the plurality of radio cells. The path loss of a communication signal of a communication terminal and the path loss due to interference from adjacent sectors for the communication signal may be measured e.g. at a base station, and the communication terminal may be assigned to a subcarrier block of a subcarrier block set in a sector based on the measurement. In a further step a transmission power range for the communication terminal may be determined based on the measurement, and the communication terminal may be assigned to a block set based on the determined transmission power range. According to another embodiment, it may also be considered to assign a block set to a communication terminal first and to choose the respective transmission power level based on the assignment. Hence, the transmission power range may be determined based on the assigned block set. The transmission power ranges in different sectors may vary as well as the transmission power ranges in sectors of a radio cell. Independent of the use of single or multi-beam antennas, the subcarrier block set size in corresponding subcarrier block sets may be equal, i.e. each of the subcarrier block sets comprises the same number of subcarrier blocks and/or subcarriers. Further, the subcarrier block sets may be reconfigured in a sector of radio cell. Same applies to the transmission power ranges of a sector as well. The reconfiguration of the power ranges and/or the subcarrier block sets in the sector may be performed in accordance with the other sectors of its sector cluster. Further, the reconfiguration may be based on channel quality measurements in the sector and/or the other sectors of its sector cluster. In the context of reconfiguration, information related to a reconfiguration of the subcarrier block sets in a sector may be signaled from its radio cell to radio cells comprising sectors of the sector cluster. Also, information related to channel qualities in a sector may be signaled from its radio cell to radio cells comprising sectors of the sector cluster. Independent from the system architecture, i.e. the usage of sectorized radio cells or not, the information related to the reconfiguration of power levels or subcarrier block sets may be signaled to a control unit in the communication system. Taking the example of the Release 99/415 UTRAN (UMTS Terrestrial Radio Access Network) architecture, such a control unit may be a radio network controller (RNC) or, in the evolved architecture an functional enhanced Node B, the Node B+. Further, also independent from the system architecture, information related to a subcarrier block assignment and/or a subcarrier block set assignment may be signaled to a communication terminal. The communication terminal may further comprise receiving means for receiving information indicating a subcarrier block assignment and/or a subcarrier block set assignment, and selection means for selecting the signaled assigned subcarrier block and/or signaled assigned subcarrier block set for data transmission. All the different embodiments of the inventive method for balancing the co-channel interference in radio cells may be advantageously used in a base station. The base station may be equipped with the respective means for performing the different method steps according to the different embodiments of method as outlined above. Further, the present invention provides a communication terminal adapted for its operation in the above described communication systems. In the communication terminal a power control means may be adapted to perform power control in a transmission power control range in an interval defined by a transmission power level of 0 and a maximum transmission power level. The present invention also provides radio communication system comprising a base station adapted to carry out the method according to the different embodiments and at least one communication terminal and the communication terminal described above. BRIEF DESCRIPTION OF THE DRAWINGS In the following the present invention is described in more detail in reference to the attached figures and drawings. Similar or corresponding details in the figures are marked with the same reference numerals. FIG. 1 shows a transmission power distribution for subcarrier blocks according to the prior-art, FIGS. 2, 3 & 4 show three examples for a transmission power distribution for subcarrier blocks according to an embodiment of the present invention, FIG. 5 shows a transmission power distribution for subcarrier blocks in adjacent cells on a frame-by-frame basis according to the prior-art, FIG. 6 shows a transmission power distribution for subcarrier blocks in, adjacent cells on a frame-by-frame basis according to an embodiment of the present invention, FIG. 7 shows an example for a subcarrier block set power range distribution for subcarrier blocks in adjacent cells according to an embodiment of the present invention, FIGS. 8, 9 & 10 show three examples for a multi-cell power range subcarrier block set configuration with equally sized subcarrier block sets according to an embodiment of the present invention, FIG. 11 shows an example for a subcarrier block set power range allocation pattern in adjacent radio cells each divided in a plurality of sectors according to an embodiment of the present invention, and FIG. 12 shows another example for a subcarrier block set power range allocation pattern in adjacent radio cells each divided in a plurality of sectors according to an embodiment of the present invention. DETAILED DESCRIPTION In the following the present invention will be described with regard to wireless communication system using OFDM. Though the examples relate to OFDM, it should be noted that the ideas underlying the present invention may be readily applied to other FDM based communication systems as well. According to an embodiment of the present invention the OFDM subcarrier blocks may be divided into N subcarrier block-sets (SBS). FIG. 1 shows the distribution of transmission power for subcarrier blocks according to a prior art system. FIGS. 2, 3 and 4 show three examples for the distribution of power limits (or ranges) with different SBS definitions according to different embodiments of the present invention. The assignment of the power limits may be performed in accordance with the SBS power limits in adjacent cells in order to control the SIR levels depending on the SBS as e.g. shown in FIGS. 8, 9 and 10. Compared to prior art, this power-limit definition has the advantage that the intercell-interference variations on subcarrier block basis are reduced, since the caused interference from a given adjacent cell cannot exceed a specific upper limit due to the SBS upper transmit power limit. In prior art the transmit power per subcarrier block may have any value between zero and a defined maximum with the constraint that the total transmit power must not exceed the maximum allowed transmit power. FIG. 1 shows such a subcarrier-block power allocation for a power controlled system. According to an embodiment of the present invention the subcarrier blocks may be divided into subcarrier block sets (SBS), wherein an upper limit (and possibly a lower limit) for the subcarrier block transmit power may be defined. FIGS. 2, 3, 4 show three examples of SBS definitions, wherein in the leftmost example a SBS is build from adjacent subcarrier blocks. Alternatively, a predetermined number of consecutive subcarrier blocks may be grouped into a subcarrier block set, which is assigned to a transmission power limit. The example shown in the middle associates subcarrier blocks spaced by a fixed interval to a subcarrier block set, while in the rightmost example in FIGS. 2, 3 and 4 a free distribution of subcarrier blocks into subcarrier block sets is shown. Further, it should be noted that the different subcarrier block sets of a radio cell do not necessarily comprise an equal number of subcarrier blocks as shown in the three examples. The definition of different transmission power ranges or limits may provide the possibility to map mobile stations in low geometry to subcarrier blocks belonging to a SBS with a transmit power control range having large power levels, to map mobile stations in medium geometry to subcarrier blocks belonging to a SBS with a transmit power control range having medium power levels and to map mobile stations in high geometry to subcarrier blocks belonging to a SBS with a transmit power control range having low power levels. It is noted again, that only exemplary three transmission power ranges are used in this embodiment. With respect to DCA and PC, different methodologies for the subcarrier assignment may be possible. PC for a given MS may be considered first and then a subcarrier block from a SBS for which the limits are not exceeded by the subcarrier block transmit power may be assigned. Alternatively, a subcarrier block and may be assigned to the MS and then the transmit power according to the allowed limits is assigned (i.e. perform the PC within the given limits). One of the benefits of the present invention is that the created intercell interference for a given subcarrier block is upper bounded by the maximum transmit power allowed for the subcarrier block by the SBS power limit definition. This way the SIR variation may be reduced and a worst case SIR may be estimated in adjacent cells. Since in prior art any transmit power (within overall power limits) is allowed for any subcarrier, the created intercell interference varies over a large range. The SIR variation (from frame-to-frame) may be even more reduced, if also a lower power limit is defined for the subcarrier blocks. FIG. 5 and FIG. 6 show an example of subcarrier block transmit power assignments of the adjacent radio cells to cell 1 (BS1) (see FIG. 7) for a prior art system and for a system according to an embodiment of the present invention. Assuming, a MS is e.g. located within radio cell 1 close to radio cell 2 and radio cell 3 (MS position in the upper right of cell 1), radio cell 2 and radio cell 3 cause the main interference. FIG. 5 indicates that the transmit power per subcarrier block in a prior art system. As apparent therefrom the intercell interference may vary significantly from frame-to-frame, since the interference caused by radio cell 2 and radio cell 3 on a given subcarrier can vary depending on the transmitted power, which can be between zero and a maximum transmit power. Since the frame-by-frame fluctuations in interference may not be known in radio cell 1, the SIR per subcarrier block may change within this large range. Hence, the DCA and AMC selection performance may be reduced significantly due to this “unknown” variation in the SIR per subcarrier block. Considering the method proposed by the present invention, FIG. 6 shows that the transmit power per subcarrier block may only fluctuate within specified limits i.e. within a predefined range of transmission power control levels when performing power control for a subcarrier block. This may allow improving the accuracy of SIR estimation/prediction which may result in an improved DCA and AMC selection performance. Moreover the definition of power ranges may be performed such that e.g. a mobile station in low geometry (i.e. close to the cell boundary) will be assigned to one or multiple subcarrier block(s) belonging to a subcarrier block set having a power range of high transmit power levels. The opposite would be applies for mobile stations in high geometry. Additionally to the division of subcarrier blocks into subcarrier block sets, the power limit definitions in adjacent radio cells may be aligned. Taking as an example the division of subcarrier blocks into subcarrier block sets as shown in FIG. 7, i.e. three subcarrier block set per radio cell, the transmission power ranges in which power control is performed may be defined according to the table below. SBS1 Power SBS2 Power SBS3 Power Cell Ranges Ranges Ranges Power Limits Upper Lower Upper Lower Upper Lower high > medium > low Limit Limit Limit Limit Limit Limit Cell 1 (BS1) PMAXSBS1 PMAXSBS2 PMAXSBS2 PMAXSBS3 pMAXSBS3 0 PMAXSBS1 > PMAXSBS2 > PMAXSBS3 (high) (medium) (low) Cell 2 (BS2) PMAXSBS1 0 PMAXSBS2 PMAXSBS3 PMAXSBS3 PMAXSBS1 PMAXSBS2 > PMAXSBS3 > PMAXSBS1 (low) (high) (medium) Cell 3 (BS3) PMAXSBS1 PMAXSBS2 PMAXSBS2 0 PMAXSBS3 PMAXSBS1 PMAXSBS3 > PMAXSBS1 > PMAXSBS2 (medium) (low) (high) Considering radio cells 1 to 3 as a cell cluster of strong interfering cells (see FIGS. 8, 9 & 10), the power limits may be coordinated such that across the considered radio cells of the cluster for each subcarrier block set a high, a medium and a low upper power limit is defined once. Regarding the intercell interference this may have the following effects: A subcarrier block belong to a SBS with a high power limit is interfered by subcarrier blocks with medium and low power limit, a subcarrier block belong to a SBS with a medium power limit is interfered by subcarrier blocks with high and low power limit, and a subcarrier block belong to a SBS with a low power limit is interfered by subcarrier blocks with high and medium power limit. Though the examples shown in FIG. 7 and also the distribution rule as defined in the table above refer to three subcarrier block sets per radio cell and three transmission power ranges, the present invention is generally applicable to any number of transmission power ranges and subcarrier block sets in a radio cell. As becomes obvious from the examples given above, certain constellation in the choice of the number of transmission power ranges and the number of subcarrier block sets may facilitate a simple assignment rule of transmission power levels to subcarrier block sets (or vice-versa). The following matrix shows an example for the generalization of the “assignment rule” stated above, wherein PRnx refers to a transmission power range in radio cell n having an transmission power range index x, identifying the X available different transmission power ranges per radio cell: SBS1 SBS2 SBS3 . . . SBSM−1 SBSM radio cell 1 PR11 PR12 PR13 . . . PR1X−1 PR1X radio cell 2 PR2X PR21 PR22 . . . PR2X−2 PR2X−1 radio cell 3 PR3X−1 PR3X PR31 . . . PR3X−3 PR3X−2 . . . . . . . . . . . . . . . . . . . . . radio cell N − 1 PRN−13 PRN−14 PRN−15 . . . PRN−11 PRN−12 radio cell N PRN2 PRN3 PRN4 . . . PRNX PRN1 In the table above, the power ranges PRnx of an power range index x may vary between different radio cells or may represent the same power range. Important to note is that in the given example the index x=1 refers to the power range PRnx in radio cell n having the lowest transmission power levels available for power control, while x=X refers to the power range PRnx in radio cell n having the largest transmission power levels available for power control. Moreover, PRnx≦PRnn−1 is valid for all x. The distribution of the power ranges among different cells may be achieved by a permutation of the index x indicating the strengths of power levels i.e. the transmission power level range of a signal emitted by a base station of radio cell n. As can be further seen in the table, each of the power range indices xε{1,2,3, . . . ,X} occurs once in each column and each row of the matrix. Hence, in the example shown, the number of subcarrier block sets M equals the numbers of transmission power ranges X. Also the number of radio cells in a cluster N is the same as the number of subcarrier block sets M or transmission power ranges X respectively. Note, that a possible embodiment allows PRnx=PRnx−1, which essentially means that in the respective cell SBSm and SBSm+1 can have an identical transmit power range. Naturally, this may only be valid for selected subcarrier block sets. This embodiment may be considered similar to the case when having less power ranges than subcarrier block sets for a given cell and a single power range is used for multiple subcarrier block sets. In case M>X, more than one subcarrier block set may be assigned to a single transmission power range. Also in case N≠M, i.e. the number of radio cells in a cluster and the number of subcarrier block sets is not equal, a distribution rule may follow the rule as stated above, i.e. that each row and column in the matrix may only comprise each of the power range indices x once. When choosing the number of transmission power ranges and subcarrier block sets equal to a multiple of the number of cells in a cell cluster, a simple distribution rule may be defined. In case the number of subcarrier block sets and the number of transmission power ranges per radio cell are also equal, a simple mapping scheme as outlined above may be used. FIG. 7 further shows that the subcarrier block set alignment according to this method may be extended to a multicell scenario while keeping the denoted interference properties. The proposed subcarrier block set multicell alignment may have the following effects/benefits. The SIR for MS in low geometries may be reduced, since they are preferably assigned to subcarrier blocks belonging to subcarrier block sets with high transmit power i.e. having an associated transmission power range comprising large transmit powers, which experience less interference e.g. by medium and low power subcarrier blocks. The SIR for MS in high geometries may be increased, since they are preferably assigned to subcarrier block belonging to SBS with low transmit power, which experience increased interference e.g. by high and low medium subcarrier blocks. Employing the principles of the present invention as outlined, the required dynamic range for the transmit power control may be decreased. According to a further embodiment of the present invention, the lower power limits (PMIN) are equal to the upper limits (PMAX) of the “next stronger” subcarrier block set, i.e. for PMAXSBS 1≧PMAXSBS 2≧PMAXSBS 3≧ . . . then PMINSBS 1=PMAXSBS 2, PMINSBS 2=PMAXSBS 3 . . . a.s.o. According to a further embodiment of the present invention, the lower power limits (PMIN) are smaller (e.g. by a defined offset) than the upper limits (PMAX) of the next subcarrier block set, i.e. for PMAXSBS 1≧PMAXSBS 2≧PMAXSBS 3≧ . . . a.s.o. then PMINSBS 1=PMAXSBS 2, PMINSBS 2=PMAXSBS 3 . . . a.s.o. According to another embodiment, a MS in low geometry may be assigned to high power subcarrier block sets and vice versa. I.e. a communication terminal is assigned a radio channel (one or multiple subcarrier block(s) of a subcarrier block set) based on its geometry. It should be noted that in a real (non-ideal hexagonal) deployment and environment the term geometry does not necessarily solely depend on the MS-BS distance (MS distance to the cell center), but it refers more to the signal path loss. I.e. a MS can be very close to the BS, but have a low average SIR, since the signal path it is shadowed by a building and the interference path(s) is(are) LOS (line-of-sight). A subcarrier block as used in the previous sections may comprise M subcarriers, where M may also be 1. I.e. in case of M=1 the system would be “reduced” to a FDM system. A subcarrier block-set (SBS) can contain S subcarrier blocks, where S can vary depending on the defined SBS, however preferably the same subcarrier blocks should be used for respective SBSs in adjacent cells A subcarrier block-set (SBS) may contain S subcarrier blocks, where S can vary depending on the defined SBS. However, according to another embodiment of the present invention, the same subcarrier blocks may be used for respective SBSs in adjacent cells. In the latter case, for each of the subcarrier block sets in each radio cell of a cell cluster there may exist a corresponding subcarrier block set in an adjacent radio cell correspond in that the same subcarriers are assigned to the corresponding subcarrier block sets. Further, the SBS power limits may vary depending on the radio cell. For x defined SBSs, up to x−1 SBSs may have the same power limit. The power limits may be reconfigured for each cell individually or in accordance with adjacent radio cells. Another aspect of the present invention is related to the signaling related to the (re)configuration of subcarrier block sets in the radio cells and the transmission power ranges or limits. Since a reconfiguration in a radio cell may be coordinated with adjacent the cell's radio cells, it may be necessary to signal information related to the reconfiguration to the adjacent cells. For example information relating to the channel quality, i.e. interference levels in a radio cell may be signaled to the neighboring radio cells in order to enable same to use this information when considering a reconfiguration of their power levels used. Also when the grouping of subcarrier blocks into subcarrier block sets has to be changed, the new distribution or mapping of subcarrier blocks to subcarrier block sets have to be signaled to the adjacent cells, as those may use the same mapping in the respective cell. Depending on the network architecture this information may also be transmitted to a supervising unit (e.g. radio network controller) controlling a cell cluster and may utilize respective information in order to initiate a (re)configuration. According to a further embodiment of the present invention, another aspect of the invention is the signaling related to the communication between transmitter and receiver. The signaling between the transmitter and the receiver may comprise the signaling of a subcarrier block set assignment and a subcarrier block assignment. Before an actual frequent (frame-by-frame) assignment of the subcarrier block, there may be a relatively less frequent pre-assignment of a mobile station to a subcarrier block set, which may basically define an “active” subcarrier block set for the respective mobile station. This may allow to reduce the signaling overhead for the subcarrier block assignment, since the signaling has only be performed with respect to the subcarrier block set to which the mobile station is pre-assigned. Moreover, it may allow reducing the signaling overhead for the channel quality feedback signaling from receiver to transmitter, which may be carried out only for the respective subcarrier block set. Further, it is noted that the ideas underlying the present invention may be applied to any cell layout. According to another embodiment of the present invention, sectorized radio cell may be used. An example for a hexagonal radio cell layout with 3 sectors per cell is shown in FIGS. 11 and 12. It may be assumed that the antenna patterns of the sectors within a radio cell interfere with each other in a neglectable manner (i.e. antenna beam width≦120°). In this case the interference of sectors of adjacent cells (within the antenna beam width) may be dominating. As shown in FIG. 11, for sector 2 of radio cell 1 (BS1) there exist two adjacent sectors in adjacent radio cells, namely sector 2 in radio cell 3 (BS3) and sector 3 in radio cell 2 (BS2). These three adjacent sectors in the different radio cells may also be considered as a sector cluster. In each of the sectors shown in a single radio cell, the same subcarrier blocks (i.e. subcarriers) may be simultaneously used. For balancing the interference the methods as proposed above for the use of single beam antennas may be employed. The method is only adopted to the new cell layout in that instead of performing interference balancing on radio cells of a cell cluster, the interference between sectors of a sector cluster is balanced. When comparing FIG. 11 to FIG. 7, it is noted that the same choice of the number of transmission power ranges and subcarrier block sets and a similar mapping between power ranges and subcarrier block sets may be employed. As illustrated in FIG. 11, the same power range-subcarrier block set combinations may be used within the sectors of a radio cell. Hence, the “pattern” of coordinated power range-subcarrier block set combinations among sectors belonging to a sector cluster may correspond to same known from FIG. 11 for coordinated power range-subcarrier block set combinations for a radio cell cluster. However, in case of employing sectorized radio cells, the power ranges chosen in the sectors of a single radio cell may differ from each other. Further, the transmission power ranges and subcarrier block sets within a sector may be reconfigured as described above. The signaling that may be necessary to inform adjacent radio cells on the reconfiguration of a sector may be transmitted to the base stations providing the antenna beam of adjacent sectors of a sector cluster. Depending on the network architecture this may be performed directly or via control unit in the communication system, e.g. an Radio Network Controller (RNC). Another example for a possible power range-subcarrier block set combination is illustrated in FIG. 12. In this embodiment of the present invention, the sectors of a single radio cell do not use the same power range-subcarrier block set combination, as in the example of FIG. 11. The resulting “pattern” of coordinated power range-subcarrier block set combinations considered on a sector basis is similar to the one shown in FIG. 7. This means that a sector in FIG. 12 corresponds to a radio cell in FIG. 7 to abstain from the fact that more than one sector is controlled by a base station of a radio cell. The proposed method can also be applied to MC-CDMA systems. Here, the transmit power limits for a given SBS should be defined for the sum of the power-per-code for a given (sub)carrier-(block). Such a MC-CDMA system may employ spreading in time and/or frequency domain. Further, it is noted that the principles underlying the present invention may be applicable to communication on the downlink and/or the uplink of a communication system.

<SOH> BACKGROUND ART <EOH>In modern packet-based cellular mobile communication systems, Dynamic Channel Assignment (DCA) schemes are popular, since they are an efficient tool to increase the (air interface) system throughput. DCA schemes utilize the short term fluctuations (fast fading) of the channel quality of the links between base stations (BS) and mobile stations (MS). In such a system a so-called scheduler (usually part of the base station) tries to assign system resources preferably to mobile stations in favorable channel conditions. In time domain DCA works on a frame-by-frame basis, where a frame duration is typically in the (sub-)millisecond region. Furthermore—depending on the multiple access scheme—the air interface resources are divided in e.g. code and/or frequency domain. The following description concentrates on downlink scenarios (BS transmits to MS), however without loss of generality, DCA can also be applied to the uplink (MS transmits to BS). In any case, the scheduler performing the DCA needs to have detailed channel knowledge of the BS-MS links, which is gathered by channel estimation. If the scheduler is located in the network and the measurement is performed in the MS, the channel information is signaled from MS to BS. It is important, that the channel quality is measured on a instantaneous basis in order to reflect the instantaneous received signal power and the instantaneous interference. In Frequency Division Multiple Access (FDMA) systems, DCA is performed in time-frequency domain, since physical layer channels are defined in frequency domain. Typically, the channel quality varies significantly in frequency domain (frequency selective fading). Hence, depending on the conditions of the channels over all available frequencies and all active mobile stations, the scheduler can assign the channels dynamically at each scheduling instant to specific BS-MS links. In an OFDMA (Orthogonal Frequency Division Multiple Access) system, the frequency resource is partitioned into narrowband subcarriers, which typically experience flat fading. Here, generally the scheduler dynamically assigns subcarrier blocks (containing M adjacent or separated subcarriers) to a specific MS in order to utilize favorable channel conditions on a link. Example of such a system is known from Rohling et al., “Performance of an OFDM-TDMA mobile communication system”, IEEE Proceedings on the Conference on Vehicular Technology (VTC 1996), Atlanta, 1996. In case of a CDMA (Code Division Multiple Access) the system resources are defined in code domain and, therefore, the scheduler dynamically assigns codes to specific BS-MS links. Note, that in contrast to FDMA, for a given link the channel quality is similar for all resources/codes (fading is not code selective) and, hence, in code domain the DCA is performed with respect to the number of codes to assign to a specific MS and not which codes to assign. The DCA is focused on the time domain scheduling utilizing the fast fading characteristics. HSDPA (High Speed Downlink Packet Access) within the 3GPP (3 rd Generation Partnership Project) standard is such a CDMA system employing DCA. A MC-CDMA (Multi-Carrier CDMA) system can be considered as a combination of CDMA and (O)FDMA. Hence, DCA can be performed as well in code as in frequency domain. Generally, the DCA throughput efficiency increases with the number of active mobile stations in a cell, since this increases the number of links in good channel conditions and, therefore, increases the probability that a channel in favorable conditions is scheduled (multi-user diversity). Typically, DCA is combined with link adaptation techniques such as Adaptive Modulation and Coding (AMC) and hybrid Automatic Repeat reQuest (ARQ). Furthermore, DCA can be combined with power control schemes, where the power assigned to a specific channel (in code, frequency domain) is controlled in order to compensate the channel power variations and/or to support the AMC operation. Properties of Non-Power Controlled Systems As described in the previous section, for efficient DCA operation the scheduler in the BS when assuming a non-power controlled system needs detailed knowledge on the instantaneous quality of all channels over all available subcarrier blocks and all involved BS-MS links. Considering a DCA OFDMA multi-cell scenario and a frequency re-use factor of 1, the system is typically interference limited. I.e. the channel quality per subcarrier block is primarily defined by the signal (S) to interference (I) ratio (SIR), where the interference is dominated by the intercell-interference (co-channel interference) caused by the transmissions on the respective channel (subcarrier block) in adjacent cells (C denotes the set of adjacent cells): ChannelQuality ≈ SIR = S I ≈ S ∑ c ⁢ I c ( 1 ) In case of an OFDMA system with DCA and frequency selective fading, the instantaneous SIR(t) for a given link to a mobile station m varies over the subcarrier blocks b, since both the signal and the interference experience fading: SIR b m ⁡ ( t ) = S b m ⁡ ( t ) I b m ⁡ ( t ) ≈ S b m ⁡ ( t ) ∑ c ⁢ ( I b m ⁡ ( t ) ) c ( 2 ) As mentioned earlier, the performance of a system employing DCA and AMC greatly depends on the accuracy of the SIR estimation. Therefore, according to equation (2) the following problems occur. All values in equation (2) experience fast fading and will change between the point in time of the measurement and the point in time of the actual transmission (after performing DCA and AMC selection). This delay causes inaccurate DCA and AMC operation. The delay even increases, if the measurement is performed at the MS and needs to be fed back by signaling to the BS. The number of interferers in the denominator depends on the actual usage (allocation) of the subcarrier block in the adjacent cells. I.e. depending on the actual load in the adjacent cells some subcarrier blocks might not be used. Generally, at the point in time of the measurement, the usage of subcarrier block at the point in time of the transmission is unknown in adjacent cells due to the following reasons: The channel quality measurement is performed based on an outdated interference caused by the subcarrier block allocation (scheduling) in the adjacent cells (measurement for the n-th frame is performed at the (n-k)-th frame, where the subcarrier allocation is most likely different). Further, there exists the so-called chicken-and-egg allocation problem: In cell A, the subcarrier block allocation and AMC can only be performed after the SIR measurement/calculation in cell A has been performed, which requires knowledge of the subcarrier block allocation in cell B (adjacent cells). However, before the subcarrier block allocation in cell B can be performed the SIR measurement/calculation in cell B needs to be performed, which requires the knowledge of the subcarrier block allocation in cell A. In case the chicken-and-egg problem may be avoided/solved by e.g. an iterative process, signaling of e.g. the allocation status between base stations would be required. However, since the scheduling frames are in the millisecond region, the signaling would introduce additional significant delay. Additionally, without any power control, the average SIR (neglecting fast fading influences) for a BS-MS link strongly depends on the geometry (e.g. distance to BS) of the MS causing the following effects: With increasing distance between BS and MS, the SIR for the respective links decreases, since the average received signal power decreases and the average received interference power increases. This translates in a significantly lower achievable data rate per subcarrier-block for links to mobile stations in low geometry. The difference in average SIR can be on the order of tens of dB, which requires a large dynamic range for the AMC scheme definition. This leads to an increased amount of signaling, since the required number of combinations of modulation schemes and code rates increases when keeping the AMC granularity with respect to smaller dynamic ranges Compared to power controlled systems, for non-power controlled systems it is more likely that multilevel modulation schemes (e.g. 8-PSK, 16-QAM, 64-QAM, etc) are chosen for links to mobile stations in high geometry. Although, this increases the available throughput for those mobile stations, it can decrease the overall system throughput compared to a system, where the available power is distributed such that only non-multilevel modulation schemes (e.g. QPSK) are used. This is caused by the reduced power efficiency of multilevel modulation schemes. Compared to power controlled systems, for non-power controlled systems it is more likely that mobile stations in low geometry cannot receive any data with single transmission attempts, but would need several retransmissions. Therefore, the average number of transmissions (ARQ retransmissions) increases, which in turn increases the transmission delay and feedback signaling, as well as decreasing the bandwidth efficiency. Data transmission to mobile stations in high geometry is burstier in the time domain, since on average higher modulation and coding schemes can be selected. This results in a burstier subcarrier block allocation. This will make the SIR estimation according to equation (2) more difficult, since the subcarrier block allocation changes more often. Properties of Power Controlled Systems DCA and AMC can also be combined with Power Control (PC) schemes. Employing PC the system tries to compensate fluctuations of the received signal power due to the signal path loss, shadowing effects (slow fading) and or fast fading effects. Generally, PC schemes can be classified into two categories: Fast PC and slow PC. In contrast to systems without PC, for slow PC systems the average SIR does not depend on the geometry of the mobile stations, assuming only slow fading effects and unlimited minimum and maximum transmit power. Hence, the achievable data rates per subcarrier block do not depend on the MS position. Note however, the slow PC can only operate within certain limits (dynamic range of the control commands), i.e. the power compensation might not be sufficient or fast enough for any link Fast power control is usually performed jointly with the AMC in order to adapt the transmission rate to short term fluctuations and in order to optimize the overall power usage. With slow/fast PC the instantaneous SIR estimation/measurement/calculation problem as outlined in the previous sections above, is more severe compared to the non-PC case. That is, the unknown number of interference components of the sum in the denominator equation (2) do not only experience fast fading, but significantly vary in amplitude due to the PC in adjacent cells. I.e. the intercell-interference on a given subcarrier block from a given adjacent cell can vary from frame to frame in tens of dB depending on which MS is scheduled on the respective subcarrier block, since the transmitted power might vary significantly depending primarily on the MS location. This is especially critical, if the interference is dominated by few interferers, since there is no interference averaging effect.

<SOH> SUMMARY OF THE INVENTION <EOH>One object of the present invention is to reduce the large intercell interference fluctuations caused by power control schemes. The object is solved by the subject matter of the independent claims. The different embodiments of the present invention are subject matters of the dependent claims. In more detail, the present invention provides a method for balancing the distribution of interference between radio cells in a wireless communication system. The system may comprise a plurality of radio cells in which a plurality of subcarrier blocks is used for communication. Each subcarrier block may comprise a plurality of subcarriers and a number of adjacent radio cells may build a cell cluster. Further, it should be noted that the term “subcarrier block” may also be understood as a (physical layer) channel in a FDM (Frequency Division Multiplex) based communication system, e.g. in case the number of subcarriers of a subcarrier block is equal to one. According to the method the subcarrier blocks may be grouped into a plurality of subcarrier block sets (SBSs) in each radio cell of the cell cluster. Further, a plurality of transmission power ranges may be determined for each of the radio cells of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, and the plurality of transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster. It is noted that according to this embodiment, the number of transmission power ranges and subcarrier block sets are independent of one another, i.e. same do not necessarily have to be of same number. According to a further embodiment, the radio cells of the cell cluster may each comprise corresponding subcarrier block sets having the same subcarriers. More specifically, a transmission power range as mentioned above may define a range of transmission power levels used to power control of a communication channel (subcarrier block) to a mobile communication terminal, i.e. when choosing a subcarrier block for communication, only a predetermined transmission power level range of the subcarrier block set to which the respective subcarrier block belongs to may be used for power control. The plurality transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single radio cell, there is a mapping of each of the plurality of transmission power ranges to a subcarrier block set of the single radio cell, and there is a mapping of each of the plurality of transmission power ranges to one of the corresponding subcarrier block sets in the radio cells of the cell cluster. This rule for the distribution of power ranges may be especially applicable in situations in which the number of available transmission power ranges is chosen to be large or equal to the number of subcarrier block sets. Further, the plurality transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single radio cell, there is a mapping of each of the plurality of subcarrier block sets of the single radio cell to a transmission power range, and there is a mapping of each of the corresponding subcarrier block sets in the radio cells of the cell cluster to one of the plurality of transmission power ranges. In contrast to the distribution rule exemplary mentioned above, this rule for the distribution of power ranges may be especially applicable in situations in which the number of available subcarrier block sets is chosen to be larger or equal to the number of transmission power ranges. According to another embodiment, the mapping used in the two above mentioned assignment rules is a unique or one-to-one mapping. This means that e.g. when mapping the transmission power ranges to subcarrier block sets, each of the transmission power ranges is mapped to a corresponding single subcarrier block set. If the subcarrier block sets are mapped to the transmission power ranges, each subcarrier block set is mapped to a corresponding single transmission power range. To simplify the distribution of transmission power ranges and subcarrier block sets, their number may be determined based on the number of radio cells forming a cell cluster. Hence, in a further embodiment, the present invention provides a method for balancing the distribution of interference between radio cells in a wireless communication system, comprising a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers. Further, N adjacent radio cells may build a cell cluster, wherein N is an integer number of 2 or more. According to this embodiment of the present invention the subcarrier blocks may be grouped into N subcarrier block sets in each radio cell of the cell cluster, wherein the radio cells of the cell cluster each comprise corresponding subcarrier block sets having the same subcarriers. Hence, the number of subcarrier block sets corresponds to the number of radio cells in a cluster in this embodiment. Further, N transmission power ranges may be determined for each of the radio cells of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, and the N transmission power ranges may be assigned to the N subcarrier block sets of radio cells of the cell cluster, such that each of the N transmission power ranges in a radio cell is assigned to one of the N subcarrier block sets of the radio cell, and each of the N transmission power ranges is assigned to one subcarrier block set of corresponding subcarrier block sets. When choosing the number of cells in a cell cluster, the number of subcarrier block sets and the number of transmission power ranges as proposed in this embodiment the general distribution rules as defined above may be significantly simplified. Another embodiment of the present invention relates to a system in which the number of transmission power ranges and subcarrier block sets are each integer multiples of the number of radio cells in a cell cluster. This embodiment also provides a method for balancing the distribution of interference between radio cells in a wireless communication system. Again the system may comprise a plurality of radio cells in which a plurality of subcarrier blocks is used for communication, wherein each subcarrier block may comprise a plurality of subcarriers. N adjacent radio cells may build a cell cluster, wherein N may be an integer number of 2 or more. According to the method, the subcarrier blocks may be grouped into x·N subcarrier block sets in each radio cell of the cell cluster, wherein the radio cells of the cell cluster each comprise corresponding subcarrier block sets having the same subcarriers. x represents an integer number of 1 or more. Further, y·N transmission power ranges may be determined for each of the radio cells of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control, and wherein y is an integer number of 1 ore more. Next, the y·N transmission power ranges may be assigned to the x·N subcarrier block sets of radio cells of the cell cluster, such that each of the y·N transmission power ranges in a radio cell is assigned to one of the x·N subcarrier block sets of the radio cell, and y/x transmission power ranges on average are assigned to one subcarrier block set of corresponding subcarrier block sets. It is noted that the ratio y/x may also result in an non-integer number depending on the choice of the parameters x and y. Obviously, it is not possible to assign half of a transmission power range to a subcarrier block set. However, it is possible to distribute an integer number of power ranges to subcarrier block sets in that different quantities of power ranges are assigned to each of the subcarrier block sets such that on average the ratio of y/x power ranges is assigned. It is further noted that the different embodiments of the method for balancing the interference in a wireless communication system outlined above should not be understood as restricting the power ranges in the different cells of a cell cluster to identical power ranges. The individual power ranges in each radio cell of a cell cluster may be identical or may be different from each other. This is of advantage to be able to adapt to e.g. the respective channel conditions and/or cell-sizes in the different cells. In all embodiments above, the method may further comprise the steps of measuring the path loss of a communication signal of a communication terminal and the path loss of the interference from adjacent cells. The embodiments above may further comprise the assignment of the communication terminal to at least one subcarrier block of one of the subcarrier block sets based on the measurement. A transmission power range for the communication terminal may be determined based on the above mentioned measurement, and the communication terminal may be assigned to at least one subcarrier block set based on the determined transmission power range. It should be noted that the actual channel assignment may be carried out onto a subcarrier block. In this context, the assignment to a subcarrier block set may be regarded as a pre-selection. In an alternative embodiment, it may also be considered to assign a block set to a communication terminal first and to choose the respective transmission power level based on the assignment. Hence, the transmission power range may be determined based on the assigned block set. The transmission power range of the assigned subcarrier block set may be chosen based on the ratio of the measured signal path loss and the measured interference path loss. Consequently, for a communication terminal that is located close to a base station of a radio cell the measurement results may indicate that a transmission power range comprising low transmission power levels may be sufficient for a communication between the communication terminal and the base station. In contrast, for a communication terminal that is located near to the cell boundaries of a radio cell the measurement results may indicate an accordingly transmission power range comprising large transmission power levels may be required for a communication between the communication terminal and the base station. Further, it should be noted the channel quality fluctuations may be countered by changing the transmission power level within the allowed power range for the respective subcarrier block set, by changing the transmit power range (i.e. changing the subcarrier block set), or by performing link adaptation by changing the modulation and coding scheme. It is of further advantage, if the transmission power ranges in different radio cells of a cell cluster vary, such that same may be adapted to the respective channel conditions in each of the radio cells of the cell cluster. Further, the transmission power ranges in a radio cell may vary between the radio cells. As explained above, this allows individual control of the transmission power ranges in each of the cells to adapt same to changing channel quality conditions in the respective cell. To be able to adapt to changing channel quality conditions also the subcarrier block sets in a radio cell may be reconfigured. For the same reason as above also the transmission power ranges in a radio cell may be reconfigured. The reconfiguration of the power ranges and/or the subcarrier block sets in the radio cell may be performed in accordance with the other radio cells of its cell cluster. The reconfiguration may be based on channel quality measurements in the radio cell and/or the other radio cells of its cell cluster. Further, information related to a reconfiguration of the subcarrier block sets in a radio cell may be signaled from the radio cell to the other radio cells of its cell cluster or may be signaled from a control unit (e.g. radio network controller) to the radio cells forming a cell cluster. According to a further embodiment of the present invention also information related to channel qualities in a radio cell may be signaled from the radio cell to the other radio cells of its cell cluster. By signaling the channel qualities in a radio cell to adjacent radio cells, same may include the information when reconfiguring the transmission power ranges or subcarrier block sets in the respective radio cell. The main idea underlying the present invention may also be applicable to systems in which radio cells are divided into sectors, i.e. to systems using multi-beam antennas or multiple antennas. Employing this layout, a single cell may be divided in a plurality of sectors each covered by an antenna beam. According to another embodiment, the present invention therefore provides a method for balancing the distribution of interference between radio cells in a wireless communication system. The system may comprise a plurality of radio cells each of them comprising at least two sectors, wherein in each sector a plurality of subcarrier blocks is used for communication. Each subcarrier block may comprise a plurality of subcarriers, and a number of adjacent radio cells build a cell cluster. The subcarrier blocks may be grouped into a plurality of subcarrier block sets in each of the sectors of each radio cell of the cluster. A plurality of transmission power ranges may be determined for each sector of each radio cell of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control. Next, the plurality of transmission power ranges may be assigned to the plurality of subcarrier block sets of a sector of a radio cell and its adjacent sectors of the other radio cells. In another embodiment, each sector of a radio cell may have adjacent sectors in the other radio cells of the cell cluster. Further, a sector of a radio cell and its adjacent sectors belonging to other radio cells may build a sector cluster and each may comprise corresponding subcarrier block set having the same subcarriers. The plurality of transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single sector of a radio cell, there is a mapping of each of the plurality of transmission power ranges to a subcarrier block set of the sector, and there is a mapping of each of the plurality of transmission power ranges to one of the corresponding subcarrier block sets in the sector cluster. Alternatively, the plurality of transmission power ranges may be assigned to the subcarrier block sets of radio cells of the cell cluster, such that in a single sector of a radio cell, there is a mapping of each of the plurality of subcarrier block sets of the sector to a transmission power range, and there is a mapping of each of the plurality of the corresponding subcarrier block sets in the sector cluster to one transmission power range. As outlined above, the mapping may be a unique or one-to-one mapping. To simplify the distribution of transmission power ranges and subcarrier block sets, their number may be determined in relation to the number of radio cells forming a cell cluster. Hence, in a further embodiment, the present invention provides a method for balancing the distribution of interference between radio cells in a wireless communication system. The system may comprise a plurality of radio cells each of them comprising at least two sectors, wherein in each sector a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers. A number of adjacent radio cells may build a cell cluster. The subcarrier blocks may be grouped into N subcarrier block sets in each of the sectors of each radio cell of the cluster, wherein each sector of a radio cell has N−1 adjacent sectors in the other radio cells of the cell cluster, and wherein a sector of a radio cell and its adjacent sectors in the other radio cells each comprise corresponding subcarrier block set having the same subcarriers and wherein N may be an integer number of 2 or more. Further, N transmission power ranges may be determined for each sector of each radio cell of the cell cluster, wherein a transmission power range defines a range of transmission power levels used for transmission power control. The N transmission power ranges may be assigned to the N subcarrier block sets of a sector of a radio cell and its adjacent sectors of the other radio cells, such that in a sector, each of the N transmission power ranges In a sector of a radio cell is assigned to one of the N subcarrier block sets of the sector, and each of the N transmission power ranges is assigned to one subcarrier block set of corresponding sectors. Another embodiment of the present invention relates to a system in which the number of transmission power ranges and subcarrier block sets are each integer multiples of the number of radio cells in a cell cluster. This embodiment also provides a method for balancing the distribution of interference between radio cells in a wireless communication system. Again, the system may comprise a plurality of radio cells each of them comprising at least two sectors, wherein in each sector a plurality of subcarrier blocks is used for communication, wherein each subcarrier block comprises a plurality of subcarriers. A number of adjacent radio cells may build a cell cluster. In this embodiment, the subcarrier blocks may be grouped into x·N subcarrier block sets in each of the sectors of each radio cell of the cluster, wherein each sector of a radio cell has N−1 adjacent sectors in the other radio cells of the cell cluster, and wherein a sector of a radio cell and its adjacent sectors in the other radio cells each comprise corresponding subcarrier block set having the same subcarriers. x may be an integer number of 1 ore more and N may be an integer number of 2 or more. Further, y·N transmission power ranges may be determined for each sector of each radio cell of the cell cluster, wherein y may be an integer number of 1 ore more. The y·N transmission power ranges may be assigned to the x·N subcarrier block sets of a sector of a radio cell and its adjacent sectors of the other radio cells, such that in a sector, each of the y·N transmission power ranges in a sector of a radio cell is assigned to one of the x·N subcarrier block sets of the sector, and y/x transmission power ranges on average are assigned to one subcarrier block set of corresponding sectors. The communication system may further comprise a plurality of communication terminals communicating with base stations associated to the plurality of radio cells. The path loss of a communication signal of a communication terminal and the path loss due to interference from adjacent sectors for the communication signal may be measured e.g. at a base station, and the communication terminal may be assigned to a subcarrier block of a subcarrier block set in a sector based on the measurement. In a further step a transmission power range for the communication terminal may be determined based on the measurement, and the communication terminal may be assigned to a block set based on the determined transmission power range. According to another embodiment, it may also be considered to assign a block set to a communication terminal first and to choose the respective transmission power level based on the assignment. Hence, the transmission power range may be determined based on the assigned block set. The transmission power ranges in different sectors may vary as well as the transmission power ranges in sectors of a radio cell. Independent of the use of single or multi-beam antennas, the subcarrier block set size in corresponding subcarrier block sets may be equal, i.e. each of the subcarrier block sets comprises the same number of subcarrier blocks and/or subcarriers. Further, the subcarrier block sets may be reconfigured in a sector of radio cell. Same applies to the transmission power ranges of a sector as well. The reconfiguration of the power ranges and/or the subcarrier block sets in the sector may be performed in accordance with the other sectors of its sector cluster. Further, the reconfiguration may be based on channel quality measurements in the sector and/or the other sectors of its sector cluster. In the context of reconfiguration, information related to a reconfiguration of the subcarrier block sets in a sector may be signaled from its radio cell to radio cells comprising sectors of the sector cluster. Also, information related to channel qualities in a sector may be signaled from its radio cell to radio cells comprising sectors of the sector cluster. Independent from the system architecture, i.e. the usage of sectorized radio cells or not, the information related to the reconfiguration of power levels or subcarrier block sets may be signaled to a control unit in the communication system. Taking the example of the Release 99/415 UTRAN (UMTS Terrestrial Radio Access Network) architecture, such a control unit may be a radio network controller (RNC) or, in the evolved architecture an functional enhanced Node B, the Node B+. Further, also independent from the system architecture, information related to a subcarrier block assignment and/or a subcarrier block set assignment may be signaled to a communication terminal. The communication terminal may further comprise receiving means for receiving information indicating a subcarrier block assignment and/or a subcarrier block set assignment, and selection means for selecting the signaled assigned subcarrier block and/or signaled assigned subcarrier block set for data transmission. All the different embodiments of the inventive method for balancing the co-channel interference in radio cells may be advantageously used in a base station. The base station may be equipped with the respective means for performing the different method steps according to the different embodiments of method as outlined above. Further, the present invention provides a communication terminal adapted for its operation in the above described communication systems. In the communication terminal a power control means may be adapted to perform power control in a transmission power control range in an interval defined by a transmission power level of 0 and a maximum transmission power level. The present invention also provides radio communication system comprising a base station adapted to carry out the method according to the different embodiments and at least one communication terminal and the communication terminal described above.

20061004

20110125

20070315

96313.0

H04B100

SAFAIPOUR, BOBBAK

TRANSMISSION POWER RANGE SETTING DURING CHANNEL ASSIGNMENT FOR INTERFERENCE BALANCING IN A CELLULAR WIRELESS COMMUNICATION SYSTEM

UNDISCOUNTED

ACCEPTED

H04B

ACCEPTED

Switching device

An electrical switching device, especially a high-voltage circuit breaker, contains arcing contacts and nominal current contacts. At least one of the nominal current contacts has a surface formed of an arc-resistant material provided with a galvanic coating. In this configuration, the contact points can withstand high mechanical and thermal loads and at the same time maintain a high current carrying capacity.

1-8. (canceled) 9. A switching device, comprising: a first and a second arcing contact piece, lying axially opposite one another; a first and a second rated current contact piece, disposed coaxially with respect to said arcing contact pieces, at least one of said rated current contact pieces having a hollow-cylindrical basic body with a front at an end facing a switching path of the switching device; and an arc-resistant material covering said front, said arc-resistant material having an electroplating. 10. The switching device according to claim 9, wherein said arc-resistant material is fixed to said hollow-cylindrical basic body in a form of a ring, so as to cover said front of said hollow-cylindrical basic body. 11. The switching device according to claim 10, wherein said ring has a smaller radial wall thickness at a further end facing away from said switching path than at said end facing said switching path. 12. The switching device according to claim 10, further comprising a bolt connection, said ring being pressed against said hollow-cylindrical basic body in a axial direction by said bolt connection. 13. The switching device according to claim 9, further comprising an insulating body; further comprising a pressure element; and wherein said hollow-cylindrical basic body has a radial projection, against which said insulating body, is pressed axially by said pressure element. 14. The switching device according to claim 13, wherein said hollow-cylindrical basic body has an inner casing side and a reduced outer diameter at said end facing said switching path, said radial projection is disposed on said inner casing side in a region of said reduced outer diameter. 15. The switching device according to claim 11, wherein said ring has an enlarged radial wall thickness region and fixing devices in a region of said enlarged radial wall thickness region. 16. The switching device according to claim 9, further comprising contact-making points disposed between said first and second rated current contact pieces and lying axially in a region of said arc-resistant material in a switched-on state of the switching device. 17. The switching device according to claim 13, wherein said insulating body is an insulating material nozzle.

The invention relates to a switching device having a first and a second arcing contact piece, which lie axially opposite one another, and a first and a second rated current contact piece, which are arranged coaxially with respect to the arcing contact pieces, at least one of the rated current contact pieces having a hollow-cylindrical basic body; which is covered at the front by an arc-resistant material at its end facing a switching path of the switching device. Such a switching device has been disclosed, for example, in the European patent application EP 0 982 748 A1. Therein, the arcing contact pieces are covered by an arc-resistant material by means of plasma spraying such that an arc drawn between the arcing contact pieces does not cause any erosion, or only causes a very low amount of erosion. Furthermore, the rated current contact pieces likewise have an erosion-resistant protective coating, which is applied by means of plasma spraying, in sections on their sliding faces. The stationary rated current contact piece is silver-plated on top of the erosion-resistant protective coating. When two or more materials; such as the erosion-resistant material, the electrically conductive silver and a further metal such as the aluminum of the rated current contact piece, impact against one another, the respective points of impact always have irregularities. The point of impact can only be subjected to a mechanical load to a reduced extent. Surface friction occurring in the event of the sliding faces of the rated current contact pieces running against one another can result in disintegration phenomena and thus in a weakening of the individual layers. It is thus possible for individual layers to be chipped off starting from the point of impact. This reduces the switching capacity of the switching device. The invention is based on the object of designing a switching device of the type mentioned initially such that the contact points withstand high mechanical and thermal loads while having a high current-carrying capacity. The object is achieved according to the invention in the case of the switching device of the type mentioned initially by the fact that the arc-resistant material has an electroplating. The electroplating may consist, for example, of an electrically highly conductive material, such as silver or gold. This reduces the contact resistance of the electrical contact. At the same time, the electroplating prevents oxidation on the arc-resistant material in the event that the individual components are stored for a relatively long period of time. By including the arc-resistant material in an electroplating treatment process, it is possible to cover points of impact or boundary layers of different materials, which improves the mechanical loadability and the mechanical endurance of these points. One advantageous refinement can furthermore provide for the arc-resistant material to be fixed to the hollow-cylindrical basic body in the form of a ring, so as to cover front faces of the hollow-cylindrical basic body. Owing to the fact that the front faces of the hollow-cylindrical basic body are covered, the electric field in the direction of the switching path of the switching device is substantially controlled by the form of the ring. This results in the possibility of using manufacturing methods for manufacturing the basic body with a lesser degree of precision, for example a reduced surface quality, than in the case of the ring used for field control. Furthermore, it is possible to equip the basic body with various ring forms so as to achieve various electric field effects in the region of the switching path of the switching device. Furthermore, when the front faces of the hollow-cylindrical basic body are completely covered, the basic body itself is protected against the effect of a switching arc. It is thus possible for an arc to act on many points on the ring. The stability of the ring is thus increased. Splitting into a hollow-cylindrical basic body and a ring also furthermore has the advantage that the hollow-cylindrical basic body can be produced, for example, from a material having a low density, such as aluminum, as a result of which the total mass of the hollow-cylindrical basic body and the arc-resistant material fixed thereto is reduced. Arc-resistant materials are, for example, mixtures of molybdenum (Mo), tungsten (W), copper (Cu) and silver (Ag). For example, CuCrZr, CuZn39Pb3 or Ecu57 can be used for the arc-resistant material. These materials have a very high density, which results in the ring having a comparatively high mass. In particular in the event of a movement of the rated current contact piece equipped with the arc-resistant material, the multi-part design of the rated current contact piece limits the mass to be moved. Provision may advantageously further be made for the ring to have a smaller radial wall thickness at its end facing away from the switching path than at its end facing the switching path. Owing to the high density which has already been mentioned above, even small components consisting of an arc-resistant material have a comparatively high mass. A reduction in the wall thicknesses to the absolute minimum required therefore makes it possible to make savings on the arc-resistant material. Furthermore, in the case of a stepped design of the ring, in which the end facing the switching path has a greater wall thickness than the end facing away from the switching path, it is possible for the ring to be pushed onto the hollow-cylindrical basic body in a simple manner. Owing to this design for the form of the ring, it can be pushed onto the hollow-cylindrical basic body automatically in a centering manner. This simplifies assembly. At the same time, the points of the hollow-cylindrical basic body and the arc-resistant ring which are coming into contact with one another are increased in number owing to the enlarged area. Owing to an increased number of contact points, the electrical contact resistance between the arc-resistant ring and the hollow-cylindrical basic body is reduced. One further advantageous refinement may provide for the ring to be pressed against the hollow-cylindrical basic body of the rated current contact piece in the axial direction by means of a bolt connection. A bolt connection in the axial direction between the ring and the hollow-cylindrical basic body makes it possible to keep the outer contours of the ring and the hollow-cylindrical basic body free from drilled holes or other fixing means. The outer contour of the rated current contact piece is thus maintained. Furthermore, owing to an arrangement of the bolt connections in the axial direction in the interior of the hollow-cylindrical basic body, a sufficient volume remains free for accommodating, for example, further assemblies or for deflecting or guiding the quenching gas flows occurring in the event of a switching operation in the interior. Threaded rods, screws, pressed or crimped bolts or bolts which have been adhesively bonded-in etc. can be used for bolting purposes. In this case, the bolts form a type of cage with their longitudinal axes parallel to the cylinder axis of the hollow-cylindrical basic body. Owing to an even distribution over the circumference of the hollow-cylindrical basic body, the ring can be pressed uniformly against the hollow-cylindrical basic body. One further advantageous refinement may provide for the hollow-cylindrical basic body to have a radical projection, against which an insulating body, in particular an insulating material nozzle, is pressed axially by means of a pressure element. The radial projection represents a fixed stop for the insulating body. The position of the insulating body with respect to the hollow-cylindrical basic body is thus clearly fixed. The incorporation of the insulating body takes place by means of a pressure element over a short period of time. Additional measurements, adaptations or adjustments of the insulating body are thus not required. An annular disk, which transfers the contact-pressure force evenly over the insulating body, can be used, for example, as the pressure element. In this case, it is advantageous if the radial projection is likewise designed to be annular and circumferential. Provision may advantageously also be made for the hollow-cylindrical basic body to have a reduced outer diameter at its end facing the switching path and for the radial projection to be arranged on the hollow-cylinder inner casing in the region of the reduced outer diameter. With such an arrangement of the radial projection, a sufficient distance is produced between the contact-pressure cheeks of the projection and the pressure element to make advantageous use of the intrinsic elasticity of the insulating body material. Owing to thermal influences, expansions or shrinkages of the insulating material result. It is therefore necessary when using a clamping connection to cover a sufficient insulating body volume. Only in this manner is it possible for sufficient holding force to act on the insulating body in the case of various thermal loads. A clamping region which is too small would not be suitable for permanently applying the required forces. Furthermore, the insulating body can be stopped very close to the front of the hollow-cylindrical basic body. The required physical length for the total construction of fixing the erosion-resistant ring and the insulating material nozzle to the hollow-cylindrical basic body is thus reduced. A further advantageous refinement may provide for the ring to have fixing devices in the region of its enlarged radial wall thickness. Sections having an enlarged wall thickness make it possible to flexibly select the location of fixing devices. At the same time, such sections have a comparatively high mechanical strength. For example, threaded holes or other anchoring points may be provided as the fixing devices. Provision may advantageously be made for contact-making points between the two rated current contact pieces to lie axially in the region of the arc-resistant material in the switched-on state of the switching device. An arrangement of the contact-making points of the two rated current contact pieces in the region of the arc-resistant material prevents, from the outset, a situation in which the individual contact faces need to be moved over joints during a switching operation. As a result, the joints are protected against mechanical loading resulting from the corresponding contact parts of the rated current contact pieces being pushed on and pushed away. For this reason it is possible to manufacture the joints with increased tolerance. It is barely possible for an electroplating to be removed at this joint owing to mechanical loading of the rated current contact pieces. The robustness of the contact pieces of the switching device is thus improved. The invention will be shown schematically in a drawing and described in more detail below with reference to an exemplary embodiment. In the drawing FIG. 1 shows a section through a switching device, FIG. 2 shows a further section through the switching device, and FIG. 3 shows a section through the switching device shown in FIGS. 1 and 2, along the axis A-A. The switching device illustrated in FIG. 1 is a high-voltage power breaker 1. A high-voltage power breaker 1 is used to switch rated currents and short-circuit currents. The high-voltage power breaker 1 has a first arcing contact piece 2 and a second arcing contact piece 3. The first arcing contact piece 2 is essentially cylindrical and has a coating of an arc-resistant material at its end facing the switching path of the high-voltage power breaker 1. The second arcing contact piece 3 is in the form of a tulip contact, in which the first arcing contact piece 2 can be inserted. At its end facing the switching path, the second arcing contact piece 3 likewise has a coating of arc-resistant material. The two arcing contact pieces 2, 3 are arranged axially opposite one another on a main axis 4. A first rated current contact piece 5 is arranged concentrically with respect to the first arcing contact piece 2. A second rated current contact piece 6 is arranged concentrically with respect to the second arcing contact piece 3. The first rated current contact piece 5 has a large number of elastic contact fingers 7 at its end facing the switching path, said contact fingers 7 being in electrically conductive contact with the outer casing of the second rated current contact piece 6 in the closed stated of the high-voltage power breaker 1. Furthermore, the second arcing contact piece 3 is surrounded by an insulating material nozzle 8. The insulating material nozzle 8 is held on the second rated current contact piece 6. The rated current contact pieces 5, 6 and the arcing contact pieces 2, 3 can be moved in relation to one another along the main axis 4, to be precise such that, in the case of a switch-on operation, initially the arcing contact pieces 2, 3 and then the rated current contact pieces 5, 6 come into contact with one another. In the event of a switch-off operation, initially the rated current contacts 5, 6 open, and then the arcing contact pieces 2, 3 are isolated from one another. The second rated current contact piece 6 has an essentially hollow-cylindrical basic body 6a. The hollow-cylindrical basic body 6a is covered at the front by a ring 9 of an arc-resistant material. The ring likewise has an essentially hollow-cylindrical structure, the hollow cylinder top face, which faces the switching path of the high-voltage power breaker 1, being rounded off. Furthermore, the wall thickness of the ring 9 on the side facing away from the switching path is less than on its side facing the switching path. In the present exemplary embodiment, this is achieved by the inner diameter of the ring 9 being enlarged on its side facing away from the switching path. Furthermore, a conical or parabolic profile of the inner casing surface of the ring 9 or other suitable geometric shapes can also be used. The hollow-cylindrical basic body 6a has a reduced outer diameter at its end facing the switching path. The reduced outer diameter of the hollow-cylindrical basic body 6a and the enlarged inner diameter of the ring 9 are matched to one another such that the ring 9 can be pushed onto the hollow-cylindrical basic body 6a. In order to press the ring 9 against the hollow-cylindrical basic body 6a, the ring 9 has a plurality of threaded holes, into which bolts 10 can be screwed. The bolts 10 are supported in each case at edges of cutouts, which are arranged distributed symmetrically, parallel to the main axis 4, in the casing of the hollow-cylindrical basic body 6a. The surface of the ring 9 is electroplated. This electroplating is, for example, a silver plating. The hollow-cylindrical basic body 6a is likewise provided with an electroplating. In the switched-on state of the high-voltage power breaker 1, the contact points of the electrical contact fingers 7 rest in the region 11 of the ring 9. Owing to the arrangement of the ring 9 of an arc-resistant material, high switching powers can also be controlled, in the case of which switching arcs occur, despite the use of arcing contact pieces, even on the rated current contact pieces. The use of the arc-resistant ring 9 allows for a compact design of a high-voltage power breaker. FIG. 2 illustrates a section through the high-voltage power breaker 1 known from FIG. 1. However, the sectional plane is pivoted about the main axis 4 such that it is now possible to see the fixing of the insulating material nozzle 8. The insulating material nozzle 8 is held by means of further bolts 11, which can be screwed into threaded holes in the essentially hollow-cylindrical basic body 6a. In this case, the threaded holes are aligned such that the further bolts 11, just like the bolts 10, are arranged parallel to the main axis 4. The hollow-cylindrical basic body 6a has an annular projection 12. A circumferential shoulder of the insulating material nozzle 8 is pressed against the annular projection 12. The contact-pressure force of the shoulder against the annular projection 12 is produced by means of a pressure element 13 in the form of a pressure disk, which is held by the further bolts 11. The annular projection 12 is arranged on the inner casing side of the essentially hollow-cylindrical basic body 6a, to be precise in the section 14 in which the outer diameter of the hollow-cylindrical basic body 6a is reduced. FIG. 3 shows a section along the sectional plane A-A illustrated in FIGS. 1 and 2. The pressure element 13 has a structure which is in the form of an annular disk and which has cutouts, through which the further bolts 11 pass. The pressure element 13 is pressed against the projection 12 by means of the further bolts 11, with the interposition of the projecting shoulder of the insulating material nozzle 8. Furthermore, the pressure element 13 is designed such that, in order to achieve a small total diameter for the arrangement, the pressure element 13 has lateral notches in order to make it possible to fix the ring 9 by means of the bolts 10. This design makes it possible to fix the ring 9 or the insulating material nozzle 8 independently of one another. As a result, the two connections are decoupled from one another. Any interference or thermal expansions etc. at one connection point are thus largely kept away from the other connection.

20060508

20100316

20070405

63556.0

H01H3128

FISHMAN, MARINA

SWITCHING DEVICE

UNDISCOUNTED

ACCEPTED

H01H

ACCEPTED

Conditional access method and devices

A data stream contains content data that can be decrypted using control words. ECM messages that are included in the stream and contain the control words that is required for decrypting nearby content data. EMM messages contain management information for entitling selected stream receiving devices to decrypt content data from the data stream using control words from ECM messages. Further management information is included in at least some of the the ECM messages. The secure device detects the further management information when the control words are supplied and tests whether the further management information is targeted at the stream receiving device (12). If so the secure device indefinitely disables subsequent decryption of at least part of the stream in the stream receiving device (12). In one embodiment, the further management information is targeted by means of a specified condition on entitlement information stored in the secure device. The secure device tests whether any of it's entitlement information meets this condition and, if so, disables supply of valid control words.

1. A method of providing conditional access to an encrypted data stream with a stream receiving device (12), the method comprising including encrypted content data, the decryption of which requires temporally changing control words (CW), in the data stream; including first decryption control messages (ECM's) in the data stream, each first decryption control message (ECM) containing at least one of the control words that is required for decrypting content data that is substantially contemporaneous with the first decryption control message (ECM) in the stream; including second decryption control messages (EMM's) which contain management information for entitling selected stream receiving devices to decrypt content data from the data stream using control words from the first decryption control messages (ECM's), including further management information in at least part of the first decryption messages (ECM's); extracting a control word from a first decryption message (ECM) from the stream in a stream receiving device (12), together with said extracting, testing whether the first decryption message (ECM) contains further management information targeted at the stream receiving device (12), indefinitely disabling subsequent decryption of at least part of the stream in the stream receiving device (12) upon said detection. 2. A method according to claim 1, wherein the stream receiving device (12) contains identification information that individually identifies the stream receiving device (12), said first decryption message (ECM) containing further identification information, said testing comprising comparing the identification information and the further identification information. 3. A method according to claim 1, wherein the first encryption message (ECM) contains information that specifies a condition upon entitlement data, said testing comprising searching for entitlement data stored in said stream receiving device (12) to detect whether any of the searched entitlement data meets said condition, and performing the disabling if such entitlement data is found. 4. A method of generating an encrypted data stream, the method comprising including encrypted content data, the decryption of which requires temporally changing control words, in the data stream; including first decryption control messages (ECM's), which contain the control words, in the data stream; including second decryption control messages (EMM's) which contain management information for entitling selected stream receiving devices to decrypt content data from the data stream using control words from the first decryption control messages (ECM), including further management information in at least part of the first decryption messages (ECM's), the further management information being arranged to target selected stream receiving devices (12) to indefinitely disable subsequent decryption of at least part of the stream in the stream receiving device (12). 5. A method according to claim 4, wherein the further management information targets the selected stream receiving devices (12) with identification information corresponding to individual identification information of selected stream receiving devices. 6. A method according to claim 4, wherein the further management information targets the selected stream receiving devices (12) with information that specifies a condition upon a content of entitlement data in said stream receiving devices. 7. A stream receiving device (12) for providing conditional access to an encrypted data stream, wherein the data stream comprises encrypted content data, the decryption of which requires temporally changing control words, the data stream further comprising first decryption control messages (ECM's), which each contain a control word, substantially contemporaneously with the content data that can be decrypted with that control word, and second decryption control messages (EMM's) which contain management information for entitling the stream receiving device to decrypt content data from the data stream using control words from the first decryption control messages (ECM's), the stream receiving device comprising a circuit (124) arranged to extract a control word from a first decryption message from the stream, and, together with said extracting, to test whether the first encryption messages (ECM's) contain further management information targeted at the stream receiving device (12), the stream receiving device (12) indefinitely disabling subsequent decryption of at least part of the stream upon said detection. 8. A stream receiving device according to claim 7, wherein said testing whether the further management information is targeted at the stream receiving device comprises comparing identification information from the further management information with an identification of the stream receiving device. 9. A stream receiving device according to claim 7, wherein said testing whether the further management information is targeted at the stream receiving device comprises searching for entitlement data stored in said stream receiving device (12) that meets a condition specified in the further management information. 10. A smart card for use in a stream receiving device according to claim 7, the smart card comprising a processor (124) and an entitlement memory (126), the processor (124) being programmed to extract a control word from a first decryption control message (ECM) from the stream and to supply the control word for use in decrypting content data; update the entitlement memory using information from a second decryption control message (EMM); together with said extracting, test whether the first encryption messages (ECM's) contain further management information targeted at the stream receiving device, and indefinitely disable subsequent supply of control words of at least part of the stream upon said detection. 11. A stream generating device for generating an encrypted data stream, the stream generating device comprising a source of content data, comprising an encryption unit for encrypting the content data so that temporally changing control words are required; a source of first decryption control messages, that generates first control word messages in the stream containing control words for decrypting the content data; a source of access management information, that generates first control word messages in the stream containing management information for entitling selected stream receiving devices to decrypt content data, the source of access management information being coupled to the source of first decryption control messages, the source of first decryption control messages being arranged to include further management information in at least part of the first decryption messages, the further management information being arranged to target selected stream receiving devices to indefinitely disable subsequent decryption of at least part of the stream in the stream receiving device.

U.S. Pat. No. 5,799,081 describes a use of an encrypted data stream. This patent discusses an MPEG transport stream that provides for conditional access to data. MPEG conditional access is managed by two types of messages: Entitlement control messages (ECM) and Entitlement management messages EMM's. A secure device (e.g. smart card) in a stream receiver receives both ECM's and EMM's. The ECM's and EMM's provide the broadcaster of an MPEG transport stream control over whether individual stream receivers can access the stream. The ECM's contain control words (keys CW) for use by all entitled stream receivers to decrypt data such as video data. The necessary control words CW are changed regularly, for example every 10 seconds, and ECM's are provided at an even higher frequency, for example every tenth of a second. Typically, the secure device decrypts the control words CW from the ECM's and supplies these control words to a decoder that uses the control words to decrypt data such as video data. The EMM's are used to control which stream receivers are entitled to decrypt data. The EMM's are directed at individual stream receivers and are used to instruct the secure device of a stream receiver whether it should make the control words CW available for decrypting data. This may involve providing the necessary keys for decrypting ECM's and/or other instructions about entitlement. Typically the transmission of EMM's is dependent on payment of a subscriber fee for a particular stream receiver. U.S. Pat. No. 5,799,081 describes how copy control information can be included in the ECM's. Thus the ECM's are used in a recording system to prevent that too many copies are made of an MPEG transport stream. The possibility to tamper with EMM's forms a weak point of this type of conditional access stream. If an EMM contains an instruction to disable decryption at a stream receiver, a hacker can prevent disabling by blocking transfer of the EMM to the secure device. Similarly, by supplying a falsified EMM, or a copy of an old, enabling EMM entitlement can be tampered with. Of course, various precautions can be taken against this, but these measures are not always watertight. Moreover, such measures may require additions to the secure device, such as a time of day/calendar counter that are not always compatible with smart cards. Among others, it is an object of the invention to provide measures that control conditional access to an encrypted data stream in a way that make it more difficult to get access to the stream by tampering. According to the invention management information for disabling decryption in selected stream receivers is included in messages, such as ECM's, that supply control words for decrypting data. Thus, at least some ECM's are made “poisonous” for selected stream receivers. The idea behind this is that hackers on one hand need to supply ECM's to the secure device to profit from the stream and on the other hand cannot determine beforehand which ECM's are poisonous for their secure device. Accordingly a device for generating a stream is provided that adds “poison” information directed at selected stream receivers to messages with control words for decrypting the stream. A secure device is provided that uses messages with control words to supply control words from the messages, but also detects whether these messages contain “poison” information directed at the secure device and, if so, such a secure device indefinitely disables supply of control words. (By indefinitely is meant not for a predetermined normal period, such as a subscription period or the period of validity of a control word). Disabling may be performed in a similar way as for EMM processing, but preferably special forms of disabling are available for disabling in response to EMM's, such as completely and permanently disabling the secure device, or disabling all programs from a specific supplier until further notice, removing or disabling keys needed for decryption etc. The poisonous ECM's are targeted at selected secure devices for example by specifying a condition in the ECM that must be met by entitlement information that is stored in a secure device. In response to the ECM the secure device disables decryption if it detects any entitlement information that meets the condition. Thus, a system manager can cause all secure devices to start searching for the presence of falsified entitlement information that has not been supplied normally. These and other objects and advantages of the invention will be described in a non-limitative way using the following figures. FIG. 1 shows a conditional access system FIG. 2 shows a flow chart of the operation of a secure device FIG. 3 symbolically shows a stream. FIG. 1 shows a conditional access system. The system comprises a transmitter/multiplexer 110, which receives inputs from a data source 100 via a data encryption unit 106, from a control word source 102 via an ECM generator 108 and from a source of management information 104. Control word source 102 supplies encryption control words to data encryption unit 106. Source of management information 104 supplies management information to ECM generator 108. Furthermore, the system comprises a plurality of stream receivers 12 (only one shown explicitly). Each receiver comprises a demultiplexer 120 with outputs coupled to a secure device 122 and a decoder 128. In the secure device measures (known per se) have been taken against tampering. The secure device is typically a smart card. The secure device 122 is shown to contain a processor 124 and a memory 126. Processor 124 has an output coupled to decoder 128 and decoder 128 has an output coupled to an output of stream receiver 12. In operation transmitter/multiplexer 110 receives and multiplexes encrypted content data, ECMs and EMMs and transmits the resulting stream to a plurality of stream receivers 12. The stream receivers demultiplex the stream, and decrypt the content data if the secure device 122 so permits. FIG. 3 symbolically shows a stream made of messages, including ECM's and EMM's interspersed between content data. Data source 100 produces content data, such as audio and/or video data, which is encrypted by data encryption unit 106 for transmission by transmitter/multiplexer 110. Decoder 128 receives the encrypted content data and if it receives the appropriate control words from secure device 122 it decrypts the content data and supplies the decrypted content data at its output. Source of management information 104 generates EMM's with instructions for secure devices in individual stream receivers 12 or groups of stream receivers 12. Demultiplexer 120 demultiplexes the transmitted EMM's from the stream and supplies them to secure device 122. Processor 124 of secure device 122 detects whether the EMM is directed at the particular secure device 122 and, if so, executes the instruction that is implied by the EMM, for example by updating entitlement information and/or keys in memory 126. Entitlement information indicates for example information to identify programs from the stream that stream receiver 12 is entitled to decrypt, and/or the time and date at which stream receiver 12 is entitled to decrypt etc. Typically the entitlement information for a particular stream receiver 12 depends on whether or not the user of the stream receiver 12 has acquired a subscription for a particular service and/or has paid subscription fees. Control word source 102 generates control words for encrypting the data from data source and corresponding control words for decrypting the encrypted data. Typically the control words are changed every few seconds, e.g. every ten seconds. Data encryption unit 106 uses the encryption control words to encrypt the content data and ECM generator 108 includes the control words for decryption in ECM messages, which are transmitted contemporaneously with, or slightly before the content data that can be encrypted with the control words. Demultiplexer 120 demultiplexes the transmitted ECM's from the stream and supplies them to secure device 122. Processor 124 of secure device 122 tests whether information in memory 126 indicates that the secure device is entitled to permit decryption with the control word from the ECM and, if so, processor 124 extracts the control word from the ECM (typically by decrypting the ECM) and supplies the control word to decoder 128. According to the invention source of management information 104 also supplies management information to ECM generator 108 and ECM generator 108 includes this information in the ECM's (however, without deviating from the invention the management information may also be supplied externally). Typically, this is “poison” information, instructing selected secure devices 122 to disable decryption of content information. Processor 124 in secure device 122 is programmed to inspect received ECM's to detect whether it contains such poison information directed at the particular secure device 122. If so, processor 124 updates the entitlement information in memory 126 so as to disable supply of control words to decoder 128, at least for an identified period or program from the stream, but preferably for all programs, or for all programs from a selected program provider. In this embodiment processor 124 gives effect to the information from the ECM much like it gives effect to information from EMM's. In another embodiment processor 124 is arranged to disable secure device 122 in a more irreversible way, for example by blowing a fuse that enables operation. The management information supplied to ECM generator 108 and included in the ECM's may also be conditional, e.g. in the form of a command to secure devices 122 to disable decryption if certain data in its memory (e.g. among the entitlement data) meets a condition specified in the command. In response to the command, secure device 122 searches its memory to detect whether there is data that meets the condition, and if so executes the disable operation. The condition may for example test for entitlements of a type that have not been issued in the EMM's, having for example aberrant periods of validity. Also, the condition may test for a type of entitlement that is needed to decrypt a stream that has been transmitted (or is being transmitted), but for which no entitlements have been transmitted in EMM's for at least for a group of users. The secured device of hackers who have constructed entitlement information for this stream are thus detected. In addition to the condition one may include an identification of a secure device or a group of secure devices for which the command is intended. Instead of conditional disabling, conditional enabling (e.g. for a specified period) may also be used. FIG. 2 shows a flow chart of the operation of processor 124. In a first step 21 processor 124 receives a message and tests whether this message is an ECM or an EMM. The test may also be performed before the message is supplied to processor 124, using for example a identification information from the stream. In this case selectively only ECM or EMM's may be supplied to processor, optionally with additional information to distinguish ECM and EMM's. If the message is an ECM processor 124 executes a second step 22, decrypting the ECM, optionally checking whether the syntax of the ECM is correct and optionally verifying whether the ECM is authorized (such a check is known per se). In a third step processor 124 tests whether the decrypted ECM contains poison information addressed at the secure device to which the processor belongs, e.g. by comparing an address ID value in the ECM with an ID code in the secure device 122. If there is no poison information for the secure device, processor 124 executes a fourth step 24, to extract one or more control words from the ECM. In a fifth step 25 processor 124 supplies the control word or words to decoder 128. Subsequently the process returns to first step 21. When in first step 21 processor 124 detects an EMM, processor 124 proceeds with a sixth step 26, decrypting the EMM if necessary and optionally authenticating the EMM; decryption and authentication are known per se (it will be noted that different decryption keys are generally used for decrypting ECM's and EMM's, the decryption key for decrypting ECM's being common to all secure devices that have access to a stream). Subsequently, in a seventh step 27 processor 124 extracts management information from the decrypted EMM. In an eight step 28 processor 124 uses this management information to update entitlement information or keys in memory 126. Subsequently the process returns to first step 21. When in third step 23 processor 124 detects that the ECM contains poison information for the secure device, processor 124 executes steps to give effect to the poison information. In one embodiment these may be the same steps as those used for effecting EMM's, in order to modify entitlements, but preferably dedicated steps are used, which alter the functioning of the secure device in a way that cannot be undone by any EMM. Thus hackers that are able to falsify EMM's cannot prevent countermeasures. In the embodiment wherein the steps of EMM processing are used processor 124 executes a ninth step 29 and proceeds to eight step 28, now using management information from the ECM (instead of information from an EMM) to update entitlement information in memory 126, or to disable supply of control words for certain programs or all programs altogether until further notice. Optionally, in this case when the entitlement information comes from an ECM, processor 124 may proceed to fourth step 24 after eight step 28, as shown by dashed. line 20. Thus, it is not immediately visible to a user that the ECM did contain poison information. This makes it more difficult for hackers to screen ECM's for ECM's with poison information. Although, as shown, program steps that are used for EMM's may be reused for entering information received from ECM's as well, one may of course use steps dedicated to entering management information from ECM's (for example by providing dedicated computer programs to processor to do so). Thus, it is possible to execute functions that are not available for EMM's. Processor 124 may for example be arranged to entering additional control data (not conventional entitlements) into memory for blocking decryption. During processing of subsequent ECM's processor 124 may each time test this additional control data to determine whether control words from the ECM's may be supplied for decrypting a program in the stream, or for any program in the stream, or for a group of programs from the same program supplier. It is also possible to add a function to disable the secure device altogether in response to a command from an ECM, or to overwrite or disable certain keys that are needed in the secure device for supplying control words. Similarly, a countdown value may be entered, processor 124 counting ECM's until a number of ECM's corresponding to countdown value has been counted, after which effect is given to the poison information. Processor 124 may use various methods to decide whether an ECM is targeted at the secure device of which processor 124 is part In one example, the management information contains an identification of the secure device for which the poison information is intended. In this case, processor 124 compares this identification with an identification that is stored in the secure device and gives effect to the poison information (disabling supply of control words) only if the identification matches. In another example the ECM contains a conditional command, specifying an entitlement, or properties of an entitlement that must be present. If processor 124 detects such a command in an ECM, it searches memory 126 for an entitlement that meets the condition. Only if processor 124 finds such an entitlement processor 124 gives effect to the poison information (disabling supply of control words). Typically, a system manager decides to distribute poison information in cases where the manager fears that specific secure devices may be used for tampering. For example to disable a secure device when no subscription is extant any longer for that secure device, or to specifically disable decryption of certain programs that the subscriber has not validly subscribed to. This type of poison information is preferably included in ECM's at random, so that it cannot be predicted when an ECM will contain poison information for a specific secure device. For this purpose source of management information 104 preferably contains a random generator to decide when and in which ECM's to include poison information for a selected secure device 122 that has to receive such information. As another example, if the system manager finds out that hackers have succeeded in falsely creating a certain type of entitlement information, the system manager can decide to start broadcasting ECM's command with a condition that causes the secure devices to tests for entitlement information of this type and to disable decryption if this type of entitlement is detected (provided of course that untampered secure devices do not, or do no longer, contain such entitlements). A system manager could also intentionally broadcast a program for which no entitlements are supplied at all. If hackers, in an excess of enthusiasm, create entitlements for this program, supply of a command to disable secure devices for all programs that if they contain such entitlements can be used as a countermeasure against hacking. Although the invention has been described in terms of ECM's, it will be appreciated that the poison information may be included in any message that contains information (control words) that is vital to decrypting content data. It will be appreciated that not all such ECM-like messages need to include such poison information. Indeed different ECM's may contain poison information for different secured devices. However, since normal management information is supplied using EMM's relatively many ECM's may contain poison information directed at specific secure devices. From transmitted ECM's it is not possible to see whether they contain poison information directed at a specific device, for example because all ECM's have the same length and are encrypted. Thus a hacker permanently risks that his or her secure device will be disable when decrypting content data. Although the invention has been described for “poison data”, i.e. data aimed at disabling entitlements in a selected secure device, it will be understood that the invention can be applied to other updates of entitlement information that should not be blocked.

20060509

20090818

20070614

83837.0

H04N7167

CHAI, LONGBIT

CONDITIONAL ACCESS METHOD AND DEVICES

UNDISCOUNTED

ACCEPTED

H04N

ACCEPTED

Chainless container-transporting device

The present invention provides a container-transporting device which fundamentally avoids the problems caused by elongations and the structure of endless chains, which is inevitably created by using endless chains in the container-transporting conveyors for conventional filling-and-packaging machines. It is a container-transporting device for holding and transporting a square-cylindrical container 36 by a container holder 34 formed between container-transporting means 32 and 33 disposed to face parallel with each other, wherein the container conveying means 32 and 33 are equipped with: a number of blocks 40 having a holding part 38 constituting a part of a container holder 34; outward block-support members 42 and homeward block-support members 44, arranged by extending in the conveying direction, for supporting a number of blocks 40 in a movable condition along the conveying direction; a first transfer means 46 capable of sequentially transferring the blocks 40 that have been conveyed while being supported by the outward block-support members 42 to the homeward block-support members 44; a second transfer means 48 capable of sequentially transferring the blocks 40 that have been conveyed while being supported by the homeward block-support members 44 to the outward block-support members 42; and a block delivering means 50 capable of delivering and conveying the blocks 40 so that each block 40 can be circulated.

1. A chainless container-transporting device for transporting square-cylindrical containers by holding them with container holders formed between container-transporting means arranged to face parallel with each other, wherein the container-transporting means is equipped with: a number of blocks having a holding part constituting a part of the container holders; an outward block-support member and a homeward block-support member, arranged by extending in the conveying direction, for supporting the number of blocks in a movable condition along the conveying direction; a first transfer means provided between the terminal end of the outward block-support member and the start end of the homeward block-support member, capable of sequentially transferring the blocks that have been conveyed while being supported by the outward block-support member to the homeward block-support member; a second transfer means provided between the terminal end of the homeward block-support member and the start end of the outward block-support member, capable of sequentially transferring the blocks that have been conveyed while being supported by the homeward block-support member to the outward block-support member; and a block delivering means capable of delivering and conveying blocks so that each block can circulate in the order of outward block-support member, first transfer means, homeward block-support member, second transfer means and outward block-support member . . . . 2. The chainless container-transporting device according to claim 1, wherein the block-delivering means is so constructed that it can deliver one or more blocks to the downstream side of the conveying direction, and that an adjacent block can be sequentially conveyed by the block being delivered, to the downstream side of the conveying direction. 3. The chainless container-transporting device according to claim 1, wherein the block-delivering means is so constructed that it can intermittently deliver and convey one or more blocks by a given pitch, to the downstream side of the conveying direction. 4. The chainless container-transporting device according to claim 1, wherein the block-delivering means is so constructed that it can deliver blocks supported by the outward block-support member and/or homeward block-support member to the downstream side of the conveying direction. 5. The chainless container-transporting device according to claim 1, wherein two or more block-delivering means are provided. 6. The chainless container-transporting device according to claim 1, wherein the block-delivering means is equipped with a drive shaft and a pair of discs or a column having on its circumferential surface convex parts or concave parts capable of engaging with and delivering the blocks to the downstream side of the conveying direction. 7. The chainless container-transporting device according to claim 6, wherein the block is equipped with a rotatable rod-shaped member which gears into the concave parts formed on the outer circumferential surface of the pair of discs or the column. 8. The chainless container-transporting device according to claim 1, wherein the block-delivering means is equipped with a block engaging-and-pushing member which moves forward and backward by a given stroke, capable of delivering one or more blocks while engaging therewith to the downstream side of the conveying direction. 9. The chainless container-transporting device according to claim 1, wherein the outward block-support member and the homeward block-support member are two respective guide rails disposed above and beneath the block. 10. The chainless container-transporting device according to claim 9, wherein the guide rails are rod-shaped guide rails having a circular or polygonal cross-section. 11. The chainless container-transporting device according to claim 9, wherein the portion supporting the blocks delivered by the block-delivering means of the guide rails has a rectangular cross-section. 12. The chainless container-transporting device according to claim 9, wherein the portion other than the portion supporting the block delivered by the block-delivering means of the guide rails has a circular cross-section. 13. The chainless container-transporting device according to claim 9, wherein the guide rail has a roller for reducing the slide-friction factor at a part in contact with the block. 14. The chainless container-transporting device according to claim 13, wherein the roller is provided on the portion supporting blocks delivered by the block-delivering means of the guide rails. 15. The chainless container-transporting device according to claim 1, wherein the first transfer means and/or the second transfer means are equipped with a pair of discs or a column having on its circumferential surface concave parts or convex parts capable of guiding and transferring the block while engaging therewith. 16. The chainless container-transporting device according to claim 1, wherein the first transfer means and/or the second transfer means are equipped with a U-shaped connection block-support member connected to the outward block-support member or the homeward block-support member. 17. The chainless container-transporting device according to claim 16, wherein the connection block-support member is a connection guide rail having a rectangular cross-section. 18. The chainless container-transporting device according to claim 16, wherein the connection block-support member has a roller for reducing the slide-friction factor at a part in contact with the block. 19. The chainless container-transporting device according to claim 18, wherein the roller is provided on a linear part near a bent part of the U-shaped connection block-support member. 20. The chainless container-transporting device according to claim 19, wherein the roller provided on both the linear parts flanking the bent part of the U-shaped connection block-support member, is provided in a larger number on the downstream-side linear part compared to the upstream-side linear part. 21. The chainless container-transporting device according to claim 1, wherein the first transfer means and/or the second transfer means have a U-shaped guide member for supporting the blocks from the inner side and/or outer side of the blocks. 22. The chainless container-transporting device according to claim 1, wherein the container holder is constituted by a holding part for holding at least two opposing angular corners of a square-cylindrical container. 23. The chainless container-transporting device according to claim 1, wherein the adjacent blocks are connected with a permanent magnet. 24. The chainless container-transporting device according to claim 1, which is equipped with a container-support member situated on the lower side of the transported container, for providing a bottom support for the container. 25. The chainless container-transporting device according to claim 1, wherein an upwardly and downwardly penetrating opening is formed at a given position of the container-support member, and a container lifting-and-lowering means is equipped, which means being capable of inserting through the opening a container lifting-and-lowering member for pushing up the container from the bottom part to the upper side and for lowering it to its original position. 26. The chainless container-transporting device according to claim 1, wherein the device is constructed to be equipped on a filling-and-packaging machine for filling and packaging content in the container.

TECHNICAL FIELD The present invention relates to a container-transporting device which is equipped, for example, on a filling machine for filling milk cartons and the like with contents. BACKGROUND ART Conventionally, a high-speed liquid-filling machine equipped with a filling station illustrated in FIG. 9 for example, is known as a high-speed liquid-filling machine for filling liquid such as milk and juice to paper containers. Such a high-speed liquid-filling machine is equipped with: a machine frame 1 having a filling station; a transporting conveyor 2 capable of transporting containers in such a manner that they stop in succession at the filling station; a rotative body 4 having a radial mandrel 3, disposed upward of the starting end of the transport path of the transporting conveyor 2; a filling device 8 having a filling tank 5, a quantifying cylinder 6, and a filling nozzle 7, and a container lifting-and-lowering means 9, disposed at the filling station located in the midpoint of the transport path; a heat sealer 10 disposed on the latter half of the transport path, and so on. Filling and packaging by the above high-speed liquid-filling machine is effected by the following steps of: unfolding a container material (carton blank) into a square-cylindrical shape, while taking it out from a magazine 11 retaining the container material which is capable of being formed into a square-cylindrical shape; inserting and setting the unfolded material in succession to the mandrel 3; heating the edged of the material that will form the bottom of the container by a bottom-heating device 12; folding flat the heated circumferential edge of the container by a container-edge folding device 13; crimping the above flat-folded edge by a container-bottom-application device 14 to form a square-cylindrical container with a bottom; and shifting the square-cylindrical container with a bottom from the mandrel to container holders fixed to endless chains 15. The above transporting conveyor 2 is comprised of: the endless chains 15 coupled with a plurality of the container holders; and a pair of sprockets 16 and 17 provided at the starting end and the terminal end of the transport path respectively, where the endless chains 15 are bridged. The square-cylindrical containers with a bottom shifted onto the transporting conveyor are transported intermittently by the container holders fixed to the endless chains 15, over a rail 18 which provides a bottom support for and guides the containers. The square-cylindrical containers are then transported through a preparative folding device 19 which marks fold lines on the square-cylindrical containers with a bottom so that the top of the containers can be easily interfolded into a roof shape, and through a sterilizer 20 which sterilizes the inside of the container by oxygenated-water spray and/or ultraviolet irradiation, and finally reach the filling station. The square-cylindrical containers with a bottom intermittently transported and stopped at the filling station are then pushed up by the container lifting-and-lowering device 9. When the container reaches the top dead center, the filling nozzle 7 starts filling the descending container with liquid until the head of the filling nozzle 7 is withdrawn from the descended container, and the container-transporting starts almost at the same time as the filling is completed. The square-cylindrical containers with a bottom filled with liquid are then transported via a main-folding device 21 which finally interfolds the container top with the pre-folded lines into a roof shape, and via a container-top heating device 22 which heats the sealing surface of the interfolded container top. The container top is then heat-sealed by crimping by a heat sealer 10 and is printed with a date and the like by a printer 23, and then the containers are discharged as liquid-filled, packaged products. Incidentally, chain conveyors used as container-transporting conveyors are commonly known to generate chain elongation due to abrasions of endless chains over a long period of use. For example, in roller endless chains, constituted by sequential combinations of pin links and roller links, wherein each pin link has pin link plates at both ends of the two pins, and each roller link has roller link plates at both ends of the two bushings on which the rollers are fitted rotatably, it is known that the pin and the bushing which respectively constitute slide portions are brought into contact with each other in use and hence, the pin and the bushing are abraded thus decreasing thickness thereof whereby the elongation of the endless chain is generated. The generated endless-chain elongations displace the center position of the container holders into the transporting direction resulting in various drawbacks such as the seizure of endless chain into a sprocket wheel or a conveyor rail at the time of transportation and the leaking of liquid from the container after filling besides the displacement of centering between the device such as the filling device operable in each group of devices and the container. Particularly, with respect to the displacement of centering, it has been absorbed by moving the filling device or the like in the conveying direction. However, there exists a limit with respect to the absorption of the displacement and hence, when the absorption of the displacement reached the limit, it has been determined that the lifetime of the endless chain had almost run down and the endless chains have been exchanged at the same time. Meanwhile, as a technique for applying a preferred tension to the chains, a take-up of a chain conveyor is known, such take-up comprising: a holding arm which is freely pivotable within a given area where a driven sprocket bridged with chains is fixed at the head position and is so arranged that it can be moved closer to or further away from a drive sprocket; a biasing means biasing the holding arm into the direction to which the driven sprocket can be moved away from the drive sprocket; and a locking means which lock-releasably locks the pivot of the holding arm at any given position within the pivot area (see Japanese Laid-Open Patent Application No. 5-338758). The latest type of this high-speed liquid-filling machine is made with a view to achieving an even higher performance (speeding up of the operation) without changing the number of rows and conveying pitches and hence, a time cycle of the intermittent operations of the conveyor is shortened. In order to conduct the given container supplying, filling, lid-material sealing and the like within this short time cycle, particularly within a short intermittent stop time, sections for container supplying, filling, lid-material sealing and the like are provided at plural sections. Providing plural sections for filling, sealing, sterilizing and the like inevitably leads to an elongated machine length. In the latest type of this filling-and-packaging machine with elongated machine length, in order to achieve higher performance, positioning accuracy of container holders transported to each station of container supplying, filling and lid-material sealing should be as precise as possible. However, as long as conventional endless chains are used in transporting conveyors, problems resulting from elongation of endless chains in use, more specifically, regular positioning adjustment of each station and replacement of endless chains for making as precise as possible the center-position accuracy of the container holders transported to each station for container supplying, filling and lid-material sealing, were simply unavoidable. Particularly, in conventional container transporting conveyor apparatuses, the drive source (drive sprocket) has to be provided at the downstream-side end of the transport path, and in this case, the displacement of the container holders due to chain elongation would arise more significantly as the distance from drive source of the transporting apparatus increases, namely, notably at the starting-end of the transport path. Hence, the container supplying device which is situated at the very starting-end side of the transport path is most susceptible to positioning displacement of container holders, which has been a serious problem. Moreover, another problem has been that, as stated above, as there is a limit to the chain-adjustment task, and chains that have elongated beyond this adjustment limit have to be replaced; and further that link parts are provided with some allowance which resulted in poor accuracy of stop position for the objects transported. DISCLOSURE OF THE INVENTION Problem to be solved by the invention The present invention has been made in view of the above circumstances. The problem to be solved by the present invention is to provide a container-transporting device capable of fundamentally avoiding the problems caused by elongations and the structure of endless chains, which is inevitably created by using endless chains in the container-transporting conveyor of a conventional filling-and-packaging machine, and of ensuring precise positioning accuracy of container holders transported to each station for container supplying, filling and lid-material sealing in the filling-and-packaging machine. Means for Solving the Problem The present inventors have made a keen study to solve the above problems, and they have manufactured various container-transporting chain conveyors in terms of material and structure and the like of endless chains, and also in terms of tensioners and the like for absorbing elongations of endless chains. They have, however, reached the conclusion that any means, as long as endless chains are used, would never solve the problem fundamentally. They have therefore made a keen study to develop a chainless-container transporting device without chains and actually manufactured a chainless-container transporting device equipped with a block circulation system capable of: sequentially conveying a number of blocks having a holding part constituting a part of a container holder for holding containers, by a block-transfer means on outward block-supporting rails in the transporting direction by a given pitch; transferring container blocks that have been conveyed to the terminal-end of the outward block-support rails to the start end of the homeward block-support rails; subsequently conveying blocks at the start end of the homeward block-support rails to the terminal end of the homeward block-support rails; and thus transferring blocks that have been conveyed to the terminal end of the homeward block-support rails to the start-end of the outward block-support rails. Inconsequence, the present inventors have confirmed that containers can be accurately transported without using endless chains and that positioning displacement is not created with time, and thus completed the present invention. More specifically, the present invention relates to (1) a chainless container-transporting device for transporting square-cylindrical containers by holding them with container holders formed between container-transporting means arranged to face parallel with each other, wherein the container-transporting means is equipped with: a number of blocks having a holding part constituting a part of the container holders; an outward block-support member and a homeward block-support member, arranged by extending in the conveying direction, for supporting the number of blocks in a movable condition along the conveying direction; a first transfer means provided between the terminal end of the outward block-support member and the start end of the homeward block-support member, capable of sequentially transferring the blocks that have been conveyed while being supported by the outward block-support member, to the homeward block-support member; a second transfer means provided between the terminal end of the homeward block-support member and the start end of the outward block-support member, capable of sequentially transferring the blocks that have been conveyed while being supported by the homeward block-support member to the outward block-support member; and a block delivering means capable of delivering and conveying blocks so that each block can circulate in the order of outward block- support member, first transfer means, homeward block-support member, second transfer means and outward block-support member. The present invention also relates to (2) the chainless container-transporting device according to (1), wherein the block-delivering means is so constructed that it can deliver one or more blocks to the downstream side of the conveying direction, and that an adjacent block can be sequentially conveyed by the block being delivered, to the downstream side of the conveying direction; (3) the chainless container-transporting device according to (1) and (2), wherein the block-delivering means is so constructed that it can intermittently deliver and convey one or more blocks by a given pitch, to the downstream side of the conveying direction; (4) the chainless container-transporting device according to any one of (1) to (3), wherein the block-delivering means is so constructed that it can deliver blocks supported by the outward block-support member and/or homeward block-support member to the downstream side of the conveying direction; (5) the chainless container-transporting device according to any one of (1) to (4), wherein two or more block-delivering means are provided; (6) the chainless container-transporting device according to any one of (1) to (5), wherein the block-delivering means is equipped with a drive shaft and a pair of discs or a column having on its circumferential surface convex parts or concave parts capable of engaging with and delivering the blocks to the downstream side of the conveying direction; (7) the chainless container-transporting device according to (6), wherein the block is equipped with a rotatable rod-shaped member which gears into the concave parts formed on the outer circumferential surface of the pair of discs or the column; (8) the chainless container-transporting device according to any one of (1) to (5), wherein the block-delivering means is equipped with a block engaging-and-pushing member which moves forward and backward by a given stroke, capable of delivering one or more blocks while engaging therewith to the downstream side of the conveying direction; (9) the chainless container-transporting device according to any one of (1) to (8), wherein the outward block-support member and the homeward block-support member are two respective guide rails disposed above and beneath the block; (10) the chainless container-transporting device according to (9), wherein the guide rails are rod-shaped guide rails having a circular or polygonal cross-section; (11) the chainless container-transporting device according to (9) or (10), wherein the portion supporting the blocks delivered by the block-delivering means of the guide rails has a rectangular cross-section; (12) the chainless container-transporting device according to any one of (9) to (11), wherein the portion other than the portion supporting the block delivered by the block-delivering means of the guide rails has a circular cross-section; (13) the chainless container-transporting device according to any one of (9) to (12), wherein the guide rail has a roller for reducing the slide-friction factor at a part in contact with the block; and (14) the chainless container-transporting device according to (13), wherein the roller is provided on the portion supporting blocks delivered by the block-delivering means of the guide rails. The present invention further relates to (15) the chainless container-transporting device according to any one of (1) to (14), wherein the first transfer means and/or the second transfer means are equipped with a pair of discs or a column having on its circumferential surface concave parts or convex parts capable of guiding and transferring the block while engaging therewith; (16) the chainless container-transporting device according to any one of (1) to (15), wherein the first transfer means and/or the second transfer means are equipped with a U-shaped connection block-support member connected to the outward block-support member or the homeward block-support member; (17) the chainless container-transporting device according to (16), wherein the connection block-support member is a connection guide rail having a rectangular cross-section; (18) the chainless container-transporting device according to (16) or (17), wherein the connection block-support member has a roller for reducing the slide-friction factor at a part in contact with the block; (19) the chainless container-transporting device according to (18), wherein the roller is provided on a linear part near a bent part of the U-shaped connection block-support member; (20) the chainless container-transporting device according to (19), wherein the roller provided on both the linear parts flanking the bent part of the U-shaped connection block-support member, is provided in a larger number on the downstream-side linear part compared to the upstream-side linear part; (21) the chainless container-transporting device according to any one of (1) to (20), wherein the first transfer means and/or the second transfer means have a U-shaped guide member for supporting the blocks from the inner side and/or outer side of the blocks; (22) the chainless container-transporting device according to any one of (1) to (21), wherein the container holder is constituted by a holding part for holding at least two opposing angular corners of a square-cylindrical container; (23) the chainless container-transporting device according to any one of (1) to (22), wherein the adjacent blocks are connected with a permanent magnet; (24) the chainless container-transporting device according to any one of (1) to (23) which is equipped with a container-support member situated on the lower side of the transported container, for providing a bottom support for the container; (25) the chainless container-transporting device according to any one of (1) to (24), wherein an upwardly and downwardly penetrating opening is formed at a given position of the container-support member, and a container lifting-and-lowering means is equipped, which means being capable of inserting through the opening a container lifting-and-lowering member for pushing up the container from the bottom part to the upper side and for lowering it to its original position; and (26) the chainless container-transporting device according to any one of (1) to (25), wherein the device is constructed to be equipped on a filling-and-packaging machine for filling and packaging content in the container. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a schematic plan view of the chainless container-transporting device according to one of the embodiments of the present invention. FIG. 2 is a perspective view of the area around the block-delivering means of the chainless container-transporting device of FIG. 1. FIG. 3 is a perspective view of the block of the chainless container-transporting device of FIG. 1. FIG. 4 is a cross-sectional view of the area around the block-delivering means of the chainless container-transporting device of FIG. 1. FIG. 5 is a plan view of the area around the first transfer means of the chainless container-transporting device of FIG. 1. FIG. 6 is a cross-sectional view of the area around the block-delivering means of the chainless container-transporting device of FIG. 1. FIG. 7 is a longitudinal sectional view of the area around the block-delivering means according to a modified example of the chainless container-transporting device of FIG. 1. FIG. 8 is a perspective view of the area around the block-delivering means according to another modified example of the chainless container-transporting device of FIG. 1. FIG. 9 is a schematic explanatory drawing of a filling-and packaging machine equipped with a conventional chain container-transporting device. Explanation of Letters or Numerals 30. chainless container-transporting device 32. container-transporting means 33. container-transporting means 34. container holder 36. square-cylindrical container 38. holding piece 40. block 42. outward guide rail 44. homeward guide rail 46. first sprocket 48. second sprocket 50. block-delivering sprocket 51. rod-shaped support member 52. outer surface 54. guide-rail engagement member 54a. inner portion 56. guide-rail engagement member 56a. inner portion 57. abutting part 58. rod-shaped member 59. abutting part 60. connection guide rail 62. concave part 64. driven shaft 66. roller 68. concave part 70. drive shaft 72. outward guide rail 74. homeward guide rail 76. block 78. concave part 80. rod-shaped pushing member BEST MODE OF CARRYING OUT THE INVENTION The chainless container-transporting device of the present invention can be used while being equipped, for example, on a filling-and-packaging machine for filling and packaging content in a container held by a container holder, or on a sterilizer for sterilizing a container and the like. The chainless container-transporting device of the present invention is not particularly limited, provided that it is a chainless container-transporting device for transporting square-cylindrical containers by holding them with a container holder formed between container-transporting means arranged to face parallel with each other, wherein the container transporting means is equipped with: a number of blocks having a holding part constituting a part of the container holder; an outward block-support member and a homeward block-support member, arranged by extending in the conveying direction, for supporting the number of blocks in a movable condition along the conveying direction; a first transfer means provided between the terminal end of the outward block-support member and the start end of the homeward block-support member, capable of sequentially transferring the blocks that have been conveyed while being supported by the outward block-support member to the homeward block-support member; a second transfer means provided between the terminal end of the homeward block-support member and the start end of the outward block-support member, capable of sequentially transferring the blocks that have been conveyed while being supported by the homeward block-support member to the outward block-support member; and a block-delivering means capable of delivering and conveying blocks so that each block can circulate in the order of outward block-support member, first transfer means, homeward block-support member, second transfer means, and outward block-support member. . . . The term “chainless” used herein for the chainless container-transporting device of the present invention means that endless chains are not used for transporting a number of blocks supported by block-support members. According to the chainless container-transporting device of the present invention, the stop-position displacement of container holders generated from chain elongations and chain structure can be prevented, and for example, the tasks of container supplying, content feeding, sealing and the like can be performed precisely, effectively, and stably. It also eliminates the necessity for the maintenance required upon chain elongation. Further, the container-transporting means can be designed and manufactured without estimating chain elongations, which eliminates the necessity for the mechanism that is responsive to elongations, and thus achieves simpler mechanism, permitting manufacturing of low-cost and clean (be efficiently cleaned)container-transporting means. Further, it eliminates the necessity for chain lubricant (mainly water for food related machines) that was essential for chains conventionally, and thus achieves functional improvement in the aspect of hygiene, because water was potentially hazardous in that its droplet could be mixed in the container resulting in a bacterial contamination. Furthermore, conventionally, wear was created on chains due to contact of the gear edge (lateral face) of sprockets with roller-link plate of chains, and abrasion powder was inevitably generated on the area under high surface pressure. According to the chainless container-transporting device of the present invention, drive sections can be decentralized, which decreases surface pressure and thus prevents generation of abrasion powder. The block in the chainless container-transporting device of the present invention is not particularly limited, provided that it has a holding part constituting a part of the container holder. Examples of the holding part include, for example, a concave part so formed as to support one angular corner or two angular corners of a container, and a platy holding part having an L-shaped, channel-shaped, or U-shaped cross-section, that supports one angular corner or two angular corners of the container. When one holding piece having an L-shaped cross-section is provided on one block, the four angular corners of a square-cylindrical container are held by the four holding pieces provided on two blocks of the container-transporting means on one side, and on two blocks of the container-transporting means on the other side. Still further, a square-cylindrical container is a carton with a bottom, made of a carton blank which is unfolded into a square-cylindrical shape and sealed at the bottom. It has been known that a carton with a bottom unfolded into a square-cylindrical shape exhibits a diamond-shape (rhomboid) in cross-section in the natural state due to force trying to restore the original state of the folded carton blank (buckling; diamond transformation), and that the rate of buckling increases proportionally according to the stiffness of the paper. Container holders for such square-cylindrical containers can be constituted by holding parts (holding pieces) for holding the opposing angular corners (acute-angular part) of the square-cylindrical containers. The shape or size of the block can be determined as desired, which include, for example, a block of about 30 mm-65 mm long in the conveying direction. Further, its material is not particularly limited although abrasion-resistant materials with a low slide-friction factor between the above outward block-support member and the homeward block-support member (also referred to as block-support members if it meant to represent both) is preferable, specific examples including hard plastics, stainless-steel alloys, and aluminum alloys. The block can also be provided with a roller at an area in contact with the block-support member in order to reduce the slide-friction factor between the block and the block-support member. This block is preferably provided with a delivering-engagement part which engages with block-delivering means. Examples of such delivering-engagement parts include one or more concave parts or openings which engage with the convex part of the block-delivering means, and one or more convex parts or rod-shaped members which engage with the concave parts or openings of the block-delivering means, which facilitates and ensures the delivering of blocks. Particularly, when using a pair of discs or a column having on its circumferential surface the concave parts capable of engaging with and delivering the blocks to the downstream side of the conveying direction, the delivering-engagement part can be a fixed rod-shaped member or convex part, although a rotatable rod-shaped member which gears into the concave parts formed on the circumferential surface of the pair of discs or the column is preferable for achieving smooth block delivering and for reducing load on the pair of discs or the column and the rod-shaped member. Further, when using the pair of discs or the column such as those described above as a block-delivering means, it is preferable that a block is provided with two or more delivering-engagement parts for achieving more stable delivering and for reducing radii of the pair of discs or the column, and it is most preferable that they are provided at two places from the standpoint of component-designing and processing. Still further, a preferred block has a support-member-engagement part which engages with a block-support member, examples of such support-member-engagement parts including a U-shaped or channel-shaped engagement part which supports by accommodating the rod-shaped support member. A number of these blocks are preferably connected with the adjacent blocks with permanent magnets, by which stable block conveyance is achieved. The above outward block-support member and homeward block-support member are not particularly limited provided that they are support-members arranged by extending in the conveying direction, which support a number of blocks in a movable condition along the conveying direction, and at least the outward block-support members are arranged by extending along the container conveying direction. This block-support members are preferably constituted by two guide rails disposed above and beneath the block respectively, and specific examples of such guide rails include rod-shaped guide rails having a circular (including oval hereinafter) or polygonal cross-section, or grooved guide rails comprising a member having a U-shaped or channel-shaped cross-section. In the case of a rod-shaped guide rail, it is preferable that the portion supporting the block delivered by the block-delivering means has a rectangular cross-section, and that the portion other than the portion for supporting the blocks delivered by the block-delivering means has a circular cross-section. In this case, a great force is applied to the portion supporting the block delivered by the block-delivering means, making the blocks unstable. However, by making such a section rectangular in cross-section, the blocks can be conveyed more stably. Further, by making the portion other than the portion supporting the block delivered by the block-delivering means circular in cross-section, the rod-shaped guide rail will be in line contact with the channel-shaped or U-shaped support-member-engagement portion, and thus the contact abrasion can be reduced. Moreover, the broadened cleaning space gives the portion increased cleaning efficiency. At the contact area of the guide rail and a block, a roller can be provided for reducing the slide-friction factor to achieve smooth block delivering and conveyance. This roller is preferably provided at a specific section for supporting the block delivered by the block-delivering means of the guide rail. In this case, a great load is applied to the block delivered by the block-delivering means and the guide rail as well as the block conveyance is not conducted smoothly compared to other portion, but this problem can be overcome by providing the roller. The length of a block-support member can be selected as desired. However, the preferred outward block-support member and homeward block support member are long enough to support container holders between the starting end of the conveying direction (upstream end) and the terminal end of the conveying direction (downstream end), or between the first delivering means and the second delivering means. Further, the material of the block-support member is not particularly limited, although abrasion-resistant materials with a small slide-friction factor are preferable, specific examples including hard plastics, alloys of stainless steel, and hard plastics-coated stainless steel, of which, stainless steel coated with high-density polyethylene (HDPE) is preferable to use. The above block-delivering means is not particularly limited in terms of movement/mechanism or the setting position, provided that it is capable of delivering and conveying a number of blocks intermittently and/or continuously so that each block can circulate in the order of outward block-support member, first transfer means, homeward block-support member, second transfer means, and outward support member. . . . Preferred examples includes: a block-delivering means so constructed that it delivers one or more blocks to the downstream side of the conveying direction, and by such delivered blocks, the adjacent block is sequentially conveyed to the downstream side of the conveying direction; and a block-delivering means so constructed that it can intermittently deliver and convey one or more blocks by a given pitch to the downstream side of the conveying direction. This block-delivering means is preferably constructed so that it can deliver the block supported by the outward block-support member and/or homeward block-support member (blocks on the linear part), and in this case, block-delivering means can be provided in plural numbers, thus it is possible to manufacture very long conveyors with an unlimited conveyor length which save us the annoying problem of chain elongations. Furthermore, by delivering the blocks on the linear part, the V of the so called PV value (P: surface pressure; V: slide velocity) or the abrasion-deciding value, becomes approximately zero, which suggests no rubbing is caused between the blocks. Thus the abrasion of blocks does not occur, which ensures the prevention of block-size change. More specific examples of the above block-delivering means include: a block-delivering means equipped with a drive shaft and a pair of discs or a column having on its circumferential surface concave part or convex part capable of engaging with and delivering blocks to the downstream side of the conveying direction (a sprocket-system delivering means); and a block-delivering means equipped with a block engaging-and-pushing member which advances or retreats by a given stroke and is capable of delivering one or more blocks while engaging therewith, to the downstream side of the conveying direction. The sprocket-system delivering means is equipped with a drive shaft and a pair of discs or a column having on its circumferential surface concave parts or convex parts, and is so constructed that it delivers the blocks by rotating the drive shaft with the above concave or convex parts geared into the concave part or a rod-shaped member, or into a concave part or an opening formed on the block. According to this sprocket-system delivering means, container holders can be continuously delivered and conveyed by continuously rotating the drive shaft of the pair of discs or the column, and the container holders can be intermittently delivered and conveyed by a given pitch by intermittently rotating the drive shaft of the above pair of discs or the column. Meanwhile, the sprocket-system delivering means which is provided at the starting end or the terminal end of the block support member can be also used as a first and/or a second transfer means which will be described later. Examples of block engaging-and-pushing members include: one or more rod-shaped pushing members with a circular or rectangular cross-section, having a convex part (engaging-and-pushing convex part) engaging with a concave part or opening formed on the block; and one or more rod-shaped pushing members with a circular or rectangular cross-section, having a concave part or opening (an engaging-and-pushing concave part or an engaging-and-pushing opening) engaging with the convex part or a rod-shaped member of the block. For moving forward and backward the block engaging-and-pushing member along the conveying direction, a fluid cylinder such as air cylinder or a servo motor and the like can be used. The above given stroke can be one, two, three pitches or the like, and preferably one or two pitches, when the block length in the conveying direction is defined as one pitch. According to the type of block-delivering means which moves this block engaging-and-pushing means forward and backward by a given stroke, one or more blocks are delivered to the downstream side of the conveying direction, and the delivered container holder can intermittently deliver and convey sequentially a plurality of blocks situated adjacent to each other by a given pitch, and the filling is conducted during the stop time. Further, it is possible to provide the holder engaging-and-pushing member arranged by extending along almost the full length of the block-support member in the conveying direction, with a convex part or concave part, or an opening which corresponds to a concave part or an opening, or a convex part or a rod-shaped member on almost all the blocks supported by the block-support member, and in this case, almost all the blocks supported by the block-support member can be delivered and conveyed together intermittently by a given pitch to the downstream side of the conveying direction without close contact between the container holders. As for the type of block-delivering means which delivers and conveys intermittently by a given pitch a block with its concave part or opening being engaged with the engaging-and-pushing convex part provided on the block-engaging-and-pushing member, examples of the specific embodiments includes: a ratchet click system that delivers blocks by repeating a simple reciprocating movement, wherein a block is delivered by a given pitch after being advanced by a given stroke with the concave part or opening formed on the block engaged with the engaging-and-pushing convex part of the ratchet click and the like, and subsequently, when the block engaging-and-pushing member starts to move backward by a given stroke, the engagement of engaging-and-pushing convex part of the ratchet click and the like provided on the block engaging-and-pushing member with the concave part or an opening formed on the block is released, and the block is advanced by a given pitch as a result; a turn-click system that delivers blocks by repeating a reciprocating forward-and-reverse turning movement, wherein a block is delivered by a given pitch after being advanced by a given stroke with the concave part or opening formed on the block engaged with engaging-and-pushing convex part, and subsequently, the disengaged condition is made by rotating axially the block engaging-and-pushing member, and after moving backward the block by a given stroke in this disengaged condition, the engagement is made again by turning it reversely; and a box-motion click system that delivers blocks by repeating box movement, wherein a block is delivered by a given pitch after being advanced by a given stroke with the concave part or opening formed on the block engaged with the engaging-and-pushing convex part, and subsequently a disengaged condition is made by moving the block engaging-and-pushing member in the perpendicular direction to the block, and after moving backward the block by a given stroke in this disengaged condition, the engagement is made again by returning the block engaging-and-pushing member to its original position. The first transfer means and/or the second transfer means of the chainless container-transporting device of the present invention is not particularly limited provided it is a transfer means capable of guiding the blocks that have been conveyed while being supported by the block-support members to the other block-support members, and is preferably equipped with a (reciprocal/revolution) drive source to suit the need. Specific examples of the first transfer means and/or the second transfer means include a sprocket-system transfer means equipped with a pair of discs or a column having on its circumferential surface a concave part or convex part capable of guiding and transferring the blocks while being engaged therewith. The sprocket-system transfer means may be equipped with a drive source. The pair of discs or the column is adapted to convey and transfer container holders by rotating with its concave part or convex part being geared into the concave part or convex part provided on the block. Further, examples of the first transfer means and/or the second transfer means include a guide-system transfer means equipped with a U-shaped connection block-support member connected to the outward block-support member and the homeward block-support member. The guide-system support member can be used independently, while more stable transfer of the block to other block-support member is achieved when used in combination with the above sprocket-system transfer means. Examples of the above U-shaped connection block-support members include connection guide rails having circular or polygonal cross-section, and because a great force is applied to such a portion, a connection guide rails having a rectangular cross-section to provide a surface contact is preferable. Particularly, in the case of a surface contact, it is preferable to provide a roller on a part in contact with a block, to reduce the slide-friction factor so that the blocks can be conveyed smoothly. This roller can be provided on the part or whole of the connection block-support member, and particularly because the blocks are not conveyed smoothly along the linear part near the bent part of the U-shaped connection block-support member, it is particularly preferable that this section is provided with a roller. When providing a roller on both the linear parts flanking the bent part of the U-shaped connection block-support member, it is preferable to provide more rollers on the downstream-side linear part compared to the upstream-side linear part. Because of jammed-up blocks on the downstream-side linear part, a great load is applied to the blocks and the connection support-block as compared to the upstream-side linear part, while in this case this problem will be solved and the further the abrasion of the abutted part (edge part) which pushes out the adjacent block is inhibited. Also, a preferred first transfer means and/or second transfer means have a U-shaped guide member to support the block from the inner side and/or the outer side (lateral faces) as well as the above pair of discs or column and the U-shaped connection guide rails. By means of this, blocks can be better prevented from wobbling and thus can be conveyed more smoothly. Further, it may be a U-shaped guide member that support the blocks having a bottom from the inner side and/or outer side. In this case, it can be used independently. The chainless container-transporting device of the present invention can be so constructed as to support the container bottom by a holding part of a block, while it is preferable to be equipped with a container-support member supporting the bottom of the container, situated on the lower side of the containers being transported, because it reduces the load applied on the block, block-support member or the like. This container-support member is not particularly limited in terms of shape and the like, while a rod-shaped member with a smooth top arranged by extending in the conveying direction of the containers is preferable. Examples include a rod-shaped support member having a rectangular or inverted triangular cross-section, while a rod-shaped member having a rectangular cross-section is preferable. At the given position of the container-support member, it is preferable that an opening penetrating both upwardly and downwardly is formed, and also that a container lifting-and-lowering means is equipped, which means being capable of inserting the container lifting-and-lowering member through the opening, pushing the container up from the bottom and then lowering it to its original position. The given position is, for example a position where a filling device is set when the chainless container-transport device of the present invention is equipped on a filling-and-packaging machine. When the container pushed up by the container lifting-and-lowering means reaches the top dead center, the filling nozzle starts filling the descending container with liquid until the head of the filling nozzle is withdrawn from the descended container, and the container-transporting starts almost at the same time as the filling is completed. Thus, by using the container lifting-and-lowering means for pushing up the container from the bottom and for lowering it to its original position by inserting the container lifting-and-lowering member through the upwardly and downwardly penetrating opening formed at a given position of the container-support member, container lifting-and-lowering can be carried out smoothly without applying load to each member (for example, blocks) of the container-transporting means. Further, in this case, a container-transporting means with simpler structure is achieved because each member (for example, blocks) of the container lifting-and-lowering member does not have to go up and down according to the lifting and lowering of the container, and as a result, creation of flaws can be avoided in the container-transporting means. The chainless container-transporting device of the present invention will be described in detail with reference to the drawings. FIG. 1 is a schematic plan view of the chainless container-transporting device according to one of the embodiments of the present invention. FIG. 2 is a perspective view of the area around the block-delivering means of the chainless container-transporting device of FIG. 1. FIG. 3 is a perspective view of a block of the chainless container-transporting device of FIG. 1. FIG. 4 is a cross-sectional view of the area around the block-delivering means of the chainless container-transporting device of FIG. 1. FIG. 5 is a plan view of the area around the first transfer means of the chainless container-transporting device of FIG. 1. FIG. 6 is a cross-sectional view of the area around the block-delivering means of the chainless container-transporting device of FIG. 1. FIG. 7 is a longitudinal sectional view of the area around the block-delivering means according to a modified example of the chainless container-transporting device of FIG. 1. FIG. 8 is a perspective view of the area around the block-delivering means according to another modified example of the chainless container-transporting device of FIG. 1. As shown in FIGS. 1 to 6, the chainless container-transporting device 30 according to one embodiment of the present invention is a container-transporting device for holding and transporting a square-cylindrical container 36 with a container holder 34 formed between a container-transporting means 32 and 33 arranged to face parallel with each other, wherein the container-transporting means 32 and 33 are equipped with: a number of blocks 40 having a holding piece 38 which is an example of a holing part constituting a part of the container holder 34; an outward guide rail 42 and an homeward guide rail 44, arranged by extending in the conveying direction, for supporting the number of blocks 40 in a movable condition along the conveying direction; a first sprocket 46 provided between the terminal end of the outward guide rail 42 and the start-end of the homeward guide rail 44, constituting a first transfer means capable of sequentially transferring blocks 40 that have been conveyed while being supported by the outward guide rail 42 to the homeward guide rail 44; a second sprocket 48 provided between the terminal end of the homeward guide rail 44 and the start-end of the outward guide rail 42, constituting a second transfer means capable of sequentially transferring blocks 40 that have been conveyed while being supported by the homeward guide rail 44 to the outward guide rail 42; a block-delivering sprocket 50 which is an example of a block delivering means capable of delivering and conveying blocks 40 so that each block 40 can circulate in the order of outward guide rail 42, first transfer means 46, homeward guide rail 44, second transfer means 48 and outward guide rail 42 . . . ; and a rod-shaped support member 51 (see FIG. 4) having a rectangular cross-section arranged by extending in the container-transporting direction, which is an example of a container- support member for supporting the bottom of the square cylindrical container 36 in a transportable condition, situated in the lower side of a square-cylindrical container 36 supported by the container holders 34. As shown in FIG. 3, block 40 is equipped with a platy holding piece having an L-shaped cross-section 38; guide-rail-engagement members 54 and 56 with openings having a channel-shaped cross-section each facing upward and downward, fixed at the upper part and at the lower part onto the outer surface 52 of the holding piece 38; and two rod-shaped members 58 so fixed that they connect guide rail engagement members 54 and 56. On the lateral side of the guide-rail engagement members 54 and 56, abutting parts 57 and 59 are provided where blocks 40 abut with each other. The contact parts 57 and 59 are provided outside the line joining the centers of rod-shaped members 58 (the side of holding-piece 38), and, as shown in FIG. 5, are so adapted that the adjacent abutting parts 57 and 58 do not intervene with each other when moving from the linear part to the bent part of transfer means 46 (48). Further, inner sections 54a and 56a, wherein abutting parts 57 and 59 of the lateral sides of guide-rail engagement members 54 and 56 are not provided, are chamfered, and are adapted to avoid intervening with adjacent block 40 when passing the transfer means 46 (48). Furthermore, rod-shaped members 58 are so arranged that the space between all the rod-shaped members 58 are the same in the condition where they are supported by guide rails 42 and 44, and blocks 40 are abutting with each other (in a straight lined-up condition). More specifically, as shown in FIG. 6, the rod-shaped members are so arranged that space (a) between rod-shaped members 58 arranged on a block 40 and space (b) between rod members 58 of the adjacent blocks 40 are the same; and the blocks 40 are so constructed that their width is twice as long as the space between the rod-shaped members 58. In the present embodiment, container holder 34 is constituted by four holding pieces 38. Moreover, guide-rail-engagement members 54 and 56 accommodate guide rails 42 and 44 slidably in the concave part. Rod-shaped members 58 are fitted in a rotatable condition to guide-rail-engagement members 54 and 56, and this portion engages with the block-delivering sprocket 50 to deliver blocks 40. At this time, because rod-shaped members 58 are fitted rotatably, the load applied on rod-shaped members 58 and on block-delivering sprocket 50 is reduced and the blocks 40 can be smoothly and stably delivered. As shown in FIGS. 2 and 4, outward guide rails 42 and homeward guide rails 44 are respectively two rod-shaped members having a circular cross -section disposed above and beneath blocks 40. Due to the circular shape of their cross-sections, the outward guide rails 42 and homeward guide rails 44 can be in line contact with the above guide-rail engagement members 54 and 56, thus giving such parts increased cleaning efficiency. Further, as shown in FIG. 5, the first transfer means is equipped with the first sprocket 46 and a U-shaped connection guide rail 60. The first sprocket comprises upper-and-lower two-stage gears having concave parts 62 on the outer circumference for gearing with rod-shaped members 58 of blocks 40 and is equipped with a drive shaft 64. The connection guide rail 60 is a U-shaped rod-shaped member having a rectangular cross-section, which connects the outward guide rails 42 and the homeward guide rails 44, two of them being disposed one above the other respectively. On the linear part near the bent part of the U-shaped connection guide rail 60, rollers 66 are provided in order to reduce the friction between the guide-rail engagement members 54 and 56 of blocks 40. One roller 66 is provided on the upstream side and three on the downstream side. The device is in such a construction as to be provided with more rollers on the downstream side compared to the upstream side. Meanwhile, the second transfer means has the same construction as the first transfer means. As shown in FIGS. 4 and 6, block-delivering sprocket 50 is equipped with upper-and-lower two-stage gears having on their circumferential surfaces concave parts 68 gearing with rod-shaped members 58 of blocks 40, and with a drive shaft 70 joined to a drive source which is not illustrated. The block-delivering sprocket 50 delivers a total of four blocks 40 to the downstream side of the conveying direction by gearing with rod-shaped members 58 of two blocks 40 supported by outward guide rail 42 and of two blocks 40 supported by homeward guide rail 44. By delivering the four blocks 40, adjacent blocks 40 will be sequentially conveyed to the downstream side and thus theblocks40asawholeareconveyedandcirculated. Meanwhile, in the present embodiment, outward and homeward blocks are so constructed as to be delivered at the same time from the stand point of efficiency and cost reduction, while the blocks may be delivered outwardly and homewardly independently, and in this case, for example, it can be constructed so that the blocks on the homeward side can be delivered at once at a fast speed from the start-end side to the terminal-end side by using a linear feeder and the like. Further, in the chainless container-transporting device 30, as shown in FIG. 7, a modified example of outward guide rail 42 and homeward guide rail 44 having circular cross-sections includes outward guide rails 72 and homeward guide rails 74 wherein the section supporting block 40 delivered by block delivering sprocket 50 has a rectangular cross-section. The outward guide rails 72 and homeward guide rails 74 are provided with rollers 75 in order to reduce friction between guide-rail engagement members 54 and 56 of block 40. In this case, a great load is applied to blocks 40 delivered by the block delivering sprocket 50 and to guide rails 72 and 74, and in addition, blocks 40 are not conveyed smoothly, but this problem can be overcome by providing a roller 75. Meanwhile, although not illustrated, the part other than the part supporting blocks 40 delivered by the block-delivering sprocket 50 of the outward guide rail 72 and the homeward guide rail 74 has a circular cross-section, thus giving such part increased cleaning efficiency. Moreover, in the chainless container-transporting device 30, modified examples of blocks 40 and the block-delivering sprocket 50 include, as shown in FIG. 8, a combination of blocks 76 wherein a concave part 78 is formed one above the other on the center part, and two rod-shaped pushing members 80 with a rectangular cross-section having a latchet click (engagement-and-pushing concave part) which are situated one above the other in parallel and is engaging with concave parts 78 of blocks 76, respectively. The rod-shaped pushing members 80 deliver blocks by advancing by a given stroke while engaging with blocks 76 and thus delivering the block by a given pitch; and subsequently, at the start of retreating at a given stroke, the engagement of the latchet click provided on the rod-shaped members 80 with the concave part 78 formed on blocks 76 is released; and consequently blocks 76 advance by a given pitch. Industrial Applicability According to the chainless container-transporting device of the present invention, because endless chains are not used for transporting the blocks supported by block-support members, the problems caused by elongations and the structure of endless chains which was inevitably created by using endless chains in the container-transporting conveyors for conventional filling-and-packaging machines, can be avoided fundamentally. Further, positional accuracy of container holders being transported to each station for container supplying, filling, lid-material sealing and the like in a filling-and-packaging machine can be precise, and thus the processes of container supplying, filling, lid-material sealing and the like can be conducted efficiently and stably.

<SOH> BACKGROUND ART <EOH>Conventionally, a high-speed liquid-filling machine equipped with a filling station illustrated in FIG. 9 for example, is known as a high-speed liquid-filling machine for filling liquid such as milk and juice to paper containers. Such a high-speed liquid-filling machine is equipped with: a machine frame 1 having a filling station; a transporting conveyor 2 capable of transporting containers in such a manner that they stop in succession at the filling station; a rotative body 4 having a radial mandrel 3 , disposed upward of the starting end of the transport path of the transporting conveyor 2 ; a filling device 8 having a filling tank 5 , a quantifying cylinder 6 , and a filling nozzle 7 , and a container lifting-and-lowering means 9 , disposed at the filling station located in the midpoint of the transport path; a heat sealer 10 disposed on the latter half of the transport path, and so on. Filling and packaging by the above high-speed liquid-filling machine is effected by the following steps of: unfolding a container material (carton blank) into a square-cylindrical shape, while taking it out from a magazine 11 retaining the container material which is capable of being formed into a square-cylindrical shape; inserting and setting the unfolded material in succession to the mandrel 3 ; heating the edged of the material that will form the bottom of the container by a bottom-heating device 12 ; folding flat the heated circumferential edge of the container by a container-edge folding device 13 ; crimping the above flat-folded edge by a container-bottom-application device 14 to form a square-cylindrical container with a bottom; and shifting the square-cylindrical container with a bottom from the mandrel to container holders fixed to endless chains 15 . The above transporting conveyor 2 is comprised of: the endless chains 15 coupled with a plurality of the container holders; and a pair of sprockets 16 and 17 provided at the starting end and the terminal end of the transport path respectively, where the endless chains 15 are bridged. The square-cylindrical containers with a bottom shifted onto the transporting conveyor are transported intermittently by the container holders fixed to the endless chains 15 , over a rail 18 which provides a bottom support for and guides the containers. The square-cylindrical containers are then transported through a preparative folding device 19 which marks fold lines on the square-cylindrical containers with a bottom so that the top of the containers can be easily interfolded into a roof shape, and through a sterilizer 20 which sterilizes the inside of the container by oxygenated-water spray and/or ultraviolet irradiation, and finally reach the filling station. The square-cylindrical containers with a bottom intermittently transported and stopped at the filling station are then pushed up by the container lifting-and-lowering device 9 . When the container reaches the top dead center, the filling nozzle 7 starts filling the descending container with liquid until the head of the filling nozzle 7 is withdrawn from the descended container, and the container-transporting starts almost at the same time as the filling is completed. The square-cylindrical containers with a bottom filled with liquid are then transported via a main-folding device 21 which finally interfolds the container top with the pre-folded lines into a roof shape, and via a container-top heating device 22 which heats the sealing surface of the interfolded container top. The container top is then heat-sealed by crimping by a heat sealer 10 and is printed with a date and the like by a printer 23 , and then the containers are discharged as liquid-filled, packaged products. Incidentally, chain conveyors used as container-transporting conveyors are commonly known to generate chain elongation due to abrasions of endless chains over a long period of use. For example, in roller endless chains, constituted by sequential combinations of pin links and roller links, wherein each pin link has pin link plates at both ends of the two pins, and each roller link has roller link plates at both ends of the two bushings on which the rollers are fitted rotatably, it is known that the pin and the bushing which respectively constitute slide portions are brought into contact with each other in use and hence, the pin and the bushing are abraded thus decreasing thickness thereof whereby the elongation of the endless chain is generated. The generated endless-chain elongations displace the center position of the container holders into the transporting direction resulting in various drawbacks such as the seizure of endless chain into a sprocket wheel or a conveyor rail at the time of transportation and the leaking of liquid from the container after filling besides the displacement of centering between the device such as the filling device operable in each group of devices and the container. Particularly, with respect to the displacement of centering, it has been absorbed by moving the filling device or the like in the conveying direction. However, there exists a limit with respect to the absorption of the displacement and hence, when the absorption of the displacement reached the limit, it has been determined that the lifetime of the endless chain had almost run down and the endless chains have been exchanged at the same time. Meanwhile, as a technique for applying a preferred tension to the chains, a take-up of a chain conveyor is known, such take-up comprising: a holding arm which is freely pivotable within a given area where a driven sprocket bridged with chains is fixed at the head position and is so arranged that it can be moved closer to or further away from a drive sprocket; a biasing means biasing the holding arm into the direction to which the driven sprocket can be moved away from the drive sprocket; and a locking means which lock-releasably locks the pivot of the holding arm at any given position within the pivot area (see Japanese Laid-Open Patent Application No. 5-338758). The latest type of this high-speed liquid-filling machine is made with a view to achieving an even higher performance (speeding up of the operation) without changing the number of rows and conveying pitches and hence, a time cycle of the intermittent operations of the conveyor is shortened. In order to conduct the given container supplying, filling, lid-material sealing and the like within this short time cycle, particularly within a short intermittent stop time, sections for container supplying, filling, lid-material sealing and the like are provided at plural sections. Providing plural sections for filling, sealing, sterilizing and the like inevitably leads to an elongated machine length. In the latest type of this filling-and-packaging machine with elongated machine length, in order to achieve higher performance, positioning accuracy of container holders transported to each station of container supplying, filling and lid-material sealing should be as precise as possible. However, as long as conventional endless chains are used in transporting conveyors, problems resulting from elongation of endless chains in use, more specifically, regular positioning adjustment of each station and replacement of endless chains for making as precise as possible the center-position accuracy of the container holders transported to each station for container supplying, filling and lid-material sealing, were simply unavoidable. Particularly, in conventional container transporting conveyor apparatuses, the drive source (drive sprocket) has to be provided at the downstream-side end of the transport path, and in this case, the displacement of the container holders due to chain elongation would arise more significantly as the distance from drive source of the transporting apparatus increases, namely, notably at the starting-end of the transport path. Hence, the container supplying device which is situated at the very starting-end side of the transport path is most susceptible to positioning displacement of container holders, which has been a serious problem. Moreover, another problem has been that, as stated above, as there is a limit to the chain-adjustment task, and chains that have elongated beyond this adjustment limit have to be replaced; and further that link parts are provided with some allowance which resulted in poor accuracy of stop position for the objects transported.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a schematic plan view of the chainless container-transporting device according to one of the embodiments of the present invention. FIG. 2 is a perspective view of the area around the block-delivering means of the chainless container-transporting device of FIG. 1 . FIG. 3 is a perspective view of the block of the chainless container-transporting device of FIG. 1 . FIG. 4 is a cross-sectional view of the area around the block-delivering means of the chainless container-transporting device of FIG. 1 . FIG. 5 is a plan view of the area around the first transfer means of the chainless container-transporting device of FIG. 1 . FIG. 6 is a cross-sectional view of the area around the block-delivering means of the chainless container-transporting device of FIG. 1 . FIG. 7 is a longitudinal sectional view of the area around the block-delivering means according to a modified example of the chainless container-transporting device of FIG. 1 . FIG. 8 is a perspective view of the area around the block-delivering means according to another modified example of the chainless container-transporting device of FIG. 1 . FIG. 9 is a schematic explanatory drawing of a filling-and packaging machine equipped with a conventional chain container-transporting device. detailed-description description="Detailed Description" end="lead"?

20070123

20100608

20070607

99226.0

B65G3700

SINGH, KAVEL

CHAINLESS CONTAINER-TRANSPORTING DEVICE

UNDISCOUNTED

ACCEPTED

B65G

ACCEPTED

Grid falling film devolatilizer

The grid falling film devolatilizer according to this invention consists of a tower housing, a liquid distributor and a tower internal, said tower internal includes pillars and multiple grid trays, the cross section of said tower internal being square or rectangular, and the four pillars stand respectively at the four corners of the tower internal. Each grid tray includes a pair of beams, a plural of grid bars and corresponding guide members, among them said beams being located at opposite pair of sides of the grid tray and fixed to the pillars, said grid bars being perpendicular to the beams, and said guide member being installed between the grid gaps, so that the liquid pass through those grid gaps and generate films and thus producing huge devolatilization interfaces. The special design according to the invention ensures the substantial renewal of film surface in each grid tray. In view of the simple structure, high devolatilization efficiency, and high operation flexibility, as well as the low cost of fabrication and operation, the grid falling film devolatilizer can be used in a variety of devolatilization units in chemicals production.

1. A grid falling film devolatilizer, consisting of a tower housing (1), a liquid distributor (2) and a tower internal (3), wherein the said tower housing has a round, square or rectangle cross section; the said tower internal consists of pillars (3-1) and multiple grid trays (3-2), and four pillars stand respectively at the four corners of the tower internal which has a square or rectangle cross-section; there may be a single one or multiple tower internals arranged parallely in the tower housing; the number of the grid trays is 2 to 500 and the layer interval between two neighbor grid plate layers is 20 to 500 mm; each grid tray comprises a pair of beams (3-2-1), a plurality of grid bars (3-2-2) and corresponding guide members (3-2-3); said beams are located at opposite pair of sides of the grid tray, in a horizontal plane of same height, and are fixed to the pillars; the grid bars are fixed perpendicularly to the beams and are arranged in single tier, double tiers or multiple tiers in a parallel manner; the grid bars have a cross-section of triangle, reverse “V” shape formed by bending thin metal strips, circle or other shapes; said guide members consist of the guide mesh (wires) (3-2-3-1) and the clamp (3-2-3-2) for fixation of the guide mesh (wires), and are disposed at the grid gap between the two neighboring grid bars and parallel to the grid bars, the corresponding clamps are fixed to the beams; the outmost grid bars in a grid tray are formed as inclines or bent strips (3-2-2′) which present a larger vertical surface and serve as baffles for keeping liquid level in grid tray; or the clamps of the outmost guide members in a grid tray are extended to be higher than others and serve as baffles for keeping the liquid level in grid tray. 2. A grid falling film devolatilizer according to claim 1, wherein hangers (3-1-1) are provided on the upper part of the pillars (3-1) and supporting brackets (1-2-1) are provided on the upper part of the tower body (1-2); the hangers are mounted on the supporting brackets and fastened with bolts, so that the tower internal (3) is mounted inside the tower housing; the locating blocks (3-1-2) are provided on the lower part of the pillars and the matching stoppers (1-2-2) are provided on the lower part of the tower body for limiting the swing of the bottom of the tower internal. 3. A grid falling film devolatilizer according to claim 1, wherein the number of the said multiple grid trays (3-2) is 5 to 200 and the layer interval between two neighboring grid trays is 40 to 250 mm. 4. A grid falling film devolatilizer according to claim 1, wherein the grid bars in two neighboring grid trays are arranged in the following manners: a) arranged in the same direction but staggered by half a film interval; b) cross at 90 degrees; c) a hybrid of a) and b). 5. A grid falling film devolatilizer according to claim 1, wherein said guide meshes (wires) are woven metal wires, metal sheets, perforated metal sheets, expanded metal meshes, tube array or non-metal meshes; the guide meshes (wires) can be directly fixed below the grids, eliminating the clamps. 6. A grid falling film devolatilizer according to claim 5, wherein said tube array is formed by joining two corrugated sheets in a face-to-face manner and fixing them with butt welding, and introducing heating or cooling medium thereinto. 7. A grid falling film devolatilizer according to claim 1, wherein an overflowing film-forming mechanism is employed, in which the clamps are placed at two sides of a grid bar to constitute a grid funnel and the clamps act as overflow weirs. 8. A grid falling film devolatilizer according to claim 7, wherein a grid bar is disposed above two adjacent clamps that belong to two neighboring grid funnels respectively, and the width of the said grid bar is no less than the interval between the two clamps thereunder; and the grid funnels (or grid bars) in two adjacent grid trays cross at 90 degrees, or alternatively are arranged in the same direction while the grid funnels (or grid bars) are staggered by half an interval of the grid funnel. 9. A grid falling film devolatilizer according to the claim 7, wherein the grid funnels in two adjacent grid trays are arranged in the same direction but staggered by half an interval of grid funnel. The interval between two adjacent clamps that belong to two neighboring grid funnels is less than the interval between two clamps of a same grid funnel, or the lower portion of two neighboring guide meshes (wires) that belong to two neighboring grid funnels lean toward each other. 10. A grid falling film devolatilizer according to claim 1, wherein the grid bars in the grid trays are arranged in such a manner that width of grid gaps in said grid trays are gradually increased from top to bottom. 11. A grid falling film devolatilizer comprising: a tower housing (1); a liquid distributor; (2) and a tower internal (3); wherein the said tower housing has a round, square or rectangle cross section; and wherein said tower internal includes pillars (3-1) and multiple grid trays (3-2), and four pillars stand respectively at the four corners of said tower internal which has a square or rectangle cross-section. 12. The grid falling film devolatilizer of claim 11, wherein said tower housing comprises one or multiple tower internals arranged parallely in said tower housing; and wherein the number of the grid trays is 2 to 500 and the layer interval between two neighbor grid plate layers is 20 to 500 mm. 13. The grid falling film devolatilizer of claim 12, wherein each said grid tray comprises a pair of beams (3-2-1), a plurality of grid bars (3-2-2) and corresponding guide members (3-2-3). 14. The grid falling film devolatilizer of claim 13, wherein said beams are located at opposite pair of sides of the grid tray, in a horizontal plane of same height, and are fixed to the pillars. 15. The grid falling film devolatilizer of claim 14, wherein said grid bars are fixed perpendicularly to the beams and are arranged in single tier, double tiers or multiple tiers in a parallel manner. 16. The grid falling film devolatilizer of claim 15, wherein the grid bars have a cross-section of triangle, reverse “V” shape formed by bending thin metal strips, circle or other shapes. 17. The grid falling film devolatilizer of claim 13, said guide members comprise guide mesh (wires) (3-2-3-1) and a clamp (3-2-3-2) for fixation of said guide mesh (wires), and are disposed at a grid gap between the two neighboring grid bars and parallel to the grid bars, the corresponding clamps are fixed to the beams. 18. The grid falling film devolatilizer of claim 17, the outmost grid bars in a grid tray are formed as inclines or bent strips (3-2-2′) which present a larger vertical surface and serve as baffles for keeping liquid level in grid tray; or the clamps of the outmost guide members in a grid tray are extended to be higher than others and serve as baffles for keeping the liquid level in grid tray. 19. The grid falling film devolatilizer according to claim 11, wherein hangers (3-1-1) are provided on the upper part of the pillars (3-1) and supporting brackets (1-2-1) are provided on the upper part of the tower housing (1-2); and wherein the hangers are mounted on the supporting brackets and fastened with bolts, so that said tower internal (3) is mounted inside the tower housing; and the locating blocks (3-1-2) are provided on the lower part of the pillars and the matching stoppers (1-2-2) are provided on the lower part of the tower housing for limiting the swing of the bottom of the tower internal. 20. The grid falling film devolatilizer according to claim 11, wherein the number of the said multiple grid trays (3-2) is 5 to 200 and the layer interval between two neighboring grid trays is 40 to 250 mm. 21. The grid falling film devolatilizer according to claim 13, wherein said grid bars in two neighboring grid trays are arranged in a manner selected from the group consisting of: (a) being arranged in the same direction but staggered by half a film interval; (b) being crossed at 90 degrees; and a hybrid of (a) and (b). 22. The grid falling film devolatilizer according to claim 17, wherein said guide meshes (wires) are woven metal wires, metal sheets, perforated metal sheets, expanded metal meshes, tube array or non-metal meshes; the guide meshes (wires) can be directly fixed below the grids, eliminating the clamps. 23. The grid falling film devolatilizer according to claim 22, wherein said tube array is formed by joining two corrugated sheets in a face-to-face manner and fixing them with butt welding, and introducing heating or cooling medium thereinto. 24. The grid falling film devolatilizer according to claim 11, wherein an overflowing film-forming mechanism is employed, in which the clamps are placed at two sides of a grid bar to constitute a grid funnel and the clamps act as overflow weirs. 25. The grid falling film devolatilizer according to claim 24, wherein a grid bar is disposed above two adjacent clamps that belong to two neighboring grid funnels respectively, and the width of the said grid bar is no less than the interval between the two clamps thereunder; and the grid funnels (or grid bars) in two adjacent grid trays cross at 90 degrees, or alternatively are arranged in the same direction while the grid funnels (or grid bars) are staggered by half an interval of the grid funnel. 26. The grid falling film devolatilizer according to the claim 24, wherein the grid funnels in two adjacent grid trays are arranged in the same direction but staggered by half an interval of grid funnel. The interval between two adjacent clamps that belong to two neighboring grid funnels is less than the interval between two clamps of a same grid funnel, or the lower portion of two neighboring guide meshes (wires) that belong to two neighboring grid funnels lean toward each other. 27. The grid falling film devolatilizer according to claim 11, wherein the grid bars in the grid trays are arranged in such a manner that width of grid gaps in said grid trays are gradually increased from top to bottom.

FIELD OF THE INVENTION The present invention relates to a gravity-driven falling film devolatilizer, in particularly, to a grid falling film devolatilizer with high specific surface in which film surfaces are continuously renewed. BACKGROUND OF THE INVENTION Devolatilization is an important process in the chemical industry for transferring volatiles from the liquid phase to the gas phase. The main ways of improving the efficiency of devolatilization include: 1. Increasing the temperature of the devolatilization system; 2. Decreasing the fractional pressure of the volatile component in the gas phase; 3. Increasing the interface between the gas phase and the liquid phase; 4. Regenerating the interface frequently. The temperature of the devolatilization system is subject to the processing conditions; the decrease of fractional pressure of the volatile component in the gas phase may be achieved by controlling the operating pressure of the devolatilizer or by adopting inert gases as a carrier; while the enlargement of the gas-liquid interface and the regeneration of the interface mainly depend on the structure of the devolatilizer. At present, there are many types of devolatilizers in industrial operation. Among them, an in-tube falling film devolatilizer and a down-flowing liquid column (droplet) devolatilizer may provide fairly large gas-liquid interfaces which, however, are hardly renewed, and the residence time is not controllable, and devolatilization efficiency may be influenced adversely due to the insufficient residence time. Horizontal devolatilizers with a single/double-shaft, multiple discs (meshes) stirrer, meanwhile, can effectively renew the interface to a certain extent and control the residence time by adjusting liquid level; however, their structures are excessively complex and fabrication and operation costs are high. To ensure film coverage, the liquid layer must be kept at a sufficient depth at the bottom of such devolatilizer, in which case the hydrostatic head will have negative impact on the devolatilization efficiency. DISCLOSURE OF INVENTION A primary object of the present invention is to provide a novel grid falling film devolatilizer, which includes a large gas-liquid interface and effective film regeneration, and which is composed of thin film-like material, simple in structure and cost-effective to make and operate. The novel grid falling film devolatilizer, according to the present invention, is a further modification and development of the previous Chinese Patent No. ZL97121654.1 of the same inventor, “A GRID PLATE TYPE POLYCONDENSATION TOWER FOR POLYESTER”, but presents a distinctly different structure from the original polycondensation tower. It ensures film coverage in a wider range of viscosity and flow rate, features more stable performance and a wider variety of applications. It is considered to be the forerunner of a new generation of devolatilizers. The novel grid falling film devolatilizer, according to the present invention, comprises: (1) a tower housing, (2) a liquid distributor, and (3) a tower internal. The tower housing is formed generally in the shape of a cylinder, but it may have a square or a rectangle cross-section when used in low pressure applications. It provides the desired temperature and pressure environment according to the devolatilization operation requirements. The tower housing includes a top cover (1-1), a tower body (1-2) and a tower bottom (1-3) which are connected via flanges; or, alternatively, the tower body and the tower bottom can be fabricated as an integral part. The top cover has a feeding inlet a and a gas discharging outlet c. The tower bottom has a material discharging outlet b. The top cover, the tower body and the tower bottom are covered by thermal insulation jackets or outer coils and equipped with one or more pairs of HTM inlet d and outlet e, respectively. And besides the aforesaid nozzles, various instruments or other necessary connections may be installed. The liquid distributor is disposed below the top cover or inside the upper portion of the tower body in connection with the feeding inlet, and performs the function of distributing the materials fed into the tower uniformly on the first grid tray. The tower internal generally has a square cross-section, while it may be rectangle or other shapes as well, and consists of pillars (3-1) and multiple grid trays (3-2). The tower internal performs the function of forming a large film surface of the materials and regenerating the film surface continuously. The tower internal may have four pillars which are generally made of steel angle or other steel shapes and positioned at the corners of the square or rectangle cross-section of the tower internal. The hangers (3-1-1) provided on the upper part of the pillars (3-1) are mounted and fastened with bolts on the supporting brackets (1-2-1) fixed on the upper part of the tower body (1-2) so that the tower internal is mounted inside the tower housing in an easily removable manner. The locating blocks (3-1-2) are provided on the lower part of the pillars (3-1) and the matching stoppers (1-2-2) are provided on the lower part of the tower housing. This configuration limits the swing of the bottom of the tower internal while allowing the slide up or down of the tower internal inside the tower housing due to expansion or shrinkage of metallic materials as temperature varies. The number of the grid trays in the tower internal is subject to the desired number of times of film renewal as per process requirements, which is generally 2 to 500 and preferably 5 to 200. Each grid tray comprises a pair of beams (3-2-1), a plurality of (at least two) grid bars (3-2-2) and corresponding guide members (3-2-3). A typical unit configuration of the pillars, beams, grid bars and guide members in a grid tray is shown in FIG. 2. The beams are located at opposite pair of sides of the grid tray. Beams on the same grid tray are in the same horizontal plane, and are fixed to the pillars by welding or with bolts. Beams in two neighboring grid trays are arranged parallely or cross at 90°. The difference between the horizontal elevation of neighboring grid trays, referred to as layer interval, is usually in a range of 20 to 500 mm, preferably 40 to 250 mm, and the layer intervals between each neighboring grid trays may either be equal or not equal. The number of the grid bars in each grid tray is subject to the flow rate and viscosity of the devolatilization system, the dimension of the tower, and the perpendicularity of the grid bars to the beams. Each grid tray may have single, double or multiple tiers of grid bars arranged horizontally and parallely. The grid bars may have a cross-section of triangle or reverse “V” shape formed by bending thin metal strips. Alternatively, they may adopt circular or rhombic tube or have a cross-section in other shapes. The outmost grid bar is formed as an incline or a bent strip (3-2-2′) which presents a larger vertical surface, and serves as a baffle for maintaining the liquid level in the grid tray. The grid bars are fixed on the beams by welding or inserting perforated beams. The width and height of the grid bars are subject to (i.e. depend on) their rigidity: the longer the grid bars are, the larger the width and the height (mainly the height) of the grid bars should be. This ensures the flexibility of the grid bars will not exceed the allowable range. The gap width between two neighboring grid bars, referred to as ‘grid gap’, is one of the crucial factors determining the devolatilization efficiency. Grip gap should be determined by calculation of parameters such as viscosity, surface tension, concentration of the volatile components in the materials, flow rate and operating pressure, etc., or by experiments. Under high viscosity and high flow rate circumstances, the grid bars can be arranged in two or more tiers in a grid tray to improve the throughput capacity. Meanwhile, the grid bars in upper and lower tiers may have the same or different width. When viscosity or gas content in the materials changes greatly in the devolatilizer, the width and/or the number of the grid bars in each tier should be adjusted gradually from top to bottom so as to change the gap width. The guide member consists of the guide mesh (wires) (3-2-3-1) and the clamp (3-2-3-2) for fixation of the guide mesh (wires). The guide mesh (wires) may be metal wires, woven metal wire, metal sheet, perforated metal sheet, or expanded metal mesh that presents rhombus holes which may be formed by cutting and stretching metal sheet. If heat addition or removal is desired inside the devolatilizer, the guide mesh may employ a tube array as shown in FIG. 3. The tube array is formed by joining two corrugated sheets in a face-to-face manner and fixing them with butt welding, and introduce a heating or cooling medium thereinto. The guide mesh (wires) may be made from non-metal materials, such as plastics, etc. under lower operating temperature. The guide members are disposed between two neighboring grid bars and parallel to the grid bars, the corresponding clamps are welded with the beams or inserted in perforated beams to fix them therein. The outmost clamps (3-2-3-2′) are extended to be higher than others and serve as baffles for keeping the liquid level in grid tray; or, alternatively the guide mesh (wires) can be directly fixed under the grid bars without clamps. For further increasing the flexibility of the devolatilization operation, the present invention provides an overflowing film-forming mechanism, in which the clamps are placed at two sides of the grid bar to constitute a grid funnel and the clamps act as overflow weirs. When the flow volume or viscosity of the liquid is low, the liquid level is lower than the top end of the clamps, the materials only flow downwards through the gaps between the grid bars, and the clamp and generate films along guide meshes (wires). When the flow volume or viscosity is increased, a portion of materials will overflow the clamp, flow down along the outer side of the clamp, and converge with the materials passing through the gap between the grid bar and the clamp to generate films along the guide mesh. With this arrangement, the devolatilizer can adapt to a wider range of flow volumes and viscosities, and higher operating flexibility is achieved. In each grid tray, the materials pass through the grid gaps by gravity and generate films along the guide members, thereby obtaining high devolatilizating interface. For the purpose of interface renewal, two neighboring grid trays may be arranged as per the following configurations: Configuration A: The grid trays are arranged in the same direction, and the grid bars in upper and lower tiers are staggered by half a film interval or funnel interval: 1. The grid bars in each grid tray are arranged in one tier and in the same direction, as shown in FIG. 4; 2. The grid bars in each grid tray are arranged in two tiers and in the same direction, as shown in FIG. 5; 3. There are three alternative structures as followed for the overflowing film-forming mechanism in which grid trays are arranged in the same direction: a) The grid bars in each grid tray are arranged in two tiers, the grid funnel is located in the lower tier, and the width of the grid bars in the upper tier is no less than the interval between the two grid funnels thereunder, as shown in FIG. 6; b) The upper grid bar tier is eliminated, and the interval between two neighboring grid funnels is less than the width of the grid funnel, as shown in FIG. 7; c) The upper grid bar tier is eliminated, and the lower portion of the guide meshes (wires) in neighboring grid funnels lean toward each other, as shown in FIG. 8. Configuration B: Neighboring grid trays are arranged crosswise: 1. The grid bars in each grid tray are arranged in one tier, and grid bars in neighboring grid trays are arranged crosswise, as shown in FIG. 9; 2. The grid bars in each grid tray are arranged in two tiers, and grid bars in neighboring grid trays are arranged crosswise, as shown in FIG. 10; 3. For the overflowing film-forming mechanism in which neighboring grid trays are arranged crosswise, the grid bars in each grid tray are arranged in two tiers, and the width of the grid bars in upper tier is no less than the interval between two grid funnels thereunder, as shown in FIG. 11. Configuration C: A hybrid Configuration based on Configurations A and B. The devolatilizer provided by the present invention operates in the following manner: The materials are fed into the tower through the feeding inlet a at the top of the tower, and fall onto the first grid tray uniformly through the liquid distributor, then pass through the grid gaps and generate films along the guide meshes (wires). The films are baffled by grid bars in the second grid tray, and materials pass through the grid gaps in the second grid tray and generate films along the guide meshes (wires) in the second grid tray. Once again, the films are baffled by grid bars in the third grid tray, and materials pass through the grid gaps in the third grid tray and generate films along the guide mesh. This continues until materials pass through the grid gaps in the lowermost grid tray to fall down to the tower bottom, and then leave the tower via the material discharging outlet b. The gases which escape from the film surface during the process pass through the narrow space between the liquid films, rise upwards through the arc-shaped area between the tower housing (1) and the tower internal (3) and gather at the top of the tower, then leave the tower via the gas discharging outlet c. The renewal of film surfaces in each grid tray is achieved as follows: 1. As described in connection with configuration A above, the liquid film descending along the guide mesh (wires) of the grid tray above falls right on the angular point of the grid bar of the grid tray beneath and thereby is split into two halves. The two adjacent halves that come from two neighboring films above respectively converge in the grid gap between them, and then pass through the grid gap, generating film along the guide mesh (wires). During said split and convergence process, two face-to-face surface layers of the two adjacent films above are brought into center part of the film beneath, while the center part of the film above emerges as the surface layers of two adjacent films beneath. Thus the renewal of film surface is achieved. 2. As described in connection with configuration B above, the liquid films in a grid tray are perpendicular to those in adjacent grid trays, thereby allowing for the materials to be mixed adequately through the length and breadth and the renewal of film surface to be achieved. The grid falling film devolatilizer according to the present invention is applicable to the devolatilization of liquids whose viscosities range from 0.2 mPa·s to 2000 Pa·s and may be employed in a wide range of applications, such as petrochemical, specialty chemicals, pharmacy and food industries, etc. Compared with the conventional devolatilizer, the devolatilizer according to the present invention has the following advantages: 1. High devolatilization interface, providing larger devolatilizing area per unit volume of the materials; 2. Adequate interface renewal; 3. High operation flexibility and devolatilization efficiency; 4. Capable of a large variety of applications, can be used for the devolatilization of the materials with viscosity of 0.2 mPa·s to 2000 Pa·s; 5. No dead zones and no axial back mixing; 6. All the materials being in a form of thin film, so that eliminating the negative impact of hydrostatic head on the devolatilization efficiency; 7. Simple in structure, ease of maintenance, cost-effective fabrication and operation costs. BRIEF DESCRIPTION OF THE DRAWINGS The following best mode embodiment of the present invention should be taken in conjunction with the appended drawings, wherein: FIG. 1 is a structural section view of the grid falling film devolatilizer; FIG. 2 is a schematic diagram showing the unit configuration of the pillars, beams, grid bars and guide members in a grid tray; FIG. 3 is a schematic diagram of the guide mesh in the form of a tube array; FIG. 4 is a structural schematic diagram showing the grid bars in each grid tray arranged in one tier and in the same direction; FIG. 5 is a structural schematic diagram showing the grid bars in each grid tray arranged in two tiers and in the same direction; FIG. 6 is a structural schematic diagram showing an overflowing film-forming mechanism in which the grid bars in each grid tray are arranged in two tiers, the grid funnel is located in the lower tier and adjacent grid trays are arranged in the same direction; FIG. 7 is a structural schematic diagram showing an overflowing film-forming mechanism in which the grid bars in each grid tray are arranged in one tier, and adjacent grid trays are arranged in the same direction; FIG. 8 is a structural schematic diagram showing an overflowing film-forming mechanism in which the grid bars in each grid tray are arranged in one tier, the adjacent grid trays are arranged in the same direction, and the lower portion of the guide meshes (wires) in neighboring grid funnels lean toward each other; FIG. 9 is a structural schematic diagram showing the grid bars in each grid tray arranged in one tier, and the grid bars in neighboring grid trays arranged crosswise; FIG. 10 is a structural schematic diagram showing grid bars in each grid tray arranged in two tiers, and the grid bars in neighboring grid trays arranged crosswise; and FIG. 11 is a structural schematic diagram showing an overflowing film-forming mechanism in which the grid bars in neighboring grid trays are arranged crosswise. BEST MODE EMBODIMENTS OF THE PRESENT INVENTION The following examples are provided to further illustrate the present invention, but the scope of claims of the present invention is not limited to the followed examples. Example 1 Final Polycondensation Tower for High-Viscous Polyester The tower has a diameter of 1600 mm and a height of 8000 mm. The tower internal has a size of 1000 mm×1000 mm×6000 mm and comprises 80 layers of grid trays which are arranged crosswise in an overflowing film-forming manner. The layer interval of the two uppermost grid trays is 15 mm and that of the bottommost grid trays is 37.5 mm. The pre-polymers introduced into the tower have an intrinsic viscosity of 0.3 and a temperature of 285° Celsius and a flow rate of 2,500 kg/hr. The pressure in the tower is 100 Pa. The intrinsic viscosity of polymer leaving the tower increases to 0.85. Example 2 The Devolatilization of CO2 from the Aqueous Solution of Ethylene Oxide The devolatilization of CO2 should be performed prior to the hydration reaction of ethylene oxide so as to prevent the erosion of the apparatus. The degassing tower is 1600 mm in diameter, 7500 mm in height. The tower internal has a size of 620 mm×620 mm×5000 mm and comprises 80 layers of grid trays which arranged in a hybrid style as per the abovementioned Configuration C. The layer interval is 8 mm. The solution of ethylene oxide with 2% CO2 is fed into the tower, and the temperature is 40° Celsius, the flow rate is 60,000 kg/hr. The pressure in the tower is 0.135 MPa. The CO2 in the solution of ethylene oxide leaving the tower is removed completely.

<SOH> BACKGROUND OF THE INVENTION <EOH>Devolatilization is an important process in the chemical industry for transferring volatiles from the liquid phase to the gas phase. The main ways of improving the efficiency of devolatilization include: 1. Increasing the temperature of the devolatilization system; 2. Decreasing the fractional pressure of the volatile component in the gas phase; 3. Increasing the interface between the gas phase and the liquid phase; 4. Regenerating the interface frequently. The temperature of the devolatilization system is subject to the processing conditions; the decrease of fractional pressure of the volatile component in the gas phase may be achieved by controlling the operating pressure of the devolatilizer or by adopting inert gases as a carrier; while the enlargement of the gas-liquid interface and the regeneration of the interface mainly depend on the structure of the devolatilizer. At present, there are many types of devolatilizers in industrial operation. Among them, an in-tube falling film devolatilizer and a down-flowing liquid column (droplet) devolatilizer may provide fairly large gas-liquid interfaces which, however, are hardly renewed, and the residence time is not controllable, and devolatilization efficiency may be influenced adversely due to the insufficient residence time. Horizontal devolatilizers with a single/double-shaft, multiple discs (meshes) stirrer, meanwhile, can effectively renew the interface to a certain extent and control the residence time by adjusting liquid level; however, their structures are excessively complex and fabrication and operation costs are high. To ensure film coverage, the liquid layer must be kept at a sufficient depth at the bottom of such devolatilizer, in which case the hydrostatic head will have negative impact on the devolatilization efficiency.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The following best mode embodiment of the present invention should be taken in conjunction with the appended drawings, wherein: FIG. 1 is a structural section view of the grid falling film devolatilizer; FIG. 2 is a schematic diagram showing the unit configuration of the pillars, beams, grid bars and guide members in a grid tray; FIG. 3 is a schematic diagram of the guide mesh in the form of a tube array; FIG. 4 is a structural schematic diagram showing the grid bars in each grid tray arranged in one tier and in the same direction; FIG. 5 is a structural schematic diagram showing the grid bars in each grid tray arranged in two tiers and in the same direction; FIG. 6 is a structural schematic diagram showing an overflowing film-forming mechanism in which the grid bars in each grid tray are arranged in two tiers, the grid funnel is located in the lower tier and adjacent grid trays are arranged in the same direction; FIG. 7 is a structural schematic diagram showing an overflowing film-forming mechanism in which the grid bars in each grid tray are arranged in one tier, and adjacent grid trays are arranged in the same direction; FIG. 8 is a structural schematic diagram showing an overflowing film-forming mechanism in which the grid bars in each grid tray are arranged in one tier, the adjacent grid trays are arranged in the same direction, and the lower portion of the guide meshes (wires) in neighboring grid funnels lean toward each other; FIG. 9 is a structural schematic diagram showing the grid bars in each grid tray arranged in one tier, and the grid bars in neighboring grid trays arranged crosswise; FIG. 10 is a structural schematic diagram showing grid bars in each grid tray arranged in two tiers, and the grid bars in neighboring grid trays arranged crosswise; and FIG. 11 is a structural schematic diagram showing an overflowing film-forming mechanism in which the grid bars in neighboring grid trays are arranged crosswise. detailed-description description="Detailed Description" end="lead"?

20061211

20110614

20070719

64422.0

B01F304

BUSHEY, CHARLES S

GRID FALLING FILM DEVOLATILIZER

UNDISCOUNTED

ACCEPTED

B01F

ACCEPTED

Multi-line addressing methods and apparatus

This invention relates to methods and apparatus for driving electro-optic, in particular organic light emitting diodes (OLED) displays using multi-line addressing (MLA) techniques Embodiments of the invention are particularly suitable for use with so-called passive matrix OLED displays A method of driving an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the method comprising receiving image data for display, said image data defining an image matrix, factorising said image matrix into a product of at least first and second factor matrices, said first factor matrix defining row drive signals for said display, said second factor matrix defining column drive signals for said display, and driving said display row and column electrodes using said row and column drive signals respectively defined by said first and second factor matrices

1. A method of driving an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the method comprising: receiving image data for display, said image data defining an image matrix; factorising said image matrix into a product of at least first and second factor matrices, said first factor matrix defining row drive signals for said display, said second factor matrix defining column drive signals for said display; and driving said display row and column electrodes using said row and column drive signals respectively defined by said first and second factor matrices. 2. A method as claimed in claim 1 wherein said driving comprises driving a plurality of said row electrodes in combination with a plurality of said column electrodes. 3. A method as claimed in claim 1, wherein said driving comprises driving said display with successive sets of said row and column signals to build up a display image, each said set of signals defining a subframe of said display image, said subframes combining to define said display image. 4. A method as claimed in claim 3 wherein a number of said subframes is no greater than the smaller of a number of said row electrodes and a number of said column electrodes. 5. A method as claimed in claim 4 wherein said number of subframes is less than the smaller of a number of said row electrodes and a number of said column electrodes. 6. A method as claimed in claim 3, wherein said first factor matrix has dimensions determined by a number of said row electrodes and a number of said subframes, and wherein said second factor matrix has dimensions determined by a number of said column electrodes and said number of subframes. 7. A method as claimed in claim 1, wherein said first and second factor matrices are configured such that a peak pixel brightness of said display is reduced compared with a row-by-row driving of said display using said image data, 8. A method as claimed in claim 1, wherein said factorising comprises singular value decomposition (SVD) into three factor matrices, said first and second factor matrices and a third factor matrix, said third factor matrix being substantially diagonal, and wherein said row drive signals are defined by a combination of said first and third factor matrices and said column drive signals are defined by a combination of said second and third factor matrices. 9. A method as claimed in claim 8 further comprising selectively driving said display dependent upon diagonal values of said third factor matrix. 10. A method as claimed in claim 9 wherein said selective driving comprises omitting to drive said display with row and column drive signals defined by diagonal values of said third factor matrix less than a threshold value. 11. A method as claimed in claim 8, wherein said driving comprises driving said display with successive sets of said row and column signals to build up a display image each said set of signals defining a subframe of said display image, said subframes combining to define said display image, further comprising sorting said factor matrices such that said successive subframes are arranged to give the general appearance of a scanned display. 12. A method as claimed in claim 1, wherein said factorising comprises QR decomposition. 13. A method as claimed in claim 1, wherein said factorising comprises LU decomposition. 14. A method as claimed in claim 1, wherein said factorising comprises non-negative matrix factorisation (NMF). 15. A method as claimed in claim 14 wherein said image matrix comprises an m×n matrix I and said first and second factor matrices respectively comprise an m×p matrix W and a p×n matrix H where p is less than or equal to the smallest of n×m and where I≈W.H. 16. A method as claimed in claim 1, wherein said display comprises a multicolour display, each said pixel of which comprises subpixels of at least a green colour and a second colour, wherein said image data includes colour data defining green and second colour channels for driving said green and second colour subpixels, and wherein said image matrix factorising includes weighting said green colour channel with a greater weight than said second colour channel such that said green channel is displayed on average more accurately than said second colour channel. 17. A method as claimed in claim 16 further comprising scaling said colour data for said green and second colour channels by respective first and second weights prior to said factorisation, and wherein said second weight is less than said first weight. 18. A method as claimed in claim 16 wherein said second colour is red and wherein each said pixel further comprises a blue subpixel; wherein said colour data includes data for a blue colour channel; and wherein said factorising includes weighting said green colour channel with a greater weight than said red and blue colour channels. 19. A method as claimed in claim 1, wherein said display comprises an LCD display. 20. A method as claimed in claim 1, wherein said display comprises an organic light emitting diode display. 21. (canceled) 22. A carrier carrying a processor control code for receiving image data for display, said image data defining an image matrix; factorising said image matrix into a product of at least first and second factor matrices, said first factor matrix defining row drive signals for said display, said second factor matrix defining column drive signals for said display; and driving said display row and column electrodes using said row and column drive signals respectively defined by said first and second factor matrices. 23. A driver for an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the driver comprising; an input for receiving image data for display, said image data defining an image matrix; a system for factorising said image matrix into a product of at least first and second factor matrices, said first factor matrix defining row drive signals for said display, said second factor matrix defining column drive signals for said display; and output means to output said row and column drive signals respectively defined by said first and second factor matrices. 24. A method of driving an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the method comprising: receiving image data for display; formatting said image data into a plurality of subframes, each said subframe comprising data for driving a plurality of said row electrodes simultaneously with a plurality of said column electrodes; and driving said row and column electrodes with said subframe data. 25. A method as claimed in claim 24 wherein said formatting comprises compressing said image data into said plurality of subframes. 26. A method as claimed in claim 25 wherein said display comprises a multicolour display, wherein said image data comprises colour image data, and wherein said compressing comprises compressing data for a green colour channel of said display less than data for at least one of a red and a blue colour channel of said display. 27. A method as claimed in claim 24, wherein said formatting is configured to generate subframe data such that data from more than one said subframe drives a said pixel of said display, whereby more than one said subframe contributes to an apparent brightness of pixels of the display. 28. A method as claimed in claim 24, wherein said compressing comprises singular value decomposition (SVD). 29. A method as claimed in claim 24, wherein said compressing comprises non-negative matrix factorisation (NMF). 30. A method as claimed in claim 29 wherein said image data comprises an m×n matrix I and said first and second factor matrices respectively comprise an m×p matrix W and a p×n matrix H where p is less than or equal to the smallest of n×m and where I≈W.H. 31. A method as claimed in claim 24, wherein said display comprises an organic light emitting diode display. 32. (canceled) 33. A carrier carrying processor control code for receiving image data for display: formatting said image data into a plurality of subframes, each said subframe comprising data for driving a plurality of said row electrodes simultaneously with a plurality of said column electrodes; and driving said row and column electrodes with said subframe data. 34. A driver for an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the driver comprising: an input to receive image data for display; a system for formatting said image data into a plurality of subframes, each said subframe comprising data for driving a plurality of said row electrodes simultaneously with a plurality of said column electrodes; and an output to output said subframe data for driving said row and column electrodes. 35. A driver for an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the driver comprising: an input to receive image data for display, said image data defining an image matrix; an output to provide data for driving said row and column electrodes of said display; data memory to store said image data; program memory storing processor implementable instructions; and a processor coupled to said input, to said output, to said data memory and to said program memory to load and implement said instructions, said instructions comprising instructions for controlling the processor to: input said image data; factorise said image matrix into a product of at least first and second factor matrices said first factor matrix defining row drive signals for said display, said second factor matrix defining column drive signals for said display; and output said row and column drive signals respectively defined by said first and second factor matrices. 36. A driver for an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the driver comprising: an input to receive image data for display, said image data defining an image matrix; an output to provide data for driving said row and column electrodes of said display; data memory to store said image data; program memory storing processor implementable instructions; and a processor coupled to said input, to said output, to said data memory and to said program memory to load and implement said instructions, said instructions comprising instructions for controlling the processor to: input said image data; format said image data into a plurality of subframes. each said subframe comprising data for driving a plurality of said row electrodes simultaneously with a plurality of said column electrodes; and output said subframe data for driving said row and column electrodes.

This invention relates to methods and apparatus for driving electro-optic, in particular organic light emitting diodes (OLED) displays using multi-line addressing (MLA) techniques. Embodiments of the invention are particularly suitable for use with so-called passive matrix OLED displays. This application is one of a set of three related applications sharing the same priority date. Multi-line addressing techniques for liquid crystal displays (LCDs) have been described, for example in US2004/150608, US2002/158832 and US2002/083655, for reducing power consumption and increasing the relatively slow response rate of LCDs. However these techniques are not suitable for OLED displays because of differences stemming from the fundamental difference between OLEDs and LCDs that the former is an emissive technology whereas the latter is a form of modulator. Furthermore, an OLED provides a substantially linear response with applied current and whereas an LCD cell has a non-linear response which varies according to the RMS (root-mean-square) value of the applied voltage. Displays fabricated using OLEDs provide a number of advantages over LCD and other flat panel technologies. They are bright, colourful, fast-switching (compared to LCDs), provide a wide viewing angle and are easy and cheap to fabricate on a variety of substrates. Organic (which here includes organometallic) LEDs may be fabricated using materials including polymers, small molecules and dendrimers, in a range of colours which depend upon the materials employed. Examples of polymer-based organic LEDs are described in WO 90/13148, WO 95/06400 and WO 99/48160; examples of dendrimer-based materials are described in WO 99/21935 and WO 02/067343; and examples of so called small molecule based devices are described in U.S. Pat. No. 4,539,507. A typical OLED device comprises two layers of organic material, one of which is a layer of light emitting material such as a light emitting polymer (LEP), oligomer or a light emitting low molecular weight material, and the other of which is a layer of a hole transporting material such as a polythiophene derivative or a polyaniline derivative. Organic LEDs may be deposited on a substrate in a matrix of pixels to form a single or multi-colour pixellated display. A multicoloured display may be constructed using groups of red, green, and blue emitting pixels. So-called active matrix displays have a memory element, typically a storage capacitor and a transistor, associated with each pixel whilst passive matrix displays have no such memory element and instead are repetitively scanned to give the impression of a steady image. Other passive displays include segmented displays in which a plurality of segments share a common electrode and a segment may be lit up by applying a voltage to its other electrode. A simple segmented display need not be scanned but in a display comprising a plurality of segmented regions the electrodes may be multiplexed (to reduce their number) and then scanned. FIG. 1a shows a vertical cross section through an example of an OLED device 100. In an active matrix display part of the area of a pixel is occupied by associated drive circuitry (not shown in FIG. 1a). The structure of the device is somewhat simplified for the purposes of illustration. The OLED 100 comprises a substrate 102, typically 0.7 mm or 1.1 mm glass but optionally clear plastic or some other substantially transparent material. An anode layer 104 is deposited on the substrate, typically comprising around 150 nm thickness of ITO (indium tin oxide), over part of which is provided a metal contact layer. Typically the contact layer comprises around 500 nm of aluminium, or a layer of aluminium sandwiched between layers of chrome, and this is sometimes referred to as anode metal. Glass substrates coated with ITO and contact metal are available from Corning, USA. The contact metal over the ITO helps provide reduced resistance pathways where the anode connections do not need to be transparent, in particular for external contacts to the device. The contact metal is removed from the ITO where it is not wanted, in particular where it would otherwise obscure the display, by a standard process of photolithography followed by etching. A substantially transparent hole transport layer 106 is deposited over the anode layer, followed by an electroluminescent layer 108, and a cathode 110. The electroluminescent layer 108 may comprise, for example, a PPV (poly(p-phenylenevinylene)) and the hole transport layer 106, which helps match the hole energy levels of the anode layer 104 and electroluminescent layer 108, may comprise a conductive transparent polymer, for example PEDOT:PSS (polystyrene-sulphonate-doped polyethylene-dioxythiophene) from Bayer AG of Germany. In a typical polymer-based device the hole transport layer 106 may comprise around 200 nm of PEDOT; a light emitting polymer layer 108 is typically around 70 nm in thickness. These organic layers may be deposited by spin coating (afterwards removing material from unwanted areas by plasma etching or laser ablation) or by inkjet printing. In this latter case banks 112 may be formed on the substrate, for example using photoresist, to define wells into which the organic layers may be deposited. Such wells define light emitting areas or pixels of the display. Cathode layer 110 typically comprises a low work function metal such as calcium or barium (for example deposited by physical vapour deposition) covered with a thicker, capping layer of aluminium. Optionally an additional layer may be provided immediately adjacent the electroluminescent layer, such as a layer of lithium fluoride, for improved electron energy level matching. Mutual electrical isolation of cathode lines may achieved or enhanced through the use of cathode separators (not shown in FIG. 1a). The same basic structure may also be employed for small molecule and dendrimer devices. Typically a number of displays are fabricated on a single substrate and at the end of the fabrication process the substrate is scribed, and the displays separated before an encapsulating can is attached to each to inhibit oxidation and moisture ingress. To illuminate the OLED power is applied between the anode and cathode, represented in FIG. 1a by battery 118. In the example shown in FIG. 1a light is emitted through transparent anode 104 and substrate 102 and the cathode is generally reflective; such devices are referred to as “bottom emitters”. Devices which emit through the cathode (“top emitters”) may also be constructed, for example by keeping the thickness of cathode layer 110 less than around 50-100 nm so that the cathode is substantially transparent. Organic LEDs may be deposited on a substrate in a matrix of pixels to form a single or multi-colour pixellated display. A multicoloured display may be constructed using groups of red, green, and blue emitting pixels. In such displays the individual elements are generally addressed by activating row (or column) lines to select the pixels, and rows (or columns) of pixels are written to, to create a display. So-called active matrix displays have a memory element, typically a storage capacitor and a transistor, associated with each pixel whilst passive matrix displays have no such memory element and instead are repetitively scanned, somewhat similarly to a TV picture, to give the impression of a steady image. Referring now to FIG. 1b, this shows a simplified cross-section through a passive matrix OLED display device 150, in which like elements to those of FIG. 1a are indicated by like reference numerals. As shown the hole transport 106 and electroluminescent 108 layers are subdivided into a plurality of pixels 152 at the intersection of mutually perpendicular anode and cathode lines defined in the anode metal 104 and cathode layer 110 respectively. In the figure conductive lines 154 defined in the cathode layer 110 run into the page and a cross-section through one of a plurality of anode lines 158 running at right angles to the cathode lines is shown. An electroluminescent pixel 152 at the intersection of a cathode and anode line may be addressed by applying a voltage between the relevant lines. The anode metal layer 104 provides external contacts to the display 150 and may be used for both anode and cathode connections to the OLEDs (by running the cathode layer pattern over anode metal lead-outs). The above mentioned OLED materials, in particular the light emitting polymer and the cathode, are susceptible to oxidation and to moisture and the device is therefore encapsulated in a metal can 111, attached by UV-curable epoxy glue 113 onto anode metal layer 104, small glass beads within the glue preventing the metal can touching and shorting out the contacts. Referring now to FIG. 2, this shows, conceptually, a driving arrangement for a passive matrix OLED display 150 of the type shown in FIG. 1b. A plurality of constant current generators 200 are provided, each connected to a supply line 202 and to one of a plurality of column lines 204, of which for clarity only one is shown. A plurality of row lines 206 (of which only one is shown) is also provided and each of these may be selectively connected to a ground line 208 by a switched connection 210. As shown, with a positive supply voltage on line 202, column lines 204 comprise anode connections 158 and row lines 206 comprise cathode connections 154, although the connections would be reversed if the power supply line 202 was negative and with respect to ground line 208. As illustrated pixel 212 of the display has power applied to it and is therefore illuminated. To create an image connection 210 for a row is maintained as each of the column lines is activated in turn until the complete row has been addressed, and then the next row is selected and the process repeated. Preferably, however, to allow individual pixels to remain on for longer and hence reduce overall drive level, a row is selected and all the columns written in parallel, that is a current driven onto each of the column lines simultaneously to illuminate each pixel in a row at its desired brightness. Each pixel in a column could be addressed in turn before the next column is addressed but this is not preferred because, inter alia, of the effect of column capacitance. The skilled person will appreciate that in a passive matrix OLED display it is arbitrary which electrodes are labelled row electrodes and which column electrodes, and in this specification “row” and “column are used interchangeably. It is usual to provide a current-controlled rather than a voltage-controlled drive to an OLED because the brightness of an OLED is determined by the current flowing through the device, this determining the number of photons it generates. In a voltage-controlled configuration the brightness can vary across the area of a display and with time, temperature, and age, making it difficult to predict how bright a pixel will appear when driven by a given voltage. In a colour display the accuracy of colour representations may also be affected. The conventional method of varying pixel brightness is to vary pixel on-time using Pulse Width Modulation (PWM). In a conventional PWM scheme a pixel is either full on or completely off but the apparent brightness of a pixel varies because of integration within the observer's eye. An alternative method is to vary the column drive current. FIG. 3 shows a schematic diagram 300 of a generic driver circuit for a passive matrix OLED display according to the prior art. The OLED display is indicated by dashed line 302 and comprises a plurality n of row lines 304 each with a corresponding row electrode contact 306 and a plurality m of column lines 308 with a corresponding plurality of column electrode contacts 310. An OLED is connected between each pair of row and column lines with, in the illustrated arrangement, its anode connected to the column line. A y-driver 314 drives the column lines 308 with a constant current and an x-driver 316 drives the row lines 304, selectively connecting the row lines to ground. The y-driver 314 and x-driver 316 are typically both under the control of a processor 318. A power supply 320 provides power to the circuitry and, in particular, to y-driver 314. Some examples of OLED display drivers are described in U.S. Pat. No. 6,014,119, U.S. Pat. No. 6,201,520, U.S. Pat. No. 6,332,661, EP 1,079,361A and EP 1,091,339A and OLED display driver integrated circuits employing PWM are sold by Clare Micronix of Clare, Inc., Beverly, Mass., USA. Some examples of improved OLED display drivers are described in the Applicant's co-pending applications WO 03/079322 and WO 03/091983. In particular WO 03/079322, hereby incorporated by reference, describes a digitally controllable programmable current generator with improved compliance. There is a continuing need for techniques which can improve the lifetime of an OLED display. There is a particular need for techniques which are applicable to passive matrix displays since these are very much cheaper to fabricate than active matrix displays. Reducing the drive level (and hence brightness) of an OLED can significantly enhance the lifetime of the device—for example halving the drive/brightness of the OLED can increase its lifetime by approximately a factor of four. The inventors have recognised that multi-line addressing techniques can be employed to reduce peak display drive levels, in particular in passive matrix OLED displays, and hence increase display lifetime. MLA Addressing with Matrix Decomposition According to a first aspect of the present invention there is therefore provided a method of driving an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the method comprising: receiving image data for display, said image data defining an image matrix; factorising said image matrix into a product of at least first and second factor matrices, said first factor matrix defining row drive signals for said display, said second factor matrix defining column drive signals for said display; and driving said display row and column electrodes using said row and column drive signals respectively defined by said first and second factor matrices. In embodiments of this method factorising the image matrix into at least two factor matrices defining row and column drive signals for the display (which in embodiments may be scaled as described later) enables the drive to pixels of the display to be spread over a longer time interval, thus reducing the maximum pixel drive for a given apparent brightness, taking into account integration within a viewer's eye. Thus preferably the driving comprises driving a plurality of the row electrodes in combination with a plurality of the column electrodes. In this way advantage may be taken of correlations between the luminescence of pixels in different rows to build the required luminescent profile of each line or row of the display over a plurality of lines scan periods, rather than as an impulse in a single line scan period. Some benefit can be obtained even when the total number of line scan periods is the same as for a conventionally line-by-line scanned display. In preferred embodiments neither of the first and second factor matrices is predefined or predetermined. Instead both the first and second factor matrices for each new image, that is they are re-calculated for each block of image data received defining an image for display. Preferably therefore the method drives the display with successive sets of row and column signals to build up a displayed image, each set of signals defining a subframe of the displayed image, the subframes combining to define the complete desired image. Here a subframe may refer to a portion of the desired displayed image in either time and/or space but in preferred embodiments the subframes are displayed during successive time intervals, for example each analogous to a conventional line scan period, so that when rapidly successively displayed the desired pixel brightnesses are obtained. As will be seen later, in embodiments of the method the image matrix factorisation can incorporate a degree of compression which allows essentially the same information (that is compressed to an acceptable degree) to be displayed in a shorter time or, equivalently, over the same period of time as a conventional frame period but with a reduced drive to each pixel, each line or row effectively being driven for a longer period than in a conventional display. In a colour display where the colour channels are processed (factorised) separately different degrees of compression may be applied to the different colour channels. In this case it is preferable to apply less compression to the green channel (of an RBG display) as the human eye is more sensitive to differences (errors or noise) in green level than to differences in red or blue levels. In embodiments the number of subframes is no greater than the lesser of the number of rows and the number of columns of the display; preferably the number of subframes is less than the smaller of the number of rows and the number of columns. In some applications the flexibility to define arbitrarily what is a row and what is a column of the display may be limited by, for example, a desire for compatibility with existing designs, in which case the number of subframes is preferably no greater than (and preferably less than) either the number of rows or the number of columns of the display. Displays are envisaged in which each pixel (or sub-pixel of a colour display) is addressed by a corresponding row and column electrode and hence references to row and columns of the display can be understood as references to row and column electrodes of the display. In embodiments of the method the first factor matrix has dimensions determined by the number of row electrodes and a number of subframes employed (which may be predetermined by hardware and/or software or which may be selectable dependent upon, say, display quality). Similarly, the second factor matrix has dimensions determined by the number of column electrodes and the number of subframes. As previously mentioned, preferably the first and second factor matrices are configured, for example by limiting the number of subframes or dimensions of the matrices, such that a peak pixel brightness of the display is reduced compared with row-by-row driving of the same display using the same image data (with the same overall frame period to display a substantially complete image from the received data). Reducing the peak pixel brightness, that is reducing the peak pixel drive, increases the overall display lifetime. Again, in an RBG display more subframes may be employed for one colour, in particular green, than another, to provide increased accuracy of green (as opposed to blue or red) rendering. Broadly speaking the dynamic range of pixel drive/brightness is reduced by reducing the higher pixel drive signals and this increases display lifetime roughly proportionately. This is because the lifetime reduces with the square of the pixel drive (brightness) but the length of time for which a pixel must be driven to provide the same apparent brightness to an observer increases only substantially linearly with decreasing pixel drive. In some embodiments of the method the matrix factorising comprises singular value decomposition (SVD) into three factor matrices, the first and second factor matrices and a third factor matrix, the third factor matrix being substantially diagonal (with positive or zero elements defining so-called singular values). In this case the row drive signals are defined by a combination of the first and third factor matrices and the column drive signals by a combination of the second and third factor matrices. Since these combinations give rise to matrices with either positive or negative elements embodiments of this method are best suited to liquid crystal displays (LCDs) rather than to electroluminescent displays such as OLED display. However an SVD-based method may, for example, be incorporated into an iterative scheme which forces non-negative (i.e. positive or zero) valued elements. With SVD matrix factorisation the diagonal elements of the third matrix effectively define a weight for the corresponding values in the first and second factor matrices and thus this provides a straightforward method for, in effect, compressing the image data by reducing the number of subframes displayed. Thus in embodiments of this method selective driving of the display is employed in which row and column drive signals defined by diagonal values of the third factor matrix less than a threshold value are neglected, in effect compressing the drive signals dependent upon a threshold of the diagonal values of the third factor matrix. In a colour display in which, say, separate factorisation is applied to red, green and blue colour channels, it is preferably to give the green channel a greater weight than the others, for example by using a lower threshold value for green or by scaling the colour channel information using respective colour channel weights before the factorisation and then scaling the results back or performing an inverse scaling operation after factorisation. An alternative approach is to weight individual red, green and blue data values differently during the factorisation procedure (which is generally applied to a single image data matrix for the combined colour channels). In practice this comprises multiplying the green data values by a greater-than-unity scaling factor (and dividing by a total weight) during the factorisation. This is mathematically equivalent to scaling up before and back after factorisation, but can reduce rounding errors where, for example, a fixed number of bits integer-type (rather than floating point) representation is employed. Similar techniques can be employed with other factorisation methods such as the non-negative matrix factorisation (NMF) mentioned below. In other embodiments of the method the factorising comprises QR decomposition (into a triangular and an orthogonal matrix) or LU decomposition (into upper and lower triangular matrices). However in some further preferred embodiments the image matrix factorisation comprises non-negative matrix factorisation (NMF). Broadly speaking in NMF the image matrix I (which is non-negative) is factorised into a pair of matrices W and H such that I is approximately equal to the product of W and H where W and H are chosen subject to the constraints that their elements are all equal to or greater than zero. A typical NMF algorithm iteratively updates W and H to improve the approximation by aiming to minimise a cost function such as the squared Eucliden distance between I and WH. Non-negative matrix factorisation is particularly useful for driving an emissive display such as an electroluminescent display, in particular an OLED display, as a simple OLED cannot be driven to produce a “negative” luminescence, and it is therefore necessary, at least for driving a passive matrix OLED display, for the elements of the first and second factor matrices to be positive or zero. The situation is different when driving LCD displays, and also when driving active matrix OLED displays in which the circuitry associated with a pixel is designed to allow both positive and negative drive inputs, for example adding or subtracting charge from a compacitor associated with a pixel in order that the light output is the sum or integral of a series of drive input signals. In non-negative matrix factorisation (NMF) when matrix I has dimensions m×n (row×column) matrix W has dimension m×p and matrix H has dimensions p×n where p is generally chosen to be less than both n and m. Thus W and H are smaller than I, this resulting in a compression of the original image data. Broadly speaking W can be regarded as defining a basis for the linear approximation of the image data I and in many cases a good representation of I can be achieved with a relatively small number of basis vectors since images generally contain some inherent, correlated structure rather than purely random data. This image compression is useful as it enables the image to be displayed in a smaller number of row/column drive events than would otherwise be the case (for a conventional row-by-row raster scan). This in turn means that for the same frame period each pixel can be driven for longer thus reducing the pixel drive signal necessary for the same apparent pixel brightness, and hence increasing the display lifetime. In a large display such as an active matrix display with a very large number of pixels, for example 3000 by 2000 pixels, this technique also facilitates more rapid update of the displayed data. In some instances, for example where a pre-defined graphic icon or logo is being displayed, the matrix factorisation for at least this portion of the image can be pre-calculated and stored to speed up processing of images containing the logo or icon. It is possible to order the columns in the row matrix (and the corresponding rows in the column matrix) to give the general appearance of a scanned display. This is because a pair of sets of elements comprising a row of the first factor matrix and column of the second factor matrix can be swapped with a corresponding pair without affecting the mathematical result. Sorting the matrices to give the appearance of a scanned display is useful because a computation of the image matrix factorisation can result in arbitrary ordering of drive signals to bright areas of the display, which may change from frame to frame and which can give rise to the appearance of motion artefacts or jitter. Sorting the data in the factor matrices so that bright areas of a displayed image are generally illuminated in a single direction, from top to bottom of the display, can reduce flicker. In embodiments of the above described methods a pixel comprises red, green and blue subpixels but although the image data comprises data for each of these colour channels it is preferable that these are treated together as a single “combined” matrix. However it is then preferable that the factorising is performed subject to a constraint that the factorisation of the matrix for one channel, in particular the green, is on average more accurate than the factorisation of the matrices for the other colour channels. Thus, for example, more subframes may be used for the green channel, and/or a lower error threshold may be applied to the green channel processing, and/or a greater weight may be given to the green channel as compared with the red/blue channels and/or less relatively compression may be applied to the green channel. This is because, as mentioned previously, the human eye is more sensitive to differences (errors or noise) in green level than to differences in red or blue levels. Similar techniques may be applied in the other aspects of the invention mentioned below, and the invention also contemplates means to put the above-described green-channel processing techniques into effect in the context of the other aspects of the invention mentioned below. According to a second aspect of the invention there is provided a method of driving an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the method comprising: receiving image data for display; formatting said image data into a plurality of subframes, each said subframe comprising data for driving a plurality of said row electrodes simultaneously with a plurality of said column electrodes; and driving said row and column electrodes with said subframe data. In embodiments formatting the image data into a plurality of subframes enables the same pixels to be drive by two (or more) subframes and hence the peak drive to be reduced for the same apparent brightness, thus extending display lifetime. Preferably the formatting comprises compressing the image data into the plurality of subframes; in some embodiments some scaling of the image or subframe data may also be applied. The compressing may, as described above, employ singular value decomposition (SVD) or non-negative matrix factorisation (NMF). Preferred embodiments of the above described methods are particularly useful for driving an organic light emitting diode display. In a related aspect the invention provides a driver for an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the driver comprising; means for receiving image data for display, said image data defining an image matrix; means for factorising said image matrix into a product of at least first and second factor matrices, said first factor matrix defining row drive signals for said display, said second factor matrix defining column drive signals for said display; and means for outputting said row and column drive signals respectively defined by said first and second factor matrices. The invention further provides a driver for an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the driver comprising: means for receiving image data for display; means for formatting said image data into a plurality of subframes, each said subframe comprising data for driving a plurality of said row electrodes simultaneously with a plurality of said column electrodes; and means for outputting said subframe data for driving said row and column electrodes. The invention further provides a driver for an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the driver comprising; an input to receive image data for display, said image data defining an image matrix; an output to provide data for driving said row and column electrodes of said display; data memory to store said image data; program memory storing processor implementable instructions; and a processor coupled to said input, to said output, to said data memory and to said program memory to load and implement said instructions, said instructions comprising instructions for controlling the processor to: input said image data; factorise said image matrix into a product of at least first and second factor matrices said first factor matrix defining row drive signals for said display, said second factor matrix defining column drive signals for said display; and output said row and column drive signals respectively defined by said first and second factor matrices. The invention further provides a driver for an electro-optic display, the display having a plurality of pixels each addressable by a row electrode and a column electrode, the driver comprising; an input to receive image data for display, said image data defining an image matrix; an output to provide data for driving said row and column electrodes of said display; data memory to store said image data; program memory storing processor implementable instructions; and a processor coupled to said input, to said output, to said data memory and to said program memory to load and implement said instructions, said instructions comprising instructions for controlling the processor to: input said image data; format said image data into a plurality of subframes, each said subframe comprising data for driving a plurality of said row electrodes simultaneously with a plurality of said column electrodes; and output said subframe data for driving said row and column electrodes. The invention further provides processor control code, and a carrier medium carrying the code to implement the above described methods and display drivers. This code may comprise conventional program code, for example for a digital signal processor (DSP), or microcode, or code for setting up or controlling an ASIC or FPGA, or code for a hardware description language such as Verilog™; such code may be distributed between a plurality of coupled components. The carrier medium may comprise any conventional storage medium such as a disk or programmed memory such as firmware, or a data carrier such as an optical or electrical signal carrier. These and other aspects of the of the invention will now be further described, by way of example only, with the reference to the accompanying figures in which: FIGS. 1a and 1b show, respectively, a vertical cross section through an OLED device, and a simplified cross section through a passive matrix OLED display; FIG. 2 shows conceptually a driving arrangement for a passive matrix OLED display; FIG. 3 shows a block diagram of a known passive matrix OLED display driver; FIGS. 4a to 4c, show respectively, block diagrams of first and second examples of display driver hardware for implementing an MLA addressing scheme for a colour OLED display, and a timing diagram for such a scheme; FIGS. 5a to 5g show, respectively, a display driver embodying an aspect of the present invention; column and row drivers, example digital-to-analogue current converters for the display driver of FIG. 5a, a programmable current mirror embodying an aspect of the present invention, a second programmable current mirror embodying an aspect of the present invention, and block diagrams of current mirrors according to the prior art; FIG. 6 shows, a layout of an integrated circuit die incorporating multi-line addressing display signal processing circuitry and driver circuitry; FIG. 7 shows a schematic illustration of a pulse width modulation MLA drive scheme; FIGS. 8a to 8d show row, column and image matrices for a conventional drive scheme and for a multiline addressing drive scheme respectively, and corresponding brightness curves for a typical pixel over a frame period; FIGS. 9a and 9b show, respectively, SVD and NMF factorisation of an image matrix; FIG. 10 shows example column and row drive arrangements for driving a display using the matrices of FIG. 9; FIG. 11 shows a flow diagram for a method of driving a display using image matrix factorisation; FIG. 12 shows an example of a displayed image obtained using image matrix factorisation; FIGS. 13a-d show, respectively, an original colour image (in monochrome), the image with 50% noise in the red channel, the image with 50% noise in the green channel, and the image with 50% noise in the blue channel; and FIG. 14 shows a red-green-blue noise sampler illustrating the effect of increasing noise in red, green and blue colour channels, the first, second and third rows respectively. Consider a pair of rows of a passive matrix OLED display comprising a first row A, and a second row B. In a conventional passive matrix drive scheme the rows would be driven as shown in table 1 below, with each row in either a fully-on state (1.0) or a fully-off state (0.0). TABLE 1 A B on (1.0) off (0.0) off (0.0) on (1.0) Consider the ratio A/(A+B); in the example of Table 1 above this is either zero or one, but provided that a pixel in the same column in the two rows is not fully-on in both rows this ratio may be reduced whilst still providing the desired pixel luminances. In this way the peak drive level can be reduced and pixel lifetime increased. In the first line scan the luminances might be: First period 0.0 0.361 0.650 0.954 0.0 0.0 0.015 0.027 0.039 0.0 Second period 0.2 0.139 0.050 0.046 0.0 0.7 0.485 0.173 0.161 0.0 It can be seen that: 1. Ratios between the two rows are equal in a single scan period (0.96 for the first scan period, 0.222 for the second). 2. Luminances between the two rows add up to the required values. 3. The peak luminances are equal or less than those during a standard scan. The example above demonstrates the technique in a simple two line case. If the ratios in the luminance data are similar between the two lines then more benefit is obtained. Depending upon the type of calculations on image data, luminances can be reduced by an average of 30 percent or more, which can have a significant beneficial effect on pixel lifetime. Expanding the technique to consider more rows simultaneously can provide greater benefit. An example of multiline addressing using SVD image matrix decomposition is given below. We describe the driving system as matrix multiplication where I is, an image matrix (bit map file), D the displayed image (should be the same as I), R the row drive matrix and C the column drive matrix. The Columns of R describe the drive to the rows in ‘line periods’ and the Rows or R represent the rows driven. The one row at a time system is thus an identity matrix. For a 6×4 display chequer board display: D ⁡ ( R , C ) := R · C I := ( 1 0 1 0 1 0 0 1 0 1 0 1 1 0 1 0 1 0 0 1 0 1 0 1 ) C := 1 R := ( 1 0 0 0 0 1 0 0 0 0 1 0 0 0 0 1 ) R · C = ( 1 0 1 0 1 0 0 1 0 1 0 1 1 0 1 0 1 0 0 1 0 1 0 1 ) which is the same as the image. Now consider using a two frame drive method: C := ( 1 0 1 0 1 0 0 1 0 1 0 1 ) R := ( 1 0 0 1 1 0 0 1 ) R · C = ( 1 0 1 0 1 0 0 1 0 1 0 1 1 0 1 0 1 0 0 1 0 1 0 1 ) Again this is the same as the Image matrix. The drive matrix can be calculated by using Singular Value Decomposition as follows (using MathCad nomenclature): X:=svd(1T) (gives U and V) Y:=svds(1T)(gives S as a vector of the diagonal elements) Note Y has only two elements, ie two frames: Y = ( 2.449 2.449 0 0 ) U:=submatrix (X,0,5,0,3) (ie top 6 rows) V:=submatrix (X,6,9,0,3)T (ie lower 4 rows) X = ⁢ 0 1 ⁢ 2 ⁢ ⁢ 3 0 0.577 0 0.816 0 1 0 0.577 0 0.816 2 0.577 0 - ⁢ 0.408 4.57 · 10 - ⁢ 14 3 0 0.577 0 - ⁢ 0.408 4 0.577 0 - ⁢ 0.408 - ⁢ 4.578 · 10 - ⁢ 14 5 0 0.577 0 - ⁢ 0.408 6 0.707 0 0.707 0 7 0 0.707 0 - ⁢ 0.707 8 0.707 0 - ⁢ 0.707 0 9 0 0.707 0 0.707 W:=diag(Y) (ie. Format Y as a diagonal matrix) W = ( 2.449 0 0 0 0 2.449 0 0 0 0 0 0 0 0 0 0 ) D := ( U · W · V ) T Checking D: D = ( 1 0 1 0 1 0 0 1 0 1 0 1 1 0 1 0 1 0 0 1 0 1 0 1 ) R := ( W · V ) T R = ( 1.732 0 0 0 0 1.732 0 0 1.732 0 0 0 0 1.732 0 0 ) (Note the empty last 2 columns) R:=submatrix(R,0,3,0,1) (select the non-empty columns) R = ( 1.732 0 0 1.732 1.732 0 0 1.732 ) C := U T C = ( 0.577 0 0.577 0 0.577 0 0 0.577 0 0.577 0 0.577 0.816 0 - 0.408 0 - 0.408 0 0 0.816 4.57 × 10 - 14 - 0.408 - 4.578 × 10 - 14 - 0.408 ) (As we reduced R so C is reduced to top rows only) C := submatrix ⁢ ⁢ ( C , 0 , 1 , 0 , 5 ) C = ( 0.577 0 0.577 0 0.577 0 0 0.577 0 0.577 0 0.577 ) R · C = ( 1 0 1 0 1 0 0 1 0 1 0 1 1 0 1 0 1 0 0 1 0 1 0 1 ) Which is the same as the desired image. Now consider a more general case, an image of the letter “A”: I := ( 0 0 1 1 0 0 0 1 0 0 1 0 1 1 1 1 1 1 1 0 0 0 0 1 ) X := ⁢ svd ⁡ ( I T ) Y := svds ⁡ ( I T ) (Note Y has only two elements, ie three frames) Y = ( 2.828 1.414 1.414 0 ) U := submatrix ⁢ ⁢ ( X , 0 , 5 , 0 , 3 ) V := submatrix ⁢ ⁢ ( X , 6 , 9 , 0 , 3 ) T W := diag ⁢ ⁢ ( Y ) D := ( U · W · V ) T D = ( 0 0 1 1 0 0 0 1 0 0 1 0 1 1 1 1 1 1 1 0 0 0 0 1 ) (Checking D) R := ( W · V ) T R = ( - 0.816 1.155 0 0 - 0.816 - 0.577 1 0 - 2.449 0 0 0 - 0.816 - 0.577 - 1 0 ) (Note empty last columns). R := submatrix ⁢ ⁢ ( R , 0 , 3 , 0 , 2 ) V = ( - 0.289 - 0.289 - 0.866 - 0.289 0.816 - 0.408 0 - 0.408 0 0.707 0 - 0.707 0.5 0.5 - 0.5 0.5 ) R = ( - 0.816 1.155 0 - 0.816 - 0.577 1 - 2.449 0 0 - 0.816 - 0.577 - 1 ) C := U T W = ( 2.828 0 0 0 0 1.414 0 0 0 0 1.414 0 0 0 0 0 ) C = ( - 0.408 - 0.408 - 0.408 - 0.408 - 0.408 - 0.408 - 0.289 - 0.289 0.577 0.577 - 0.289 - 0.289 - 0.5 0.5 0 0 0.5 - 0.5 - 0671 - 0.224 0 0 0.224 - 0.671 ) (As we reduced R so C is reduced to top rows only). C := submatrix ⁢ ⁢ ( C , 0 , 2 , 0 , 5 ) C = ( - 0.408 - 0.408 - 0.408 - 0.408 - 0.408 - 0.408 - 0.289 - 0.289 0.577 0.577 - 0.289 - 0.289 - 0.5 0.5 0 0 0.5 - 0.5 ) R · C = ( 0 0 1 1 0 0 0 1 0 0 1 0 1 1 1 1 1 1 1 0 0 0 0 1 ) Which is the same as the desired image. In this case there are negative numbers in R and C which is undesirable for driving a passive matrix OLED display. By inspection it can be seen that a positive factorisation is possible: R := ( 1 0 0 0 1 0 1 1 1 0 0 1 ) C := ( 0 0 1 1 0 0 0 1 0 0 1 0 1 0 0 0 0 1 ) R · C = ( 0 0 1 1 0 0 0 1 0 0 1 0 1 1 1 1 1 1 1 0 0 0 0 1 ) Non-negative matrix factorization (NMF) provides a method for achieving this in the general case. In non-negative matrix factorization the image matrix I is factorised as: I=W·H Some examples of NMF techniques are described in the following references, all hereby incorporated by reference: D. D. Lee, H. S. Seung. Algorithms for non-negative matrix factorization; P. Paatero, U. Tapper. Least squares formulation of robust non-negative factor analysis. Chemometr. Intell. Lab. 37 (1997), 23-35; P. Paatero. A weighted non-negative least squares algorithm for three-way ‘PARAFAC’ factor analysis. Chemometr. Intell. Lab. 38 (1997), 223-242; P. Paatero, P. K. Hopke, etc. Understanding and controlling rotations in factor analytic models. Chemometr. Intell. Lab. 60 (2002), 253-264; J. W. Demmel. Applied numerical linear algebra. Society for Industrial and Applied Mathematics, Philadelphia. 1997; S. Juntto, P. Paatero. Analysis of daily precipitation data by positive matrix factorization. Environmetrics, 5 (1994), 127-144; P. Paatero, U. Tapper. Positive matrix factorization: a non-negative factor model with optimal utilization of error estimates of data values. Environmetrics, 5 (1994), 111-126; C. L. Lawson, R. J. Hanson. Solving least squares problems. Prentice-Hall, Englewood Cliffs, N.J., 1974; Algorithms for Non-negative Matrix Factorization, Daniel D. Lee, H. Sebastian Seung, pages 556-562, Advances in Neural Information Processing Systems 13, Papers from Neural Information Processing Systems (NIPS) 2000, Denver, Colo., USA. MIT Press 2001; and Existing and New Algorithms for Non-negative Matrix Factorization By Wenguo Liu & Jianliang Yi (www.dcfl.gov/DCCI/rdwg/nmf.pdf; source code for the algorithms discussed therein can be found at http://www.cs.utexas.edu/users/liuwg/383CProject/CS—383C_Project.htm). The NMF factorisation procedure is diagrammatically illustrated in FIG. 9b. Once the basic above-described scheme has been implemented other techniques can be used for additional benefit. For example duplicate rows of pixels, which are not uncommon in Windows™ type applications, can be written simultaneously to reduce the number of line periods, hence shortening the frame period and reducing the peak brightness required for the same integrated brightness. Once an SVD decomposition has been obtained the lower rows with only small (drive) values can be neglected as they are of decreasing significance to the quality of the final image. As described above the multi-line addressing technique described above is applied within a single displayed frame but it will be recognised that a luminescence profile of one or more rows may be built up over the time dimension additionally or alternatively to a spatial dimension. This may be facilitated by moving picture compression techniques in which between-frame time interpolation is employed. Embodiments of the above MLA techniques are particularly useful in colour OLED displays, in which case the techniques are preferably employed for groups of red (R), green (G), and blue (B) sub-pixels as well as, optionally, between pixel rows. This is because images tend to contain blocks of similar colour, and because a correlation between R, G and B sub-pixel drives is often higher than between separate pixels. Thus in embodiments of the scheme rows for multi-line addressing are grouped into R, G, and B rows with three rows defining a complete pixel and an image being built up by selecting combinations of the R, G and B rows simultaneously. For example if a significant area of the image to be displayed is white the image can be built up by first selecting groups of R, G and B rows together while applying appropriate signals to the column drivers. Application of the MLA scheme to a colour display has a further advantage. In a conventional colour OLED display a row of pixels has the pattern “RGBRGB . . . ” so that when the row is enabled separate column drivers can simultaneously drive the R, G and B sub-pixels to provide a full colour illuminated pixel. However the three rows may have the configuration “RRRR . . . ” “GGGG . . . ”, “BBBB . . . ”, a single column addressing R, G and B sub-pixels. This configuration simplifies the application of an OLED display since a row of, say, red pixels may be (inkjet) printed in a single long trough (separated from adjacent troughs by the cathode separator) rather than separate “wells” being required to define regions for the three different coloured materials in each row. This enables the elimination of a fabrication step and also increases the pixel aperture ratio (that is the percentage of display area occupied by active pixel). Thus in a further aspect the invention provides a display of this type. FIG. 4a shows a block diagram of an example display/driver hardware configuration 400 for such a scheme. As can be seen a single column driver 402 addresses rows of red 404, green 406 and blue 408 pixels. Permutations of red, green and blue rows are addressed using row selectors/multiplexers 410 or, alternatively, by means of a current sink controlling each row as described further later. It can be seen from FIG. 4a that this configuration allows red, green and blue sub-pixels to be printed in linear troughs (rather than wells) each sharing a common electrode. This reduces substrate patterning and printing complexity and increases aperture ratio (and hence indirectly lifetime through the reduced drive necessary). With the physical device layout of FIG. 4a a number or different MLA drive schemes may be implemented. In a first example drive scheme an image is built up by addressing groups of rows in sequence as shown below: 1. White component: R, G, and B are selected and driven together 2. Red+Blue driven together 3. Blue+Green driven together 4. Red+Green driven together 5. Red only 6. Blue only 7. Green only Only the necessary colour steps are carried out to build up the image using the minimum number of colour combinations. The combinations may be optimised to increase lifetime and/or reduce power consumption, depending on the requirement of the application. In an alternative colour MLA scheme, the driving of the RGB rows is split into three line scan periods, with each line period driving one primary. The primaries are combinations of R G and B chosen to form a colour gamut which encloses all the desired colours along a line or row of the display: In one method the primaries are R+aG=aB, G+bR+bB, B+cR+cG where 0>=a,b,c>=1 and a, b and c are chosen to be the largest possible values (a+b+c=maximum) while still enclosing all desired colours within their colour gamut. In another method a, b and c are chosen in a scheme to best improve the overall performance of the display. For example, if blue lifetime is a limiting factor, a and b may be maximised at the expense of c; if red power consumption is a problem, b and c can be maximised. This is because the total emitted brightness should equal a fixed value. Consider an example where b=c=0. In this case the red brightness must be fully achieved in the first scan period. However if b,c>0 then the red brightness is built up more gradually over multiple scan periods, thus reducing the peak brightness and increasing the red subpixel lifetime and efficiency. In another variation the length of the individual scan periods can be adjusted to optimise lifetime or power consumptions (for example to provide increased scan time). In a further variation the primaries may be chosen arbitrarily, but to define the minimum possible colour gamut which still encloses all colours on a line of the display. For example in an extreme case, if there were only shades of greens on a reproducible colour gamut. FIG. 4b shows a second example of display driver hardware 450 in which like elements to those in FIG. 4a are shown by like reference minerals. In FIG. 4b the display includes additional rows of white (W) pixels 412 which are also used to build up a colour image when driven in combination with three primaries. The inclusion of white sub-pixels broadly speaking reduces the demands on the blue pixels thus increasing display lifetime; alternatively, depending on the drive scheme, power consumption for display of given colour may be reduced. Colours other than white, for example magenta, cyan, and/or yellow emitting sub-pixels may be included, for example to increase the colour gamut. The different coloured sub-pixels need not have the same area. As illustrated in FIG. 4b each row comprises sub-pixels of a single colour, as described with reference to FIG. 4a, but it will be appreciated that a conventional pixel layout may also be employed with successive R, G, B and W pixels along each row. In this case the columns will be driven by four separate column drivers, one for each of the four colours. It will be appreciated that the above described multi-line addressing schemes may be employed in connection with the display/driver arrangement of FIG. 4b, with combinations of R, G, B and W rows being addressed in different permutations and/or with different drive ratios, either using row multiplexers (as illustrated) or a current sink for each line. As described above an image is built up by successively driving different combinations of rows. As outlined above and described in more detail below, some preferred drive techniques employ a variable current drive to the OLED display pixels. However a simpler drive scheme, which has no need for row current mirrors, may be implemented using one or more row selectors/multiplexers to select rows of the display singularly and in combination in accordance with the first example colour display drive scheme given above. FIG. 4c illustrates the timing of row selection in such a scheme. In a first period 460 white, red, green and blue rows are selected and driven together; in a second period 470 white only is driven, and in a third period 480 red only is driven, all according to a pulse-width modulation drive timing. Referring next to FIG. 5a, this shows a schematic diagram of an embodiment of a passive matrix OLED driver 500 which implements an MLA addressing scheme as described above. In FIG. 5a a passive matrix OLED display similar to that described with reference to FIG. 3 has row electrodes 306 driven by row driver circuits 512 and column electrodes 310 driven by column drives 510. Details of these row and column drivers are shown in FIG. 5b. Column drivers 510 have a column data input 509 for setting the current drive to one or more of the column electrodes; similarly row drivers 512 have a row data input 511 for setting the current drive ratio to two or more of the rows. Preferably inputs 509 and 511 are digital inputs for ease of interfacing; preferably column data input 509 sets the current drives for all the m columns of display 302. Data for display is provided on a data and control bus 502, which may be either serial or parallel. Bus 502 provides an input to a frame store memory 503 which stores luminance data for each pixel of the display or, in a colour display, luminance information for each sub-pixel (which may be encoded as separate RGB colour signals or as luminance and chrominance signals or in some other way). The data stored in frame memory 503 determines a desired apparent brightness for each pixel (or sub-pixel) for the display, and this information may be read out by means of a second, read bus 505 by a display drive processor 506 (in embodiments bus 505 may be omitted and bus 502 used instead). Display drive processor 506 may be implemented entirely in hardware, or in software using, say, a digital signal processing core, or in a combination of the two, for example, employing dedicated hardware to accelerate matrix operations. Generally, however, display drive processor 506 will be at least partially implemented by means of stored program code or micro code stored in a program memory 507, operating under control of a clock 508 and in conjunction with working memory 504. Code in program memory 507 may be provided on a data carrier or removable storage 507a. The code in program memory 507 is configured to implement one or more of the above described multi-line addressing methods using conventional programming techniques. In some embodiments these methods may be implemented using a standard digital signal processor and code running in any conventional programming language. In such an instance a conventional library of DSP routines may be employed, for example, to implement singular value decomposition, or dedicated code may be written for this purpose, or other embodiments not employing SVD may be implemented such as the techniques described above with respect to driving colour displays. Referring now to FIG. 5b, this shows details of the column 510 and row 512 drivers of FIG. 5a. The column driver circuitry 510 includes a plurality of controllable reference current sources 516, one for each column line, each under control of respective digital-to-analogue converter 514. Details of example implementations of these are shown in FIG. 5c where it can be seen that a controllable current source 516 comprises a pair of transistors 522, 524 connected to a power line 518 in a current mirror configuration. Since, in this example, the column drivers comprise current sources these are PNP bipolar transistors connected to a positive supply line; to provide a current sink NPN transistors connected to ground are employed; in other arrangements MOS transistors are used. The digital-to-analogue converters 514 each comprise a plurality (in this instance three) of FET switches 528, 530, 532 each connected to a respective power supply 534, 536, 538. The gate connections 529,531, 533 provide a digital input switching the respective power supply to a corresponding current set resistor 540, 542, 544, each resistor being connected to a current input 526 of a current mirror 516. The power supplies have voltages scaled in powers of two, that is each twice that of the next lowest power supply less a Vgs drop so that a digital value on the FET gate connections is converted into a corresponding current on a line 526; alternatively the power supplies may have the same voltage and the resistors 540, 542, 544 may be scaled. FIG. 5c also shows an alternative D/A controlled current source/sink 546; in this arrangement where multiple transistors are shown a single appropriately-sized larger transistor may be employed instead. The row drivers 512 also incorporate two (or more) digitally controllable current sources 515, 517, and these may be implemented using similar arrangements to those shown in FIG. 5c, employing current sink rather than current source mirrors. In this way controllable current sinks 517 may be programmed to sink currents in a desired ratio (or ratios) corresponding to a ratio (or ratios) of row drive levels. Controllable current sinks 517 are thus coupled to a ratio control current mirror 550 which has an input 552 for receiving a first, referenced current and one or more outputs 554 for receiving (sinking) one or more (negative) output currents, the ratio of an output current to the input current being determined by a ratio of control inputs defined by controllable current generators 517 in accordance with row data on line 509. Two row electrode multiplexers 556a, b are provided to allow selection of one row electrode to provide a reference current and another row electrode to provide an “output” current; optionally further selectors/multiplexers 556b and mirror outputs from 550 may be provided. As illustrated row driver 512 allows the selection of two rows for concurrent driving from a block of four row electrodes but in practice alternative selection arrangements may be employed—for example in one embodiment twelve rows (one reference and eleven mirrors) are selected from 64 row electrodes by twelve 64 way multiplexers; in another arrangement the 64 rows may be divided into several blocks each having an associated row driver capable of selecting a plurality of rows for simultaneous driving. FIG. 5d shows details of an implementation of the programmable ratio control current mirror 550 of FIG. 5b. In this example implementation a bipolar current mirror with a so-called beta helper (Q5) is employed, but the skilled person will recognise that many other types of current mirror circuit may also be used. In the circuit of FIG. 5d V1 is a power supply of typically around 3V and I1 and I2 define the ratio of currents in the collectors of Q1 and Q2. The currents in the two lines 552, 554 are in the ratio I1 to I2 and thus a given total column current is divided between the two selected rows in this ratio. The skilled person will appreciate that this circuit can be extended to an arbitrary number of mirrored rows by providing a repeated implementation of the circuitry within dashed line 558. FIG. 5e illustrates an alternative embodiment of a programmable current mirror for the row driver 512 of FIG. 5b. In this alternative embodiment each row is provided with circuitry corresponding to that within dashed line 558 of FIG. 5d, that is with a current mirror output stage, and then one or more row selectors connects selected ones of these current mirror output stages to one or more respective programmable reference current supplies (source or sink). Another selector selects a row to be used as a reference input to the current mirror. In embodiments of the above-described row drivers row selection need not be employed since a separate current mirror output may be provided for each row either of the complete display or for each row of a block of rows of the display. Where row selection is employed rows may be grouped in blocks—for example where a current mirror with three outputs is employed with selective connection to, say a group of 12 rows, sets of three successive rows may be selected in turn to provide three-line MLA for the 12 rows. Alternatively rows may be grouped using a priori knowledge relating to the line image to be displayed, for example where it is known that a particular sub-section of the image would benefit from MLA because of the nature of the displayed data (significant correlation between rows). FIGS. 5f and 5g illustrate current mirror configurations according to the prior art with, respectively, a ground reference and a positive supply reference, showing the sense of the input and output currents. It can be seen that these currents are both in the same sense but maybe either positive or negative. FIG. 6 shows a layout of an integrated circuit die 600 combining the row drivers 512 and display drive processor 506 of FIG. 5a The die has the shape of an elongated rectangle, of example dimensions 20 mm×1 mm, with a first region 602 for a long line of driver circuitry comprising repeated implementations of substantially the same set of devices, and an adjacent region 604 used to implement the MLA display processing circuitry. Region 604 would otherwise be unused space since there is a minimum physical width to which a chip can be diced. The above described MLA display drivers employ a variable current drive to control OLED luminance but the skilled person will recognise that other means of varying the drive to an OLED pixel, in particular PWM, may additionally or alternatively employed. FIG. 7 shows a schematic illustration of a pulse width modulation drive scheme for multi-line addressing. In FIG. 7 the column electrodes 700 are provided with a pulse width modulated drive at the same time as two or more row electrodes 702 to achieve the desired luminance patterns. In the example of FIG. 7 the zero value shown could be smoothly varied up to 0.5 by gradually shifting the second row pulse to a later time; in general a variable drive to a pixel may be applied by controlling a degree of overlap of row and column pulses. Some preferred MLA methods employing matrix factorisation will now be described in more detail. Referring to FIG. 8a, this shows row R, column C and image I matrices for a conventional drive scheme in which one row is driven at a time. FIG. 8b shows row, column and image matrices for a multiline addressing scheme. FIGS. 8c and 8d illustrate, for a typical pixel of the displayed image, the brightness of the pixel, or equivalently the drive to the pixel, over a frame period, showing the reduction in peak pixel drive which is achieved through multiline addressing. FIG. 9a illustrates, diagrammatically, singular value composition (SVD) of an image matrix I according to Equation 2 below: I = U × S × V m × n m × p p × p p × n Equation ⁢ ⁢ 2 The display can be driven by any combination of U, S and V, for example driving rows US and columns with V or driving rows with U√{square root over (S)} and column with √{square root over (S)}.V other related techniques such as QR decomposition and LU decomposition can also be employed. Suitable numerical techniques are described in, for example, “Numerical Recipes in C: The Art of Scientific Computing”, Cambridge University Press 1992; many libraries of program code modules also include suitable routines. FIG. 10 illustrates row and column drivers similar to those described with reference to FIGS. 5b to 5e and suitable for driving a display with a factorised image matrix. The column drivers 1000 comprise a set of adjustable substantially constant current sources 1002 which are ganged together and provided with a variable reference current Iref for setting the current into each of the column electrodes. This reference current is pulse width modulated by a different value for each column derived from a row of a factor matrix such as row pi of matrix H of FIG. 9b. The row drive 1010 comprises a programmable current mirror 1012 similar to that shown in FIG. 5e but preferably with one output for each row of the display or for each row of a block of simultaneously driven rows. The row drive signals are derived from a column of a factor matrix such as column pi of matrix W of FIG. 9b. FIG. 11 shows a flow diagram of an example procedure for displaying an image using matrix factorisation such as NMF, and which may be implemented in program code stored in program memory 507 of display drive processor 506 of FIG. 5a. In FIG. 11 the procedure first reads the frame image matrix I (step S1100), and then factorises this image matrix into factor matrices W and H using NMF, or into other factor matrices, for example U, S and V when employing SVD (step S1102). This factorisation may be computed during display of an earlier frame. The procedure then drives the display with p subframes at step 1104. Step 1106 shows the subframe drive procedure. The subframe procedure sets W-column pi→R to form a row vector R. This is automatically normalised to unity by the row driver arrangement of FIG. 10 and a scale factor x, R←xR is therefore derived by normalising R such that the sum of elements is unity. Similarly with H, row pi→C to form a column vector C. This is scaled such that the maximum element value is 1, giving a scale factor y, C←yC. The a frame scale factor f = p m is determined and the reference current set by I ref = I 0 · f xy where I0 corresponds to the current required for full brightness in a conventionally scanned line-at-a-time system, the x and y factors compensating for scaling effects introduced by the driving arrangement (with other driving arrangements one or both of these may be omitted). Following this, at step S1108, the display drivers shown in FIG. 10 drive the columns of the display with C and rows of the display with R for 1/p of the total frame period. This is repeated for each subframe and the subframe data for the next frame is then output. FIG. 12 shows an example of an image constructed in accordance with an embodiment of the above described method; the format corresponds to that of FIG. 9b. The image in FIG. 12 is defined by a 50×50 image matrix which, in this example, is displayed using 15 subframes (p=15). The number of subframes can be determined in advance or varied according to the nature of the image displayed. In some preferred embodiments of the above described systems and methods, in particular in full colour MLA passive matrix drive schemes, the schemes are configured to preserve a low grey level noise in the green channel at the expense of the red and blue channels. This technique is applicable, in particular, to MLA employing the above-mentioned NMF and SVD factorisation procedures. One approach to MLA derives the multiline addressed sub-frames treating all three colour channels equally. However the eye perceives differences in the green much more than the red and both of these more than the blue, so overall perceived image quality may be improved if grey-level errors in the green channel are given a greater weight than those in the red or blue channels according to the eyes sensitivity to each. In embodiments this results in improved image quality for the same sub-frame compression, or improved sub-frame compression (and hence improved lifetime) for the same image quality. FIGS. 13a-d help to illustrate this effect, FIG. 13a showing an original image, FIG. 13b the image with 50% noise in the red channel, FIG. 13c the image with 50% noise in the green channel, and FIG. 13d the image with 50% noise in the blue channel. It can be seen that noise in the green has a much greater impact on image quality than noise in the blue or red. In all cases 50% average noise (that it, up to 50% error in grey level, uniformly distributed over the image) was applied to the single colour channel. Another example of the effect is illustrated in FIG. 14. This shows an RBG noise sampler in which the first row shows the visual effect of increasing noise in the red channel, the second row increasing noise in the green channel, and the third row increasing noise in the blue channel. The noise levels in FIG. 14, from left to right, are 0%, 10%, 20%, 30%, 40%. Thus modification of above described MLA algorithms to preferentially preserve a low noise in the green channel over the red and blue will result in improved image quality. How this is implemented depends on the merit function which an MLA algorithm uses to obtain the optimised solution. For example, in the case of Euclidean distance minimisation each iteration is attempting to minimise the absolute difference between the target image and the current MLA solution. For a case where the red green and blue pixels are always driven along dedicated lines, i.e. in a typical display where RGB sub-pixels are aligned along column stripes, one column signal is always driving just a single sub-pixel colour. In this case, a simple implementation of the concept is to scale the target pixel grey (ie colour luminance) levels by the sub-pixel relative luminances, that is by first, second and third weights for red, green and blue. For example for PAL primaries the green signal may be multiplied by 0.6, the red by 0.3 and the blue by 0.1. The procedure can then, for example, apply an Euclidean distance minimisation MLA algorithm to this modified image (a number of examples are described in UK patent application no. 0428191.1 and in applications derived from this (the contents of which are hereby incorporated by reference). Once a solution has been obtained the RGB column data can then be divided by the inverses of the multiplier which were previously applied (i.e. 1/0.6 for green, 1/0.3 for red and 1/0.1 for blue), prior to feeding these drive levels to the column drivers. The various above-described image manipulation calculations to be performed are not dissimilar in their general character to operations performed by consumer electronic imaging devices such as digital cameras and embodiments of the method may be conveniently implemented in such devices. In other embodiments the method can be implemented on a dedicated integrated circuit, or by means of a gate array, or in the software on a digital signal processor (DSP), or in some combination of these. As previously mentioned embodiments of the above described techniques are applicable to both emissive displays such as LED-based displays, and to non-emissive displays such as LCD-based displays. In the particular context of LED-based displays, the TMA schemes described have pulsed width modulated column drive (time control) on one axis and current division ratio (current control) on the other axis. For inorganic LEDs voltage is proportional to logarithm current (so a product of voltages is given by a sum of the log currents), however for OLEDs there is a quadratic current-voltage dependence. In consequence when the above described techniques are used to drive OLEDs it is important that PWM is employed. This is because even with current control there is a characteristic which defines the voltage across a pixel required for a given current and with only current control the correct voltage for each pixel of a subframe cannot necessarily be applied. The TMA schemes described nonetheless work correctly with OLEDs because rows are driven to achieve the desired current and columns are driven with a PWM time, in effect decoupling the column and row drives, and hence decoupling the voltage and current variables by providing two separate control variables. Referring again to the NMF factorisation of an image matrix, some particularly preferred fast NMF matrix factorisation techniques are described in the Applicant's co-pending UK patent application no. 0428191.1, filed 23 Dec. 2004, the contents of which are hereby incorporated by reference in their entirety. Some further optimizations are as follows: Because current is shared between rows, if the current in one row increases the current in the rest reduces, so preferably (although this is not essential) the reference current and sub-frame time are scaled to compensate. For example, the sub-frame times can be adjusted with the aim of having the peals pixel brightness in each subframe equal (also reducing worst-case/peak-brightness aging). In practice this is limited by the shortest selectable sub-frame time and also by the maximum column drive current, but since the adjustment is only a second order optimisation this is not a problem. Later sub-frames apply progressively smaller corrections and hence they tend to be overall dimmer whereas the earlier sub-frames tend to be brighter. With PWM drive, rather than always have the start of the PWM cycle an “on” portion of the cycle, the peak current can be reduced by randomly dithering the start of the PWM cycle. In a straightforward practical implementation a similar benefit can be achieved with less complexity by, where the off-time is greater than 50%, starting the “on” portion timing for half the PWM cycles at the end of the available period. This is potentially able to reduce the peak row drive current by 50%. With rows comprising red (R), green (G) and blue (B) (sub-)pixels (i.e. an RGB, RGB, RGB row pattern), because each (sub-)pixel has different characteristics a given voltage applied to a row may not achieve the exact desired drive currents for each differently coloured OLED (sub-)pixel. It is therefore preferable to use an OLED display with separately driveable rows of red, green and blue (sub-)pixels (i.e. groups of three rows with respective RRRR . . . , GGGG . . . and BBBB . . . patterns). The advantages of such a configuration in relation to ease of manufacture have already been mentioned above. Embodiments of the invention have been described with specific reference to OLED-based displays. However the techniques described herein are also applicable to other types of emissive display including, but not limited to, vacuum fluorescent displays (VFDs) and plasma display panels (PDPs) and other types of electroluminescent display such as thick and thin (TFEL) film electroluminescent displays, for example iFire (RTM) displays, large scale inorganic displays and passive matrix driven displays in general, as well as (in embodiments) to LCD displays and other non-emissive technology. No doubt many other effective alternatives will occur to the skilled person. It will be understood that the invention is not limited to the described embodiments and encompasses modifications apparent to those skilled in the art lying within the spirit and scope of the claims appended hereto.

20060509

20120807

20070329

94675.0

G09G330

STONE, ROBERT M

MULTI-LINE ADDRESSING METHODS AND APPARATUS

UNDISCOUNTED

ACCEPTED

G09G

ACCEPTED

Gi Track Delivery Systems

A micro encapsulation material for use with storage unstable, therapeutic and nutritional agents which release the therapeutic and nutritional agents in predetermined locations in the gastro intestinal tract in which the microencapsulation material is formed by combining a food grade treated carbohydrate with a water soluble food grade protein. The therapeutic and nutritional agents form an oil phase which is emulsified with the water dispersed or dissolved encapsulant to encapsulate the therapeutic and nutritional agents. These agents may be oils or oil soluble or oil dispersible. The agents that may be encapsulated Include lipids (oils Including oxygen sensitive oils, fatty acids, triglycerides) and oil soluble and oil dispersible ingredients (including pharmaceuticals, probiotics, protein therapeutics and bioactives). The protein used may include any film forming water soluble protein or hydrolysed protein and includes milk proteins such as casein and its derivatives or whey proteins. The carbohydrate component may be those containing reducing sugar groups, oligosaccharides and starches (raw, modified, resistant, acetylated, proprionated and butyrated starches).

1. A method of storing and administering storage unstable, therapeutic and nutritional agents for targeted delivery to predetermined locations in the gastro intestinal tract which includes the steps of encapsulating the storage unstable, therapeutic and nutritional agents in an encapsulant formed by combining a food grade treated carbohydrate with a water soluble food grade protein. 2. A method as defined in claim 1 in which the carbohydrate material is treated to make emulsions of the encapsulant material stable and to increase the number of sugar reducing groups in the carbohydrate. 3. A method as defined in claim 1 in which the carbohydrate is selected from those containing reducing sugar groups, oligosaccharides, raw, modified, resistant, acetylated, proprionylated and butylated starches. 4. A method as defined in claim 1 or 3 in which the protein is selected from milk proteins including casein and whey proteins. 5. An encapsulation material for use with storage unstable, therapeutic and nutritional agents which release the therapeutic and nutritional agents in predetermined locations in the gastro intestinal tract in which the microencapsulation material is formed by combining a food grade treated carbohydrate with a water soluble food grade protein. 6. An encapsulation material as claimed in claim 5 in which the carbohydrate material is treated to make emulsions of the encapsulant material stable and to increase the number of sugar reducing groups in the carbohydrate. 7. An encapsulation material as claimed in claim 5 in which the carbohydrate is selected from those containing reducing sugar groups, oligosaccharides, raw, modified, resistant, acetylated, proprionylated and butylated starches. 8. An encapsulation material as claimed in claim 5 or 7 in which the protein is selected from milk proteins including casein and whey proteins. 9. An orally administrable nutritional or therapeutic product for delivery of a nutritional or therapeutic agent to the gastrointestinal tract in which the agent includes an oil or an oil soluble or dispersible component which is encapsulated in a material as claimed in claim 5. 10. A method of preparing a nutritional or therapeutic product as defined in claim 9 which includes the steps a) selecting a nutritional or therapeutic oil, oil soluble or oil dispersible nutritional or therapeutic agent b) dispersing a water soluble film forming protein and a treated carbohydrate in the aqueous phase c) mixing component (a) with component (b) and homogenizing the mixture to obtain an emulsion d) optionally drying the emulsion to obtain a powdered formulation in which the nutritional or therapeutic oil or agent is surrounded by the component (b). 11. A method as defined in claim 10 in which the water soluble film forming protein is selected from milk proteins including casein and whey proteins. 12. A method as defined in claim 10 in which the carbohydrate material is treated to make emulsions of the encapsulant material stable and to increase the number of sugar reducing groups in the carbohydrate. 13. A method as defined in claim 10 in which the carbohydrate material is selected from those containing reducing sugar groups, oligosaccharides, raw, modified, resistant, acetylated, proprionylated and butylated starches. 14. A method as defined in claim 13 in which the water soluble film forming protein is selected from milk proteins including casein and whey proteins.

This invention relates to microencapsulated formulations for delivery of nutritional and pharmaceutical agents to the gastro intestinal tract and in particular the colon. The compositions may be used for protection and delivery of nutrients or nutraceuticals in processed foods. BACKGROUND TO THE INVENTION Microencapsulation involves the packaging of small particles of solid, liquid or gas within a secondary material to form a microcapsule. It has been used for targeted delivery of drugs in the body in the pharmaceutical industry. It is increasingly being seen as a technology that offers novel food processing solutions. With the use of microencapsulation, possible undesirable interactions between the added nutraceutical and other components in the food or its environment can be avoided and the site of release of the added component can be manipulated. The appropriate application of microencapsulation technology enables the fortification of food without affecting the taste, aroma or texture of food. It can afford protection to sensitive food ingredients and enhance the shelf-life and stability of fortified foods (Brazel, C. S. (1999) Microencapsulation: offering solutions for the food industry. Cereal Foods World 44(6): 388-393; Augustin, M. A., Sanguansri, L., Margetts, C. and Young. B. (2001) Microencapsulation of food ingredients. Food Australia 53 220-223). Microencapsulation can serve both the purposes of the food and health industries, as it is a key technology with potential for the delivery of dietary bioactives and development of successful marketable functional foods. Addressing this challenge, requires tailoring the performance of food grade microcapsules in a food processing environment so that essential sensitive components are protected during food manufacture and the microcapsules can also meet the need for site specific delivery within the gastrointestinal tract. Directing nutraceuticals and therapeutics of the colon is of interest for treatment of colon diseases (Rubinstein, A., Tirosh, B., Baluom, M., Nassar, T., David, A., Radai, R., Gliko-Kabir, I. And Friedman, M. (1997). The rationale for peptide drug delivery to the colon and the potential for polymeric carriers as effective tools. J. Controlled Release 46, 59-73). Targeting to colon has been carried out by formation of pro-drugs which are enzymatically cleaved in the colon, and multi-coats with pH sensitive and pressure dependent release. Often enteric acrylic polymers are used to protect cores in colon-delivery formulations. Biopolymers, particularly polysaccharides, may be used for targeting cores to the colon where the release of cores is triggered by the microflora in the colon. A range of polysaccharides such as chitosan, pectin, arabinoxylan, arabinogalactan, xylan, cellulose dextrans, guar gum, amylose, inulin and mixtures of these have been examined and shown to have potential as colon-delivery systems (Rubinstein, A. (2000) Natural Polysaccharides as targeting tools of drugs to the human colon. Drug Development Research 50, 435-439; Sinha, V. R. and Kumaria, R. (2001) Polysaccharides in colon-specific drug delivery Int. J. Pharmceutics 224, 19-38; Vandaamme, Th.F., Lenourry, A., Charrueau, C. and Chaumeil, J.-C. (2002) The use of polysaccharides to target drugs to the colon. Carbohydrate Polymers 48, 219-231; Sinha, V. R. and Kumaria. R. (2003) Microbially triggered drug delivery to the colon. Eur. J. Pharmaceutical Sciences 18, 3-18). There have been a number of attempts to use biopolymers for colon delivery and for treating colonic diseases U.S. Pat. No. 5,952,314 discloses an enteral product comprising an oil blend with fatty acids {EPA (C20:5) and DHA (C22:6)} and a source of indigestible carbohydrate which is metabolised to short chain fatty acids in the colon. It has use for improving nutritional status and treating ulcerative colitis U.S. Pat. No. 5,108,758 discloses a glassy amylose matrix for delivery of medication to the colon U.S. Pat. No. 5,840,860 is concerned with delivery of short chain fatty acids (SCFA) to the colon by way of a modified starch. Japanese patent 10324642 discloses a colon delivery system for delivery of bioactives (eg peptides) comprising inner layer of chitosan and outer-layer of gastric resistant material such as wheat gliadin or zein. U.S. Pat. No. 5,866,619 discloses a colonic delivery system for drugs such as proteins and peptides comprising a saccharide containing polymer U.S. Pat. No. 6,368,629 discloses a drug coated with an organic acid-soluble polymer and a saccharide for colon delivery. U.S. Pat. No. 544,054 discloses a method of treating colitis with a composition containing oil blend (with DHA/EPA) and a source of indigestible carbohydrate (CHO) which is metabolised to short chain fatty acids. U.S. Pat. No. 5,952,314 is concerned with an enteral nutritional product for treatment of colitis which comprises oil containing EPA/DHA and a source of indigestible carbohydrate which is metabolised to short chain fatty acids. U.S. Pat. No. 6,531,152 describes a drug delivery system containing a water soluble core (Ca pectinate or other water-insoluble polymers) and outer coat which bursts (eg hydrophobic polymer—Eudragrit) for delivery of enterally-administered drugs to specific locations along the gastrointestinal tract There are proposals using combinations of proteins and polysaccharides for the formation of coating systems. U.S. Pat. No. 6,234,464 discloses a system in which oils/polyunsaturated fatty acids (PUFA)/fatty acids are provided with capsules comprised of two layers in which the inner layer consists of gelatin, casein or alginate and the outer layer consists of gelatin, gum arabic, chitosan to provide a product stable in boiling water U.S. Pat. No. 6,403,130 discloses a coating composition comprising a polymer containing casein and high methoxy pectin (amide formed by reaction of ester group R′COOCH3 of pectin with free amino group of protein R″NH2) WO 01/74175 discloses the encapsulation of oxygen sensitive materials such as polyunsaturated oils in a protein carbohydrate film treated to form a Maillard reaction product. It is an object of this invention to provide a gastrointestinal delivery system that can be used with storage unstable ingredients as well as providing protection during delivery through the gut. BRIEF DESCRIPTION OF THE INVENTION To this end the present invention provides a micro encapsulation material for use with storage unstable, therapeutic and nutritional agents which release the therapeutic and nutritional agents in predetermined locations in the gastro intestinal tract in which the microencapsulation material is formed by combining a food grade treated carbohydrate with a water soluble food grade protein. The therapeutic and nutritional agents form an oil phase which is emulsified with the water dispersed or dissolved encapsulant to encapsulate the therapeutic and nutritional agents. These agents may be oils or oil soluble or oil dispersible which in the latter case may include water soluble ingredients. The agents that may be encapsulated include lipids (oils including oxygen sensitive oils, fatty acids, triglycerides) and oil soluble and oil dispersible ingredients (including pharmaceuticals, probiotics, and bioactives). Water dispersible components including those that partition between oil and water phases may also be encapsulated. When water dispersible therapeutic and nutritional agents are used they may not be encapsulated with the oil phase but may be dispersed in the encapsulant film. The emulsions may be used as food ingredients or therapeutic agents but preferably the emulsions are dried to form powders. Prior art encapsulation systems did not consider the use of combinations of proteins with other biopolymers for formation of capsules for target delivery of sensitive cores to the colon. The delivery systems of this invention enable pharmaceutical and food manufacturers to offer a range of nutritionally and physiologically functional food ingredients and bioactive compounds in convenient formats and using all natural ingredients which will also enable the delivery of these products to the colon. Some of the encapsulants used for colon delivery in this invention have the added benefits of being effective matrices for encapsulating oxygen sensitive ingredients. The film-forming and anti-oxidant properties of some of the encapsulants used work synergistically to preserve sensitive ingredients such as polyunsaturated fatty acids from being oxidised during storage and also protects them during exposure to high temperature, pressure and moisture encountered during the processing of foods. In addition, this invention uses readily available proteins and carbohydrates. There are no solvents used in the preparation of the encapsulated formulations as the process is an all-aqueous based system. The processes can be easily incorporated or adapted to suit most food and pharmaceutical manufacturing plants with drying operations. The protein used may include any film forming water soluble protein or hydrolysed protein and includes milk proteins such as casein and its derivatives or whey proteins. The carbohydrate component may be those containing reducing sugar groups, oligosaccharides and starches (raw, modified, resistant, acetylated, proprionated and butylated starches). The proteins and carbohydrates may be reacted in aqueous solutions to obtain conjugates. The reaction, which occurs, can be between free amine groups of amino acids in the protein and reducing sugar groups in the carbohydrate. This type of reaction is generally termed a Maillard reaction typically occurring in the non-enzymatic browning of foods. This reaction occurs during heat processing of foods and has previously been shown to be beneficial for engineering desirable encapsulating properties for protection of oxygen sensitive components. For example, microencapsulated formulations containing oxygen sensitive oils are protected against oxidation as the Maillard reaction products [MRP] in the encapsulating matrix are good film-formers and also exhibit anti-oxidation activity as disclosed in WO 01/74175. The starches used in the formulations may also be pre-processed using conventional and emerging processing technologies to modify the starch properties to provide improved processing characteristics during the preparation of the delivery systems. The pretreatments are chosen to break down the long starch molecules so that they form more stable emulsions and also to provide a larger number of terminal sugar reducing groups for Maillard reaction with the protein component of the encapsulant. Colon delivery systems may be used for range of bioactives (e.g. oils), pharmaceuticals and therapeutics, which are unstable in the upper gastrointestinal tract. The protection afforded to the encapsulated components by the encapsulating material enable target release in the colon where the release is achieved after the encapsulant is degraded (e.g. by the action of microbial enzymes in the colon). Delivery of bioactives, pharmaceuticals and therapeutic components to the colon is desirable for treatment and prevention of diseases of the colon such as colorectal cancer, ulcerative colitis and inflammatory bowel disorder. In some cases the encapsulants used in the formulations such as selected polysaccharides, can also serve as gut wall adherents or as prebiotics that facilitate growth of beneficial bacteria, and can offer added advantages. For example delivery systems containing resistant starch have potential benefits on colonic health. DETAILED DESCRIPTION OF THE INVENTION A number of formulations will be described, some according to the invention and some for comparative purposes to show that some formulations are suitable to delivery to the colon whilst others could be more suitable for release in the small intestine. These formulations demonstrate that the core is protected from digestion in the stomach and the environment in the small intestine. FIGS. 1 to 19 of the drawings graphically illustrate the solvent extractable fat content and other properties of the formulations of the invention as illustrated in examples 1 to 19 below. The process of microencapsulating the active component involves the following manufacturing steps: (a) Selection of the biologically active core (e.g. oil, oil soluble or oil dispersible material, bioactives, therapeutics, pharmaceuticals) (b) Dispersion of the protein and carbohydrates (or starch that has been pre-processed by conventional means such as heating or extrusion or by the use of emerging processing technologies such as high pressure processing, microfluidisation or ultrasonics) in the aqueous phase and treatment of the mixture. If desired, the protein-carbohydrate blends may be further heat processed to induce the formation of conjugates (e.g. Maillard reaction products) (c) Mixing the core with the encapsulant (i.e. protein-carbohydrate mixture) and homogenizing the mixture to obtain an emulsion, in which the core is surrounded by the encapsulant. (d) Optionally, spray drying the emulsion to obtain a powdered formulation in which the core is surrounded by the encapsulating matrix Emulsion Formulations Tuna fish oil was used as an oil of choice in most of these examples since it contains a high amount of long chain polyunsaturated fatty acids and this need to be protected from oxidation prior to consumption. In addition there is interest in delivering these to the colon because of their potential for prevention of colorectal cancer and promotion of bowel health (Karmeli, R A. (1996) Historical Perspective and Potential Use of n-3 Fatty Acids in Therapy of Cancer Cachia. Nutrition, Vol 12 (1) S2-S4; Dommels Y E M, Alink, G M, van Bladeren, P J, van Ommen, B (2002) Dietary n-6 and n-3 polyunsaturated fatty acids and colorectal carcinogenesis: results from cultured colon cells, animal models and human studies, Environmental Toxicology and Pharmacology, Vol 12 (4), 233-244). Tributyrin and lutein were also included as examples. The encapsulation of probiotics (i.e. an example of a water dispersible component) using this technology has been previously disclosed in WO 01/74175. A range of formulations was prepared using protein and/or carbohydrate (raw or pre-processed) and oil mixtures at different ratios. The formulations were made-up to contain 25 and 50% fat in the final powder. The protein used in these examples were sodium caseinate, whey protein isolate and hydrolysed milk proteins. The carbohydrates used, alone or in combination, were glucose, oligosaccharides, dried glucose syrup, modified starches, resistant starches and native starches. Polysaccharides, including high-methoxy pectin, alginate, carrageenan, guar gum, were added to protein-carbohydrate mixtures in some formulations. Manufacture of Microcapsules Materials The core materials used in the examples include: tuna oil, tributyrin and 15% (w/w) lutein (mostly as dipalmitate and dimyristate lutein esters) in soy bean oil. Proteins used as encapsulant in the examples include: sodium caseinate (NaCas), whey protein isolate (WPI), hydrolysed casein protein (HCP) and hydrolysed whey protein (HWP). Carbohydrates used in the examples include: dextrose monohydrate (Glu), waxy maize, maize starch, dried glucose syrup (DGS), wheat starch, oligofructose (oligo), tapioca dextrin (K4484), modified starch (Capsul), modified starch (Hi-Cap 100), Hi-Maize, Hylon VII, Novelose 260 and Novelose 330, potato starch, sodium alginate, kappa carrageenan, high methoxy pectin (HMP) and guar gum. Preparation of Protein-Carbohydrate Encapsulants In some cases, unreacted blends of protein and carbohydrates (referred to as NonMRP formulations since these were not heated to induce the formation of Maillard reaction products) were used as the encapsulating matrix. For the preparation of reacted protein-carbohydrate encapsulants (referred to as MRP formulations as these were heated to induce the formation of Maillard reaction products), protein was dissolved in 60° C. water, using a high shear mixer, and then the sugars, starch or the selected carbohydrate were added. Where a polysaccharide was also added, the polysaccharide was first allowed to hydrate in water at 90° C. temperature before addition into the protein-sugar mixture. The pH of the protein-sugar/starch/gum mixtures was adjusted to 7.5. The mixture were then filled into 3 litre cans, sealed and heated in the retort to 98° C. and held for 30 minutes, then cooled down to room temperature. Microcapsule formulations are given in the examples below together with the methods used for the manufacture of microcapsules. Preparation of Protein-Starch Encapsulants Protein was dissolved in 60° C. water to make 15% total solids (TS) solution, using a high shear mixer. Starch (raw or heated, heated and microfluidised, extruded, high pressure processed and ultrasonicated) was prepared and processed separately to make a 10% TS solutions or dispersions in 70° C. water (See Preparation of Starches for Microencapsulation detailed below). The 15% TS protein solution were mixed together with the 10% TS starch to get a 12% TS mixture with a 1:1 protein:starch ratio. Where MRP was required, the mixture were then filled into 3 litre cans, sealed and heated in the retort to 98° C. and held for 30 minutes, then cooled down to 60° C. Preparation of Starches for Microencapsulation Raw or Unprocessed 10% TS starch dispersion (no pre-treatment applied) was mixed with 15% TS of protein solution at 60° C. Heat Processing 20% TS of each starch dispersion (except for potato starch where a 10% TS dispersion was used due to high viscosity at 20% TS) were heated at 121° C. for 60 minutes in a 73×82 mm cans. Once heat processed, 70° C. deionised water was added to dilute the sample to 10% TS in a high shear mixer. This heat processed starch was mixed with 15% TS of protein solution at 60° C. This mixture was then used for microencapsulation of bioactives. Heat Processing and Microfluidisation Treatment 20% TS of each starch dispersion (except for potato starch where a 10% TS dispersion was used due to high viscosity at 20% TS) were heated at 121° C. for 60 minutes in a 73×82 mm cans. Once heat processed, 70° C. deionised water was added to dilute the sample to 10% TS in a high shear mixer, and processed at 60° C. through a pilot scale M-210B EH microfluidiser (MFIC, Newton Mass., USA). The plant was operated at 800 bars and 3 passes using a combination of 425 μm Q50Z auxiliary processing module and 200 μm E230Z interaction chamber (for dispersion and cell disruption). The microfluidised (MF) starch was mixed with 15% TS of protein solution at 60° C. for microencapsulation. Heat Processing and Ultra-High Pressure Treatment 20% TS of a starch dispersion was heated at 121° C. for 60 minutes in a 73×82 mm cans. Once heat processed, 70° C. deionised water was added to dilute the sample to 10% TS in a high shear mixer, and processed by ultra-high pressure treatment at 6,000 bars for 15 minutes using HPP-QFP 35L unit. The ultra-high pressure treated (HPP) starch was mixed with 15% TS of protein solution at 60° C. for microencapsulation. Heat Processing and Ultrasonics Treatment 20% TS of a starch dispersion was heated at 121° C. for 60 minutes in 73×82 mm cans. Once heat processed, 70° C. deionised water was added to dilute the sample to 10% in a high shear mixer, and processed with ultrasound treatment at 50 ml/min @ 380 watts using 20 KHz unit. The ultrasound treated (US) starch was mixed with 15% TS of protein solution at 60° C. for microencapsulation. Extrusion Resistant starches were processed using a twin-screw extruder (model MPF 40, APV Baker, Peterborough PE3-6TA, England) 40 mm screw diameter and length to diameter ratio of 25:1, and a low shear screw configuration. A 4 mm die was used throughout the trial. Raw materials were fed into feed port 1 at 15 kg h−1 for resistant starch processing using a gravimetric feeder (Ktron Soder AG CH-5702, Niederlenz) and water was injected into port 2 with a volumetric pump (Brook Crompton, Huddersfield, England). Barrel moisture was injected at 20-40% and the die melt temperature was varied from 140 to 178° C. with increasing screw speed from 150-250 rpm. The extruded resistant starches were milled to 0.2 mm particle size powder. 10% TS extruded starch dispersion was mixed with 15% TS of protein solution at 60° C. for microencapsulation. Preparation of Oil in Water Emulsions The protein-carbohydrate mixtures and the tuna oil were pre-heated to 60° C. separately. The bioactive core was added into the protein-carbohydrate mixture using a Silverson high shear mixer. The mixture were then homogenised at 350 and 100 bar pressures in two stages using a Rannie homogeniser. Spray Drying of Emulsions The homogenised emulsions were spray dried at 50-60° C. feed temperature, 180° C. inlet temperature and 80° C. outlet temperature using a Niro production minor spray dryer. The powder was collected from the main chamber and packed. Estimation of Solvent Extractable Fat in Tuna Oil Powders The estimation of solvent-extractable was based on the method by Pisecky (Handbook of Milk Powder Manufacture, 1997) except that petroleum ether was used in place of carbon tetrachloride. Fifty ml of petroleum ether (b.p. 40-60° C.) was added to 10 g powder. The mixture was agitated in a stoppered flask for 15 minutes. The mixture was filtered and the solvent evaporated at 60° C. using a rotary evaporator. The remaining fat residue was then dried in an oven at 105° C. for 1 h. In-vitro Testing of Microcapsules The stability of the microcapsules in the stomach and the small-intestine was estimated by assessment of oil-release properties of microcapsules (a) incubated in simulated gastric fluid (SGF) (pH 1.2) for 2 h at 37° C. and 100 rpm in a shaker water-bath incubator and (b) incubated in SGF (2 h at 37° C. and 100 rpm in a shaker water-bath incubator) followed by exposure to simulated intestinal fluid (SIF) (pH 6.8) (3 h at 37° C. and 100 rpm). SGF and SIF were prepared according to the methods given in the US Pharmacopoeia (US Pharmacopeia 2000 & National Formulatory (USP 24 NF 19), Rockville, Md.) For Estimation of Released Oil from Microcapsules in-vitro: The solvent extractable fat from the incubated samples were measured. The sample was transferred into a 250 ml stoppered separating funnel and extracted with petroleum ether (75 ml plus 2×25 ml). The sample was filtered through a phase separation filter paper to obtain the solvent phase after each extraction. The solvent was removed to recover the oil released. For Estimation of Released Lutein in-vitro: The microcapsule containing the lutein (1.0 g) was incubated sequentially with SGF (pH 1.2) and SIF (pH6.8) as outlined above. For estimation of released lutein, the solvent extractable lutein from the incubated samples was measured. The extraction was performed in a centrifuge tube. The sample was extracted with petroleum ether (15 ml plus 2×10 ml). The sample was centrifuged (2000 rpm for 10 min) after each extraction and the top solvent layer removed. The combined solvent extracts were filtered through a phase separation filter paper prior to dilution with petroleum ether. The absorbance of the diluted extract was measured at 444 nm and the concentration of extracted lutein was determined. For Estimation of Released Tributyrin in-vitro: The microcapsule containing the tributyrin (1.0 g) was incubated sequentially with SGF (pH 1.2) and SIF (pH 6.8) as outlined above. For estimation of released tributyrin samples that were exposed to SGF only were used directly and that exposed sequentially to SGF and SIF was adjusted to pH 2. To this mixture was added 2.5 g NaCl and 15 ml dichloromethane and the mixture was centrifuged at 2500 rpm for 10 min at 5 C. The aqueous layer was removed and kept while the dichloromethane layer was decanted into a conical flask without disturbing the gelatinous precipitate floating on top of the dichloromethane layer. The aqueous layer with the gelatinous precipitate was extracted with another 15 ml dichloromethane. The dichloromethane extracts were dried over anhydrous Na2SO4, before filtering (0.45 μm PTFE syringe filter). The dichloromethane was removed under Nitrogen in a warm water bath. The extracted material was dissolved in 10 ml hexane/iso-propyl alcohol (99:1, v/v) and the solution stored in freezer. The amount of tributyrin and butyric acid in the extract was analysed by normal-phase HPLC. [Column: PVA-Sil guard and analytical (250 mm×4.6 mm I.D.) columns; UV detector (210 nm)]. In-vivo Testing of Microcapsules Male Sprague-Dawley rats, approximately 10 weeks of age were used for the in-vivo study. Rats were denied solid food for 24 hours prior to dosing, but were allowed free access to drinking water containing 2.5% glucose, 0.5% NaCl and 0.005% KCl (all w/v). Preparation of radiolabelled tuna oil: 0.5 ml or 25 μCi radiolabelled tracer [1-14C] 18:3 ([14C] trilinolenin, 50-60 mCi/mmol; 50 μCi/mL) was added to 4.56 g tuna oil. Two lots of tuna oil samples with radiolabelled trilinolenin were prepared, one for encapsulated oil treatment (see example 19 for formulation and manufacture) and one for free (unencapsulated) oil treatment. Rat treatment: On the day of treatment rats were fed intra-gastrically using a stainless steel gavage needle either with 0.3 ml fish oil mixed with radiolabelled tracer [14C] 18:3 (0.27 g tuna oil+0.03 ml tracer [14C] 18:3) for control treatment or 2 ml emulsion (0.09 g tuna oil+0.01 ml tracer [14C] 18:3) for the microencapsulated treatment. Tissue sampling: At time points of 4, 9 and 14 hours following treatment, rats were anesthetised and a blood sample taken by cardiac puncture. The stomach, small intestine, caecum and colon were removed. The small intestine was divided into two sections, each GI tract segment was flushed with 0.9% NaCl and the washings collected and frozen. The GI tract segments were then frozen for subsequent analysis. Faeces were also collected for analysis at time points. The tissues and faeces were weighed and samples taken for analysis and weighed. Tissue sample analysis: Radioactivity of GI tract washings containing all unabsorbed oil (both released and encapsulated oil) was counted to estimate the total amount of radioactivity. Tissue samples were dissolved overnight in BTS-450R tissue solubiliser. Faecal matters were dissolved in BTS-450R, with some prior treatment. The liquid scintillation cocktail Ready OrganicR was added to each sample and the sample subjected to liquid scintillation counting in a Packard 1500 Tri-Carb Scintillation Counter. EXAMPLE 1 Formulations and Manufacture of Powders with 25% Oil Loading with Unheated or Heated Blends of Protein-Glucose/Dried Glucose Syrup or Protein-Oligosaccharide as Encapsulants powder emulsion Ingredient composition composition Processing steps Water 69.2% Prepare NaCas solution (Alanate) at 60° C., add Alanate 180 25.0% 7.7% sugars [glucose and DGS (Maltostar)], Glucose.H2O 25.0% 7.7% (preferably, adjust pH of solution to 7.5, heat to Maltostar 30 25.0% 7.7% 98° C. and hold for 30 minutes, cool down to Tuna oil 25.0% 7.7% 60° C.), add oil heated to 60° C., homogenise at Total 100.0% 100.0% 350/100 bar, spray dry at 180/80° C. Inlet temperature (Ti)/Outlet temperature (To). powder Emulsion Ingredient composition composition Processing steps Water 69.2% Prepare NaCas solution at 60° C., add Alanate 180 25.0% 7.7% oligosaccharide, (preferably, adjust pH of Raftilose P95 50.0% 15.4% solution to 7.5, heat to 98° C. and hold for 30 Tuna oil 25.0% 7.7% minutes, cool down to 60° C.), add oil heated to Total 100.0% 100.0% 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. powder emulsion Ingredient composition composition Processing steps Water 69.2% Prepare WPI solution (Alacen) at 60° C., add Alacen 895 25.0% 7.7% sugars, (preferably, adjust pH of solution to 7.5, Glucose.H2O 25.0% 7.7% heat to 98° C. and hold for 30 minutes, cool down Maltostar 30 25.0% 7.7% to 60° C.), add oil heated to 60° C., homogenise at Tuna oil 25.0% 7.7% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 69.2% Prepare WPI solution at 60° C., add Alacen 895 25.0% 7.7% oligosaccharidesugars, (preferably, adjust pH of Raftilose P95 50.0% 15.4% solution to 7.5, heat to 98° C. and hold for 30 Tuna oil 25.0% 7.7% minutes, cool down to 60° C.), add oil heated to Total 100.0% 100.0% 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 2 Formulations and Manufacture of Powders with 50% Oil Loading with Unheated or Heated Blends of Protein-Glucose/Dried Glucose Syrup or Protein-Oligosaccharide as Encapsulants powder emulsion Ingredient composition composition Processing steps Water 60.0% Prepare NaCas solution at 60° C., add sugars, Alanate 180 16.7% 6.7% (preferably, adjust pH of solution to 7.5, heat to Glucose.H2O 16.7% 6.7% 98° C. and hold for 30 minutes, cool down to Maltostar 30 16.7% 6.7% 60° C.), add oil heated to 60° C., homogenise at Tuna oil 50.0% 20.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 60.0% Prepare NaCas solution at 60° C., add Alanate 180 16.7% 6.7% oligosaccharide (Raftilose), (preferably, adjust pH Raftilose P95 33.3% 13.3% of solution to 7.5, heat to 98° C. and hold for 30 Tuna oil 50.0% 20.0% minutes, cool down to 60° C.), add oil heated to Total 100.0% 100.0% 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Water 60.0% Prepare WPI solution at 60° C., add sugars, Alacen 895 16.7% 6.7% (preferably, adjust pH of solution to 7.5, heat to Glucose.H2O 16.7% 6.7% 98° C. and hold for 30 minutes, cool down to Maltostar 30 16.7% 6.7% 60° C.), add oil heated to 60° C., homogenise at Tuna oil 50.0% 20.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 60.0% Prepare WPI solution at 60° C., add Alacen 895 16.7.0% 6.7% oligosaccharidesugars, (preferably, adjust pH of Raftilose P95 33.3% 13.3% solution to 7.5, heat to 98° C. and hold for 30 Tuna oil 50.0% 20.0% minutes, cool down to 60° C.), add oil heated to Total 100.0% 100.0% 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 3 Formulations and Manufacture of Powders with 25% Oil Loading with Heated Blends of Protein-Starch as Encapsulants powder emulsion Ingredient composition composition Processing steps Water 69.2% Prepare NaCas solution at 60° C., add starch Alanate 180 25.0% 7.7% (Capsul), (preferably, adjust pH of solution to 7.5, Capsul 50.0% 15.4% heat to 98° C. and hold for 30 minutes, cool down Tuna oil 25.0% 7.7% to 60° C.), add oil heated to 60° C., homogenise at Total 100.0% 100.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Water 69.2% Prepare NaCas solution at 60° C., add starch (Hi- Alanate 180 25.0% 7.7% Cap), (preferably, adjust pH of solution to 7.5, Hi-Cap 100 50.0% 15.4% heat to 98° C. and hold for 30 minutes, cool down Tuna oil 25.0% 7.7% to 60° C.), add oil heated to 60° C., homogenise at Total 100.0% 100.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Water 69.2% Prepare NaCas solution at 60° C., add dextrin, Alanate 180 25.0% 7.7% (preferably, adjust pH of solution to 7.5, heat to Tapioca dextrin 50.0% 15.4% 98° C. and hold for 30 minutes, cool down to K4484 60° C.), add oil heated to 60° C., homogenise at Tuna oil 25.0% 7.7% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 69.2% Prepare WPI solution at 60° C., add dextrin, Alacen 895 25.0% 7.7% (preferably, adjust pH of solution to 7.5, heat to Tapioca dextrin 50.0% 15.4% 98° C. and hold for 30 minutes, cool down to K4484 60° C.), add oil heated to 60° C., homogenise at Tuna oil 25.0% 7.7% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% EXAMPLE 4 Formulations and Manufacture of Powders with 50% Oil Loading with Heated Blends of Protein-Starch as Encapsulants powder emulsion Ingredient composition composition Processing steps Water 60.0% Prepare NaCas solution at 60° C., add starch, Alanate 180 16.7% 6.7% (preferably, adjust pH of solution to 7.5, heat to Capsul 33.3% 13.3% 98° C. and hold for 30 minutes, cool down to Tuna oil 50.0% 20.0% 60° C.), add oil heated to 60° C., homogenise at Total 100.0% 100.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Water 60.0% Prepare NaCas solution at 60° C., add starch, Alanate 180 16.7% 6.7% (preferably, adjust pH of solution to 7.5, heat to Hi-Cap 100 33.3% 13.3% 98° C. and hold for 30 minutes, cool down to Tuna oil 50.0% 20.0% 60° C.), add oil heated to 60° C., homogenise at Total 100.0% 100.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Water 60.0% Prepare NaCas solution at 60° C., add dextrin, Alanate 180 16.7% 6.7% (preferably, adjust pH of solution to 7.5, heat to Tapioca dextrin 33.3% 13.3% 98° C. and hold for 30 minutes, cool down to K4484 60° C.), add oil heated to 60° C., homogenise at Tuna oil 50.0% 20.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 60.0% Prepare WPI solution at 60° C., add dextrin, Alacen 895 16.7% 6.7% (preferably, adjust pH of solution to 7.5, heat to Tapioca dextrin 33.3% 13.3% 98° C. and hold for 30 minutes, cool down to K4484 60° C.), add oil heated to 60° C., homogenise at Tuna oil 50.0% 20.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% EXAMPLE 5 Formulations and Manufacture of Powders with 25% Oil Loading with Heated Blends of Protein-Glucose/Glucose Syrup or Protein-Oligosaccharide in Combination with Gums as Encapsulants powder emulsion Ingredient composition composition Processing steps Water 69.2% Prepare NaCas solution at 60° C., add sugars and Alanate 180 25.0% 7.7% alginate (Protanal), (preferably, adjust pH of Glucose.H2O 25.0% 7.7% solution to 7.5, heat to 98° C. and hold for 30 Maltostar 30 22.5% 6.9% minutes, cool down to 60° C.), add oil heated to Protanal 2.5% 0.8% 60° C., homogenise at 350/100 bar, spray dry at Tuna oil 25.0% 7.7% 180/80° C. Ti/To. Total 100.0% 100.0% Water 77.7% Prepare NaCas solution at 60° C., add Alanate 180 25.0% 5.6% oligosaccharide and guar gum solution, Raftilose P95 48.75% 10.9% (preferably, adjust pH of solution to 7.5, heat to Guar 1.25% 0.3% 98° C. and hold for 30 minutes, cool down to WW250F 60° C.), add oil heated to 60° C., homogenise at Tuna oil 25.0% 5.6% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 73.2% Prepare NaCas solution at 60° C., add Alanate 180 25.0% 6.7% oligosaccharide and carrageenan solution Raftilose P95 48.75% 13.0% (Gelcarin), (preferably, adjust pH of solution to Gelcarin 1.25% 0.3% 7.5, heat to 98° C. and hold for 30 minutes, cool GP 812 down to 60° C.), add oil heated to 60° C., Tuna oil 25.0% 6.7% homogenise at 350/100 bar, spray dry at Total 100.0% 100.0% 180/80° C. Ti/To. Water 73.1% Prepare NaCas solution at 60° C., add Alanate 180 25.0% 6.7% oligosaccharide and high methoxy pectin (HMP) Raftilose P95 47.5% 12.7% solution, (preferably, adjust pH of solution to 7.5, HMP RS400 2.5% 0.7% heat to 98° C. and hold for 30 minutes, cool down Tuna oil 25.0% 6.7% to 60° C.), add oil heated to 60° C., homogenise at Total 100.0% 100.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Water 73.1% Prepare NaCas solution at 60° C., add glucose- Alacen 895 25.0% 6.7% DGS and high methoxy pectin (HMP) solution, 1:1 Glu: DGS 47.5% 12.7% (preferably, adjust pH of solution to 7.5, heat to HMP RS400 2.5% 0.7% 98° C. and hold for 30 minutes, cool down to Tuna oil 25.0% 6.7% 60° C.), add oil heated to 60° C., homogenise at Total 100.0% 100.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Water 77.7% Prepare WPI solution at 60° C., add Alacen 895 25.0% 5.6% oligosaccharide and guar gum solution, Raftilose P95 48.75% 10.9% (preferably, adjust pH of solution to 7.5, heat to Guar 1.25% 0.3% 98° C. and hold for 30 minutes, cool down to WW250F 60° C.), add oil heated to 60° C., homogenise at Tuna oil 25.0% 5.6% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 73.2% Prepare NaCas solution at 60° C., add Alacen 895 25.0% 6.7% oligosaccharide and 60° C. carrageenan solution, Raftilose P95 48.75% 13.0% (preferably, adjust pH of solution to 7.5, heat to Gelcarin 1.25% 0.3% 98° C. and hold for 30 minutes, cool down to GP 812 60° C.), add oil heated to 60° C., homogenise at Tuna oil 25.0% 6.7% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% water 73.1% Prepare NaCas solution at 60° C., add Alacen 895 25.0% 6.7% oligosaccharide and 60° C. HMP solution, Raftilose P95 47.5% 12.7% (preferably, adjust pH of solution to 7.5, heat to HMP RS400 2.5% 0.7% 98° C. and hold for 30 minutes, cool down to Tuna oil 25.0% 6.7% 60° C.), add oil heated to 60° C., homogenise at Total 100.0% 100.0% 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 6 Formulations and Manufacture of Powders with 50% Oil Loading with Heated Blends of Protein-Glucose/Glucose Syrup or Protein-Oligosaccharide in Combination with Gums as Encapsulants powder emulsion Ingredient composition composition Processing steps water 60.0% Prepare NaCas solution at 60° C., add sugars and Alanate 180 16.7% 6.7% alginate, (preferably, adjust pH of solution to 7.5, Glucose 16.7% 6.7% heat to 98° C. and hold for 30 minutes, cool down Maltostar 30 15.0% 6.0% to 60° C.), add oil heated to 60° C., homogenise at Protanal 1.7% 0.7% 350/100 bar, spray dry at 180/80° C. Ti/To. Tuna oil 50.0% 20.0% Total 100.0% 100.0% Water 69.9% Prepare HWP solution at 60° C., add NaCas 16.7% 5.0% oligosaccharide and guar gum solution, Raftilose P95 32.5% 9.8% (preferably, adjust pH of solution to 7.5, heat to Guar 0.8% 0.3% 98° C. and hold for 30 minutes, cool down to WW250F 60° C.), add oil heated to 60° C., homogenise at Tuna oil 50.0% 15.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 64.6% Prepare NaCas solution at 60° C., add Alanate 180 16.7% 5.9% oligosaccharide and carrageenan solution, Raftilose P95 32.5% 11.5% (preferably, adjust pH of solution to 7.5, heat to Gelcarin 0.8% 0.3% 98° C. and hold for 30 minutes, cool down to GP 812 60° C.), add oil heated to 60° C., homogenise at Tuna oil 50.0% 17.7% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 64.5% Prepare NaCas solution at 60° C., add Alanate 180 16.7% 5.9% oligosaccharidesugars and HMP solution, Raftilose P95 31.7% 11.2% (preferably, adjust pH of solution to 7.5, heat to HMP RS400 1.7% 0.6% 98° C. and hold for 30 minutes, cool down to Tuna oil 50.0% 17.8% 60° C.), add oil heated to 60° C., homogenise at Total 100.0% 100.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Water 69.9% Prepare WPI solution at 60° C., add Alacen 895 16.7% 5.0% oligosaccharide and guar gum solution, Raftilose P95 32.5% 9.8% (preferably, adjust pH of solution to 7.5, heat to Guar 0.8% 0.3% 98° C. and hold for 30 minutes, cool down to WW250F 60° C.), add oil heated to 60° C., homogenise at Tuna oil 50.0% 15.0% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 53.1% Prepare WPI solution at 60° C., add Alacen 895 16.7% 5.9% oligosaccharide and carrageenan solution, Raftilose P95 32.5% 11.5% (preferably, adjust pH of solution to 7.5, heat to Gelcarin 0.8% 0.3% 98° C. and hold for 30 minutes, cool down to GP 812 60° C.), add oil heated to 60° C., homogenise at Water for gum 11.5% 350/100 bar, spray dry at 180/80° C. Ti/To. dispersion Tuna oil 50.0% 17.7% Total 100.0% 100.0% Water 53.3% Prepare WPI solution at 60° C., add Alacen 895 16.7% 5.9% oligosaccharide and 60° C. HMP solution, Raftilose P95 31.7% 11.2% (preferably, adjust pH of solution to 7.5, heat to HMP RS400 1.7% 0.6% 98° C. and hold for 30 minutes, cool down to Water for gum 11.2% 60° C.), add oil heated to 60° C., homogenise at dispersion 350/100 bar, spray dry at 180/80° C. Ti/To. Tuna oil 50.0% 17.8% Total 100.0% 100.0% EXAMPLE 7 Formulations and Manufacture of Powders with 25% Oil Loading with Heated Blends of Protein Hydrolysate-Oligosaccharide in Combination with Gums as Encapsulants powder emulsion Ingredient composition composition Processing steps Water 73.2% Prepare hydrolysed casein protein (HCP) HCP 102 25.0% 6.7% solution at 60° C., add oligosaccharide, and 60° C. Raftilose P95 48.75% 13.0% carrageenan solution (preferably, adjust pH of Gelcarin 1.25% 0.3% solution to 7.5, heat to 98° C. and hold for 30 GP 812 minutes, cool down to 60° C.), add oil heated to Tuna oil 25.0% 6.7% 60° C., homogenise at 350/100 bar, spray dry at Total 100.0% 100.0% 180/80° C. Ti/To. Water 73.1% Prepare HCP solution at 60° C., add HCP 102 25.0% 6.7% oligosaccharide and HMP solution, (preferably, Raftilose P95 47.5% 12.7% adjust pH of solution to 7.5, heat to 98° C. and HMP RS400 2.5% 0.7% hold for 30 minutes, cool down to 60° C.), add oil Tuna oil 25.0% 6.7% heated to 60° C., homogenise at 350/100 bar, Total 100.0% 100.0% spray dry at 180/80° C. Ti/To. Water 73.2% Prepare hydrolysed whey protein (HWP) solution HWP 205 25.0% 6.7% at 60° C., add oligosaccharide and carrageenan Raftilose P95 48.75% 13.0% solution, (preferably, adjust pH of solution to 7.5, Gelcarin 1.25% 0.3% heat to 98° C. and hold for 30 minutes, cool down GP 812 to 60° C.), add oil heated to 60° C., homogenise at Tuna oil 25.0% 6.7% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 73.1% Prepare HWP solution at 60° C., add HWP 205 25.0% 6.7% oligosaccharide and HMP solution, (preferably, Raftilose P95 47.5% 12.7% adjust pH of solution to 7.5, heat to 98° C. and HMP RS400 2.5% 0.7% hold for 30 minutes, cool down to 60° C.), add oil Tuna oil 25.0% 6.7% heated to 60° C., homogenise at 350/100 bar, Total 100.0% 100.0% spray dry at 180/80° C. Ti/To. Water 73.1% Prepare HWP solution at 60° C., add glucose- HWP 205 25.0% 6.7% DGS and HMP solution, (preferably, adjust pH of 1:1 Glu: DGS 47.5% 12.7% solution to 7.5, heat to 98° C. and hold for 30 HMP RS400 2.5% 0.7% minutes, cool down to 60° C.), add oil heated to Tuna oil 25.0% 6.7% 60° C., homogenise at 350/100 bar, spray dry at Total 100.0% 100.0% 180/80° C. Ti/To. EXAMPLE 8 Formulations and Manufacture of Powders with 50% Oil Loading with Heated Blends of Hydrolysate-Oligosaccharide in Combination with Gums as Encapsulants powder emulsion Ingredient composition composition Processing steps Water 64.6% Prepare HCP solution at 60° C., add HCP 102 16.7% 5.9% oligosaccharide and carrageenan solution, Raftilose P95 32.5% 11.5% (preferably, adjust pH of solution to 7.5, heat to Gelcarin 0.8% 0.3% 98° C. and hold for 30 minutes, cool down to GP 812 60° C.), add oil heated to 60° C., homogenise at Tuna oil 50.0% 17.7% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 64.5% Prepare HCP solution at 60° C., add HCP 102 16.7% 5.9% oligosaccharide and HMP solution, (preferably, Raftilose P95 31.7% 11.2% adjust pH of solution to 7.5, heat to 98° C. and HMP RS400 1.7% 0.6% hold for 30 minutes, cool down to 60° C.), add oil Tuna oil 50.0% 17.8% heated to 60° C., homogenise at 350/100 bar, Total 100.0% 100.0% spray dry at 180/80° C. Ti/To. Water 64.6% Prepare HWP solution at 60° C., add HWP 205 16.7% 5.9% oligosaccharide and carrageenan solution, Raftilose P95 32.5% 11.5% (preferably, adjust pH of solution to 7.5, heat to Gelcarin 0.8% 0.3% 98° C. and hold for 30 minutes, cool down to GP 812 60° C.), add oil heated to 60° C., homogenise at Tuna oil 50.0% 17.7% 350/100 bar, spray dry at 180/80° C. Ti/To. Total 100.0% 100.0% Water 64.5% Prepare HWP solution at 60° C., add HWP 205 16.7% 5.9% oligosaccharide and HMP solution, (preferably, Raftilose P95 31.7% 11.2% adjust pH of solution to 7.5, heat to 98° C. and HMP RS400 1.7% 0.6% hold for 30 minutes, cool down to 60° C.), add oil Tuna oil 50.0% 17.8% heated to 60° C., homogenise at 350/100 bar, Total 100.0% 100.0% spray dry at 180/80° C. Ti/To. EXAMPLE 9 Formulations and Manufacture of Powders with 25% Oil Loading with Blends of Sodium Caseinate with Raw or Processed Resistant Starch (Potato Starch) powder emulsion Ingredient composition composition Processing steps (using raw potato starch) Water 84.6% Prepare 10% TS starch dispersion at 70° C. Potato starch 37.5% 5.8% Prepare 15% TS NaCas solution at 60° C. and mix Alanate 180 37.5% 5.8% with starch dispersion above. (Preferably heat Tuna oil 25.0% 3.8% protein-starch mixture in cans at 98° C.-30 Total 100.0% 100.0% minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed potato starch) Water 84.6% Prepare 10% TS starch dispersion at 70° C., Potato starch 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down. Prepare 15% TS NaCas Tuna oil 25.0% 3.8% solution at 60° C. and mix with processed starch Total 100.0% 100.0% above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed and microfluidised potato starch) Water 84.6% Prepare 10% TS starch dispersion at 70° C., Potato starch 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, microfluidise at 800 bar-3 Tuna oil 25.0% 3.8% passes. Prepare 15% TS NaCas solution at 60° C. Total 100.0% 100.0% and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using extruded potato starch) Water 84.6% Prepare 10% TS extruded starch dispersion at Potato starch 37.5% 5.8% 70° C. Prepare 15% TS NaCas solution at 60° C. Alanate 180 37.5% 5.8% and mix with starch dispersion above. Tuna oil 25.0% 3.8% (Preferably heat protein-starch mixture in cans at Total 100.0% 100.0% 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 10 Formulations and Manufacture of Powders with 25% Oil Loading with Blends of Sodium Caseinate with Hylon VII or Pre-Processed Resistant Starch (Hylon VII) powder emulsion Ingredient composition composition Processing steps (using Hylon VII starch) Water 84.6% Prepare 10% TS starch dispersion at 70° C. Hylon VII 37.5% 5.8% Prepare 15% TS NaCas solution at 60° C. and mix Alanate 180 37.5% 5.8% with starch dispersion above. (Preferably heat Tuna oil 25.0% 3.8% protein-starch mixture in cans at 98° C.-30 Total 100.0% 100.0% minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed Hylon VII starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Hylon VII 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS Prepare 15% TS NaCas Total 100.0% 100.0% solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed and microfluidised Hylon VII starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Hylon VII 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, microfluidise at 800 bar-3 Total 100.0% 100.0% passes. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using extruded Hylon VII starch) Water 84.6% Prepare 10% TS extruded starch dispersion at Hylon VII 37.5% 5.8% 70° C. Prepare 15% TS NaCas solution at 60° C. Alanate 180 37.5% 5.8% and mix with starch dispersion above. Tuna oil 25.0% 3.8% (Preferably heat protein-starch mixture in cans at Total 100.0% 100.0% 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 11 Formulations and Manufacture of Powders with 25% Oil Loading with Blends of Sodium Caseinate with Hi-Maize 1043 or Pre-Processed Resistant Starch (Hi-Maize 1043) powder emulsion Ingredient composition composition Processing steps (using Hi-Maize starch) Water 84.6% Prepare 10% TS starch dispersion at 70° C.. Hi-Maize 1043 37.5% 5.8% Prepare 15% TS NaCas solution at 60° C. and mix Alanate 180 37.5% 5.8% with starch dispersion above. (Preferably heat Tuna oil 25.0% 3.8% protein-starch mixture in cans at 98° C.-30 Total 100.0% 100.0% minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed Hi- Maize starch) Water 84.6% Prepare 20% TS starch dispersion at 60° C., Hi-Maize 1043 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS. Prepare 15% TS NaCas Total 100.0% 100.0% solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed and microfluidised Hi-Maize starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Hi-Maize 1043 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, microfluidise at 800 bar-3 Total 100.0% 100.0% passes. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using extrude Hi-Maize starch) Water 84.6% Prepare 10% TS extruded starch dispersion at Hi-Maize 1043 37.5% 5.8% 70° C.. Prepare 15% TS NaCas solution at 60° C. Alanate 180 37.5% 5.8% and mix with starch dispersion above. Tuna oil 25.0% 3.8% (Preferably heat protein-starch mixture in cans at Total 100.0% 100.0% 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 12 Formulations and Manufacture of Powders with 25% Oil Loading with Blends of Sodium Caseinate with Novelose 260 or Pre-Processed Resistant Starch (Novelose 260) powder emulsion Ingredient composition composition Processing steps (using Novelose 260 starch) Water 84.6% Prepare 10% TS starch dispersion at 70° C.. Novelose 260 37.5% 5.8% Prepare 15% TS NaCas solution at 60° C. and mix Alanate 180 37.5% 5.8% with starch dispersion above. (Preferably heat Tuna oil 25.0% 3.8% protein-starch mixture in cans at 98° C.-30 Total 100.0% 100.0% minutes, cool down to 60° C.). Add oil heated to 60° C. homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed Novelose 260 starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Novelose 260 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS. Prepare 15% TS NaCas Total 100.0% 100.0% solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed and microfluidised Novelose 260 starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Novelose 260 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, microfluidise at 800 bar-3 Total 100.0% 100.0% passes. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps Water 84.6% Prepare 10% TS extruded starch dispersion at Novelose 260 37.5% 5.8% 70° C.. Prepare 15% TS NaCas solution at 60° C. Alanate 180 37.5% 5.8% and mix with starch dispersion above. Tuna oil 25.0% 3.8% (Preferably heat protein-starch mixture in cans at Total 100.0% 100.0% 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 13 Formulations and Manufacture of Powders with 25% Oil Loading with Blends of Sodium Caseinate with Novelose 330 or Pre-Processed Resistant Starch (Novelose 330) powder emulsion Ingredient composition composition Processing steps (using Novelose 330 starch) Water 84.6% Prepare 10% TS starch dispersion at 70° C.. Novelose 330 37.5% 5.8% Prepare 15% TS NaCas solution at 60° C. and mix Alanate 180 37.5% 5.8% with starch dispersion above. (Preferably heat Tuna oil 25.0% 3.8% protein-starch mixture in cans at 98° C.-30 Total 100.0% 100.0% minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed Novelose 330 starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Novelose 330 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS. Prepare 15% TS NaCas Total 100.0% 100.0% solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed and microfluidised Novelose 330 starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Novelose 330 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, microfluidise at 800 bar-3 Total 100.0% 100.0% passes. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using extruded Novelose 330 starch) Water 84.6% Prepare 10% TS extruded starch dispersion at Novelose 330 37.5% 5.8% 70° C.. Prepare 15% TS NaCas solution at 60° C. Alanate 180 37.5% 5.8% and mix with starch dispersion above. Tuna oil 25.0% 3.8% (Preferably heat protein-starch mixture in cans at Total 100.0% 100.0% 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 14 Formulations and Manufacture of Powders with 25% Oil Loading with Blends of Sodium Caseinate with Hylon VII or High Pressure Processed or Ultrasonicated Resistant Starch (Hylon VII) powder emulsion Ingredient composition composition Processing steps (using Hylon VII starch) Water 84.6% Prepare 10% TS starch dispersion at 70° C. Hylon VII 37.5% 5.8% Prepare 15% TS NaCas solution at 60° C. and mix Alanate 180 37.5% 5.8% with starch dispersion above. (Preferably heat Tuna oil 25.0% 3.8% protein-starch mixture in cans at 98° C.-30 Total 100.0% 100.0% minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed and microfluidised x1 pass Hylon VII starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Hylon VII 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, microfluidise at 800 bar-1 Total 100.0% 100.0% pass. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bars, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed and microfluidised x3 pass Hylon VII starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Hylon VII 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, microfluidise at 800 bar-3 Total 100.0% 100.0% passes. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bars, spray dry at 180/80° C. Ti/To. Processing steps (using extruded Hylon VII starch) Water 84.6% Prepare 10% TS extruded starch dispersion at Hylon VII 37.5% 5.8% 70° C.. Prepare 15% TS NaCas solution at 60° C. Alanate 180 37.5% 5.8% and mix with starch dispersion above. Tuna oil 25.0% 3.8% (Preferably heat protein-starch mixture in cans at Total 100.0% 100.0% 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bars, spray dry at 180/80° C. Ti/To. Processing steps (using high pressure treated Hylon VII starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Hylon VII 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, HPP at 600 MPa, for 15 Total 100.0% 100.0% minutes. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using ultrasound treated Hylon VII starch) Water 84.6% Prepare 20% TS starch dispersion at 70° C., Hylon VII 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, US using 20 KHz unit @ 50 Total 100.0% 100.0% ml per minute, 380 Watts. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 15 Formulations and Manufacture of Powders with 25% Oil Loading with Unheated and Heated Blends of Sodium Caseinate with Raw Starches or Pre-Processed Starch powder emulsion Ingredient composition composition Processing steps Water 84.6% Prepare 10% TS starch dispersion at 70° C.. Waxy maize 37.5% 5.8% Prepare 15% TS NaCas solution at 60° C. and Alanate 180 37.5% 5.8% mix with starch dispersion above. Tuna oil 25.0% 3.8% (Preferably heat protein-starch mixture in Total 100.0% 100.0% cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Water 84.6% Prepare 20% TS starch dispersion at 70° C., Waxy maize 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, Microfluidise at 800 Total 100.0% 100.0% bar-1 pass. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Water 84.6% Prepare 10% TS starch dispersion at 70° C.. Maize starch 37.5% 5.8% Prepare 15% TS NaCas solution at 60° C. and Alanate 180 37.5% 5.8% mix with starch dispersion above. Tuna oil 25.0% 3.8% (Preferably heat protein-starch mixture in Total 100.0% 100.0% cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Water 84.6% Prepare 20% TS starch dispersion at 70° C., Maize starch 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, Microfluidise at 800 bar-1 pass. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.) Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Water 84.6% Prepare 10% TS starch dispersion at 70° C., Wheat starch 37.5% 5.8% Prepare 15% TS NaCas solution at 60° C. and Alanate 180 37.5% 5.8% mix with starch dispersion above. Tuna oil 25.0% 3.8% (Preferably heat protein-starch mixture in Total 100.0% 100.0% cans at 98° C.-30 minutes, cool down to 60° C.) Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Water 84.6% Prepare 20% TS starch dispersion at 70° C., Wheat starch 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, Microfluidise at 800 Total 100.0% 100.0% bar-1 pass. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.) Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 16 Formulations and Manufacture of Powders with 25% (Lutein-in-Oil) in Heated and Unheated Blends of Protein-Sugar-Starch as Encapsulants powder emulsion Ingredient composition composition Processing steps Water 69.2% Prepare NaCas solution at 60° C., add DGS and Alanate 180 25.0% 7.7% starch, (preferably, adjust pH of solution to 7.5, Maltostar 30 25.0% 7.7% heat to 98° C. and hold for 30 minutes, cool down Tapioca dextrin 25.0% 7.7% to 60° C.), add lutein heated to 90° C., homogenise K4484 at 350/100 bars, spray dry at 180/80° C. Ti/To. Lutein in oil 25.0% 7.7% Total 100.0% 100.0% EXAMPLE 17 Formulations and Manufacture of Powders with 25% Tributyrin in Heated Blends of Protein-Sugar or Protein-Sugar-RS Starch as Encapsulants powder emulsion Ingredient composition composition Processing steps Water 69.2% Prepare NaCas solution at 60° C., add sugars, Alanate 180 25.0% 7.7% (preferably, adjust pH of solution to 7.5, heat to Glucose 25.0% 7.7% 98° C. and hold for 30 minutes, cool down to Maltostar 30 25.0% 7.7% 60° C.), add tributyrin, homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Tributyrin 25.0% 7.7% Total 100.0% 100.0% Processing steps (using heat processed and microfluidised Hylon VII starch) Water 69.2% Prepare 20% TS starch dispersion at 70° C., Alanate 180 25.0% 7.7% process in 73 × 82 mm cans at 121° C.-60 Glucose 25.0% 7.7% minutes, cool down, add remaining water to Hylon VII 25.0% 7.7% make-up to 10% TS, microfluidise at 800 bar-3 Tributyrin 25.0% 7.7% passes. Prepare 15% TS NaCas solution at Total 100.0% 100.0% 60° C., add sugar and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add tributyrin, homogenise at 350/100 bars, spray dry at 180/80° C. Ti/To. EXAMPLE 18 Formulations and Manufacture of Powders with 25% Tuna Oil in Heated Blends of NaCas-Sugar-HylonMF or NaCas-HylonMF or NaCas-StarPlus MF as Encapsulants powder emulsion Ingredient composition composition Processing steps (using heat processed and microfluidised Hylon VII starch) Water 69.2% Prepare 20% TS starch dispersion at 70° C., Alanate 180 25.0% 7.7% process in 73 × 82 mm cans at 121° C.-60 Glucose 25.0% 7.7% minutes, cool down, add remaining water to Hylon VII 25.0% 7.7% make-up to 10% TS, microfluidise at 800 bar-3 Tuna oil 25.0% 7.7% passes. Prepare 15% TS NaCas solution at Total 100.0% 100.0% 60° C., add sugar and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add tuna oil, homogenise at 350/100 bars, spray dry at 180/80° C. Ti/To. Water 84.6% Prepare 20% TS starch dispersion at 70° C., Hylon VII 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, microfluidise at 800 bar-3 Total 100.0% 100.0% passes. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed and microfluidised Star Plus A) Water 84.6% Prepare 20% TS Star Plus A dispersion at 70° C., Star Plus A 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, microfluidise at 800 bar-3 Total 100.0% 100.0% passes. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C.). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. Processing steps (using heat processed and microfluidised Star Plus P) Water 84.6% Prepare 20% TS Star Plus P dispersion at 70° C., Star Plus P 37.5% 5.8% process in 73 × 82 mm cans at 121° C.-60 Alanate 180 37.5% 5.8% minutes, cool down, add remaining water to Tuna oil 25.0% 3.8% make-up to 10% TS, microfluidise at 800 bar-3 Total 100.0% 100.0% passes. Prepare 15% TS NaCas solution at 60° C. and mix with processed starch above. (Preferably heat protein-starch mixture in cans at 98° C.-30 minutes, cool down to 60° C). Add oil heated to 60° C., homogenise at 350/100 bar, spray dry at 180/80° C. Ti/To. EXAMPLE 19 Formulations and Manufacture of Powders with 25% Tuna Oil (+Radiolabelled Tracer) in Heated Blends of Protein-Sugar-RS Starch as Encapsulants for in-vivo Testing emulsion Ingredient composition Processing steps (using heat processed and Ingredient Wt. (g) (%) microfluidised Hylon VII starch) Water 82.47 82.04% Prepare 20% TS starch dispersion at 70° C., process Alanate 180 4.33 4.31% in 73 × 82 mm cans at 121° C.-60 minutes, cool Glucose 4.33 4.31% down, add remaining water to make-up to 10% TS, Hylon VII 4.33 4.31% microfluidise at 800 bar-3 passes. Prepare 15% TS Tuna oil 4.56 4.54% NaCas solution at 60° C., add sugar and mix with Radiolabelled 0.50 ml 0.50% processed starch above. (Preferably heat protein- tracer [14C] 18:3 (25 μCi) glucose-starch mixture in cans at 98° C.-30 minutes, Total solids 18.05 18.0% cool down to 60° C.). Add radiolabelled tuna oil, Total 100.52 100.0% homogenise at 350/100 bars, spray dry at 180/80° C. Ti/To. Characteristics of Microcapsules in-vitro The properties of the example 1 formulations are shown in FIG. 1 of the drawings. Solvent-extractable fat in all powders (25% fat in powder) were less than 3% (of total fat) indicating that the encapsulating efficiency was good. Released oil in SGF was less than 2% of total fat for all formulations. Released oil in SGF+SIF were less than 4% of total fat for casein based microcapsules and up to 22% of total fat for WPI based microcapsules. In these examples NaCas based formulations offer better protection than WPI based formulations. Also heat treatment applied to WPI-sugar encapsulant can increase the release in SGF+SIF. Depending on the type of protein and whether heat treatment is applied to the encapsulant the core may be released targeted to a specific site in the GI tract. The properties of the example 2 formulations are shown in FIG. 2 of the drawings. Solvent-extractable fat in all powders (50% fat in powder) were less than 3% (of total fat) indicating that the good encapsulating efficiency was maintained when that ratio of the fat to encapsulating material was increased from 1:3 in 25% fat powders to 1:1 in 50% fat powders. Released oil in SGF was less than 2% of total fat for all formulations. Released oil in SGF+SIF were less than 4% of total fat for casein based microcapsules and up to 30% of total fat for WPI based microcapsules. The trend in the release properties of the microcapsules in FIG. 2 with 50% fat powders mirror those observed in FIG. 1 for 25% fat powders. In these examples NaCas based formulations offer better protection than WPI based formulations. Also heat treatment applied to WPI-sugar encapsulant can increase the release in SGF+SIF. Depending on the type of protein and whether heat treatment is applied to the encapsulant the core may be released targeted to a specific site in the GI tract. The properties of the example 3 formulations are shown in FIG. 3 of the drawings. Formulations (25% fat powders) made with heated protein-starch as encapsulants had low solvent extractable fat (<1% of total fat). Released oil in SGF was less than 2% of total fat for all formulations. Released oil in SGF+SIF were less than 4% of total fat for casein based microcapsules and up to 12.5% of total fat for WPI based microcapsules. In these examples NaCas based formulations offers better protection than the WPI based formulation. Depending on the type of protein used the core may be released targeted to a specific site in the GI tract. The properties of the example 4 formulations are shown in FIG. 4 of the drawings. Formulations (50% fat powders) made with heated protein-starch as encapsulants had higher solvent extractable fat (1 to 20% of total fat) than corresponding formulation for 25% fat powders. Released oil in SGF was less than 2% of total fat for all formulations. Released oil in SGF+SIF were less than 5% of total fat for casein based microcapsules and up to 15% of total fat for WPI based microcapsules. In these examples NaCas based formulations offer better protection than the WPI based formulation. Depending on the type of protein used the core may be released targeted to a specific site in the GI tract. Solvent-extractable fat in powder was not related to solvent extractable fat in SGF and SIF fluids. The properties of the example 5 formulations are shown in FIG. 5 of the drawings. For 25% fat powders the use of gums in combination with protein-glucose/dried glucose syrup or protein-oligosaccharide as encapsulant resulted in powders with low extractable fat in powder (<3% of total fat) and in SGF (<2% of total fat). Released oil in SGF+SIF were less than 7% of total fat for casein based microcapsules and up to 22.8% of total fat for WPI based microcapsules. Caseinate-based formulations with gums released more fat (FIG. 5) than similar formulations without gum (FIG. 1) after sequential exposure to SGF and SIF. In these examples NaCas based formulations offer better protection than WPI based formulations. Depending on the type of protein used the core may be released targeted to a specific site in the GI tract. The properties of the example 6 formulations are shown in FIG. 6 of the drawings. The trends observed for 50% fat powders containing gums in combination with protein-glucose/dried glucose syrup or oligosaccharide (FIG. 6) are similar to those observed for compositions with 25% fat powders (FIG. 5). All formulations had low extractable fat in powder (<4% of total fat) and SGF (<2% of total fat). Released oil in SGF+SIF were less than 5% of total fat for casein based microcapsules and up to 23% of total fat for WPI based microcapsules. The amount of oil released in 50% fat powders (FIG. 6) is significantly more than that in 25% fat powders (FIG. 5) after sequential exposure to SGF and SIF for WPI based formulations. In these examples NaCas based formulations offers better protection than WPI based formulations. Depending on the type of protein used the core may be released targeted to a specific site in the GI tract. The properties of the example 7 formulations are shown in FIG. 7 of the drawings. Hydrolysed milk proteins can be used in place of whole proteins for encapsulation of oil. For 25% fat powders use of hydrolysed protein in combination with oligosaccharide and polysaccharide as encapsulant resulted in powders with low extractable fat in powder (<3% of total fat). Released oil in SGF was less than 9% of total fat for all formulations. Released oil in SGF+SIF was less than 12% in all formulations. While combinations of hydrolysed casein with oligosaccharide and polysaccharides were less effective for protecting oils from release in SGF+SIF compared to corresponding formulations with the parent protein (Na caseinate), the reverse trend was found with the use of hydrolysed whey protein with oligosaccharide and carrageenan (Compare FIGS. 5 and 7). The properties of the example 8 formulations are shown in FIG. 8 of the drawings. For 50% fat powders use of hydrolysed protein in combination with oligosaccharide and polysaccharide as encapsulant resulted in powders with low extractable fat in powder (<3% of total fat). While solvent-extractable fat in powders (50% fat) was low, the hydrolysed casein-based formulation containing carrageenan released a significant amount of the oil in SGF (77% of total fat) and in SGF+SIF (51% of total fat). This formulation will be a suitable delivery system if the site for target delivery is the stomach or small intestine. Those containing hydrolysed casein or hydrolysed whey protein with high methoxy pectin were comparatively better at protecting their load than those with carrageenan with release in SGF+SIF less than 3% of total fat. In these examples HWP based formulation offers better protection than HCP based formulation. Depending on the type of protein-polysaccharide combination used the core may be released targeted to a specific site in the GI tract. The properties of the example 9 formulations are shown in FIG. 9 of the drawings. The results show that 25% fat powders made with unheated and heated combinations of caseinate and raw or pre-processed potato starch had solvent-extractable fat of between 3-8% of total fat, which was generally higher than those made with combinations of proteins with sugar/dried glucose syrup or oligosaccharides. All formulations with potato starch have very low oil release in-vitro. Exposure to SGF resulted in release of <0.6% of total fat and sequential exposure to SGF and SIF resulted in between 4-8% of total fat being released. The properties of the example 10 formulations are shown in FIG. 10 of the drawings. The results show that 25% fat powders made with unheated and heated combinations of caseinate and unprocessed or pre-processed Hylon VII had solvent-extractable fat of between 13-26% of total fat, which was generally higher than those made with combinations of proteins with sugar/dried glucose syrup or oligosaccharides or potato-starch-indicating-that encapsulation efficiencies of formulations with Hylon VII were significantly lower. Use of Hylon VII that had been subjected to microfluidisation or extrusion prior to combination with protein improved encapsulation efficiency. All formulations with Hylon VII have very low oil release in-vitro. Exposure to SGF which results in hydration of the capsule resulted in minimal release of <0.8% of total fat and sequential exposure to SGF and SIF resulted in between 3-7% of total fat being released. The properties of the example 11 formulations are shown in FIG. 11 of the drawings. The results show that 25% fat powders made with unheated and heated combinations of caseinate and unprocessed or pre-processed Hi-Maize had solvent-extractable fat of between 13-26% of total fat. Use of Hi-Maize that had been subjected to microfluidisation or extrusion prior to combination with protein improved encapsulation efficiency. All formulations with Hi-Maize have very low oil release in-vitro. Exposure to SGF which results in hydration of the capsule resulted in minimal release of <1% of total fat and sequential exposure to SGF and SIF resulted in between 4-6% of total fat being released. The properties of the example 12 formulations are shown in FIG. 12 of the drawings. The results show that 25% fat powders made with unheated and heated combinations of caseinate and unprocessed or pre-processed Novelose 260 had solvent-extractable fat of between 14-25% of total fat. Use of Novelose 260 that had been subjected to microfluidisation prior to combination with protein improved encapsulation efficiency. All formulations with Novelose 260 have very low oil release in-vitro. Exposure to SGF which results in hydration of the capsule resulted in minimal release of <1% of total fat and sequential exposure to SGF and SIF resulted in between 2-6% of total fat being released. The characteristics of formulations with Novelose 260 were similar to those observed for formulations with Hylon VII (FIG. 10) or Hi-Maize (FIG. 11), which like Novelose 260 (FIG. 12) are RS2 type starches. The properties of the example 13 formulations are shown in FIG. 13 of the drawings. The results show that 25% fat powders made with unheated and heated combinations of caseinate and unprocessed or pre-processed Novelose 330 (an RS3 type starch) had solvent-extractable fat of between 13-33% of total fat. Use of Novelose 330 that had been subjected to extrusion prior to combination with protein improved encapsulation efficiency. All formulations with Novelose 330 have very low oil release in-vitro. Exposure to SGF which results in hydration of the capsule resulted in minimal release of <1% of total fat and sequential exposure to SGF and SIF resulted in between 3.1-8.0% of total fat being released. The properties of the example 14 formulations are shown in FIG. 14 of the drawings. The results demonstrate that pre-processing of starches using emerging food processing technologies (i.e. microfluidisation, high pressure processing or ultrasonication) and extrusion could improve the properties of starches used in combination with casein as delivery systems to the GI tract. Released oil in SGF was less than 1.2% of total fat for pre-processed starches. Released oil in SGF+SIF was less than 10% in pre-processed starches. All pre-processed starches have lower oil released in-vitro compared to the formulation containing unprocessed starch. The properties of the example 15 formulations are shown in FIG. 15 of the drawings. The results demonstrate that use of native non-RS starch and their pre-processed counterparts in combination with protein produced powders with solvent extractable fat of between 5.5-13.6% of total fat. Released oil in SGF was less than 2% of total fat. Released oil in SGF+SIF was between 12-14% (FIG. 15), which was slightly higher than that observed when resistant starches were used in combination with protein for microencapsulation (See FIGS. 9-14). The properties of the example 16 formulations containing lutein-in-oil are shown in FIG. 16 of the drawings. The results demonstrate that lutein was protected in the powder microcapsule (0.4-2.5% unencapsulated lutein). Released lutein in SGF was also very low (2.5-4% of total lutein). Released lutein in SGF+SIF was between 34-51% (FIG. 16). The properties of the example 17 formulations containing tributyrin are shown in FIG. 17 of the drawings. All the tributyrin was released after sequential exposure to SGF and SIF in NaCas-sugar formulation, and up to 83% in NaCas-sugar-RS starch formulation. These results suggest that formulation with RS starch has improved the protection of tributyrin in the GI tract The properties of the example 18 formulations containing 25% tuna oil in heated blends of NaCas-sugar-HylonMF or NaCas-HylonMF or NaCas-StarPlus MF as encapsulants are shown in FIG. 18 of the drawings. The results demonstrate that addition of Glucose into an NaCas-Hylon formulation can improve the encapsulation efficiency of the powder microcapsule without affecting the release in SGF and SGF+SIF. Use of acetylated starch (StarPlus A) or proprionylated starch (Starplus P) in place of Hylon in formulations containing resistant starch in combination with NaCas increased the release in SGF+SIF from 5% for Hylon to 12% and 25% for Star Plus A and StarPlus P respectively (FIG. 18), but there was no difference in the amount of release in SGF. Release Characteristics of Tuna Oil Microcapsules in-vivo The result of the in-vivo experiment (example 19 formulation) is shown in FIGS. 19a and 19b of the drawings. Lumen contents were expressed as a percentage of dose of radioactivity given to indicate relative abundance between the treatment groups. The figures show the percentage of administered dose of radioactivity recovered after dosing with C14 trilinolenein as free oil after 4, 9, and 14 hours. This includes lumen contents, tissue and faeces. Data is expressed as percentage of total lumen radioactivity to show relative distribution across the system. All rats n=5 in each case except for FIG. 19b at 14 hours where n=4. The results indicated that the treatment with microencapsulated oil at 9 hours resulted in greater caecum and colon (18% and 35%) radioactivity (FIG. 19a) than treatment with free oil, where only about 5% in caecum at 4 hours and about 10% in colon at 4 hours, with minimal amounts of radioactivity at 9 hours (FIG. 19b). Radioactivity levels in the lumen for the treatment with free oil were low at all time points, which indicates that even by 4 hours there may be significant uptake and metabolism to CO2. Overall the in-vivo study indicates that the process of microencapsulation was reasonably successful in protecting the fish oil against early uptake and metabolism in the stomach and upper GI tract. For the treatment with microencapsulated oils the recovery was high at 4 and 9 hours, and at these time points the radioactivity was either in the stomach at 4 hours or caecum and colon at 9 hours. High amounts in the caecum and colon indicates that the microencapsulated oil passed the small intestine without significant absorption. For the free oil, smaller amounts reached the caecum and colon, primarily because the recovery of the given dose was low at all time points indicating greater metabolism. Even at 4 hour time point the oil had already transited the small intestine. There was little radiolabel retained in the tissues at 14 hour in either group, which indicates that conversion to endogenous lipids was not significant. From the above those skilled in the art will see that the present invention provides a simple to use yet effective delivery vehicle to the colon as well as preserving sensitive core ingredients during storage and processing. Those skilled in the art will also realise that this invention can be implemented in a number of different embodiments by varying the encapsulant proteins and carbohydrates without departing from the teachings of this invention.

<SOH> BACKGROUND TO THE INVENTION <EOH>Microencapsulation involves the packaging of small particles of solid, liquid or gas within a secondary material to form a microcapsule. It has been used for targeted delivery of drugs in the body in the pharmaceutical industry. It is increasingly being seen as a technology that offers novel food processing solutions. With the use of microencapsulation, possible undesirable interactions between the added nutraceutical and other components in the food or its environment can be avoided and the site of release of the added component can be manipulated. The appropriate application of microencapsulation technology enables the fortification of food without affecting the taste, aroma or texture of food. It can afford protection to sensitive food ingredients and enhance the shelf-life and stability of fortified foods (Brazel, C. S. (1999) Microencapsulation: offering solutions for the food industry. Cereal Foods World 44(6): 388-393; Augustin, M. A., Sanguansri, L., Margetts, C. and Young. B. (2001) Microencapsulation of food ingredients. Food Australia 53 220-223). Microencapsulation can serve both the purposes of the food and health industries, as it is a key technology with potential for the delivery of dietary bioactives and development of successful marketable functional foods. Addressing this challenge, requires tailoring the performance of food grade microcapsules in a food processing environment so that essential sensitive components are protected during food manufacture and the microcapsules can also meet the need for site specific delivery within the gastrointestinal tract. Directing nutraceuticals and therapeutics of the colon is of interest for treatment of colon diseases (Rubinstein, A., Tirosh, B., Baluom, M., Nassar, T., David, A., Radai, R., Gliko-Kabir, I. And Friedman, M. (1997). The rationale for peptide drug delivery to the colon and the potential for polymeric carriers as effective tools. J. Controlled Release 46, 59-73). Targeting to colon has been carried out by formation of pro-drugs which are enzymatically cleaved in the colon, and multi-coats with pH sensitive and pressure dependent release. Often enteric acrylic polymers are used to protect cores in colon-delivery formulations. Biopolymers, particularly polysaccharides, may be used for targeting cores to the colon where the release of cores is triggered by the microflora in the colon. A range of polysaccharides such as chitosan, pectin, arabinoxylan, arabinogalactan, xylan, cellulose dextrans, guar gum, amylose, inulin and mixtures of these have been examined and shown to have potential as colon-delivery systems (Rubinstein, A. (2000) Natural Polysaccharides as targeting tools of drugs to the human colon. Drug Development Research 50, 435-439; Sinha, V. R. and Kumaria, R. (2001) Polysaccharides in colon-specific drug delivery Int. J. Pharmceutics 224, 19-38; Vandaamme, Th.F., Lenourry, A., Charrueau, C. and Chaumeil, J.-C. (2002) The use of polysaccharides to target drugs to the colon. Carbohydrate Polymers 48, 219-231; Sinha, V. R. and Kumaria. R. (2003) Microbially triggered drug delivery to the colon. Eur. J. Pharmaceutical Sciences 18, 3-18). There have been a number of attempts to use biopolymers for colon delivery and for treating colonic diseases U.S. Pat. No. 5,952,314 discloses an enteral product comprising an oil blend with fatty acids {EPA (C20:5) and DHA (C22:6)} and a source of indigestible carbohydrate which is metabolised to short chain fatty acids in the colon. It has use for improving nutritional status and treating ulcerative colitis U.S. Pat. No. 5,108,758 discloses a glassy amylose matrix for delivery of medication to the colon U.S. Pat. No. 5,840,860 is concerned with delivery of short chain fatty acids (SCFA) to the colon by way of a modified starch. Japanese patent 10324642 discloses a colon delivery system for delivery of bioactives (eg peptides) comprising inner layer of chitosan and outer-layer of gastric resistant material such as wheat gliadin or zein. U.S. Pat. No. 5,866,619 discloses a colonic delivery system for drugs such as proteins and peptides comprising a saccharide containing polymer U.S. Pat. No. 6,368,629 discloses a drug coated with an organic acid-soluble polymer and a saccharide for colon delivery. U.S. Pat. No. 544,054 discloses a method of treating colitis with a composition containing oil blend (with DHA/EPA) and a source of indigestible carbohydrate (CHO) which is metabolised to short chain fatty acids. U.S. Pat. No. 5,952,314 is concerned with an enteral nutritional product for treatment of colitis which comprises oil containing EPA/DHA and a source of indigestible carbohydrate which is metabolised to short chain fatty acids. U.S. Pat. No. 6,531,152 describes a drug delivery system containing a water soluble core (Ca pectinate or other water-insoluble polymers) and outer coat which bursts (eg hydrophobic polymer—Eudragrit) for delivery of enterally-administered drugs to specific locations along the gastrointestinal tract There are proposals using combinations of proteins and polysaccharides for the formation of coating systems. U.S. Pat. No. 6,234,464 discloses a system in which oils/polyunsaturated fatty acids (PUFA)/fatty acids are provided with capsules comprised of two layers in which the inner layer consists of gelatin, casein or alginate and the outer layer consists of gelatin, gum arabic, chitosan to provide a product stable in boiling water U.S. Pat. No. 6,403,130 discloses a coating composition comprising a polymer containing casein and high methoxy pectin (amide formed by reaction of ester group R′COOCH 3 of pectin with free amino group of protein R″NH 2 ) WO 01/74175 discloses the encapsulation of oxygen sensitive materials such as polyunsaturated oils in a protein carbohydrate film treated to form a Maillard reaction product. It is an object of this invention to provide a gastrointestinal delivery system that can be used with storage unstable ingredients as well as providing protection during delivery through the gut.

<SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>To this end the present invention provides a micro encapsulation material for use with storage unstable, therapeutic and nutritional agents which release the therapeutic and nutritional agents in predetermined locations in the gastro intestinal tract in which the microencapsulation material is formed by combining a food grade treated carbohydrate with a water soluble food grade protein. The therapeutic and nutritional agents form an oil phase which is emulsified with the water dispersed or dissolved encapsulant to encapsulate the therapeutic and nutritional agents. These agents may be oils or oil soluble or oil dispersible which in the latter case may include water soluble ingredients. The agents that may be encapsulated include lipids (oils including oxygen sensitive oils, fatty acids, triglycerides) and oil soluble and oil dispersible ingredients (including pharmaceuticals, probiotics, and bioactives). Water dispersible components including those that partition between oil and water phases may also be encapsulated. When water dispersible therapeutic and nutritional agents are used they may not be encapsulated with the oil phase but may be dispersed in the encapsulant film. The emulsions may be used as food ingredients or therapeutic agents but preferably the emulsions are dried to form powders. Prior art encapsulation systems did not consider the use of combinations of proteins with other biopolymers for formation of capsules for target delivery of sensitive cores to the colon. The delivery systems of this invention enable pharmaceutical and food manufacturers to offer a range of nutritionally and physiologically functional food ingredients and bioactive compounds in convenient formats and using all natural ingredients which will also enable the delivery of these products to the colon. Some of the encapsulants used for colon delivery in this invention have the added benefits of being effective matrices for encapsulating oxygen sensitive ingredients. The film-forming and anti-oxidant properties of some of the encapsulants used work synergistically to preserve sensitive ingredients such as polyunsaturated fatty acids from being oxidised during storage and also protects them during exposure to high temperature, pressure and moisture encountered during the processing of foods. In addition, this invention uses readily available proteins and carbohydrates. There are no solvents used in the preparation of the encapsulated formulations as the process is an all-aqueous based system. The processes can be easily incorporated or adapted to suit most food and pharmaceutical manufacturing plants with drying operations. The protein used may include any film forming water soluble protein or hydrolysed protein and includes milk proteins such as casein and its derivatives or whey proteins. The carbohydrate component may be those containing reducing sugar groups, oligosaccharides and starches (raw, modified, resistant, acetylated, proprionated and butylated starches). The proteins and carbohydrates may be reacted in aqueous solutions to obtain conjugates. The reaction, which occurs, can be between free amine groups of amino acids in the protein and reducing sugar groups in the carbohydrate. This type of reaction is generally termed a Maillard reaction typically occurring in the non-enzymatic browning of foods. This reaction occurs during heat processing of foods and has previously been shown to be beneficial for engineering desirable encapsulating properties for protection of oxygen sensitive components. For example, microencapsulated formulations containing oxygen sensitive oils are protected against oxidation as the Maillard reaction products [MRP] in the encapsulating matrix are good film-formers and also exhibit anti-oxidation activity as disclosed in WO 01/74175. The starches used in the formulations may also be pre-processed using conventional and emerging processing technologies to modify the starch properties to provide improved processing characteristics during the preparation of the delivery systems. The pretreatments are chosen to break down the long starch molecules so that they form more stable emulsions and also to provide a larger number of terminal sugar reducing groups for Maillard reaction with the protein component of the encapsulant. Colon delivery systems may be used for range of bioactives (e.g. oils), pharmaceuticals and therapeutics, which are unstable in the upper gastrointestinal tract. The protection afforded to the encapsulated components by the encapsulating material enable target release in the colon where the release is achieved after the encapsulant is degraded (e.g. by the action of microbial enzymes in the colon). Delivery of bioactives, pharmaceuticals and therapeutic components to the colon is desirable for treatment and prevention of diseases of the colon such as colorectal cancer, ulcerative colitis and inflammatory bowel disorder. In some cases the encapsulants used in the formulations such as selected polysaccharides, can also serve as gut wall adherents or as prebiotics that facilitate growth of beneficial bacteria, and can offer added advantages. For example delivery systems containing resistant starch have potential benefits on colonic health. detailed-description description="Detailed Description" end="lead"?

20070108

20170314

20070920

58876.0

A61K948

YU, HONG

Gi Track Delivery Systems

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Phenyl-furan compounds as vitamin d receptor modulators

The present invention relates to novel, non-secosteroidal, phenyl-furan compounds with vitamin D receptor (VDR) modulating activity that are less hypercalcemic than 1α,25dihydroxy vitamin D3. These compounds are useful for treating bone disease and psoriasis.

1. A compound represented by formula I or a pharmaceutically acceptable salt derivative thereof: wherein; R and R′ are independently C1-C4 alkyl, C1-C4 fluoroalkyl, or together R and R′ form a substituted or unsubstituted, saturated or unsaturated carbocyclic ring having from 3 to 8 carbon atoms; RP, RP, and RF are independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, —O—C1-C4 alkyl, —S—C1-C4 alkyl, —O—C1-C4 fluoroalkyl, —CN, —NO2, acetyl, —S—C1-C4 fluoroalkyl, C2-C4 alkenyl, C3-C4 cycloalkyl, and C3-C4 cycloalkenyl; (L1), (L2), (L3), and (LF) are divalent linking groups independently selected from the group consisting of a bond, oxygen where each R40 is independently hydrogen, C1-C5 alkyl or C1-C5 fluoroalkyl; where X1 is O, CH2, or [H, OH]; ZF is where R4 and R5 are independent hydrogen, C1-C4 alkyl, —O—C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, —NH(C1-C4 alkyl), or cyclopropyl, with the proviso that only one of R4 or R5 may be hydrogen; ZP is methyl, ethyl, n-propyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-hydroxy-2,2-dimethylpropyl, 1-hydroxy-1,2,2-trimethylpropyl, 2-hydroxy-2-methylbutoxy 2-hydroxy-2-ethylbutoxy 2-hydroxy-2-ethyl-3-methylbutoxy 2-hydroxy-2-methyl-3-methylbutoxy 2-hydroxy-1,3,3-trimethylbutoxy 2-hydroxy-1-ethyl-3,3-dimethylbutoxy 2-hydroxy-1,2-diethylbutoxy 2-hydroxy-2-ethyl-1-methylbutoxy 3-methyl-3-hydroxypentyl, 3-methyl-3-hydroxypentenyl, 3-methyl-3-hydroxypentynyl, 3-ethyl-3-hydroxypentyl, 3-ethyl-3-hydroxypentenyl, 3-ethyl-3-hydroxypentynyl, 3-ethyl-3-hydroxy-4-methylpentyl, 3-ethyl-3-hydroxy-4-methylpentenyl, 3-ethyl-3-hydroxy-4-methylpentynyl, 3-propyl-3-hydroxypentyl, 3-propyl-3-hydroxypentenyl, 3-propyl-3-hydroxypentynyl, 1-hydroxy-2-methyl-1-(methylethyl)propyl 1-hydroxycycyclopentenyl, 1-hydroxycyclohexenyl, 1-hydroxycycloheptenyl, 1-hydroxycyclooctenyl, 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, 1-hydroxycyclohexyl, 1-hydroxycycloheptyl, or 1-hydroxycyclooctyl. 2. The compound of claim 1 wherein ZP is 1,1-dimethylethyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-hydroxy-2,2-dimethylpropyl, or 1-hydroxy-1,2,2-trimethylpropyl, provided that (L1), (L2), (L3) are all bonds; ZF is selected from: —C(O)NHMe, —C(O)NHEt, —C(O)NHOMe. —C(O)NHOEt. —C(O)NH(iPr), —C(O)NH(tBu), —C(O)NH(CF3), —C(O)N(Me)2, —C(O)NMeEt, —C(O)NMe(iPr), —C(O)NMe(tBu), —C(O)NMe(CF3), —C(O)N(Me)F, —C(O)N(Et)F —C(O)N(iPr)F, —C(O)N(tBu)F, —C(O)N(Et)2, or —C(O)NEt(iPr); or a pharmaceutically acceptable salt or prodrug thereof. 3. The compound of claim 2 wherein ZF is selected from: —C(O)NHMe, —C(O)NHEt, —C(O)NH(iPr), —C(O)NH(tBu), —C(O)N(Me)2, —C(O)NMeEt, —C(O)NMe(iPr), —C(O)NMe(tBu), —C(O)N(Et)2, or —C(O)NEt(iPr); or a pharmaceutically acceptable salt or prodrug thereof. 4. A compound or a pharmaceutically acceptable salt or ester prodrug derivative thereof represented by formulae A to J as follows: 5. The salt derivative of the compound according to claim 1 wherein the salt is sodium or potassium. 6. A pharmaceutical formulation comprising the compound of claim 1 together with a pharmaceutically acceptable carrier or diluent. 7. A formulation for treating osteoporosis comprising: Ingredient (A1): a vitamin D receptor modulator of claim 1; Ingredient (B1): one or more co-agents selected from the group consisting of: a. estrogens, b. androgens, c. calcium supplements, d. vitamin D metabolites, e. thiazide diuretics, f. calcitonin, g. bisphosphonates, h. SERMS, and i. fluorides; and Ingredient (C1): optionally, a carrier or diluent. 8. The formulation of claim 7 wherein the weight ratio of (A1) to (B1) is from 10:1 to 1:1000. 9. A formulation for treating psoriasis comprising: Ingredient (A2): a vitamin D receptor modulator according to claim 1; Ingredient (B2): one or more co-agents that are conventional for treatment psoriasis selected from the group consisting of: a. topical glucocorticoids, b. salicylic acid, c. crude coal tar; and Ingredient (C2): optionally, a carrier or diluent. 10. The formulation of claim 9 wherein the weight ratio of (A2) to (B2) is from 1:10 to 1:100000. 11. A method of treating a mammal to prevent or alleviate the pathological effects of Acne, Actinic keratosis, Alopecia, Alzheimer's disease, Bone maintenance in zero gravity, Bone fracture healing, Breast cancer, Chemoprovention of Cancer, Crohn's disease, Colon cancer, Type I diabetes, Host-graft rejection, Hypercalcemia, Type II diabetes, Leukemia, Multiple sclerosis, Myelodysplastic syndrome, Insufficient sebum secretion, Osteomalacia, Osteoporosis, Insufficient dermal firmness, Insufficient dermal hydration, Psoriatic arthritis, Prostate cancer, Psoriasis, Renal osteodystrophy, Rheumatoid arthritis, Scleroderma, Skin cancer, Systemic lupus erythematosus, Skin cell damage from Mustard vesicants, Ulcerative colitis, Vitiligo, or Wrinkles; wherein the method comprises administering a pharmaceutically effective amount of at least one compound of claim 1. 12. The method of claim 11 for the treatment of psoriasis. 13. The method of claim 11 for the treatment of osteoporosis. 14. The method of claim 11 for treating a mammal to prevent or alleviate skin cell damage from Mustard vesicants. 15. The method of treating a mammal to prevent or alleviate the pathological effects of Benign prostatic hyperplasia or bladder cancer wherein the method comprises administering a pharmaceutically effective amount of at least one compound according to claim 1. 16. The method of treating or preventing disease states mediated by the Vitamin D receptor, wherein a mammal in need thereof is administered a pharmaceutically effective amount of a compound of claim 1. 17-22. (canceled)

BACKGROUND OF THE INVENTION Vitamin D3 Receptor (VDR) is a ligand dependent transcription factor that belongs to the superfamily of nuclear hormone receptors. The VDR protein is 427 amino acids, with a molecular weight of ˜50 kDa. The VDR ligand, 1α,25-dihydroxyvitamin D3 (the hormonally active form of Vitamin D) has its action mediated by its interaction with the nuclear receptor known as Vitamin D receptor (“VDR”). The VDR ligand, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) acts upon a wide variety of tissues and cells both related to and unrelated to calcium and phosphate homeostasis. The activity of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in various systems suggests wide clinical applications. However, use of conventional VDR ligands is hampered by their associated toxicity, namely hypercalcemia (elevated serum calcium). Currently, 1α,25(OH)2D3, marketed as Rocaltrol® pharmaceutical agent (product of Hoffmann-La Roche), is administered to kidney failure patients undergoing chronic kidney dialysis to treat hypocalcemia and the resultant metabolic bone disease. Other therapeutic agents, such as Calcipotriol® (synthetic analog of 1α,25(OH)2D3) show increased separation of binding affinity on VDR from hypercalcemic activity. Recently, chemical modifications of 1α,25(OH)2D3 have yielded analogs with attenuated calcium mobilization effects (R. Bouillon et. al., Endocrine Rev. 1995, 16, 200-257). One such analog, Dovonex® pharmaceutical agent (product of Bristol-Meyers Squibb Co.), is currently used in Europe and the United States as a topical treatment for mild to moderate psoriasis (K. Kragballe et. al., Br. J. Dermatol. 1988, 119, 223-230). Other vitamin D3 mimics have been described in the publication, Vitamin D Analogs: Mechanism of Action of Therapeutic Applications, by Nagpal, S.; Lu, J.; Boehm, M. F., Curr. Med. Chem. 2001, 8, 1661-1679. Although some degree of separation between the beneficial action and calcium raising (calcemic) effects has been achieved with these VDR ligands, to date the separation has been insufficient to allow for oral administration to treat conditions such as osteoporosis, cancers, leukemias, and severe psoriasis. One example of a major class of disorder that could benefit from VDR mediated biological efficacy in the absence of hypercalcemia is osteoporosis. Osteoporosis is a systemic disorder characterized by decreased bone mass and microarchitectural deterioration of bone tissue leading to bone fragility and increased susceptibility to fractures of the hip, spine, and wrist (World Health Organization WHO 1994). Osteoporosis affects an estimated 75 million people in the United States, Europe, and Japan. Within the past few years, several antiresorptive therapies have been introduced. These include bisphosphonates, hormone replacement therapy (HRT), a selective estrogen receptor modulator (SERM), and calcitonins. These treatments reduce bone resorption, bone formation, and increase bone density. However, none of these treatments increase true bone volume nor can they restore lost bone architecture. Synthetic vitamin D receptor (VDR) ligands with reduced calcemic potential have been synthesized. For example, a class of bis-phenyl compounds stated to mimic 1α, 25-dihydroxyvitamin D3 is described in U.S. Pat. No. 6,218,430 and the article; “Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1α, 25-Dihydroxyvitamin D3” by Marcus F. Boehm, et. al., Chemistry& Biology 1999, Vol 6, No. 5, pgs. 265-275. There remains a need for improved treatments using alternative or improved pharmaceutical agents that mimic 1α, 25-dihydroxyvitamin D3 to stimulate bone formation, restore bone quality, and treat other diseases without the attendant disadvantage of hypercalcemia. SUMMARY OF THE INVENTION Novel compounds having a nucleus of formula “(A)” have been found effective as Vitamin D Receptor (VDR) modulators: Compounds of the present invention with VDR modulating activities are represented by formula (I) wherein the variables R, R′, Rp, Rp′, L1, L2, L3, Zp, RF, LF, and ZF, and are as hereinafter defined. The inventors have discovered that compounds described herein display the desirable cell differentiation and antiproliferative effects of 1,25(OH)2D3 with reduced calcium mobilization (calcemic) effects. In another aspect, the present invention is directed towards pharmaceutical compositions containing pharmaceutically effective amounts of compounds of formulae I or a pharmaceutically acceptable salt or prodrug thereof, either singly or in combination, together with pharmaceutically acceptable carriers and/or auxiliary agents. Another aspect of the invention are novel chemical intermediates suitable for preparing the compounds of Formula I. Another aspect of the invention is to use the compounds of the invention to treat or prevent disease states responsive to Vitamin D receptor ligands. Another aspect of the invention is the prevention and treatment of Acne, Actinic keratosis, Alopecia, Alzheimer's disease, Benign prostatic hyperplasia, Bladder cancer, Bone maintenance in zero gravity, Bone fracture healing, Breast cancer, Chemoprovention of Cancer, Crohn's disease, Colon cancer, Type I diabetes, Host-graft rejection, Hypercalcemia, Type II diabetes, Leukemia, Multiple sclerosis, Myelodysplastic syndrome, Insufficient sebum secretion, Osteomalacia, Osteoporosis, Insufficient dermal firmness, Insufficient dermal hydration, Psoriatic arthritis, Prostate cancer, Psoriasis, Renal osteodystrophy, Rheumatoid arthritis, Scleroderma, Skin cancer, Systemic lupus erythematosus, Skin cell damage from Mustard vesicants, Ulcerative colitis, Vitiligo, or Wrinkles; by administering to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula I. Another aspect of the invention is the use of the compounds of Formula I for treating or preventing disease states mediated by the Vitamin D receptor. DETAILED DESCRIPTION OF THE INVENTION I. Definitions: The word “adhesion” refers to the abnormal union of surfaces normally separate by the formulation of new fibrous tissue resulting from an inflammatory process. The word “abscess” is a complication often associated with surgery, trauma, or diseases that predispose the host to abscess formation from encapsulated bacteria lymphocytes, macrophages, and etc. The term “alkenyl” refers to aliphatic groups wherein the point of attachment is a carbon-carbon double bond, for example vinyl, 1-propenyl, and 1-cyclohexenyl. Alkenyl groups may be straight-chain, branched-chain, cyclic, or combinations thereof, and may be optionally substituted. Suitable alkenyl groups have from 2 to about 20 carbon atoms. The term “alkoxy” refers to —OR wherein R is an aliphatic or aromatic group which may be optionally substituted. Methoxy, ethoxy, propoxy, butoxy, and phenoxy are examples of alkoxy groups. The term “alkyl” refers to saturated aliphatic groups including straight-chain, branched-chain, cyclic and any combinations thereof. Alkyl groups may further be divided into “primary”, “secondary”, and “tertiary” alkyl groups. In primary alkyl groups, the carbon atom of attachment is substituted with zero (methyl) or one organic radical. In secondary alkyl groups, the carbon atom of attachment is substituted with two organic radicals. In tertiary alkyl groups, the carbon atom of attachment is substituted with three organic radicals. The term “cycloalkyl” includes organic radicals such as cyclopropanyl, cyclobutanyl, and cyclopentyl. The term, “cycloalkenyl” includes organic radicals such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. The term, “C1-C5 fluoroalkyl” refers to an alkyl group containing fluorine and includes organic radicals such as —CF3, —CHF2, —CH2F, —CF2CF3, —CHFCF3, —CH2CF3, —CH2CHF2, and —CH2CH2F, with —CF3 being preferred. The term, “Active Ingredient” refers to a compound of the invention represented by any of (i) formulae I, II, III, IV, (ii) the product of any example set out herein, or (iii) a compound identified in any row of Tables 1, 2, 3, or 4; or a salt or prodrug derivative of the preceding compound. The term “carboxamide” refers to a group represented by the formulae: where R4 and R5 are independently hydrogen, C1-C4 alkyl, —O—C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, —NH(C1-C4 alkyl), or cyclopropyl, with the proviso that only one of R4 or R5 may be hydrogen. The abbreviation, “Me” means methyl. The abbreviation, “Et” means ethyl. The abbreviation, “iPr” means 1-methylethyl. The abbreviation, “tbu” means 1,1-dimethylethyl. The symbol “-(CH2)2- is equivalent to —CH2—CH2—. The univalent symbol “—O” in any structural formula is a hydroxyl group (—OH). The term, “C1-3 alkyl” refers to an alkyl group selected from methyl, ethyl, n-propyl, and isopropyl. The term, “branched C3-C5 alkyl” is an alkyl group selected from 1-methylethyl; 1-methylpropyl; 2-methylpropyl; 1,1-dimethylethyl; 1,1-dimethylpropyl; 1,2-dimethylpropyl; or 2,2-dimethylpropyl. Preferred branched C3-C5 alkyl groups are 2-methylpropyl and 1,1-dimethylethyl, with the 1,1-dimethylethyl group being most preferred. The term “alkenyl” refers to aliphatic groups wherein the point of attachment is a carbon-carbon double bond, for example vinyl, 1-propenyl, and 1-cyclohexenyl. Alkenyl groups may be straight-chain, branched-chain, cyclic, or combinations thereof, and may be optionally substituted. Suitable alkenyl groups have from 2 to about 20 carbon atoms. The term “C1-C5 alkyl” refers to saturated aliphatic groups including straight-chain, branched-chain, and cyclic groups and any combinations thereof. Alkyl groups may further be divided into “primary”, “secondary”, and “tertiary” alkyl groups. In primary alkyl groups, the carbon atom of attachment is substituted with zero (methyl) or one organic radical. In secondary alkyl groups, the carbon atom of attachment is substituted with two organic radicals. In tertiary alkyl groups, the carbon atom of attachment is substituted with three organic radicals. Examples of C1-C5 alkyl groups are methyl, ethyl, n-propyl, from 1-methylethyl; n-butyl, 1-nethylpropyl; 2-methylpropyl; 1,1-dimethylethyl; n-amyl, 1,1-dimethylpropyl; 1,2-dimethylpropyl; and 2,2-dimethylpropyl. The term “cycloalkyl” includes organic radicals such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term, “cycloalkenyl” includes organic radicals such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. The term, “C1-C5 fluoroalkyl” is an alkyl group containing fluorine and includes organic radicals such as —CF3, —CHF2, —CH2F, —CF2CF3, —CHFCF3, —CH2CF3, —CH2CHF2, and —CH2CH2F, with —CF3 being preferred. The abbreviation, “Me” means methyl. The abbreviation, “Et” means ethyl. The abbreviation, “iPr” means 1-methylethyl. The abbreviation, “tBu” means 1,1-dimethylethyl. The term, “terminal hydroxyalkyl” refers to a group selected from 3-methyl-3-hydroxypentyl, 3-methyl-3-hydroxypentenyl, 3-methyl-3-hydroxypentynyl, 3-ethyl-3-hydroxypentyl, 3-ethyl-3-hydroxypentenyl, 3-ethyl-3-hydroxypentynyl, 3-ethyl-3-hydroxy-4-methylpentyl, 3-ethyl-3-hydroxy-4-methylpentenyl, 3-ethyl-3-hydroxy-4-methylpentynyl, 3-propyl-3-hydroxypentyl, 3-propyl-3-hydroxypentenyl, 3-propyl-3-hydroxypentynyl, 1-hydroxy-2-methyl- 1-(methylethyl)propyl, 1-hydroxy-2,2-dimethylpropyl, 1-hydroxy-1,2,2-trimethylpropyl, 1-hydroxycycloalkenyl; and 1-hydroxycycloalkyl. The term, “3-methyl-3-hydroxypentyl” refers to the radical having the structural formula: The term, “3-methyl-3-hydroxypentenyl” refers to the radical having the structural formula (both cis and trans isomers): The term, “3-methyl-3-hydroxypentynyl” refers to the radical having the structural formula: The term, “3-ethyl-3-hydroxypentyl” refers to the radical having the structural formula: The term, “3-ethyl-3-hydroxypentenyl” refers to the radical having the structural formula (both cis and trans isomers): The term, “3-ethyl-3-hydroxypentynyl” refers to the radical having the structural formula: The term, “3-propyl-3-hydroxypentyl” refers to the radical having the structural formula: The term, “3-propyl-3-hydroxypentenyl” refers to the radical having the structural formula (both cis and trans isomers): The term, “3-propyl-3-hydroxypentynyl” refers to the radical having the structural formula: The term, “3-ethyl-3-hydroxy-4-methylpentyl” refers to the radical having the structural formula: The term, “3-ethyl-3-hydroxy-4-methylpentenyl” refers to the radical having the structural formula (both cis and trans isomers): The term, “3-ethyl-3-hydroxy-4-methylpentynyl” refers to the radical having the structural formula: The term, “1-hydroxy-2-methyl-1-(methylethyl)propyl” refers to the radical having the structural formula: The term, “1-hydroxy-2,2-dimethylpropyl” refers to the radical having the structural formula: The term, “1-hydroxy-1,2,2-trimethylpropyl” refers to the radical having the structural formula: The term, “1-hydroxycycloalkenyl” refers to a radical selected from 1-hydroxycyclopentenyl, 1-hydroxycyclohexenyl, 1-hydroxycycloheptenyl, or 1-hydroxycyclooctenyl. The term “hydroxycycloalkyl” refers to a radical having the general structural formula: where w is an integer from 1 to 6 and the hydroxyl radical is substituted on any ring carbon atom. The term “1-hydroxycycloalkyl” refers to a radical having the general structural formula: Examples of 1-hydroxycycloalkyl radicals are 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, 1-hydroxycyclohexyl, 1-hydroxycycloheptyl, and 1-hydroxycyclooctyl. The abbreviation, “Me” means methyl. The abbreviation, “Et” means ethyl. The abbreviation, “iPr” means 1-methylethyl. The abbreviation, “nPr” means n-propyl. The abbreviation, “3Me3OH-Pentyl” means 3-methyl-3-hydroxypentyl. The abbreviation, “3Me3OH-Pentenyl” means 3-methyl-3-hydroxypentenyl The abbreviation, “3Me3OH-Pentynyl” means 3-methyl-3-hydroxypentynyl The abbreviation, “3Et30OH-Pentyl” means 3-ethyl-3-hydroxypentyl. The abbreviation, “3Et3OH-Pentenyl” means 3-ethyl-3-hydroxypentenyl The abbreviation, “3Et3OH-Pentynyl” means 3-ethyl-3-hydroxypentynyl The abbreviation, “3Pr3OH-Pentyl” means 3-propyl-3-hydroxypentyl. The abbreviation, “3Pr3OH-Pentenyl” means 3-propyl-3-hydroxypentenyl. The abbreviation, “3Pr3OH-Pentynyl” means 3-propyl-3-hydroxypentynyl. The abbreviation, “3Et3OH4Me-Pentyl” means 3-ethyl-3-hydroxy-4-methylpentyl. The abbreviation, “3Et3OH4Me-Pentenyl” means 3-ethyl-3-hydroxy-4-methylpentenyl, The abbreviation, “3Et3OH4Me-Pentynyl” means 3-ethyl-3-hydroxy-4-methylpentynyl. The abbreviation, “1OH2Me1MeEt-Propyl” means 1-hydroxy-2-methyl-1-(methylethyl)propyl. The term “C1-C5 alkyl” is an alkyl substituent selected from the group consisting of: methyl; ethyl; propyl; 1-methylethyl; 1-methylpropyl; 2-methylpropyl; 1,1-dimethylethyl; 1,1-dimethylpropyl; 1,2-dimethylpropyl; and 2,2-dimethylpropyl. The preferred groups are 2-methylpropyl and 1,1-dimethylethyl, with the 1,1-dimethylethyl group being most preferred. The dotted line symbol crossing a solid line representing a bond means that the bond so marked is point of attachment. The term, “mammal” includes humans. The term “halo” refer to fluorine, chlorine, bromine, and iodine. The term “pharmaceutically acceptable salt” refers to concentional non-toxic anionic or cationic salts conventionally used in therapeutic compounds, for example, sodium and potassium. Compounds of the Invention: The compounds of the invention are Vitamin D Receptor Modulators represented by formula I or a pharmaceutically acceptable salt or prodrug derivative thereof: wherein; R and R′ are independently C1-C4 alkyl, C1-C4 fluoroalkyl, or together R and R′ form a substituted or unsubstituted, saturated or unsaturated carbocyclic ring having from 3 to 8 carbon atoms; RP, RP′, and RF are independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 fluoroalkyl, —O—C1-C4 alkyl, —S—C1-C4 alkyl, —O—C1-C4 fluoroalkyl, —CN, —NO2, acetyl, —S—C1-C4 fluoroalkyl, C2-C4 alkenyl, C3-C4 cycloalkyl, and C3-C4 cycloalkenyl; (L1), (L2), (L3), and (LF) are divalent linking groups independently selected from the group consisting of a bond, oxygen where each R40 is independently hydrogen, C1-C5 alkyl or C1-C5 fluoroalkyl; where X1 is O, CH2 or [H, OH]; ZF is where R4 and R5 are independently hydrogen, C1-C4 alkyl, —O—C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, —NH(C1-C4 alkyl), or cyclopropyl, with the proviso that only one of R4 or R5 may be hydrogen. ZP is methyl, ethyl, n-propyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-hydroxy-2,2-dimethylpropyl, 1-hydroxy-1,2,2-trimethylpropyl, 2-hydroxy-2-methylbutoxy 2-hydroxy-2-ethylbutoxy 2-hydroxy-2-ethyl-3-methylbutoxy 2-hydroxy-2-methyl-3-methylbutoxy 2-hydroxy-1,3,3-trimethylbutoxy 2-hydroxy-1-ethyl-3,3-dimethylbutoxy 2-hydroxy-1,2-diethylbutoxy 2-hydroxy-2-ethyl-1-methylbutoxy 3-methyl-3-hydroxypentyl, 3-methyl-3-hydroxypentenyl, 3-methyl-3-hydroxypentynyl, 3-ethyl-3-hydroxypentyl, 3-ethyl-3-hydroxypentenyl, 3-ethyl-3-hydroxypentynyl, 3-ethyl-3-hydroxy-4-methylpentyl, 3-ethyl-3-hydroxy-4-methylpentenyl, 3-ethyl-3-hydroxy-4-methylpentynyl, 3-propyl-3-hydroxypentyl, 3-propyl-3-hydroxypentenyl, 3-propyl-3-hydroxypentynyl, 1-hydroxy-2-methyl-1-(methylethyl)propyl 1-hydroxycycyclopentenyl, 1-hydroxycyclohexenyl, 1-hydroxycycloheptenyl, 1-hydroxycyclooctenyl, 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, 1-hydroxycyclohexyl, 1-hydroxycycloheptyl, or 151-hydroxycyclooctyl. Preferred compounds of the invention are when ZP is 1,1-dimethylethyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-hydroxy-2,2-dimethylpropyl, and 1-hydroxy-1,2,2-trimethylpropyl; provided that (L1), (L2), (L3) are all bonds (viz., ZP is attached directly to the phenyl ring of the nucleus). Preferred compound have ZF selected from: —C(O)NHMe, —C(O)NHEt, —C(O)NH(iPr), —C(O)NH(tBu), —C(O)NH(CF3), —C(O)N(Me)2, —C(O)NMeEt, —C(O)NMe(iPr), —C(O)NMe(tBu), —C(O)NMe(CF3), —C(O)N(Me)F, —C(O)N(Et)F —C(O)N(iPr)F, —C(O)N(tBu)F, —C(O)N(Et)2, —C(O)NEt(iPr), or —C(O)NEt(tBu). Other preferred compounds have ZF selected from: —C(O)NHMe, —C(O)NHEt, —C(O)NH(iPr), —C(O)NH(tBu), —C(O)N(Me)2, —C(O)NMeEt, —C(O)NMe(iPr), —C(O)NMe(tBu), —C(O)N(Et)2, —C(O)NEt(iPr), or —C(O)NEt(tBu). A preferred carboxamide group ZF is Preferred Compounds of the Invention are represented by formulae A to K as follows: EXAMPLES General Experimental Conditions: The starting material/intermediate is the compound from the immediate preceding experimental unless otherwise indicated. All reactions are performed under nitrogen/argon atmosphere, in a stirred reaction vessel, and at room temperature unless indicated otherwise. Concentration is performed from RT to about 70° C. under vacuum (0.05 to 1 mm Hg). Unless otherwise indicated, the organic layer is MgSO4/Na2SO4 dried is defined as stirring the solution with a dessicant for 5-15 m and filtering off the dessicant to give an anhydrous filtrate. For analogous multi-step reaction procedures, the yield is given either for the ultimate step or overall multi-steps as indicated. Solutions are “concentrated” at a range of 25-75° C. with reduced pressure. in-vacuo −25-75° C.; 0.05 to 1 mm Unless otherwise indicated, “the residue is chromatographed” is defined as silica gel chromatography of residue with moderate nitrogen pressure (flash chromatography) or a medium pressure chromatography systems using a silica gel to crude product ratio of ˜10-100. Thin layer chromatography is performed with silica gel plates with UV and/or appropriate staining solution. NMR spectra are obtained with either 300 or 400 mHz spectrometer. NMR—denotes NMR spectrum is consistent with assigned structure. HRMS—high resolution mass spectrum ES-MS—electrospray mass spectrum Abbreviations: Aq—aqueous d—day eq—equivalent h—hour m—minute satd—saturated disp—dispersion quant—quantitative rt for retention time (both small caps to minimize confusion with RT) RT—room temperature Chemical Definitions: BnBr—benzyl bromide CH2Cl2-dichloromethane CH3CN—acetonitrile DIBA1H—Diisobutyl Aluminum Hydride DMAP —4-(dimethylamino)pyridine DMF—N,N-dimethylformamide DMSO—dimethylsulfoxide DPPB —1,4-bis(diphenylphosphino)butane DPPF—dichloro[1,1′-bis(diphenylphosphino)ferrocene EDCI —3-Ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride Et3N—triethylamine EtMgBr—ethyl magnesium bromide EtOAc—ethyl acetate EtOH—ethanol H2NCH2CO2Me—methyl glycinate Hept—heptane Hex—hexanes HN(OMe)Me —N-methyl-O-methyl hydroxylamine HNMe2—dimethyl amine HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HOAT —7-aza-1-hydroxybenzotriazole HOBT —1-hydroxybenzotriazole K2CO3—potassium carbonate KOH—potassium hydroxide LAH—lithium aluminum hydride LiHMDS—lithium hexamethyldisilazide mCPBA—meta-chloroperbenzoic acid MeI—methyl iodide MeOH—methanol NaBH4—sodium borohydride MgSO4—magnesium sulfate NaH—sodium hydride NaHCO3-sodium bicarbonate NaI—sodium iodide Na2SO4—sodium sulfate NH4Cl—ammonium chloride NMO —4-methylmorpholine N-oxide NMP—N-methylpyrrolidin-2-one Na—S—R3—sodium alkylmercaptide PBr3—phosphorus tribromide Pd(DPPF)—palladium dichloro[1,1′-bis(diphenylphosphino)ferrocene Pd(OAc)2—palladium (II) acetate Pd(TPP)4—palladium tetrakistriphenylphosphine Pd—C—palladium on carbon (PhO)2P(O)N3—diphenyl phosphorus azide pTSA—para-toluenesulfonic acid Pyr—pyridine Red-Al—sodium bis(2-methoxyethoxy)aluminum hydride R2MgBr—alkyl magnesium bromide R3MgBr—alkyl magnesium bromide R5MgBr—alkyl magnesium bromide R2S(O)2NH2— alkylsulfonamide TBAF—tetrabutylammonium fluoride TBSCl—tert-butyldimethylsilyl chloride tBuC(O)CH2Br —1-bromopinacolone Tf2O—triflic anhydride TFA—trifluoroacetic acid THF—tetrahydrofuran TPAP—tetrapropylammonium perruthenate Zn(OTf)2— zinc trifluoromethane sulfonate. Compounds of the Invention—Salts. Stereoisomers. & Prodrugs: Salts of the compounds represented by formulae I are an additional aspect of the invention. The skilled artisan will also appreciate that the family of compounds of formulae I include acidic and basic members and that the present invention includes pharmaceutically acceptable salts thereof. In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, ammonium, calcium, magnesium, aluminum, zinc, and the like. Sodium and potassium saltgs are particularly preferred. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. For example, a carboxylic acid substituent on the compound of Formula I may be selected as —CO2H and salts may be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium and potassium salt. Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, choline, clavulanate, citrate, chloride, chloroprocaine, choline, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate, estolate, esylate, ethylenediamine, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, bromide, chloride, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, malseate, mandelate, meglumine, mesylate, mesviate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate, polygalacturonate, procane, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate. Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans-isomeric forms of the compounds. The R— and S— isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a chiral column may be used such as those sold by Daicel Chemical Industries identified by the trademarks: CHIRAL AK AD, CHIRALPAK AS, CHIRALPAK OD, CHIRALPAK OJ, CHIRALPAK OA, CHIRALPAK OB, CHIRALPAK OC, CHIRAIPAK OF, CHIRALPAK OG, C ALPAK OK, and CHIRALPAK CA-1. By another conventional method, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers. These diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization. The present invention is also embodied in mixtures of compounds of formulae I. Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Pharmaceutical Formulations Containing the Novel Compounds of the Invention: Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the compound of the invention (compounds of Formula I) together with a pharmaceutically acceptable carrier or diluent. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the compounds of Formula I will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the compound. The compounds of the present invention are preferably formulated prior to administration. The compounds of the invention may also be delivered by suitable formulations contained in a transderm patch. Alternatively, the compounds of the invention may be delivered to a patient by sublingual administration. For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material. Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc. In powders the carrier is a finely divided solid which is in admixture with the finely divided Active ingredient. In tablets the compound of Formula I is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the compound which is the novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter. Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs. The Active Ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The compounds can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided compounds of the invention in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil. Methods of Using the Compounds of the Invention: Many disease states are benefited by treatment with the compounds of Formula I include, but are not limited to: disease states characterized by abnormal calcium regulation disease states characterized by abnormal cell proliferation disease states characterized by abnormal cell differentiation disease states characterized by abnormal immune response disease states characterized by abnormal dermatological conditions disease states characterized by neurodegenerative condition disease states characterized by inflammation disease states characterized by vitamin D sensitivity disease states characterized by hyperproliferative disorders. Specific disease states benefited by treatment of the compounds of Formula I and II include, but are not limited to: Acne Actinic keratosis Alopecia Alzheimer's disease Benign prostatic hyperplasia Bladder cancer Bone maintenance in zero gravity Bone fracture healing Breast cancer Chemoprovention of Cancer Crohn's disease Colon cancer Type I diabetes Host-graft rejection Hypercalcemia Type II diabetes Leukemia Multiple sclerosis Myelodysplastic syndrome Insufficient sebum secretion Osteomalacia Osteoporosis Insufficient dermal firmness Insufficient dermal hydration Psoriatic arthritis Prostate cancer Psoriasis Renal osteodystrophy Rheumatoid arthritis Scleroderma Skin cancer Systemic lupus erythematosus Skin cell damage from Mustard vesicants Ulcerative colitis Vitiligo Wrinkles Particularly preferred is the treatment of psoriasis and osteoporosis by administration to a mammal (including a human) of a therapeutically effective amount of compounds of Formulae I. By “pharmaceutically effective amount” it is meant that quantity of pharmaceutical agent corresponding to formulae I which prevents, removes or reduces the deleterious effects of a disease state in mammals, including humans. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a pharmaceutically effective amount typically in the range of from about 0.0001 mg/kg/day to about 50 mg/kg/day of body weight of an active compound of this invention. Preferably the dose of compounds of the invention will be from 0.0001 to 5 mg/kg/day of body weight. Preferably compounds of the invention (e.g., per Formula I) or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.0001 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it is necessary to make routine variations to the dosage depending on the age and condition of the patient. Dosage will also depend on the route of administration. The compounds of the invention may be administered by a variety of routes including oral, aerosol, rectal, transdermal, sublingual, subcutaneous, intravenous, intramuscular, and intranasalt Particularly preferred is the treatment of psoriasis with an ointment type formulation containing the compounds of the invention. The ointment formulation may be applied as needed, typically from one to 6 times daily. Treatment of psoriasis is preferably done with topical application by a formulation in the form of a cream, oil, emulsion, paste or ointment containing a therapeutically effective amount of a compound of the invention. The formulation for topical treatment contains from 0.5 to 0.00005 weight percent, preferably from 0.05 to 0.0005 weight percent, and most preferably from 0.025 to 0.001 of a Active Ingredient. For example, two semisolid topical preparations useful as vehicles for VDR modulators in treatment and prevention of psoriasis are as follows: Polyethylene Glycol Ointment USP (p. 2495) Polyethylene Glycol 3350 400 g. Polyethylene Glycol 400 600 g. To make 1000 g. Heat the two ingredients on a water bath to 65 C. Allow to cool, and stir until congealed. If a firmer preparation is desired, replace up to 100 g of the polyethylene glycol 400 with an equal amount of polyethylene glycol 3350. Hydrophilic Ointment USP (p. 1216) Prepare Hydrophilic Ointment as follows: Methylparaben 0.25 g. Propylparaben 0.15 g. Sodium Lauryl Sulfate 10 g. Propylene Glycol 120 g. Stearyl Alcohol 250 g. White Petrolatum 250 g. Purified Water 370 g. To make about 1000 g. The Stearyl Alcohol and White Petrolatum are melted on a steam bath, and warmed to about 75 C. The other ingredients, previously dissolved in the water are added, warmed to 75 C, and the mixture stirred until it congeals. For each of the above formulations the Active Ingredient is added during the heating step in an amount that is from 0.5 to 0.00005 weight percent, preferably from 0.05 to 0.0005 weight percent, and most preferably from 0.025 to 0.001 weight percent of the total ointment weight. (Source:—United States Pharmacopoeia 24, United States Pharmacopeial Convention, 1999) Conventional therapy for osteoporosis includes; (i) estrogens, (ii) androgens, (iii) calcium supplements, (iv) vitamin D metabolites, (v) thiazide diuretics, (vi) calcitonin, (vii) bisphosphonates, (viii) SERMS, and (ix) fluorides (see, Harrison's Principles of Internal Medicine, 13th edition, 1994, published by McGraw Hill Publ., ISBN 0-07-032370-4, pgs. 2172-77; the disclosure of which is incorporated herein by reference.). Any one or combination of these conventional therapies may be used in combination with the method of treatment using compounds of Formulae I as taught herein. For example, in a method of treating osteoporosis, the vitamin D receptor modulator compounds of the invention (e.g., as defined by formula I) may be administered separately or simultaneously with a conventional therapy. Alternatively, the vitamin D receptor modulator compounds of the invention may be combined with conventional therapeutic agents in a formulation for treatment of osteoporosis such as set out below: A formulation for treating osteoporosis comprising: Ingredient (A1): a vitamin D receptor modulator represented by formula (I), or a pharmaceutically acceptable salt or prodrug derivative thereof; Ingredient (B 1): one or more co-agents that are conventional for treatment osteoporosis selected from the group consisting of: a. estrogens, b. androgens, c. calcium supplements, d. vitamin D metabolites, e. thiazide diuretics, f. calcitonin, g. bisphosphonates, h. SERMS, and i. fluorides; and Ingredient (C1): optionally, a carrier or diluent. Typically useful formulations are those wherein the weight ratio of (A1) to (B1) is from 10:1 to 1:1000 and preferably from 1:1 to 1:100. Combination Therapy for Psoriasis: Conventional therapy for psoriasis includes topical glucocorticoids, salicylic acid, crude coal tar, ultraviolet light, and methotrexate (see, Harrison's Principles of Internal Medicine, 13th edition, 1994, published by McGraw Hill Publ., ISBN 0-07-032370-4, pgs. 2172-77). Any one or combination of these conventional therapies may be used in combination with the method of treatment using compounds of Formulae I as taught herein. For example, in a method of treating osteoporosis, the vitamin D receptor modulator compounds of the invention (e.g., as defined by formula I) may be topically administered separately or simultaneously with a conventional therapy. Alternatively, the vitamin D receptor modulator compounds of the invention may be combined with conventional therapeutic agents in a topically applied formulation for treatment of osteoporosis such as set out below: A formulation for treating psoriasis comprising: Ingredient (A2): a vitamin D receptor modulator represented by formula (I), or a pharmaceutically acceptable salt or prodrug derivative thereof; Ingredient (B2): one or more co-agents that are conventional for treatment psoriasis selected from the group consisting of: a. topical glucocorticoids, b. salicylic acid, or c. crude coal tar. Ingredient (C2): optionally, a carrier or diluent. Typically useful formulations are those wherein the weight ratio of (A2) to (B2) is from 1:10 to 1:100000 and preferably from 1:100 to 1:10000. General Procedures General Procedures Scheme I. To a furan-2-carboxylic acid is added lithium diisopropylamine (2-2.5 equivalents) from −80 to 0° C. in diethylether or THF solvent under nitrogen. A substituted ketone is added and the mixture is brought to room temperature from 1 to 48 h. The mixture is worked up from ether and water to give the carbinol A. The carbinol A. is reacted with an o-substituted phenol (0.9 to 5 equivalents) with a Lewis acid, e.g., boron trifluoride etherate (0.01 to 10 equivalents) at from 0° C. to room temperature for 30 min to 48 h. The reaction is worked up from ether and water, removing excess phenol under vacuum to give diarylmethane B. Diarylmethane B. can be activated with an alkylchloroformate and base such as trialkylamines followed by treatment with a substituted primary or secondary amine to give the amide C. Amide C. is alkylated with an α-haloketone in the presence of a base such as sodium hydroxide or potassium carbonate in a polar aprotic solvent to give the amide D. Reduction of amide D. with sodium or lithium borohydride or cyanoborohydride in lower molecular weight alkanols gives the secondary carbinol E. as a racemate. The Racemates, of course, can be separated into enantiomers by chiral chromatography on, e.g., a ChiralPak AD column. Scheme II. Alternately, the ester of diarylmethane B. can be generally prepared as follows: A furanyl carboxylate is reacted with an alkyl magnesium bromide or alkyl lithium (2.0 to 2.5 equivalents) at from 0° C. to room temperature in ether or THF solvent over 30 min to 48 h to give the tert-carbinol F. The tert-carbinol F. is deprotonated with of an alkyl lithium reagent (1.9 to 2.5 equivalents) at from −80° C. to 0° C. over a period of 10 min to 2 h, then excess carbon dioxide gas is bubbled into the mixture, and the mixture is allowed to come to room temperature from 30 min to 48 h. The mixture is worked up from water and ether to give the carboxylic acid A. The carboxylic acid A. may be simultaneously dehydrated and esterified by heating with an alkanol saturated with hydrogen halides such as hydrogen chloride or hydrogen bromide to give the Z/E-olefin G. The olefin G. like carbinol A. may alkylate a substituted o-phenol in the presence of a Lewis acid, e.g., boron trifluoride etherate (0.01 to 5 equivalents) to give the ester of B, which can be saponified from room temperature to reflux in an alkanol with sodium, potassium, or lithium hydroxide to B. Scheme III. To a 4-hydroxy-3-alkyl benzoate ester is added alkylmagnesium halide in a reaction analogous to Scheme II, product F. to give the tert-carbinol H. The phenolic H intermediate is alkylated with an alpha-halo ketone or alpha-halo ester in a reaction analogous to Scheme I, product D. to give the intermediate I. Reacting I. with a substituted or unsubstituted furan in the presence of a Lewis acid, such as, boron trifluoride etherate at room temperature for 30 min to 60 h gives the diarylmethane J. The diarylmethane J. is reacted with an excess of Grignard reagent, analogous to the reaction in Scheme II, product F. to produce the intermediate tert-carbinol K. Treatment of carbinol K. with an alkyllithium in a reaction analogous to Scheme II, product A. gives the acid L. The acid L. is coupled with a primary or secondary amine in the presence of a coupling reagent, such as, EDCI/HOAT in a polar aprotic solvent, such as, DMF to give the amide M. Scheme IV: The synthesis of carbon linked actylenic carbinols S is also described in Scheme IV. The starting material N. is produced from Scheme III intermediate H. and a substituted or unsubstituted furan in the presence of Lewis acid, analogous to the synthesis of Scheme III, product J. Furan N. is reacted with triflic anhydride in a chlorocarbon solvent and trialkylamine base over 30 min to 48 h to give the triflate O. The triflate O. is coupled to TMS-acetylene with palladium in the present of a base, such as CsF or trialkylamine in DMF or acetonitrile/water solvent over 30 min to 48 h from room temperature to 110° C. to produce the acetylene P. Acetylene P. is de-protonated and reacted with a dialkyl ketone or aldehyde to produce the secondary or tert-carbinol Q. The carbinol Q. in reactions analogous to Scheme III, acid L. and amide M. is used to produce the intermediate acid R. and amide S. Scheme V. The bis-pinacolone T. can be formed by reacting a diaryl B. with t-butyl carbonyl chloride (2.0 to 2.5 equivalents) in the presence of potassium iodide (0.01 to 0.10 equivalents), K2CO3 (4 to 5 equivalents) and cyanomethane at refux from about 2 to about 6 hours. The bis-pinacolone T. is dealkylated with a suitable base such as sodium hydroxide (4 to 6 equivalents) in the presence of a suitable solvent such as a methanol/H2O mixture to provide the pinacolone-acid U. The N-alkyl amide V. can be prepared by activating the pinacolone-acid U. with thionyl chloride in the presence of a suitable amine, such as pyridine and subsequently reacted with a suitable alkyl amine in a suitable organic solvent. Example 1 Preparation of 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[5-dimethylaminocarbonyl-2-furanyl]pentane A. 3′-[5-Carboxy-2-furanyl]-3′-hydroxypentane To a solution of i-propylamine (44.8 mL, 0.32 mole) in THF (980 mL) is added 1.6 M n-butyllithium (200 mL, 0.32 mole) in hexanes at −15 to −8° C. with stirring. The mixture is diluted with THF (640 mL) and cooled to −74° C. The 2-furoic acid (17.92 g, 0.16 mole) in THF (320 mL) is added so as to keep the temperature at −70 to −77° C. After 30 min in the cold, 3-pentanone (15.15 g, 0.176 mole) in THF (20 mL) is added dropwise while keeping the temperature below −70° C., and then the reaction mixture is allowed to come to room temperature. The mixture is quenched with water, and most of the THF is removed by evaporation under vacuum. The aqueous residue is extracted with diethylether (2×200 mL) and acidified with 5N HCl. The product is extracted with diethylether (3×600 mL), MgSO4 dried, concentrated, to give the title compound as an oil (31.3 g, 99% crude) which is used as is. B. 3′-[4-Hydroxy-3-methylphenyl]-3′-[5-carboxy-2-furanyl]pentane To 3′-[5-carboxy-2-furanyl]-3′-hydroxypentane (5.94 g, 30 mmol) and o-cresol (19.44 g, 180 mmol) in methylene chloride (30 mL) is added borontrifluoride etherate (1.5 ml., 12 mmol) at room temperature under nitrogen. The mixture is stirred for 5 h, and the mixture is partitioned between diethylether (100 mL) and satd sodium carbonate (100 mL). The aqueous phase is washed one more time with diethylether (100 mL). The combined ether layers are extracted twice with satd sodium carbonate (2×30 mL), and the combined aqueous phases are washed with diethylether (2×50 mL) prior to acidification with 5N HCl to pH ˜2. The product is extracted into diethylether (2×100 mL), dried over MgSO4, and evaporated under vacuum to give an oil. The residue is crystallized from ethylacetate and isooctane to give the title product as white crystals (5.33 g, 62%). 1H NMR (CDCl3) δ 9.12 (s, 1H), 7.13 (d, 1H, J=3.6 Hz), 6.80 (s, 1H), 6.75 (d, 1H, J=8.2 Hz), 6.68 (d, 1H, J=8.2 Hz), 6.36 (d, 1H, J=3.6 Hz), 2.06 (s, 3H), 1.97 (q, 4H, J=7.0), 0.60 (t, 6H, J=7.0 Hz). ES/MS: 289.0 (M+1). C. 3′-[4-Hydroxy-3-methylphenyl]-3′-[5-dimethylaminecarbonyl-2-furanyl]pentane To 3′-[4-hydroxy-3-methylphenyl]-3′-[5-carboxy-2-furanyl]pentane (0.75 g, 2.6 mmol) in THF (50 mL) is added tri-n-butylamine (0.67 mL, 2.86 mmol), and the mixture is cooled in an ice bath. To the cooled solution is added isobutylchloroformate (0.372 mL, 2.86 mmol) dropwise, and it is allowed to stir 5 min. To the mixture is added 2.0 M dimethylamine in methanol (7.8 mL, 15.6 mmol) and the reaction is allowed to come to room temperature and stirred 30 min. The mixture is evaporated under vacuum, and the residue is partitioned between water (100 mL0 and diethylether (100 mL). The organic phase is washed with satd sodium bicarbonate (2×30 mL); with satd brine (30 mL); with 0.3 N HCl (3×30 mL); and with satd brine (10 mL). The organic phase is dried over MgSO4, and evaporated under vacuum to give the title product as an oil (538 mg, 66%) ES/MS: 316.3 (M+1), 314.2 (M−1). D. 3′-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[5-dimethylaminocarbonyl-2-furanyl]pentane To 3′-[4-hydroxy-3-methylphenyl]-3′-[5-dimethylaminecarbonyl-2-furanyl]pentane (0.53 g, 1.7 mmol) in acetonitrile (15 mL) is added 1-chloropinacolone (0.23 mL, 1.76 mmol), potassium carbonate (1.16 g, 8.4 mmol), and catalytic potassium iodide (14 mg, 0.08 mmol). The mixture is heated at reflux for 45 min; cooled to room temperature; and evaporated under vacuum. The residue is partitioned between methylene chloride and water, and the water layer is extracted one time more with methylene chloride. The combined organic layers are dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum to give an oil. The residue is crystallized from hexane to give the title compound (0.41 g, 59%) 1H NMR (CDCl3) δ6.92 (m 2H), 6.84 (d, 1H, J=8.0 Hz), 6.62 (d, 1H, J=8.0 Hz), 6.41 (d, 1H, J=3.0 Hz), 5.07 (s, 2H), 2.92 (s, 6H), 2.15 (s, 3H), 2.00 (q, 4H, J=7.6 Hz), 1.16 (s, 9H), 0.61 (t, 6H, J=7.6 Hz). ES/MS: 414.2 (M+1). Example 2 Preparation of 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[5-dimethylaminocarbonyl-2-furanyl]pentane 3′-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[5-dimethylaminocarbonyl-2-furanyl]pentane (0.32 g, 0.79 mmol) and sodium borohydride (30 mg, 0.79 mmol) are combined in methanol (30 mL) at ambient temperature and allowed to stir at room temperature overnight. Acetone (1 mL) is added, and mixture is evaporated under vacuum. The residue is partitioned between methylene chloride and water, and the water layer is extracted with methylene chloride twice more. The combined organic extracts are dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give the title product as a colorless oil (0.325 g, 99%). 1H NMR (CDCl3) δ7.01 (d, 1H, J=3.3 Hz), 6.92 (m, 2H), 6.73 (d, 1H, J=8.3 Hz), 6.26 (d, 1H, J=3.6 Hz), 5.30 (s, 1H), 4.08 (d, 1H, J=7.2 Hz), 3.86 (t, 1H, J=7.2 Hz), 3.84 (d, 1H, J=7.2 Hz), 3.04 (s, 6H), 2.20 (s, 3H), 2.04 (m, 4H), 1.03 (s, 9H), 0.72 (t, 6H, J=7.0 Hz). ES/MS: 416.2 (M+1). Example 3 and Example 4 Preparation of enantiomers 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[5-dimethylaminocarbonyl-2-furanyl]pentane A mixture of racemic 3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[5-dimethylaminocarbonyl-2-furanyl]pentane, Example 2 (300 mg), is chromatographed on a ChiralPak AD column with 40:60 IPA/hexane to give enantiomer 1, Example 3 (110 mg, 37%) and enantiomer 2, Example 4 (110 mg, 37%). Enantiomer 1, Example 3 HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/40% IPA/60% heptane; 1 ml/m (flow rate); Rt=5.6 m NMR eq. To Example 2. Enantiomer 2, Example 4 HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/40% IPA/60% heptane; 1 ml/m (flow rate); Rt=8.6 m Example 5 Preparation of 3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-(2-butyl)phenyl]-3′-[5-dimethylaminocarbonyl-furan-2-yl]pentane A. 3-(2-Furanyl)pentan-3-ol 2-methyl furate (10.0 g, 79 mmol) is dissolved in THF (100 mL) under a nitrogen atmosphere. Ethyl magnesium bromide (3.0 M in Et2O, 55 ml, 166 mmol) is added initially at room temperature. The reaction is cooled to −30° C., and the remaining ethyl Grignard added. The mixture is stirred overnight at room temperature. Saturated sodium bicarbonate solution (10 mL) is added to the stirring solution followed by diethyl ether (100 mL) and water (50 mL). The organic layer is separated and washed with water. The ether layer is dried over magnesium sulfate, filtered, and evaporated under vacuum to give 10.7 g of a oil, which was used without further purification. 1H NMR (CDCl3) δ 7.37 (s, 1H), 6.31 (d, 1H), 6.18 (d, 1H), 1.83 (m, 4H), 0.88 (t, 6H). B. 3-(5-Carboxy-2-furanyl)pentan-3-ol 3-(2-Furanyl)pentan-3-ol (3.0 g, 19 mmol) is added to THF (20 mL) under a nitrogen atmosphere. The solution is stirred and cooled to −78° C. Sec-BuLi (1.3 M in cyclohexane, 31 mL, 41 mmol) is added dropwise maintaining the temperature below −55° C. After complete addition, the ice bath is removed and the solution slowly warmed to room temperature where it is stirred for 18 hours. The mixture is cooled to 48° C. and CO2 gas is bubbled through the solution. A thick yellow past results and the temperature is increased to −10° C. Water (50 mL) is added and the solution is stirred at room temperature for 30 minutes. Ethyl acetate is added followed by water and the ph is adjusted to 1 with 1 N HCl. The organic layer is separated and the water layer was discarded. The organic layer is added to 1N NaOH solution and extracted. The pH of the water layer is adjusted to 1 with 1N HCl followed by addition of EtOAc. The organic layer is separated, dried over sodium sulfate, filtered, and evaporated under vacuum to give 2.7 grams of an oil. 1H NMR (CDCl3) δ8.5-10.0 (br,1H), 7.22 (d, 1H), 6.40 (d, 1H), 1.88 (m, 5H), 1.80 (t, 6H). C. Z/E-3-(5-Methoxycarbonyl-2-furanyl)pent-2-ene 3-(5-Carboxy-2-furanyl)pentan-3-ol (200 mg, 1.1 mmol) is dissolved in methanol (20 mL). HCl (g) is bubbled through the solution for 30 seconds. The reaction is stirred for 20 minutes at room temperature with no reaction. The solution is heated to 60° C. for 2 hours. The solution is concentrated and water is added followed by solid NaHCO3 until the pH was basic. Ethyl acetate is added and the solution is extracted. The organic layer is washed with water, dried over MgSO4 and filtered. The filtrate is concentrated to 213 mg of an orange oil which is used as is. 1H NMR (CDCl3) δ 6.35 (q, 0.95H, J=6.8 Hz, E-isomer), 5.72 (q, 0.05H, J=6.8 Hz, Z-isomer). Irradiation of major isomer methyl doublet (1.83 ppm) produced a significant nuclear Overhauser effect upon the methylene quartet of the major isomer (2.40 ppm) as well as the vinyl H of the major isomer (6.35 ppm) confirming the major isomer as E. D. 3′-[4-Hydroxy-3-(2-butyl)phenyl]-3′-[5-methoxycarbonyl-furan-2-yl]pentane To Z/E-3-(5-methoxycarbonyl-2-furanyl)pent-2-ene (0.97 g, 5 mmol) in 2-(2-butyl)phenol (3.75 g, 25 mmol) is added boron trifluoride etherate (213 mg, 1.5 mmol) in methylene chloride (0.5 mL), and the mixture is stirred for 9 d at room temperature. The mixture is partitioned between diethyl ether and water, and the organic phase is washed twice more with water, once with satd brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under vacuum, and the residue is chromatographed on 12 g of silica gel with a step gradient from 4% ethylacetate in hexanes to 6% ethylacetate in hexanes to give the title compound (1.12 g, 65%). 1H NMR (CDCl3) δ 7.10 (d, 1H, J=3.6 Hz), 6.93 (s, 1H), 6.82 (d, 1H, J=8.4 Hz), 6.22 (d, 1H, J=3.6 Hz), 4.56 (s, 1H), 3.82 (s, 3H), 2.91 (m, 1H), 1.97-2.19 (m, 4H), 1.59 (m, 2H), 1.19 (d, 3H, J=6.8 Hz), 0.82 (t, 3H, J=7.2 Hz), 0.69 (t, 6H, J=7.4 Hz). ES/MS: 345.3 (M+1), 343.3 (M−1). E. 3′-[4-Hydroxy-3-(2-butyl)phenyl]-3′-[5-carboxyl-furan-2-yl]pentane To 3′-[4-hydroxy-3-(2-butyl)phenyl]-3′-[5-methoxycarbonyl-furan-2-yl]pentane (0.2 g, 0.6 mmol) in methanol (5 mL) is added 5N NaOH (232 UL, 11.2 mmol), and the mixture is heated at 70° C. for 1.5 h in an open flask. Water is intermittently added to replace the evaporated methanol. The mixture is cooled to rt, and made acidic to pH paper with 5 N HCl. The product is extracted into methylene chloride, dried over anhydrous sodium sulfate, and evaporated to give the title compound (0.165 g, 87%). 1H NMR (CDCl3) δ 6.93 (d, 1H, J=2.4 Hz), 6.82 (d, 1H, J=8.4 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=3.6 Hz), 4.56 (s, 1H), 2.91 (m, 1H), 1.97-2.19 (m, 4H), 1.59 (m, 2H), 1.18 (d, 3H, J=6.8 Hz), 0.82 (t, 3H, J=7.2 Hz), 0.69 (t, 6H, J=7.2 Hz). Exact mass: 331.192, calcd. 331.1909 for C20H27O4. F. 3′-[4-Hydroxy-3-(2-butyl)phenyl]-3′-[5-dimethylaminocarbonyl-furan-2-yl]pentane To 3′-[4-hydroxy-3-(2-butyl)phenyl]-3′-[5-carboxyl-furan-2-yl]pentane (0.164 g, 0.5 mmol) in DMF (0.5 mL) is added EDCI (120 mg, 0.6 mmol), 0.5 M HOAt in DMF (1.24 mL, 0.6 mmol), triethylamine (250 mg, 2.5 mmol), and dimethylamine hydrochloride (50 mg, 0.6 mmol). The mixture is stirred at rt for 64 h and partitioned between methylene chloride and satd sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and evaporated. The residue is chromatographed on 4 g of silica gel with a step gradient from 20% ethylacetate in hexanes to 25% ethylacetate in hexanes to give the title compound (80 mg, 45%). 1H NMR (400 mHz, CDCl3) δ 7.01 (d, 1H, J=3.6 Hz), 6.92 (s, 1H), 6.79 (d, 1H, J=8.4 Hz), 6.63 (d, 1H, J=8.4 Hz), 6.24 (d, 1H, J=3.6 Hz), 4.91 (s, 1H), 3.03 (s, 6H), 2.92 (m, 1H), 1.97-2.05 (m, 4H), 1.52-1.63 (m, 2H), 1.18 (d, 3H, J=7.2 Hz), 0.82 (t, 3H, J=7.2 Hz), 0.70 (t, 6H, J=7.2 Hz). LC/MS: 358.3 (M+1), 356.3 (M−1). G. 3′-[4-(2-Oxo-3,3-dimethylbutoxy)-3-(2-butyl)phenyl]-3′-[5-dimethylaminocarbonyl-furan-2-yl]pentane Using a procedure analogous to Example 1D, 3′-[4-hydroxy-3-(2-butyl)phenyl]-3′-[5-dimethylaminocarbonyl-furan-2-yl]pentane (80 mg, 0.22 mmol) is reacted with 1-chloropinacolone to give the title compound as an oil (90 mg, 90%). to give the title compound (80 mg, 45%). 1H NMR (400 mHz, CDCl3) δ 7.01 (d, J=3.6 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.25 (d, J=3.6 Hz, 1H), 4.82 (s, 2H), 3.03 (s, 6H), 3.14 (m, 1H), 1.98-2.12 (m, 4H), 1.48-1.64 (m, 2H), 1.25 (s, 9H), 1.17 (d, J=7.2 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H), 0.70 (t, J=7.2 Hz, 6H). ES/MS: 456.3 (M+1). In procedures analogous to those above, the following examples are prepared: Example Oxo/Carbinol No. Rac/isomer R1 R2 R3 R4 6 Oxo Ethyl H Methyl H 7 Oxo Ethyl Ethyl Methyl H 8 Oxo Methyl Methyl Methyl 4- methyl 9 Racemate Methyl Ethyl Methyl H 10 Isomer 1 Methyl Methyl Ethyl H 11 Isomer 2 Methyl Methyl Ethyl H 12 Isomer 1 Methyl Methyl n- H propyl 13 Isomer 1 Methyl Methoxy Ethyl H Example Name Physical Data 6 3′-[4-(2-oxo-3,3-dimethyl- 1H NMR(300 mHz, butoxy)-3-methylphenyl]-3′- DMSO-d6) δ 8.09(m, [5-ethylaminocarbonyl-2- 1H), 6.98(d, J=3.2Hz, furanyl]-pentane 1H), 6.94(s, 1H), 6.86(d, J=8.4Hz, 1H), 6.62(d, J=8.4Hz, 1H), 6.40(d, J=3.2Hz, 1H), 5.09(s, 2H), 3.19(m, 2H), 2.18(s, 3H), 1.95-2.10(m, 4H), 1.18(s, 9H), 1.03(t, J=7.0Hz, 3H), 0.60(t, J=7.0Hz, 6H). ES/MS: 414.3(M+1). 7 3′-[4-(2-oxo-3,3-dimethyl- 1H NMR(CDCl3) δ 7.00(d, butoxy)-3-methylphenyl]-3′- J=3.2Hz, 1H), 6.90(s, 1H), [5-diethylaminocarbonyl-2- 6.88(d, J=8.4Hz, 1H), furanyl]-pentane 6.49(d, J=8.4Hz, 1H), 6.26(d, J=3.2Hz, 1H), 4.83(s, 2H), 3.37(m, 4H), 2.24(s, 3H), 1.95-2.10(m, 4H), 1.24(s, 9H), 1.15(m, 3H), 1.95(m, 3H), 0.68(t, J=7.2Hz, 6H). Exact Mass: calcd for C27H40NO4(M+1) 442.2957, found 442.2950. 8 3′-[4-(2-oxo-3,3-dimethyl- 1H NMR(300mHz, butoxy)-3-methylphenyl]-3′- CDCl3) δ 6.95(s, 1H), [5-dimethylaminocarbonyl- 6.90(d, J=9.0Hz, 1H), 3-methyl-2-furanyl]-pentane 6.52(d, J=9.0Hz, 1H), 6.13(s, 1H), 4.85(s, 2H), 2.98(s, 6H), 2.50(s, 3H), 2.46(s, 3H), 1.95-2.12(m, 4H), 1.27(s, 9H), 0.70(t, J=7.2Hz, 6H). ES/MS: 428.4(M+1). 9 3′-[4-(2-hydroxy-3,3- 1H NMR(CDCl3) δ dimethyl-butoxy)-3 - 7.00(d, J=3.2Hz, 1H), methylphenyl]-3′-[5-N- 6.92(d, J =8.4Hz, 1H), ethyl-N-methylamino- 6.90(s, 1H), 6.70(d, carbonyl-2-furanyl]pentane J=8.8Hz, 1H), 6.25(d, J=3.2Hz, 1H), 4.06(d, J=8.8Hz, 1H), 3.84(t, J=9.0Hz, 1H), 3.70(d, J=8.8Hz, 1H), 3.40(m, 2H), 2.98(m, 3H), 2.44(s, 1H), 2.18(s, 3H), 1.98-2.10(m, 4H), 1.10(m, 3H), 1.02(s, 9H), 0.68(t, J=7.2Hz, 6H). ES/MS: 430.2(M+1). 10 3′-[4-(2-hydroxy-3,3- 1H NMR(CDCl3) δ 7.00(d, dimethyl-butoxy)-3- J=3.2Hz, 1H), 6.92(m, 2H), ethylphenyl]-3′-[5- 6.71(d, J=8.8Hz, 1H), dimethylaminocarbonyl-2- 6.25(d, J=3.2Hz, 1H), furanyl]pentane enantiomer 4.08(d, J=8.8Hz, 1H), 1 3.85(t, J=8.8Hz, 1H), 3.70(d, J=8.8Hz, 1H), 3.04(s, 6H), 2.59(q, J=8.0Hz, 2H), 2.41(m, 1H), 1.98-2.13(m, 4H), 1.14(t, J=7.4Hz, 3H), 1.01(s, 9H), 0.70(t, J=7.4Hz, 6H). ES/MS: 430.2(M+1), 447.2(M+NH4). 11 3′-[4-(2-hydroxy-3,3- 1H NMR(CDCl3) δ 7.00(d, dimethyl-butoxy)-3- J=3.2Hz, 1H), 6.92(m, 2H), ethylphenyl]-3′-[5- 6.71(d, J=8.8Hz, 1H), dimethylaminocarbonyl-2- 6.25(d, J=3.2Hz, 1H), furanyl]pentane enantiomer 4.08(d, J=8.8Hz, 1H), 2 3.85(t, J=8.8Hz, 1H), 3.70(d, J=8.8Hz, 1H), 3.04(s, 6H), 2.59(q, J=8.0Hz, 2H), 2.41(m, 1H), 1.98-2.13(m,4H), 1.14(t, J=7.4Hz, 3H), 1.01(s, 9H), 0.70(t, J=7.4Hz, 6H). 12 3′-[4-(2-hydroxy-3,3- 1H NMR(CDCl3) δ 7.00(d, dimethyl-butoxy)-3-n- J=3.2Hz, 1H), 6.92(m, 2H), propyl-phenyl]-3′-[5- 6.72(d, J=8.8Hz, 1H), dimethylaminocarbonyl-2- 6.25(d, J=3.2Hz, 1H), furanyl]pentane enantiomer 4.08(d, J=8.8Hz, 1H), 1 3.85(t, J=8.8Hz, 1H), 3.70(d, J=8.8Hz, 1H), 3.02(s, 6H), 2.54(t, J=7.0Hz, 2H), 2.39(m, 1H), 1.98-2.13(m, 4H), 1.55(m, 2H), 1.12(m, 1H), 1.01(s, 9H), 0.88(t, J=7.0Hz, 3H), 0.70(t, J=7.2Hz, 6H). ES/MS: 443.3(M+1), 461.3(M+NH4). 13 3′-[4-(2-hydroxy-3,3- 1H NMR(CDCl3) δ 7.09(d, dimethyl-butoxy)-3- J=3.2Hz, 1H), 6.96(s, 1H), ethylphenyl]-3′-[5-N- 6.95(d, J=8.8Hz, 1H), methoxy-N-methylamino- 6.71(d, J=8.8Hz, 1H), carbonyl-2-furanyl]pentane 6.25(d, J=3.2Hz, 1H), enantiomer 1 4.08(d, J=8.8Hz, 1H), 3.85(t, J=8.8Hz, 1H), 3.70(d, J=8.8Hz, 1H), 3.60(s, 3H), 3.26(s, 3H), 2.59(q, J=7.2Hz, 2H), 2.40(d, J=2.4Hz, 1H), 2.0-2.19(m, 4H), 1.14(t, J=7.0Hz, 3H), 1.01(s, 9H), 0.71(t, J=7.4Hz, 6H). ES/MS: 446.2(M + 1). Example 14 Preparation of 3′-[4-(2-hydroxy-2-ethylbutoxy)-3-methylphenyl]-3′-[5-dimethylaminocarbonyl-2-furanyl]pentane A. 3′-(4-Hydroxy-3-methyl-phenyl)-3′-pentanol To methyl, 4-hydroxy-3-methylbenzoate (21.8 g, 0.13 mol) in 200 mL of THF is added 1.0 M ethylmagnesiuim bromide (433 mL, 0.43 mol) dropwise under nitrogen at ambient temperature. The mixture is stirred for 64 h and quenched with dilute sodium bicabonate. The mixture is triturated with diethyl ether five times (5×), and the combined organic layers are washed with dilute sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give the title compound (27 g, 99%). 1H NMR (400 mHz, CDCl3) δ 7.29 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.72 (d, J=8.4 Hz, 1H), 4.74 (s, 1H), 3.75 (s, 1H), 2.26 (s, 3H), 1.82 (m, 4H), 0.76 (t, J=7.6 Hz, 6H). ES/MS: 193.2 (M−1). B. 3′(4-Methoxycarbonylmethoxy-3-methyl-phenyl)-3′-pentanol To 3′-(4-hydroxy-3-methyl-phenyl)-3′-pentanol (1.5 g, 7.7 mmol) in 20 mL of acetonitrile is added methyl, bromoacetate (0.73 mL, 7.7 mmol), potassium carbonate (4.26 g, 31 mmol) and catalytic potassium iodide (˜0.1 g). the mixture is heated at 80° C. for 6 hr. The mixture is cooled and the solvent evaporated under vacuum. The residue is partitioned between diethylether and water. The organic layer is washed with water four times (4×), dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give the title compound (2.06 g, 99%). 1H NMR (400 mHz, CDCl3) 7.14 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 4.64 (s, 2H), 3.80 (s, 3H), 2.30 (s, 3H), 1.80 (m, 4H), 0.76 (t, J=7.4 Hz, 6H). C. 3′(4-Methoxycarbonylmethoxy-3-methyl-phenyl)-3′-(2-furanyl)pentane To 3′(4-methoxycarbonylmethoxy-3-methyl-phenyl)-3′-pentanol (2.0 g, 7.7 mmol) in furan (25 mL) is added borontrifluoride etherate (0.39 mL, 0.3 mmol) at ambient temperature under nitrogen. The mixture is stirred for 4 hr, and quenched with satd. sodium bicarbonate. The product is extracted into diethylether, washed with water, satd. brine, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The residue is chromatographed on 40 g of silica gel with a gradient from 0-10% ethylacetate in hexanes to give a fraction containing the title compound (1.3 g, 53%). 1H NMR (400 mHz, CDCl3) 7.28 (s, 1H), 6.95 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 4.61 (s, 2H), 3.79 (s, 3H), 2.24 (s, 3H), 1.96-2.12 (m, 4H), 0.67 (t, J=7.4 Hz). ES/MS: 317.1 (M+1). D. 3′-[4-(2-Hydroxy-2-ethylbutoxy)-3-methylphenyl]-3′-[2-furanyl]pentane To 3′(4-methoxycarbonylmethoxy-3-methyl-phenyl)-3′-(2-furanyl)pentane (1.3 g, 4.1 mmol) in 10 mL of diethylether is added 1M ethylmagnesium bromide (10.2 mL, 10.2 mmol) dropwise, and the mixture is stirred over night. The mixture is quenched with sat sodium bicarbonate and triturated with diethylether five times (5×). The combined organic layers are washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give the title compound (1.33 g, 94%). 1H NMR (400 mHz, CDCl3) 7.29 (s, 1H), 6.93 (m, 2H), 6.72 (d, J=8.0 Hz), 6.29 (s, 1H), 6.18 (s, 1H), 3.79 (s, 2H), 2.20 (s, 3H), 1.16-2.12 (m, 4H), 1.66 (m, 4H), 0.93 (t, J=7.4 Hz, 6H), 0.67 (t, J=7.6 Hz, 6H). ES/MS: 345.3 (M+1), 362.3 (M+NH4). E. 3′-[4-(2-Hydroxy-2-ethylbutoxy)-3-methylphenyl]-3′-[5-carboxy-2-furanyl]pentane To 3′-[4-(2-hydroxy-2-ethylbutoxy)-3-methylphenyl]-3′-[2-furanyl]pentane (1.3 g, 3.8 mmol) in 10 mL cyclohexane and 2 mL diethylether at 0-5° C. under nitrogen is added 1.3 M sec-buthyllithium (6.5 mL, 8.5 mmol). After 5 min, excess carbon dioxide gas is bubbled in, and the mixture is stirred for 2 h. The mixture is partitioned between diethylether and water. The aqueous phase is made acidic with 6N HCl, and the product is extracted into diethylether. The ether layer is washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give the title compound (0.66 g, 44%) which is used as is. ES/MS: 387.3 (M−1), 406.3 (M+NH4). F. 3′-[4-(2-Hydroxy-2-ethylbutoxy)-3-methylphenyl]-3′-[5-dimethylaminocarbonyl-2-furanyl]pentane To 3′-[4-(2-hydroxy-2-ethylbutoxy)-3-methylphenyl]-3′-[5-carboxy-2-furanyl]pentane (0.66 g, 1.7 mmol) is added EDCI (0.38 g 2.0 mmol), 0.5 M HOAT in DMF (3.4 mL, 1.7 mmol), and 2M dimethylamine in THF (1.7 mL, 3.4 mmol) in DMF (2 mL). The mixture is stirred at room temperature for 2 h, and partitioned between diethylether and satd sodium bicarbonate. The organic layer is washed with water, satd brine, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The residue is chromatographed on 10 g of silica gel with a gradient from 5-30% ethylacetate in hexane to give a fraction containing the title compound (0.16 g, 23%). 1H NMR (400 mHz, CDCl3) 7.00 (d, J=3.6 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.90 (s, 1H), 6.70 (d, J=8.2 Hz, 1H), 6.25 (d, J=3.6 Hz, 1H), 3.79 (s, 2H), 3.04 (s, 6H), 2.19 (s, 3H), 2.06 (m, 4H), 1.67 (m, 4H), 0.93 (t, J=7.4 Hz, 6H), 0.70 (t, J=7.4 Hz, 6H). ES/MS: 416.3 (M+1), 433.3 (M+NH4). TABLE 1 Summary of Experimental Results (Compounds of the Invention) RXR-VDR VDR OCN Mouse Test heterodimer 2 EC50 (nM) Promoter 4 Hypercal 5 Cmpd. 1 EC50 (nM) (Caco-2 cells) 3 EC50 (nM) μg/Kg/d Ex. 1 3.3/0.6 191 5/3 >1500 Ex. 2 25 3 Ex. 3 42/0.6 391 4.6/2.5 >2000 Ex. 4 10/0.5 333 2/1 >2000 Ex. 5 135/40 129 33/44 Ex. 6 320 315 >1000 Ex 7 95 >9000 Ex. 8 156 758 125 Ex. 9 16 616 30 Ex. 10 13/0.1 191 1.6/0.5 >1000 Ex. 11 17.6 572 20 >3000 Ex. 12 188 187 0.5/0.1 Ex. 13 18 572 20 >3000 Ex 14 104 635 101 TABLE 2 Summary of Experimental Results (Compounds of the Invention) Test Kera. Prolif. IL-10. Cmpd. 1 IC50 (nM) IC50 (nM) Ex. 1 15 Ex. 2 Ex. 3 1 Ex. 4 4 Ex. 5 1000 Ex. 6 112 Ex 7 23 Ex. 8 >1000 Ex. 9 28 Ex. 10 7 Ex. 11 18 Ex. 12 17 Ex. 13 18 4.6 Ex 14 487/1000 TABLE 3 Summary of Experimental Results (Comparison Compounds) RXR-VDR (SaOS-2 VDR CTF OCN Mouse Test cells) 2 (Caco-2 cells) 3 Promoter 4 Hypercal 5 Cmpd. 1 EC50 (nM) EC50 (nM) EC50 (nM) μg/Kg/d AA 5.02 16 5 0.06 BB 10.32 169.81 8.24 >=20 CC 2427.7 >1000 DD 109.44 31.1 1000 EE 429.99 891.16 341.25 1000 FF 3 57 TABLE 4 Summary of Experimental Results (Comparison Compounds) Test Kera. Prolif. IL-10 Cmpd. 1 IC50 (nM) IC50 (nM) AA 120 1.2 BB 10 28 CC — — DD 1060 EE FF 103 0.5 Explanation of Tables 1, 2, 3, and 4: Test Compound numbers refer to the products of the corresponding Example Nos. A slash mark “/” between numbers in a Table cell separates different experimental results obtained. The control experiments are done with the double letter coded compounds identified as follows: “AA”=1α,25-dihydroxyvitamin D3 “BB”=3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1,2-diol “CC”=1-(4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-cyclohexyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one DD”=compound represented by the formula: “EE”=compound represented by the formula: calcipotriol (structural formula below): 2. The RXR-VDR heterodimerization (SaOS-2 cells) test is described in the “Assay” section of the Description, infra. 3. The VDR CTF (Caco-2 cells) test is described in the “Assay” section of the Description, infra. 4. The OCN Promoter test is described in the “Assay” section of the Description, infra. 5. The Mouse Hypercalcemia test is described in the “Assay” section of the Description, infra. 6. The keratinocyte proliferation assay is described in the “Assay” section of the Description, infra. 7. The IL-10 induction assay is described in the “Assay” section of the Description, infra. Assay Methods Use of the Assay Methods: The evaluation of the novel compounds of the invention for osteoporosis and other related diseases is done using a plurality of test results. The use of multiple assays is necessary since the combined properties of (i) high activity for the vitamin D receptor, and (ii) prevention of hypercalcemia must be achieved to have utility for the methods of treating diseases, which are also, aspects of this invention. Some of the tests described below are believed related to other tests and measure related properties of compounds. Consequently, a compound may be considered to have utility in the practice of the invention if is meets most, if not all, of the acceptance criteria for the above described tests. The evaluation of the novel compounds of the invention for psoriasis is done using the Keratinocyte Proliferation Assay in combination with other assays that measure inhibition of IL-2 production and stimulation of IL-10 production in peripheral blood mononuclear cells (PBMCs). Brief Description, Utility and Acceptance Criteria for the Assay Methods: 1. The RXR-VDR Heterodimer Assay: This assay provides the VDR activity of a test compound. It is desirable to have low EC50 values for a compound in this assay. The lower the EC50 value, the more active the compound will be as a VDR agonist. Desired assay results are EC50 values less than or equal to 600 nM. Preferred assay results are less than 250 nM, and most preferably less than 150 nM. 2. The Caco-2 Cell Co-Transfection Assay: The Caco-2 cell assay is an indicator for the undesirable condition of hypercalcemia. This co-transfection assay is a surrogate assay for in vivo calcemic activity of VDR ligands. It is desirable to have high EC50 values for a test compound in this assay. The higher the EC50 values for a compound the less calcemic it will be in vivo. Desired assay results are EC50 greater than or equal to 300 nM. Preferred assay results are greater than 1000 nM. 3. The OCN (osteocalcin) Promoter Assay The OCN Promoter Assay is an indicator and marker for osteoporosis. Desired assay results are EC50 less than or equal to 325 nM. Preferred assay results are less than 50 nM. 4. The Mouse Hypercalcemia Assay The Mouse Hypercalcemia Assay is a six day hypercalcemia test for toxicity and selectivity. Acceptable test results are levels greater than 300 μg/kg/day. Preferred assay results are levels greater than 1000 μg/kg/day. 5. The Keratinocyte Proliferation Assay This Assay is indicative for the treatment of psoriasis. An acceptable test result is IC50 value of less than or equal to 300 nM. Preferred assay results are IC50 values of less than 100 nM. 6. The IL-10 induction Assay This is an in vitro efficacy assay for psoriasis, abscess and adhesion. Psoriasis involves both keratinocytes and immune cells. IL-10 is a unique cytokine because it is anti-inflammatory and immunosuppressive. This assay tells us whether a VDRM is able to function as an agonist in PBMCs (primary blood mononuclear cells) or not. A lower EC50 value is desirable in this assay since a compound with a lower EC50 value will be a better agonist in PBMCs. An acceptable test result is an EC50 value of less than 200 nM. Preferred assay results are EC50 values of less than 100 nM. 7. Other Compound Assay Standards An alternative measure of the efficacy of compounds of the invention for treatment of osteoporosis is a numerical ratio calculated as follows: Dose Threshold needed to induce hypercalcemia divided by Dose Threshold needed for bone efficacy An alternative measure of the efficacy of compounds of the invention for treatment of psoriasis is a numerical ratio calculated as follows: Dose Threshold needed to induce hypercalcemia divided by Dose Threshold needed to induce keratinocyte proliferation For the above ratios, Dose Thresholds are determined from dose response curve data. 8. The CaT1 (calcium transporter 1) Assay The CaT1 Assay is an indicator for the undesirable condition of hypercalcemia. The higher the EC50 values for a compound the less calcemic it will be in vivo. Desired assay results are EC50 greater than or equal to 500 nM. Preferred assay results are greater than 1000 nM. Details of the Assay Methods: (1) Materials and Method for RXR-VDR Heterodimerization Assay: Transfection Method: FuGENE 6 Transfection Reagent (Roche Cat #1 814 443) Growth Media: D-MEM High Glucose (Gibco BRL Cat #11054-020), 10% FBS, 1% antibiotic-antimycotic (Ab-Am) FBS heat inactivated (Gibco BRL Cat #10092-147) Ab-Am (Gibco BRL Cat #15240-062) Cells: Grow SaOs-2 cells in T-152 cm2 culture flasks in growth media. Keep the density at 5-6×105 cells/ml Passage cells 1:3 twice a week Add Trypsin EDTA (Gibco BRL Cat #25300-020)and incubate Resuspend cells in plating media and transfer into growth media. Wash Media: HBSS Low Glucose Without Phenol Red (Gibco BRL Cat #14175-095), 1% Ab-Am Plating Media: D-MEM Low Glucose Without Phenol Red (Gibco BRL Cat #11054-020), 1% Ab-Am D-MEM Stripped FBS (Hyclone Cat#SH30068.03 Lot #AHM9371) Ab-Am Transfection/Treatment Media: D-MEM Low Glucose Without Phenol Red only T-152 cm2 culture flask: Use Corning Coastar T-152 cm2 culture flask (Cat #430825) to grow the cells Flat well Plates: Use well plate to plate cells Use Deep well plate sterile to make up treatment media. Luciferase Assay Reagent: Use Steady-Glo Luciferase Reagent from Promega (Cat #E2550) Consists of: a. E2533 Assay Substrate, lyopholized product and b. E2543 Assay Buffer. Thaw at room temperature Store Day 1: Cell Plating: Cell Harvesting Aspirate media from culture flask, rinse cells with HBSS and aspirate. Add trypsin and incubate. When cells appear detached, resuspend cells in growth media. Transfer into a new flask with fresh growth media for passaging the cells. Plate well plates and two extra plates A. Cell Count Mix the cell suspension using pipette Use Hematocytometer to count the cells Load cell suspension onto the hemocytometer chamber Count cells. Plate seeding: Use plating media 10% Stripped FBS in D-MEM Low Glucose, Without Phenol Red, 1% Ab-Am Plate 14 plates @ 165 μl/well. In sterile flask add cell suspension to plating media. Mix. Add cells/well. Place the cells in the incubator. Cells should be about 75% confluent prior to transfection. Day 2: Transfection Step 1: DNA and Media Add plain DMEM media to tubes for mixing the DNA Add the Reporter gene pFR-LUC Add the Gal-4-RXR-DEF and VP16-VDR-LBD Step 2: FuGENE and Media Prepare plain DMEM media in a ubes for mixing PuGENE Add FuGENE 6 Transection Reagent Incubate Step 3: FuGENE, DNA and Media Complex Add FuGENE Media complex from step 2 to DNA Media complex from step1 Incubate Step 4: FuGENE, DNA and Media Complex to-well plate Add FuGENE-DNA-Media complex from step 3 to each plate Incubate. Day 3: Dosing Treatment preparation Allow for transfection time Make a stock solution of the compounds in DMSO Vortex until all the compounds has been dissolved. Further dilute in D-MEM (Low Glucose—With out Phenol Red) Add compounds in quadruplicate to give final volume Incubate. Day 4: Luciferase Assay Read the plates after drug treatment Remove part of media from all the wells and leave remainder Add Steady-Glo Luciferase Reagent mixture/wells Incubate Count each well using a Luminescence counter, Top Count NXT by Packard Set a delay between plates to reduce the background. (2) Materials and Method for The Caco-2 Cell Assay: Caco-2 cells, grown in phenol red free, DMEM (Invitrogen, Carlsbad, Calif.) containing 10% charcoal-stripped FCS (Hyclone, Logan, Utah), were transfected with Fugene 6 reagent (Roche Diagnostics, Indianapolis, Ind.). Cells (5000/well) were plated 18 h before transfection in a 96 well plate. The Cells were transfected with Gal-4-responsive reporter pFRLuc (150 ng, Stratagene, La Jolla Calif.) and the receptor expression vector pGal-4-VDR-LBD (10 ng), along with Fugene 6 reagent (0.2 μl/well). The DNA-Fugene complex was formed by incubating the mixture for 30 min at room temperature. The cells were transfected in triplicate for 5 h, and treated with various concentrations of VDR ligands (form 0.01 nM to 10,000 nM concentration range) 18 h post-transfection. The luciferase activity was quantified using Steady-Glo reagent kit (Promega, Madison, Wis.) as per manufacturer's specifications. (3) Materials and Method for The OCN Promoter Assay: The activation of osteocalcin by VDR ligands was evaluated in a rat osteoblast-like cell line RG-15 (ROS 17/2.8) stably expressing rat osteocalcin promoter fused with luciferase reporter gene. The stable cell lines were established as reported before (Activation of Osteocalcin Transcription involves interaction of protein kinase A- and Protein kinase C-dependent pathways. Boguslawski, G., Hale, L. V., Yu, X.-P., Miles, R. R., Onyia, J. E., Santerre R. F., Chandrasekhar, S. J. Biol. Chem. 275, 999-1006, 2000). Confluent RG-15 cells maintained in DMEM/F-12 medium (3:1) containing 5% FBS, 3001 μg/ml G418 and at 37° C. under 5% CO2/95% air atmosphere were trypsinized (0.25% trypsin) and plated into white opaque 96-well cell culture plates (25000 cells/well). After 24 hr, cells (in DMEM/F-12 medium +2% FBS) were treated with various concentrations of compounds, dissolved in DMSO. The final DMSO concentration remained at 0.01% (v/v). After 48 hr treatment, the medium was removed, cells were lysed with 50 μl of lysis buffer (From Luciferase reporter assay system, Roche Diagnostics, Indianapolis, Ind.) and assayed for luciferase activity using the Luciferase Reporter Gene Assay kit from Boehringer Mannheim as per manufacturer's specifications. (4) Materials and Method for The Mouse Hypercalcemia Assay: Weanling, virus-antibody-free, five to six weeks old female DBF mice (Harlan, Indianapolis, Ind.) are used for all the studies. Animals are allowed to acclimate to local vivarium conditions for 2 days. Mice are maintained on a 12 hr light/dark cycle at 22° C. with ad lib access to food (TD 5001 with 1.2% Ca and 0.9% P, Teklad, Madison, Wis.) and water. The animals then are divided into groups with 4-5 mice per group. Different doses of test compounds prepared in 10% Ethanol and 90% sesame oil are administered to mice orally via gavage for 6 days. 1α-25(OH)2D3 0.5 μg/kg/d was also given to one group of mice as the positive control. Serum ionized calcium is evaluated at 6 hours after the last dosing under isoflurane anesthesia by Ciba-Corning Ca++/PH Analyzer, (Model 634, Chiron Diagnostics Corp., East Walpole, Mass.). Raw data of group differences is assessed by analysis of variance (ANOVA) using Fisher's protected least significant difference (PLSD) where the significance level was P<0.05. (5) The Keratinocyte Proliferation Assay: KERtr cells (Human skin keratinocyte transformed with a retrovirus vector, obtained from ATCC) were plated in 96-well flat-bottomed plates (3000 cells/well) in 100 μl keratinocyte serum free medium supplemented with bovine pituitary extract in the absence of EGF (Life Technologies, Rockville, Md.) and incubated at 37° C. for two days. The cells were treated with various concentrations of VDR ligands (ten-fold serial dilution from 10,000 nM to 0.1 nM in triplicate), dissolved in 100 μl keratinocyte serum free medium supplemented with bovine pituitary extract in the absence of EGF and incubated at 37° C. for 72 hr. BrdU (5-bromo-2′-deoxyuridine) incorporation was analyzed as a measure of DNA replication (Cell proliferation ELISA kit, Roche Diagnostics, Indianapolis, Ind.) and absorbance was measured at 405 nm. Potency values (IC50) values were determined as the concentration (nM) of compound that elicited a half-maximal response. (6) Materials and Method for human IL-10 Induction Assay: Isolation of peripheral blood mononuclear cells (PBMCs): A. Collect 50 ml of human blood and dilute with media, RPMI-1640. B. Prepare sterile tubes with ficol. C. Add diluted blood to tubes. D. Centrifuge. E. Discard the top layer and collect the cells from middle layer. F. Divide all cells into four tubes and add media. G. Centrifuge. H. Aspirate off media and resuspend. I. Collect all cells J. Centrifuge. at 1200 rpm for 10 minutes. K. Resuspend in RPMI-1640 with 2% FBS and count cells Stimulation of PBMC: L. Prepare TPA in DMSO. M. Dissolve PHA in water. N. Plate TPA/PHA treated PBMCs in well plates. O. Incubate. Treatment: P. Prepare all compound dilutions in plain RPMI-1640 media. Q. Add diluted compound. R. Incubate. Sample Collection and assay: S. Remove all the cells by centrifugation and assay the supernatant for IL-10 by immunoassay. 1) T. Perform IL-10 assay using anti-human IL-10 antibody coated beads, as described by the manufacturer (Linco Research Inc., St. Charles, Mo.). (8) CaT1 assay Human colon carcinoma, Caco-2 cells, maintained in DMEM (high glucose with mM Hepes buffer; Invitrogen, Carlsbad, Calif.) supplemented with 10% fetal bovine serum (Invitrogen, Carlsbad, Calif.), are plated at 5500 cell per well in a 96-well plate in a total volume of 100 μl/well. The cells are kept in the 96-well plate for 6 days to differentiate them to small intestinal cells that express the calcium transporter, CaT1. On day 3 after plating, old media is removed and replaced with fresh media (150 μl/well). On day 6 the old media is removed and the cells are kept in treatment media (180 μl/well) that contained 10% charcoal stripped fetal bovine serum (Hyclone, Logan, Utah) in DMEM (low glucose, without phenol red; Invitrogen, Carlsbad, Calif.). The cells are treated with various concentrations of VDR ligands (from 0.01 nM to 10,000 nM concentration range) prepared in treatment media (20 μl/well). Twenty hours post-treatment, total RNA is prepared by RNeasy 96 method as described by the manufacturer (Qiagen, Valencia, Calif.). The RNA is reverse transcribed and amplified for human CaT1 and GAPDH (control) messages by quantitative RT-PCR using ABI PRISM 7900HT Sequence Detection System according to manufacturer's instructions (Applied Biosystems, Foster City, Calif.). Optimized primer pairs and probes for human CaT1 and GAPDH genes are obtained commercially (Applied Biosystems, Foster City, Calif.). Each 20 μl quantitative RT-PCR reaction in a 384-well Taqman PCR plate consists of forward and reverse primers (900 nM), Taqman probe (200 nM), total RNA (4 μl form each well of the 96-well culture plate) and 10 μl of Taqman Universal PCR Master Mix (Roche Diagnostics, Indianapolis, Ind.). Reactions are incubated at 48° C. for 30 minutes, followed by 10 minutes at 95° C. and subjected to 40 cycles of PCR (95° C. for 15 seconds followed by 60° C. for 1 minute). GAPDH is used as an internal control and its primer and probe set are obtained commercially (Applied Biosystems, Foster City, Calif.).

<SOH> BACKGROUND OF THE INVENTION <EOH>Vitamin D 3 Receptor (VDR) is a ligand dependent transcription factor that belongs to the superfamily of nuclear hormone receptors. The VDR protein is 427 amino acids, with a molecular weight of ˜50 kDa. The VDR ligand, 1α,25-dihydroxyvitamin D3 (the hormonally active form of Vitamin D) has its action mediated by its interaction with the nuclear receptor known as Vitamin D receptor (“VDR”). The VDR ligand, 1α,25-dihydroxyvitamin D3 (1α,25(OH) 2 D 3 ) acts upon a wide variety of tissues and cells both related to and unrelated to calcium and phosphate homeostasis. The activity of 1α,25-dihydroxyvitamin D3 (1α,25(OH) 2 D 3 ) in various systems suggests wide clinical applications. However, use of conventional VDR ligands is hampered by their associated toxicity, namely hypercalcemia (elevated serum calcium). Currently, 1α,25(OH) 2 D 3 , marketed as Rocaltrol® pharmaceutical agent (product of Hoffmann-La Roche), is administered to kidney failure patients undergoing chronic kidney dialysis to treat hypocalcemia and the resultant metabolic bone disease. Other therapeutic agents, such as Calcipotriol® (synthetic analog of 1α,25(OH) 2 D 3 ) show increased separation of binding affinity on VDR from hypercalcemic activity. Recently, chemical modifications of 1α,25(OH) 2 D 3 have yielded analogs with attenuated calcium mobilization effects (R. Bouillon et. al., Endocrine Rev. 1995, 16, 200-257). One such analog, Dovonex® pharmaceutical agent (product of Bristol-Meyers Squibb Co.), is currently used in Europe and the United States as a topical treatment for mild to moderate psoriasis (K. Kragballe et. al., Br. J. Dermatol. 1988, 119, 223-230). Other vitamin D 3 mimics have been described in the publication, Vitamin D Analogs: Mechanism of Action of Therapeutic Applications , by Nagpal, S.; Lu, J.; Boehm, M. F., Curr. Med. Chem. 2001, 8, 1661-1679. Although some degree of separation between the beneficial action and calcium raising (calcemic) effects has been achieved with these VDR ligands, to date the separation has been insufficient to allow for oral administration to treat conditions such as osteoporosis, cancers, leukemias, and severe psoriasis. One example of a major class of disorder that could benefit from VDR mediated biological efficacy in the absence of hypercalcemia is osteoporosis. Osteoporosis is a systemic disorder characterized by decreased bone mass and microarchitectural deterioration of bone tissue leading to bone fragility and increased susceptibility to fractures of the hip, spine, and wrist (World Health Organization WHO 1994). Osteoporosis affects an estimated 75 million people in the United States, Europe, and Japan. Within the past few years, several antiresorptive therapies have been introduced. These include bisphosphonates, hormone replacement therapy (HRT), a selective estrogen receptor modulator (SERM), and calcitonins. These treatments reduce bone resorption, bone formation, and increase bone density. However, none of these treatments increase true bone volume nor can they restore lost bone architecture. Synthetic vitamin D receptor (VDR) ligands with reduced calcemic potential have been synthesized. For example, a class of bis-phenyl compounds stated to mimic 1α, 25-dihydroxyvitamin D 3 is described in U.S. Pat. No. 6,218,430 and the article; “Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1α, 25-Dihydroxyvitamin D 3” by Marcus F. Boehm, et. al., Chemistry & Biology 1999, Vol 6, No. 5, pgs. 265-275. There remains a need for improved treatments using alternative or improved pharmaceutical agents that mimic 1α, 25-dihydroxyvitamin D 3 to stimulate bone formation, restore bone quality, and treat other diseases without the attendant disadvantage of hypercalcemia.

<SOH> SUMMARY OF THE INVENTION <EOH>Novel compounds having a nucleus of formula “(A)” have been found effective as Vitamin D Receptor (VDR) modulators: Compounds of the present invention with VDR modulating activities are represented by formula (I) wherein the variables R, R′, R p , R p′ , L 1 , L 2 , L 3 , Z p , R F , L F , and Z F , and are as hereinafter defined. The inventors have discovered that compounds described herein display the desirable cell differentiation and antiproliferative effects of 1,25(OH) 2 D 3 with reduced calcium mobilization (calcemic) effects. In another aspect, the present invention is directed towards pharmaceutical compositions containing pharmaceutically effective amounts of compounds of formulae I or a pharmaceutically acceptable salt or prodrug thereof, either singly or in combination, together with pharmaceutically acceptable carriers and/or auxiliary agents. Another aspect of the invention are novel chemical intermediates suitable for preparing the compounds of Formula I. Another aspect of the invention is to use the compounds of the invention to treat or prevent disease states responsive to Vitamin D receptor ligands. Another aspect of the invention is the prevention and treatment of Acne, Actinic keratosis, Alopecia, Alzheimer's disease, Benign prostatic hyperplasia, Bladder cancer, Bone maintenance in zero gravity, Bone fracture healing, Breast cancer, Chemoprovention of Cancer, Crohn's disease, Colon cancer, Type I diabetes, Host-graft rejection, Hypercalcemia, Type II diabetes, Leukemia, Multiple sclerosis, Myelodysplastic syndrome, Insufficient sebum secretion, Osteomalacia, Osteoporosis, Insufficient dermal firmness, Insufficient dermal hydration, Psoriatic arthritis, Prostate cancer, Psoriasis, Renal osteodystrophy, Rheumatoid arthritis, Scleroderma, Skin cancer, Systemic lupus erythematosus, Skin cell damage from Mustard vesicants, Ulcerative colitis, Vitiligo, or Wrinkles; by administering to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula I. Another aspect of the invention is the use of the compounds of Formula I for treating or preventing disease states mediated by the Vitamin D receptor. detailed-description description="Detailed Description" end="lead"?

20060511

20081223

20070510

70225.0

A61K3134

CHANDRAKUMAR, NIZAL S

PHENYL-FURAN COMPOUNDS AS VITAMIN D RECEPTOR MODULATORS

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Submerged hollow fiber membrane module

The present invention discloses a submerged hollow fiber membrane module which is of such a structure that it is easy to expand a module processing capability according to a treatment capacity, provides convenient module coupling properties and module manufacturing properties, maintains a stable flux under an efficient air diffusion condition and prevents the damage of membranes and water leakage caused by the loosening of module connecting regions. The submerged hollow fiber membrane module comprises [I] two module headers (2 and 2′) having a filtrate water collecting portion (3) for collecting filtrate water filtered through hollow fiber membranes and a filtrate water outlet (7), [II] an air diffusion unit 8 consisting of support tubes (9 and 9′) fixing the two module headers (2 and 2′) while keeping them spaced a predetermined distance and air diffusion tubes (11 and 11′) having air diffusion holes (13), and [III] a bundle of hollow fiber membranes (1) having both opposite ends fixed to the insides of the module headers (2 and 2′) by an adhesive (6) so as to form a water collecting space within the module headers (2 and 2′), the ends (5) of the hollow portions of the hollow fiber (20) membranes being opened and disposed in parallel to a filtrate water discharge surface (4).

1. A submerged hollow fiber membrane module, comprising: [I] two module headers having a filtrate water collecting portion for collecting filtrate water filtered through hollow fiber membranes and a filtrate water outlet; [II] an air diffusion unit consisting of support tubes fixing the two module headers while keeping them spaced a predetermined distance and air diffusion tubes having air diffusion holes; and [III] a bundle of hollow fiber membranes having both opposite ends fixed to the insides of the module headers by an adhesive so as to form a water collecting space within the module headers, the ends of the hollow portions of the hollow fiber membranes being opened and disposed in parallel to a filtrate water discharge surface. 2. The module of claim 1, wherein the air diffusion unit includes: an upper support tube whose opposite ends are connected vertically to the upper ends of the module headers and which has an air injection port; a lower support tube whose opposite ends are connected vertically to the lower ends of the module headers and which has an air injection port and air diffusion holes; and two air diffusion tubes which are vertically connected to the support tubes to be disposed in the bundle of hollow fiber membranes and has air diffusion holes. 3. The module of claim 1 or 2, wherein the distance between the module headers and the air diffusion tubes arranged adjacent thereto is 1 to 20 cm. 4. The module of claim 1 or 2, wherein the diameter of the air diffusion holes is 2 to 8 mm. 5. The module of claim 1 or 2, wherein the diameter of the air diffusion holes disposed on the air diffusion tubes is increased by 10 to 100% as compared to the air diffusion holes disposed right above as they go toward a lower part of the module. 6. The module of claim 2, wherein the diameter of the diffusion holes of the lower support tube is preferably 1.5 to 2.0 times larger than the diameter of smallest air diffusion holes of the air diffusion tubes. 7. The module of claim 1, wherein the tensile strength of a hollow fiber membrane constituting the bundle of hollow fiber membranes is 1 kg/strand or more. 8. The module of claim 1, wherein the hollow fiber membrane constituting the bundle of hollow fiber membranes is a composite hollow fiber membrane reinforced by braid and having a tensile strength greater than 10 kg/strand. 9. The module of claim 1, wherein the shape of the module headers is a cylindrical shape or a rectangular shape. 10. The module of claim 1, wherein the air diffusion unit and the module headers are provided with respective connecting members connected for serially coupling two or more submerged hollow fiber membrane modules. 11. The module of claim 10, wherein the connecting members are provided with a path for flowing filtrate water and air between the two module headers and the air diffusion tubes both serially coupled to each other.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a separation membrane module suitable for the field of treatment of water, such as waste water, sewage water, drinking water, etc., and more particularly, to a submerged hollow fiber membrane module which is easy to expand the processing capability of the module according to a processing capacity, suitable for the treatment of a large amount of water because the installation area is small, capable of preventing foulants by an effective air diffusion. A polymer separation membrane is being distributed to a wide variety of fields including the field of existing applications along with the development of its technology, especially, its demand is being increased in the field of water treatment along with the importance of the environment. A hollow fiber type membrane is generally such a module whose membrane is protected by a cylindrical case since it has an advantage in water treatment because of its high throughout per installation area while its mechanical strength is low due to the characteristics of a porous membrane structure. In the module of such type, in case of waste water treatment, as generally known, it is hard to remove foulants accumulated on surfaces of a membrane, and the permeability is lowered due to fouling. 2. Description of the Related Art In order to solve such a problem, submerged modules with no case had been devised. However, in a case that the strength of a membrane is not high enough, there may bring out the degradation of system reliability due to membrane damage. In this case, if air diffusion is not efficiently achieved, a fouling problem still occurs to thus increase the operation pressure and lower the flux. In order to minimize the loss of permeability of the submerged module, foulants accumulated on membranes have to be removed by air diffusion. At this time, a strong air diffusion condition is required, thus there is a possibility that hollow fiber membranes are damaged. Korean Registered Patent No. 22807 proposes a module fixed by developing a hollow fiber membrane in a conical form and folding it in a U shape in order to prevent the pollution of the membrane under a mild air diffusion condition. In this case, however, the volume of the module becomes larger and it is not easy to couple between modules for increasing a processing capacity from a structural viewpoint. A submerged module disclosed in Korean Registered Patent No. 236921 is characterized in that a hollow fiber membrane is not fold in a U shape but air injection port and a filtrate water outlet are connected to one portion of the module with both ends of the hollow fiber membrane being fixed in a I shape. Such module structure is inefficient to the arrangement of a water collecting pipe and an air injecting pipe in coupling a plurality of modules for increasing a processing capacity, and the filtrate water outlet and the air injection port coexist on one portion of the module, to thus decrease workability in the manufacture of a module. Especially, in case of a module used for the treatment of a large amount of water, a rectangular shape in which a bundle of hollow fiber membranes is widely spread is more convenient for collecting a number of modules in a small installation area than a cylindrical shape. The module of such a shape has a merit that it is capable of producing a large amount of treated water on a small installation area, while there is a big possibility that foulants would be accumulated because a bundle of hollow fiber membranes are densely concentrated, thus an efficient air diffusion process has to be accompanied. In this procedure, due to a direct impact applied to membranes, there may be occurred the degradation of quality of treated water by the damage of membranes and a water leakage caused by the loosening of joint portions between module parts when the membranes are used for a long time. Further, in a case that a number of modules are coupled according to a treatment capacity when adapted to a large-scale water treatment, an efficient arrangement is impossible and thus it is difficult to minimize the installation area and it is not easy to couple them. SUMMARY OF THE INVENTION The present invention is designed to solve the problems of the prior art, and therefore the present invention to provide a submerged hollow fiber membrane module which is of such a structure that it is easy to expand a module processing capacity according to a treatment volume, connecting regions of module parts are minimized to thus prevent water leakage due to the loosening of connecting regions when used for a long time, and the workability can be improved in the manufacture of the module. Furthermore, the present invention provides a submerged hollow fiber membrane module which is of such a structure capable of vibrating hollow fiber membranes as air is generated on three sides through an air diffusion unit mounted on the module itself so that an effective air diffusion is enabled in order to prevent a reduction in flow rate and an increase in pressure caused by the accumulation of foulants. Furthermore, the present invention provides a submerged hollow fiber membrane module which is of such a structure that air diffusion tubes for air diffusion also serve as support tubes for supporting the module for the purpose of simplification of a module structure. The present invention to provides connecting means which is capable of expanding the processing capacity of the module easily without an increase of projected installation area by coupling hollow fiber membrane module units. Accordingly, it is an object of the present invention to provide a submerged module which exhibits a high flow rate at a small installation area, provides convenient module coupling properties and module manufacturing properties, maintains a stable flux under an efficient air diffusion condition and prevents the damage of membranes and water leakage caused by the loosening of module connecting regions. To achieve the above object, there is provided a submerged hollow fiber membrane module according to the present invention, comprising: [I] two module headers having a filtrate water collecting portion for collecting filtrate water filtered through hollow fiber membranes and a filtrate water outlet; [II] an air diffusion unit consisting of support tubes fixing the two module headers while keeping them spaced a predetermined distance and air diffusion tubes having air diffusion holes; and [III] a bundle of hollow fiber membranes having both opposite ends fixed to the insides of the module headers by an adhesive so as to form a water collecting space within the module headers, the ends of the hollow portions of the hollow fiber membranes being opened and disposed in parallel to a filtrate water discharge surface . BRIEF DESCRIPTION OF THE DRAWINGS Other objects and aspects of the present invention will become apparent from the following description of embodiments with reference to the accompanying drawings in which: FIG. 1 is a schematic perspective view of a submerged hollow fiber membrane module according to the present invention; FIG. 2 is a cross sectional view showing a module header of FIG. 1 cut out vertically to a longitudinal direction of the hollow fiber membrane; FIG. 3 is a cross sectional view showing a module header of FIG. 1 cut out horizontally to a longitudinal direction of the hollow fiber membrane; FIG. 4 is a schematic view showing an air diffusion of the submerged hollow fiber membrane module according to the present invention; FIG. 5 is a perspective view showing two submerged hollow fiber module serially connected by a connecting member according to the present invention; and FIG. 6 is a perspective view of the connecting member. DESCRIPTION OF THE PREFERRED EMBODIMENT Hereinafter, a preferred embodiment of the present invention will be described in more detail referring to the drawings. FIG. 1 is a schematic perspective view of a submerged hollow fiber membrane module according to the present invention. FIG. 2 is a cross sectional view showing a module header 2 of FIG. 1 cut out vertically to a longitudinal direction of the hollow fiber membrane. FIG. 3 is a cross sectional view showing a module header 2 of FIG. 1 cut out horizontally to a longitudinal direction of the hollow fiber membrane. In FIG. 1, only one string of a hollow fiber membrane 1 is illustrated for convenience. In the present invention, as shown in FIG. 1, a submerged hollow fiber membrane module comprises: [I] two module headers 2 and 2′ having a filtrate water collecting portion 3 and a filtrate water outlet 7; [II] an air diffusion unit 8 consisting of two support tubes 9 and 9′ being transversely connected to the module headers 2 and 2′ and fixing and supporting them and two air diffusion tubes 11 and 11′ vertically connected to the support tubes 9 and 9′ and located in a bundle of hollow fiber membranes; and [III] a bundle of hollow fiber membranes 1 fixed to the insides of the module headers by an adhesive 6. The module headers 2 and 2′ consisting of the filtrate water collecting portion 3 and the filtrate water outlet 7 can prevent water leakage caused by the loosening of connecting regions between module parts because the connecting regions are omitted by minimizing the number of module parts, and exhibits the effect of reducing cost because it is easy to manufacture modules. Meanwhile, the air diffusion unit 8 consisting of the upper support tube 9, the lower support tube 9′ and the two air diffusion tubes 11 and 11′ carry out both the diffusion function and the function of a supporting element for fixing the two module headers 2 and 2′ while maintaining a predetermined distance between them, thereby distributing to the simplification of a module structure. The upper support tube 9 has both opposite end portions vertically connected to the upper end portions of the module headers 2 and 2′, respectively, and provided with an air injection port 12 on the central portion thereof. Meanwhile, the lower support tube 9 has both opposite end portions vertically connected to the lower end portions of the module headers 2 and 2′, respectively, and provided with air injection port 12 on the central portion thereof, and a plurality of air diffusion holes 13 along a longitudinal direction. Meanwhile, the air diffusion tubes 11 and 11′ are vertically connected to the upper support tube 9 and the lower support tube 9′ to be located in the bundle of hollow fiber membranes, and a plurality of air diffusion holes 13 along a longitudinal direction. Meanwhile, the hollow fiber membrane 1 is fixed to the insides of the module headers by an adhesive 6 so that both opposite ends are provided with a water collecting space inside the module headers 2 and 2′, and the ends 5 of the hollow fiber portions of the hollow fiber membrane are opened and disposed in parallel to a filtrate water discharge surface 4. Additionally, the air diffusion unit 8 and the module headers 2 and 2′ are provided with respective connecting members optionally mounted for serially coupling two or more submerged hollow fiber membrane modules according to the present invention. Preferably, the connecting members are provided with a path for flowing filtrate water and air between the two module headers and the air diffusion tubes both serially coupled to each other. Preferably, the distance between the module header 2 and the air diffusion tube 11 or the distance between the module header 2′ and the air diffusion tube 11′ is 1 to 20 cm. In other words, the distance between the module headers 2 and 2′ and the air diffusion tubes 11 and 11′ arranged adjacent thereto is preferably 1 to 20 cm. Further, the diameter of the air diffusion holes 13 formed on the two air diffusion tubes 11 and 11′ and on the lower support tube 9′ is preferably 2 to 8 mm. In this way, the present invention provides the air diffusion holes existing on the two air tubes 11 and 11′ and the lower support tube 9′, thus enabling to vibrate the hollow fiber membranes on three sides by air. Air used for air diffusion is introduced through the air injection port 12 to generate relatively large bubbles through the air diffusion holes 13, thereby causing to physically clean the membranes. Especially, air is generated through the diffusion holes located at the air diffusion tubes 11 and 11′ in the vertical direction 20 cm or less distant from the module headers 2 and 2′ where hollow fiber membranes are densely concentrated and the accumulation of foulants is concentrated. At the same time, as air is generated from the lower support tube 9′ on the lower part of the module to raise bubbles, the membranes are vibrated, thereby preventing fouling. The amount of bubbles air-diffused due to a pressure difference caused by a water head becomes different according to the disposition of the air diffusion holes. Thus, it is preferable to compensate the difference by increasing the diameter of the air diffusion holes disposed on the lower part of the module. Especially, such air diffusion unit is not an independent apparatus, but also serves as a module support tube, thereby enabling the simplification of a module structure. Further, bubbles are generated from three sides around the lower part of the module and the module header portions at the left and right, thereby enabling efficient air diffusion. The module provided by the present invention comprises a bundle of hollow fiber membranes 1 having a separation membrane function, and filtered water permeated from the outside of the membranes by a suction pressure or a natural pressure caused by a water head is collected at the water collecting portion 3 of the module headers 2 and 2′ at both sides through the insides of the membranes. At this time, on the filtrate water discharge surface 4 inside the module header, as shown in FIG. 3, the ends 5 of the hollow portions of the hollow fiber membranes are opened in parallel to the filtrate discharge surface 4 while being fixed thereto by an adhesive 6, thus it is possible to collect the filtrate water in the water collecting portion 3 through the filtrate water discharge surface 4. The filtrate water collected on the water collecting portion 3 is discharged through the filtrate water outlet 7 of the module header 2 connected to a filtrate water spouting apparatus such as a suction pump, etc. At this time, the filtrate water outlets 7 of the module headers 2 and 2′ can exist on the upper and lower surface, respectively, in consideration of expandability by the coupling of module units. In this structure, in order to carry out operation by one module unit, each individual outlet may be connected to the filtrate water spouting apparatus, or the filtrate water outlet on the lower end surface of the header is closed by using a closed connecting member and only the filtrate water outlet on the upper end surface is made useable by connection. The length of the hollow fiber membranes 1, that is, the distance between the module headers 2 and 2′, is preferably 80 to 200 cm. As seen from above, the two headers 2 and 2′ perform water collecting function symmetrically, thereby compensating a pressure drop dependent upon the length of the hollow fiber membranes 1. The water has to be permeated only through micro pores existing on the outer surface of the hollow fiber membranes during a filtration process. However, in a case that water leaks through a gap between the module parts or the like, the filtration function is degraded. In the module provided by the present invention, the module headers 2 and 2′ are configured as a single part, and combined with the hollow fiber membranes 1 only by the adhesive 6. Thus, in comparison with the assembling of a plurality of parts, the manufacturing cost of the module can be lowered and water leakage caused by the loosening of connecting regions between parts can be prevented. At this time, the shape of the module headers 2 and 2′ can be selected from a group consisting of a cylindrical shape or a rectangular shape. Meanwhile, the treatment of wastewater containing suspended solids of a high concentration may bring out a reduction of flow rate or a pressure increase due to the accumulation of foulants, and thus a filtration process is accompanied by an air diffusion process by using air. The module provided by the present invention does not require a separate air diffusion apparatus since the module itself is provided with an air diffusion function, and the air diffusion unit 8 of the module also serves as a support tube of the module headers 2 and 2′, thereby enabling the simplification of the module structure. That is, the air diffusion unit 8 of the module includes upper and lower support tubes 9 and 9′ in a transverse direction vertically connected to the headers 2 and 2′, respectively, so as to fix the module headers 2 and 2′ and two air diffusion tubes 11 and 11′ in a vertical direction vertically connected to the upper and lower support tubes 9 and 9′, respectively, and disposed in a bundle of hollow fiber membranes. At this time, the air injection port 12 is disposed on the center of the upper and lower support tubes 9 and 9′, to thus be connected to an air supply device. At this time, the air injection port 12 can exist on the upper and lower support tubes, respectively, in consideration of expandability by the coupling of module units. In this structure, in order to carry out operation by one module unit, each individual air injection port 12 may be connected to an air supply device, or the air injection port of the lower support tube 9′ is closed by using a closed connecting member and only the air injection port of the upper support tube 9 is made useable by connection. For an efficient air diffusion process, the air diffusion holes 13 are preferably disposed on the lower support tube 9′ of the air diffusion unit 8 among the support tubes of the transverse direction. Additionally, the hollow fiber bundles near the module headers 2 and 2′ are very densely concentrated around as compared to the central part of the module and have a relatively small clearance, thus the accumulation of foulants are concentrated on that portion. Therefore, in order to maximize the efficiency of air diffusion, it is preferable that another air diffusion tubes 11 and 11′ in a vertical direction are disposed around the module headers 2 and 2′, that is, on the point 1 to 20 cm distant from the module headers 2 and 2′. In a case that such a module having the air diffusion function is immersed into a raw water desired to be actually treated, as the depth of water becomes larger, that is, as it goes toward a lower part of the module, the flow rate of air from air diffusion holes 13 is reduced due to a pressure difference by the water head. Taking this into consideration, the diameters of air diffusion holes 13 disposed on the two air diffusion tubes 11 and 11′ of a vertical direction are preferably increased by 10 to 100% as compared to the holes disposed right above as they go toward a lower part of the module. The diameter of the diffusion holes 13 of the lower support tube 9′ connecting the lower part of the module is preferably 1.5 to 2.0 times the diameter of smallest air diffusion holes of the air diffusion tubes 11 and 11′ of the transverse direction, and the air diffusion holes 13 are preferably have a diameter of 2 to 8 mm. In case of bringing about air diffusion by the above-described method, as bubbles generated from the air diffusion holes 13 of the lower part of the module rise to an upper part, they continually vibrate the hollow fiber membranes 1 in transverse disposition and prevent the accumulation of foulants. The bubbles generated from the air diffusion tubes 11 and 11′ of a vertical direction at the left and right prevent the accumulation foulants on the portion where the membranes are concentrated. FIG. 4 is a schematic view showing an air diffusion of a submerged hollow fiber membrane module according to the present invention. The above-stated submerged hollow fiber membrane module is designed in such a manner that bubbles are generated on three sides in order to prevent the degradation of module performance due to the pollution of the membranes to directly vibrate the hollow fiber membranes and thus prevent the accumulation of foulants. Therefore, when the module is operated for a long time with strong air diffusion, there is a possibility that the membranes may be damaged. For this reason, it is preferable to use a high strength hollow fiber membrane having a tensile strength greater than 1 kg/strand. More preferably, a composite hollow fiber membrane having a tensile strength greater than 10 kg/strand as being reinforced by braid is used. In a case that the submerged module is adapted to a large scale water treatment process, it is advantageous to obtain a high flow rate to be treated at a small mounting area. For this, the module according to the present invention is capable of using a single unit module according to a treatment capacity as well as increasing a processing capacity as two or more unit modules are combined without an increase in projected installation area. A structure in which hollow fiber membrane module units of the present invention are connected in plural numbers by a connecting member will be explained in detail with reference to FIG. 5 showing an embodiment in which two module units are combined. FIG. 5 is a perspective view of two submerged hollow fiber membrane modules serially connected by a connecting member according to the present invention. In FIG. 5, only one string of hollow fiber membrane modules is illustrated for convenience. The units of the hollow fiber membrane modules are connected vertically as shown in FIG. 5. The filtrate water outlets of the upper end surfaces of lower module heads 14 and 14′ are connected and penetrated to the filtrate water outlets of the lower end surface of upper module headers 2 and 2′, thereby allowing the spouting of filtrate water collected in a filtrate water collecting portion of the upper and lower module headers through the filtrate water outlets 7 of the upper module headers 2 and 2′ connecting a filtrate water spouting apparatus such as a suction pump or the like. At this time, the filtrate water outlets of the lower end surfaces of the lower module headers 14 and 14′ are preferably used by being closed by a closed connecting member like the embodiment of FIG. 4. Although FIG. 6 shows a connecting member for connecting and penetrating the upper and lower module headers by an O-ring 19, but the present invention is not limited thereto. Regarding the connection of the air diffusion units, as shown in FIG. 5, the air injection port disposed on the upper support tube 15 of the air diffusion unit of the lower module is connected and penetrated to the air injection port disposed on the lower support tube 9′ of the air diffusion unit of the upper module, thereby supplying air to the entire air diffusion units of the upper and lower modules through the air injection port of the upper support tube 9 of the air diffusion unit of the upper module connecting an air supply device. At this time, the air injection port disposed on the lower support tube 15′ of the air diffusion unit of the lower module is preferably used b being closed by a closed connecting member like the embodiment of FIG. 4. The connecting member to be used may include a connecting member of a screw or a clamp coupling type, but not limited thereto. By the above-stated connecting method, a processing capacity of the module can be expanded without adding a projected installation area, thus it is possible to cope with a water treatment of various treatment scales. A conventional submerged hollow fiber membrane module is problematic in that it is difficult to expand a module processing capability and manufacture a module, many water leakages occur due to the loosening of module connecting regions, the maintenance of flux is unstable in an air diffusion condition, and hollow fiber membranes are damaged. The submerged module according to the present invention makes it easier to expand a module processing capability according to a treatment capacity, is excellent in durability owing to the minimization of module parts, makes it easier to carry out a job for manufacturing a module, and has such a structure capable of vibrating hollow fiber membranes as air is generated on three sides through an air diffusion unit, thereby effectively preventing fouling.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to a separation membrane module suitable for the field of treatment of water, such as waste water, sewage water, drinking water, etc., and more particularly, to a submerged hollow fiber membrane module which is easy to expand the processing capability of the module according to a processing capacity, suitable for the treatment of a large amount of water because the installation area is small, capable of preventing foulants by an effective air diffusion. A polymer separation membrane is being distributed to a wide variety of fields including the field of existing applications along with the development of its technology, especially, its demand is being increased in the field of water treatment along with the importance of the environment. A hollow fiber type membrane is generally such a module whose membrane is protected by a cylindrical case since it has an advantage in water treatment because of its high throughout per installation area while its mechanical strength is low due to the characteristics of a porous membrane structure. In the module of such type, in case of waste water treatment, as generally known, it is hard to remove foulants accumulated on surfaces of a membrane, and the permeability is lowered due to fouling. 2. Description of the Related Art In order to solve such a problem, submerged modules with no case had been devised. However, in a case that the strength of a membrane is not high enough, there may bring out the degradation of system reliability due to membrane damage. In this case, if air diffusion is not efficiently achieved, a fouling problem still occurs to thus increase the operation pressure and lower the flux. In order to minimize the loss of permeability of the submerged module, foulants accumulated on membranes have to be removed by air diffusion. At this time, a strong air diffusion condition is required, thus there is a possibility that hollow fiber membranes are damaged. Korean Registered Patent No. 22807 proposes a module fixed by developing a hollow fiber membrane in a conical form and folding it in a U shape in order to prevent the pollution of the membrane under a mild air diffusion condition. In this case, however, the volume of the module becomes larger and it is not easy to couple between modules for increasing a processing capacity from a structural viewpoint. A submerged module disclosed in Korean Registered Patent No. 236921 is characterized in that a hollow fiber membrane is not fold in a U shape but air injection port and a filtrate water outlet are connected to one portion of the module with both ends of the hollow fiber membrane being fixed in a I shape. Such module structure is inefficient to the arrangement of a water collecting pipe and an air injecting pipe in coupling a plurality of modules for increasing a processing capacity, and the filtrate water outlet and the air injection port coexist on one portion of the module, to thus decrease workability in the manufacture of a module. Especially, in case of a module used for the treatment of a large amount of water, a rectangular shape in which a bundle of hollow fiber membranes is widely spread is more convenient for collecting a number of modules in a small installation area than a cylindrical shape. The module of such a shape has a merit that it is capable of producing a large amount of treated water on a small installation area, while there is a big possibility that foulants would be accumulated because a bundle of hollow fiber membranes are densely concentrated, thus an efficient air diffusion process has to be accompanied. In this procedure, due to a direct impact applied to membranes, there may be occurred the degradation of quality of treated water by the damage of membranes and a water leakage caused by the loosening of joint portions between module parts when the membranes are used for a long time. Further, in a case that a number of modules are coupled according to a treatment capacity when adapted to a large-scale water treatment, an efficient arrangement is impossible and thus it is difficult to minimize the installation area and it is not easy to couple them.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is designed to solve the problems of the prior art, and therefore the present invention to provide a submerged hollow fiber membrane module which is of such a structure that it is easy to expand a module processing capacity according to a treatment volume, connecting regions of module parts are minimized to thus prevent water leakage due to the loosening of connecting regions when used for a long time, and the workability can be improved in the manufacture of the module. Furthermore, the present invention provides a submerged hollow fiber membrane module which is of such a structure capable of vibrating hollow fiber membranes as air is generated on three sides through an air diffusion unit mounted on the module itself so that an effective air diffusion is enabled in order to prevent a reduction in flow rate and an increase in pressure caused by the accumulation of foulants. Furthermore, the present invention provides a submerged hollow fiber membrane module which is of such a structure that air diffusion tubes for air diffusion also serve as support tubes for supporting the module for the purpose of simplification of a module structure. The present invention to provides connecting means which is capable of expanding the processing capacity of the module easily without an increase of projected installation area by coupling hollow fiber membrane module units. Accordingly, it is an object of the present invention to provide a submerged module which exhibits a high flow rate at a small installation area, provides convenient module coupling properties and module manufacturing properties, maintains a stable flux under an efficient air diffusion condition and prevents the damage of membranes and water leakage caused by the loosening of module connecting regions. To achieve the above object, there is provided a submerged hollow fiber membrane module according to the present invention, comprising: [I] two module headers having a filtrate water collecting portion for collecting filtrate water filtered through hollow fiber membranes and a filtrate water outlet; [II] an air diffusion unit consisting of support tubes fixing the two module headers while keeping them spaced a predetermined distance and air diffusion tubes having air diffusion holes; and [III] a bundle of hollow fiber membranes having both opposite ends fixed to the insides of the module headers by an adhesive so as to form a water collecting space within the module headers, the ends of the hollow portions of the hollow fiber membranes being opened and disposed in parallel to a filtrate water discharge surface .

20060512

20100330

20070607

71549.0

B01D6502

MENON, KRISHNAN S

SUBMERGED HOLLOW FIBER MEMBRANE MODULE

UNDISCOUNTED

ACCEPTED

B01D

ACCEPTED

Radar apparatus or like

A radar apparatus or like is provided in which a rate at which detected image data is written into an image memory is prevented from decreasing, irrespective of an enlarged amount of the detected image data. When an azimuth direction enlargement section 90a of a W data generator 9 receives detected image data of a certain sweep, the azimuth direction enlargement section 90a outputs the detected image data to an image memory 10, and delays the detected image data, depending on a cycle of an azimuth direction shift timing signal. Next, when detected image data of a next sweep is drawn into a pixel adjacent in an azimuth direction (sweep moving direction) to a pixel into which previous detected image data has been drawn and is located at the same distance in a sweep distance direction, the delayed detected image data is compared with new detected image data, and the greater data is drawn into the new pixel. Here, when the delayed detected image data is greater, this detected image data is eventually enlarged in the azimuth direction.

1. A radar apparatus or like comprising: a coordinate converter for converting detected data at each sample point obtained in a polar coordinate system into a rectangular coordinate system; a detected image data generator for generating detected image data corresponding to each pixel in an image memory based on the detected data; and an image memory for storing detected image data output from the detected image data generator, wherein the apparatus comprises data shifter for shifting detected image data input from the detected image data generator with predetermined timing and outputting the detected image data, and azimuth direction detected image data corrector for comparing detected image data of a current sweep from the detected image data generator with detected image data of a previous sweep from the data shifter at the same position in a sweep distance direction, and outputting a maximum value of the pieces of detected image data as detected image data of the current sweep. 2. A radar apparatus or like according to claim 1, wherein the azimuth direction detected image data corrector comprises a correction stopper for, when a predetermined number or more of consecutive pieces of detected image data greater than or equal to a predetermined threshold value are present over a plurality of sweeps at the same position in a distance direction, stopping replacement of detected image data of a current sweep with detected image data of a previous sweep based on a sweep on which detected image data at the same position in the distance direction has a value less than the threshold value. 3. A radar apparatus or like according to claim 1 or 2, comprising a distance direction detected image data corrector for comparing a predetermined number of consecutive pieces of detected image data in the distance direction on the same sweep, and outputting most peripheral detected image data of the pieces of detected image data as a maximum value of the consecutive pieces of detected image data. 4. A radar apparatus or like according to any of claims 1 to 3, comprising a selector for selecting the number of sweeps to be shifted by the data shifter. 5. A radar apparatus or like according to claim 4, wherein the selector selects the number of pieces of detected image data to be compared by the distance direction detected image data corrector.

TECHNICAL FIELD The present invention relates to an apparatus for converting a detected signal which is received by a radar apparatus, a sonar apparatus, or the like and is represented by a polar coordinate system, into a rectangular coordinate system, storing resultant data into an image memory, and displaying the data on a raster scan type display. Particularly, the present invention relates to an enlarged display of detected data obtained from a detected signal. BACKGROUND ART In raster scan type radar apparatuses, the size of a video of a radar is basically determined based on a horizontal beam width and a transmitted pulse width. The wider the horizontal beam width, the larger the expansion in an azimuth direction of echo, and the longer the transmitted pulse width, the larger the expansion in a distance direction of echo. Therefore, due to the expansion of the horizontal beam width of a transmitted wave beam and a received wave beam formed by an antenna, even the same target which is enlarged in the azimuth direction and displayed at a position distant from a sweep center on a display, becomes smaller as the target approaches near a ship carrying the radar apparatus (near the center). This tendency becomes more significant as the resolution of a display is increased (a smaller size of each pixel). In a display having such a high resolution, a target near the position of the own ship is displayed as having a considerably small size. When a sea surface reflection removing process is performed, the size of a target is further reduced due to an influence of the process, so that the target size reduction near the center becomes more significant, resulting in a significant reduction in visibility. As a radar apparatus which solves such a problem, there is an apparatus which, after drawing an image at a pixel where a target is present, following this write operation, accesses again a pixel adjacent thereto in a direction substantially opposite to a sweep moving direction in a rectangular coordinate system, compares data already stored at the adjacent pixel with the current input data, and writes the greater data into the adjacent pixel (see, for example, Patent Documents 1 and 2). [Patent Document 1] JP No. 2648983 B [Patent Document 2] JP No. 2003-28950 A However, in such a conventional radar apparatus, access (drawing) is performed with respect to the same pixel a plurality of times, so that the number of times of access to an image memory during one cycle of sweeping increases. Therefore, a time required to access the image memory increases with an increase in the number of pixels to be enlarged. Here, when display is performed on a high-resolution display, since each pixel in the image memory also inevitably becomes smaller, the number of pixels to be enlarged increases, so that a time required to write detected image data into the image memory increases. On the other hand, in recent years, some radar apparatuses have an antenna having a high rotational speed so as to support high-speed ships, for example. Therefore, when an attempt is made to perform the above-described enlargement/display process in such a high-speed antenna rotation type radar apparatus, it is highly likely that there is not an enough time to write data into the image memory, so that the entire image memory cannot be updated during one cycle of sweeping. In conventional radar apparatuses, detected image data is enlarged only in the azimuth direction, so that the shape of a target displayed on a display differs from its actual shape, i.e., becomes unnatural. Also in conventional radar apparatuses, detected image data is enlarged irrespective of the size of a target, so that detected image data which does not require enlargement is also enlarged, and therefore, display resolution is reduced more than necessary. An object of the present invention is to provide a radar apparatus in which a rate at which detected image data is written into an image memory, is not reduced, irrespective of the enlarged amount of the detected image data, and like apparatuses thereto. Another object of the present invention is to provide a radar apparatus which can obtain an enlarged image, depending on detected data (detected signal) of a target, by enlarging detected image data in two-dimensional directions, and like apparatuses thereto. Still another object of the present invention is to provide a radar apparatus which can reliably display a target around a ship carrying the radar (own ship) without enlarging detected image data when it is not required, and like apparatuses thereto. DISCLOSURE OF INVENTION The present invention provides a radar apparatus or like comprising a coordinate converter for converting detected data at each sample point obtained in a polar coordinate system into a rectangular coordinate system, a detected image data generator for generating detected image data corresponding to each pixel in an image memory based on the detected data, and an image memory for storing detected image data output from the detected image data generator. The apparatus comprises data shifter for shifting detected image data input from the detected image data generator with predetermined timing and outputting the detected image data, and azimuth direction detected image data corrector for comparing detected image data of a current sweep from the detected image data generator with detected image data of a previous sweep from the data shifter at the same position in a sweep distance direction, and outputting a maximum value of the pieces of detected image data as detected image data of the current sweep. In this configuration, the data shifter shifts detected image data from the detected image data generator, depending on predetermined timing (an azimuth direction shift timing signal described below), and outputs resultant data. Specifically, detected image data of a current sweep is input with predetermined timing, and at the same time, a plurality of pieces of previous detected image data at the same distance on sweeps are output from the data shifter. Next, detected image data at the same position in a sweep distance direction of a plurality of sweeps including the detected image data thus obtained of the current sweep are compared. When the detected image data of the current sweep is smaller than previous detected image data before shifting, the detected image data of the current sweep is replaced with detected image data of a previous sweep. Thereby, the previous sweep and the current sweep have the same detected image data, and as a result, detected image data of a pixel corresponding to the previous sweep is enlarged into pixels adjacent in a sweep rotational direction. Since this operation is repeatedly performed, the number of pixels for enlargement is determined, depending on the number of sweeps to be shifted. For example, when detected image data of two previous sweeps are shifted, original detected image data indicating a target is enlarged by two pixels in the sweep rotational direction. In the present invention, the azimuth direction detected image data corrector comprises a correction stopper for, when a predetermined number or more of consecutive pieces of detected image data greater than or equal to a predetermined threshold value are present over a plurality of sweeps at the same position in a distance direction, stopping replacement of detected image data of a current sweep with detected image data of a previous sweep based on a sweep on which detected image data at the same position in the distance direction has a value less than the threshold value. With this configuration, when there are consecutive pieces of detected image data greater than or equal to a predetermined threshold value at the same position in the sweep distance direction, extending over a predetermined number or more of sweeps, the correction stopper provides a predetermined value (“0”, etc.) which is smaller than the threshold value to the detected image data with azimuth direction shift timing following azimuth direction shift timing with which the consecutive pieces of detected image data greater than or equal to the predetermined threshold value are ended. Thereby, detected image data is not enlarged in the sweep azimuth direction (sweep moving direction) immediately after a predetermined number or more of consecutive pieces of detected image data at the same position in the sweep distance direction are ended, irrespective of the number of sweeps to be shifted by the data shifter. In the present invention, the radar apparatus or like comprises a distance direction detected image data corrector for comparing a predetermined number of consecutive pieces of detected image data in the distance direction on the same sweep, and outputting most peripheral detected image data of the pieces of detected image data as a maximum value the consecutive pieces of detected image data. With this configuration, most peripheral detected image data of consecutive pieces of detected image data present on the same sweep is compared with detected image data which is present closer to the center than the most peripheral detected image and within a predetermined range. When the detected image data closer to the center is greater than the most peripheral detected image data, a value of the detected image data closer to the center is provided as the most peripheral detected image data. Thereby, the most peripheral detected image data has the same value as that of predetermined detected image data present closer to the center than the most peripheral detected image data. As a result, the detected image data is enlarged in the sweep distance direction. In the present invention, the radar apparatus or like comprises a selector for selecting the number of sweeps to be shifted by the data shifter. With this configuration, by selecting the number of sweeps to be shifted by the data shifter using the selector, the number of sweeps to be compared at the time point of generating detected image data of a current sweep (newest sweep) is determined. As described above, an enlarged amount in the azimuth direction depends on the number of sweeps to be compared, i.e., the number of sweeps to be shifted. Therefore, by selecting the number of sweeps, the number of pixels by which detected image data is enlarged in the sweep azimuth direction is selected. In the present invention, the selector selects the number of pieces of detected image data to be compared by the distance direction detected image data corrector. With this configuration, the selector selects the number of pieces of detected image data to be compared by the distance direction detected image data corrector, thereby determining the number of pieces of detected image data to be compared at the time point of generating detected image data at a certain sample point on a sweep. As described above, an enlarged amount in the distance azimuth direction depends on the detected image data to be compared, i.e., the number of pieces of detected image data to be shifted. Therefore, by selecting the number of pieces of detected image data, the number of pixels by which detected image data is enlarged in the sweep distance direction is selected. According to the present invention, detected image data of a target can be enlarged without increasing the number of times of access to an image memory, thereby making it possible to display a detected image without decreasing image drawing speed. In other words, even when high speed drawing is required, a target near an own ship can be enlarged and displayed, and it is possible to prevent failure of updating an image within one cycle of sweeping. Therefore, a radar apparatus capable of reliably and clearly displaying a target, and like apparatuses thereto, can be configured. According to the present invention, the enlarged amount of detected image data is limited, so that an originally large detected image of a target is prevented from being enlarged more than necessary. Therefore, a radar apparatus capable of preventing a reduction in display resolution more than necessary, and like apparatuses thereto, can be configured. According to the present invention, an image is enlarged in a sweep azimuth direction as well as in a distance direction. Therefore, a radar apparatus which displays a detected image having a shape corresponding to an original target, resulting in excellent visibility, and like apparatuses thereto, can be configured. According to the present invention, the enlarged amount of detected image data can be selected Therefore, a radar apparatus capable of enlarging a detected image of a target, depending on a size requested by the operator, and like apparatuses thereto, can be configured. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a block diagram illustrating a main portion of a radar apparatus of an embodiment of the present invention. FIG. 2 includes a block diagram illustrating a configuration of a W data generator 9 and a block diagram illustrating target data detecting sections 91 and 94. FIG. 3 is a block diagram illustrating an azimuth direction data extractor 92. FIG. 4 is a logic circuit diagram of an azimuth direction enlargement permitting signal calculator 927. FIG. 5 is a diagram illustrating each piece of detected image data, an azimuth direction enlargement permitting signal, a delayed azimuth direction enlargement permitting signal, and azimuth direction enlargement resultant data, when enlargement is performed in an azimuth direction. FIG. 6 is a diagram illustrating each piece of detected image data, data output from each shift register, and distance direction enlargement resultant data, when enlargement is performed in a distance direction. FIG. 7 is a diagram illustrating an image memory, sample points of sweeps (points where detected image data is present), an enlarged range in the azimuth direction, and an enlarged range in the distance direction. DESCRIPTION OF THE INVENTION A radar apparatus according to an embodiment of the present invention will be described with reference to the accompanying drawings. FIG. 1 is a block diagram illustrating a main portion of the radar apparatus of this embodiment. A radar antenna 1 transmits pulsed radio waves (transmitted pulse signal) to the outside while rotating in predetermined rotation cycles on a horizontal plane during a transmission time interval. Also, the radar antenna 1 receives radio waves (detected signal) reflected from a target in a polar coordinate system during a reception time interval, and outputs the detected signal to a receiver 2, and also outputs sweep angle data (antenna angle θ) to a draw address generator 6. The receiver 2 detects the detected signal from the radar antenna 1, and subjects the detected signal to a sea surface reflection suppressing (STC) process or the like, followed by amplification, and outputs a resultant signal to an AD conversion section 3. The AD conversion section 3 samples this analog detected signal in predetermined cycles so as to convert the analog signal into digital detected data. One sweep of detected data thus converted into a digital form is written into a sweep memory 4 in real time, and this one sweep of data is output from the sweep memory 4 to a MAX extractor 8 by the time when detected data obtained by the next transmission is written again into the sweep memory 4. A selector 5 receives a write clock signal (hereinafter simply referred to as a “W clock”) and a read clock signal (hereinafter referred to as a “R clock”), and outputs the W clock when detected data is to be written into the sweep memory 4, and the R clock when detected data is to be read out from the sweep memory 4. As used herein, the W clock is a clock having a cycle corresponding to a detection distance, and the R clock is a clock which is used when detected data read out from the sweep memory 4 is subjected to a process described below and resultant data is drawn into an image memory 10. The draw address generator 6 (“coordinate converter” of the present invention) creates addresses which designate pixels in the image memory 10 arranged in a corresponding rectangular coordinate system, based on an antenna angle θ (where a predetermined direction is used as a reference) and a read position r in the sweep memory 4, directing outward from a rotation center of a sweep as a start address, and outputs the addresses to the image memory 10. Note that, specifically, the draw address generator 6 is composed of hardware which realizes the following expressions. X=Xs+r−sin θ Y=Ys+r−cos θ X, Y: an address designating a pixel in the image memory Xs, Ys: the center address of a sweep r: a distance from the center θ: the angle of a sweep (antenna) A FIRST/LAST detector 7 detects timing with which a sweep first or last accesses each pixel of the image memory 10 which is represented in the rectangular coordinate system and is set by the draw address generator 6, and outputs the detected timing as a FIRST signal or a LAST signal to the MAX extractor 8 and a W data generator 9, within one cycle of sweeping. As used herein, the timing with which a sweep first accesses a pixel refers to timing with which a sample point on the sweep (i.e., a point where detected data is present) first accesses the pixel. As used herein, the timing with which a sweep last accesses a pixel refers to timing with which a sample point on the sweep (i.e., a point where detected data is present) last accesses the pixel. The FIRST/LAST signal is detected based on a signal which is generated during a calculation process for converting polar coordinate system data into rectangular coordinate system data. The MAX extractor 8, which corresponds to “detected image data generator” of the present invention, comprises an extraction memory 80 having a capacity corresponding to detected data on one sweep, and writes detected data read from the sweep memory 4 into the extraction memory 80 with the timing of the FIRST signal, and during a period of time other than the timing of the FIRST signal, compares detected data corresponding to the pixel read from the sweep memory 4 with detected data stored in the extraction memory 80 to detect the maximum value, and writes the maximum value into the extraction memory 80 again. Thereafter, the MAX extractor 8 outputs detected data having the maximum value (MAX data) written in the extraction memory 80, as detected image data, to the W data generator 9 with the timing of the LAST signal. As illustrated in FIG. 2(a), the W data generator 9 comprises an azimuth direction enlargement section 90a corresponding to “azimuth direction detected image data corrector” of the present invention, and a distance direction enlargement section 90b corresponding to “distance direction detected image data corrector” of the present invention. Here, FIG. 2(a) is a block diagram illustrating a configuration of the W data generator. Note that the block diagram will be specifically described below. When drawing for updating is performed, the azimuth direction enlargement section 90a calculates a maximum value of past input data corresponding to a plurality of pixels adjacent to the pixel in a direction opposite to a sweep rotational direction at the same distance (r) and new input data of a pixel to be currently drawn and updated, and uses the maximum value as data to be written into the pixel to be drawn and updated. Therefore, when a pixel corresponding to a point at a distance r from the sweep center is enlarged into (m+1) pixels in the azimuth direction, there are m columns of memory each of which has a capacity corresponding to the enlarged distance and to which addresses are assigned in the distance direction, and at the time of drawing and updating a pixel positioned at an address r (LAST timing), new input data of a pixel to be drawn is stored into the address r of the first-column memory, and at the same time, data already stored is written into the address r of the second-column memory. In other words, data stored in the nth-column memory is successively shifted to the address r of the (n+1)th-column memory, and data stored in the last column is deleted. For example, when there are two columns (m=2) of memory, it is assumed that new input data of a pixel to be drawn and updated which is positioned at the address r is detected image data, data read from the address r of the first-column memory is past detected image data A, and data read from the address r of the second-column memory is past detected image data B. In this case, the maximum value of the three pieces of data, i.e., the detected image data, the past detected image data A, and the past detected image data B, is an output of the azimuth direction enlargement section 90a, which is in turn input to the next-stage distance direction enlargement section 90b. As used herein, regarding the azimuth direction shift timing, azimuth direction shift is performed when a point of interest at the distance r on a following sweep is compared with a point at the same distance r on a preceding sweep in a rectangular coordinate system, and the coordinate points corresponding to the two points are different from each other in the rectangular coordinate system. In this embodiment, the maximum value of all data corresponding to each pixel is assumed to be new input data of the W data generator. Since the maximum value is determined with the LAST timing of last access to a pixel, the azimuth direction shift timing is also determined using the LAST signal. Therefore, timing with which a pixel is drawn is the same as the azimuth direction shift timing. The distance direction enlargement section 90b performs enlargement in a distance direction for each sweep based on detected image data which has been subjected to the azimuth direction enlargement process by the azimuth direction enlargement section 90a. For example, when enlargement is performed by n pieces in a distance direction using the R clock, image data at each distance is assumed to be the maximum value of one piece of output data at the distance of the azimuth direction enlargement section 90a and (n−1) pieces of output data adjacent on the sweep center side from the distance of the azimuth direction enlargement section 90a (a total of n pieces). Specifically, the output of the azimuth direction enlargement section 90a is successively shifted using the R clock, and the maximum value of n pieces of data at respective distances (r+1), (r+2), . . . , and (r+n) of the azimuth direction enlargement section 90a is assumed to be image data at a position corresponding to at a distance r+n. This operation is successively repeated, directing outward from the sweep center. The image memory 10 is a memory which has a capacity which can store detected image data corresponding to one cycle of an antenna, i.e., one cycle of sweeping. The detected image data which is generated and enlarged in the azimuth direction and the distance direction by the W data generator 9 is drawn into pixels whose addresses are designated by the draw address generator 6. Thereafter, when raster scanning is performed with respect to the display by a display control section (not shown), detected image data drawn in the image memory 10 is read out with high speed in synchronization with the raster operation, and a detected image having a luminance and a color corresponding to the data is displayed on a display 11. Next, the W data generator 9 will be specifically described with reference to FIGS. 2 to 7. As described above, the W data generator 9 is composed of the azimuth direction enlargement section 90a and the distance direction enlargement section 90b. The azimuth direction enlargement section 90a is composed of a target data detecting section 91, an azimuth direction data extractor 92, and a maximum value detecting section 93. The distance direction enlargement section 90b is composed of a target data detecting section 94, two shift registers 95a and 95b connected in series, and a maximum value detecting section 96. The target data detecting section 91 comprises a calculation circuit 901 and a selector 902 as illustrated in FIG. 2(b). FIG. 2(b) is a block diagram illustrating the target data detecting sections 91 and 94. The calculation circuit 901 receives detected image data from the MAX extractor 8, and a predetermined threshold value. For example, assuming that the number of bits of the detected image data is 5 bits (32 levels), a value “8” which can be generated when a target is present is input as the threshold value. The calculation circuit 901 compares the input detected image data with the threshold value, and when the detected image data is greater than or equal to the threshold value, a permission signal is output to the selector 902. When receiving the permission signal from the calculation circuit 901, the selector 902 outputs the detected image data as it is. When not receiving the permission signal from the calculation circuit 901, i.e., the detected image data is smaller than the threshold value, the selector 902 does not output the input detected image data and outputs “0” as detected image data. With such an operation, the target data detecting circuit 91 determines whether or not there is a target, and also functions as a filter which prevents data, such as noise smaller than the threshold value or the like, from being enlarged by the following-stage circuit. The azimuth direction data extractor 92 has a configuration illustrated in FIG. 3. FIG. 3 is a block diagram illustrating the azimuth direction data extractor 92. When detected image data is input from the target detecting section 91 to the azimuth direction data extractor 92, the detected image data is input to a selector 921 and an azimuth direction enlargement permitting signal calculator 927. The azimuth direction enlargement permitting signal calculator 927 is composed of a logic circuit of FIG. 4. FIG. 4 is a logic circuit diagram of the azimuth direction enlargement permitting signal calculator 927. In the azimuth direction enlargement permitting signal calculator 927, detected image data of a current sweep, past detected image data A described below (detected image data of the previous sweep), and past detected image data B (detected image data of the second previous sweep) are input to OR gates 71 to 73, respectively, to determine whether or not data (i.e., “1”) is present in each bit, and if data is present, the OR gates 71 to 73 individually output a data presence signal. Next, a data presence signal from the OR gate 71 and the inverse of a data presence signal from the OR gate 72 are input to an AND gate 74. When a data presence signal is input from the OR gate 71 and a data presence signal is not input from the OR gate 72, the AND gate 74 outputs a first permission signal. In other words, when new detected image data is present and past detected image data A is not present, the first permission signal is output. A data presence signal from the OR gate 72 and the inverse of a data presence signal from the OR gate 73 are input to an AND gate 75. When a data presence signal is input from the OR gate 72 and a data presence signal is not input from the OR gate 73, the AND gate 75 outputs a second permission signal. In other words, when past detected image data A is present and past detected image data B is not present, the second permission signal is output. A data presence signal from the OR gate 71 and an azimuth direction enlargement permitting signal (shift memory read data of FIG. 3) obtained when the previous detected image data (one step before) is input from an azimuth direction enlargement permitting signal shifting memory 929 (when past detected image data A is input as new detected image data), are input to an AND gate 76. When a data presence signal is input from the OR gate 71 and an azimuth direction enlargement permitting signal is input from the azimuth direction enlargement permitting signal shifting memory 929, the AND gate 76 outputs a third permission signal. In other words, when new detected image data is present and the previous azimuth direction enlargement permitting signal is present, a third permission signal is output. The outputs of the AND gates 74 to 76 are input to an OR gate 77. The OR gate 77 outputs an azimuth direction enlargement permitting signal when a permission signal (the first to third permission signals) is input from any of the AND gates 74 to 76. Specifically, when new detected image data is present and past detected image data A is not present, when past detected image data A is present and past detected image data B is not present, or when new detected image data is present and the previous azimuth direction enlargement permitting signal is present, the OR gate 77 outputs an azimuth direction enlargement permitting signal. If otherwise, the OR gate 77 does not output an azimuth direction enlargement permitting signal. The output of the azimuth direction enlargement permitting signal calculator 927 and the output of the azimuth direction enlargement permitting signal shifting memory 929 are input to a selector 928. When receiving an azimuth direction shift timing signal, the selector 928 outputs the output of the azimuth direction enlargement permitting signal calculator 927 to the azimuth direction enlargement permitting signal shifting memory 929. When not receiving an azimuth direction shift timing signal, the selector 928 outputs the output of the azimuth direction enlargement permitting signal shifting memory 929 back to the azimuth direction enlargement permitting signal shifting memory 929. When it is shift timing, the output of the azimuth direction permission signal calculator 927 is written into the azimuth direction enlargement permitting signal shifting memory 929. When it is not shift timing, the output of the azimuth direction enlargement permitting signal shifting memory 929 is written back to hold the contents. The output of the azimuth direction enlargement permitting signal shifting memory 929 is input to the azimuth direction enlargement permitting signal calculator 927 and the selector 928. Detected image data and the output of the azimuth direction enlargement permitting signal calculator 927 are input to the selector 921. When receiving an azimuth direction enlargement permitting signal, the selector 921 outputs the detected image data to a selector 922. When not receiving an azimuth direction enlargement permitting signal, the selector 921 outputs “0”. The selector 922 receives the output of the selector 921 and the output of an azimuth direction enlargement shift memory 923. When receiving an azimuth direction shift timing signal, the selector 922 outputs detected image data or “0” to the azimuth direction enlargement shift memory 923. When not receiving an azimuth direction shift timing signal, the selector 922 outputs a signal output from the azimuth direction enlargement shift memory 923 back to the azimuth direction enlargement shift memory 923. The azimuth direction enlargement shift memory 923 delays the input detected image data or “0”, depending on the shift timing of an azimuth direction shift timing signal, and outputs the input detected image data or “0” to the selector 922 and a selector 924, and outputs the detected image data or “0” as past detected image data A. The selector 924 receives the detected image data (past detected image data A) and data “0” which are delayed once. When receiving an azimuth direction enlargement permitting signal, the selector 924 outputs the past detected image data A to a selector 925. When not receiving an azimuth direction enlargement permitting signal, the selector 924 outputs “0”. The selector 925 receives the output of the selector 924 and the output of an azimuth direction enlargement shift memory 926. When receiving an azimuth direction shift timing signal, the selector 925 outputs the past detected image data A or “0” to the azimuth direction enlargement shift memory 926. When not receiving an azimuth direction shift timing signal the selector 925 outputs a signal output from the azimuth direction enlargement shift memory 926 back to the azimuth direction enlargement shift memory 926. The azimuth direction enlargement shift memory 926 delays the input past detected image data A or “0”, depending on the shift timing of the azimuth direction shift timing signal, and outputs the past detected image data A or “0”, to the selector 925, and outputs the detected image data or “0”as past detected image data B. With such a configuration, the azimuth direction data extractor 92 receives new detected image data with azimuth direction shift timing, and outputs past detected image data A which is delayed once and past detected image data B which is delayed twice. Specifically, when detected image data of a sample point at a predetermined distance position of a current sweep is input, the previous detected image data corresponding to a pixel adjacent in a direction opposite to the sweep rotational direction and at the same position in the sweep distance direction, and the second previous detected image data corresponding to the pixel adjacent in the direction opposite to the sweep rotational direction and at the same position in the sweep distance direction, are output with respect to a pixel corresponding to the detected image data. Note that, in the above description, a block composed of the selectors 921 and 924, the azimuth direction enlargement permitting signal calculator 927, the selector 928, and the azimuth direction enlargement permitting signal shifting memory 929, corresponds to “correction stopper” of the present invention, and the selectors 922 and 925, and the azimuth direction enlargement shift memories 923 and 926, correspond to “data shifter” of the present invention. The maximum value detecting section 93 receives and compares detected image data and past detected image data A and B from the azimuth direction data extractor 92, and outputs data having the greatest value. With such a configuration, if the detected image data is greatest, the detected image data is output as it is. If past detected image data A one cycle before is greatest, the detected image data is replaced with the past detected image data A, which is in turn output. If the past detected image data B two cycles before is greatest, the detected image data is replaced with the past detected image data B, which is in turn output. An azimuth direction enlargement operation of the azimuth direction enlargement section 90a thus configured will be described with reference to FIGS. 5 and 7. FIG. 5 illustrates each piece of detected image data, an azimuth direction enlargement permitting signal, a delayed azimuth direction enlargement permitting signal, and azimuth direction enlargement resultant data (data output by the azimuth direction enlargement section), when enlargement is performed in the azimuth direction. (a) indicates the case where only one pixel of detected image data is present in the azimuth direction, (b) indicates the case where two consecutive pixels of detected image data are present in the azimuth direction, (c) indicates the case where three consecutive pixels of detected image data are present in the azimuth direction, and (d) indicates the case where eight consecutive pixels of detected image data are present in the azimuth direction. FIG. 7 is a diagram illustrating an image memory, sample points of sweeps (points where detected image data is present), an enlarged range in the azimuth direction, and an enlarged range in the distance direction. For example, as illustrated in FIGS. 5(a) and 7, when the azimuth direction shift timing is “1” at a distance position Y1 of a sweep X1, and only with this timing, detected image data is present, the detected image data is drawn at a pixel D(1, 3) corresponding to the detected image data. In this case, the detected image data is present with azimuth direction shift timing T1, and before that, no detected image data is present on the distance position Y1. Therefore, an azimuth direction enlargement permitting signal is generated, and the above-described shift operation is performed with respect to the detected image data. Next, since no detected image data is present at the distance position Y1 of a sweep X2 with azimuth direction shift timing T2, but the detected image data present at the distance position Y1 of the sweep X1 with the azimuth direction shift timing T1 is delayed by the azimuth direction data extractor 92 and is output as past detected image data A, the maximum value detecting section 93 selects and outputs the past detected image data A. As a result, the same detected image data as that of the pixel D(1, 3) is drawn at a pixel D(2, 2) corresponding to the azimuth direction shift timing T2 at the distance position Y1 of the sweep X2. Also in this case, since the past detected image data A (detected image data delayed by one cycle) and no past detected image data B is present, an azimuth direction enlargement permitting signal is output, and a further shift operation is performed. Next, since no detected image data is present at the distance position Y1 of a sweep X3 with azimuth direction shift timing T3, but the detected image data present at the distance position Y1 of the sweep X1 with the azimuth direction shift timing T1 is delayed by the azimuth direction data extractor 92 and is output as past detected image data B, the maximum value detecting section 93 selects and outputs the past detected image data B. As a result, the same detected image data as that of the pixel D(1, 3) is drawn at a pixel D(3, 2) corresponding to the azimuth direction shift timing T3 at the distance position Y1 of the sweep X3. In this case, since there is no case where an azimuth direction enlargement permitting signal is generated, an azimuth direction enlargement permitting signal is not generated, and a further shift operation is not performed. By performing the above-described operation, the detected image data of the pixel D(1, 3) can be enlarged into three pixels in the sweep azimuth direction. Next, in the case illustrated in FIG. 5(b), i.e., when two pieces of detected image data are consecutively present at the same distance, an operation with the azimuth direction shift timing T1 is the same as that of FIG. 5(a). Next, since detected image data is present with the azimuth direction shift timing T2, and detected image data present with the azimuth direction shift timing T1 is also shifted and output by the azimuth direction data extractor 92, the maximum value detecting section 93 outputs one of these pieces of data which is the greater. In other words, detected image data is output. In this case, since detected image data is present with the azimuth direction shift timing T2, and the previous azimuth direction enlargement permitting signal is also output from the azimuth direction enlargement permitting signal shifting memory, also in this case an azimuth direction enlargement permitting signal is output and the above-described shift operation is performed with respect to the detected image data. Next, since no detected image data is present with the azimuth direction shift timing T3, but the detected image data present with the azimuth direction shift timing T1 and the detected image data present with the azimuth direction shift timing T2 are output from the azimuth direction data extractor 92, the maximum value detecting section 93 outputs detected image data as in the case of the azimuth direction shift timing T2. In this case, since the condition that an azimuth direction enlargement permitting signal is output is not satisfied, an azimuth direction enlargement permitting signal is not output, and “0” is input to the azimuth direction enlargement shift memories 923 and 926. In other words, the above-described shift operation is not performed with respect to the detected image data. Next, since no detected image data is present with azimuth direction shift timing T4, and no detected image data is output from the azimuth direction data extractor 92, no detected image data is output from the maximum value detecting section 93. Thereby, two consecutive pixels of detected image data in the sweep azimuth direction are enlarged into three pixels. Next, an operation of FIG. 5(d) will be described (since operations of FIGS. 5(c) and 5(d) are similar to each other, the operation of FIG. 5(c) will not be described). In the case of FIG. 5(d), i.e., when eight pieces of detected image data are consecutively present at the same distance, operations with the azimuth direction shift timing T1 and T2 are similar to that of FIG. 5(a). In the case of azimuth direction shift timing T3 to T8, since new detected image data is present, and an azimuth direction enlargement permitting signal which is delayed once is present, an azimuth direction enlargement permitting signal continues to be output, and the above-described shift operation is repeated. And, since no new detected image data is present with azimuth direction shift timing T9, a new azimuth direction enlargement permitting signal is not output from the azimuth direction enlargement permitting signal calculator 927 and “0” is output from the selectors 921 and 924. With the azimuth direction shift timing T10, “0” is written into the azimuth direction enlargement shift memories 923 and 926. However, since past detected image data A and B are output from the azimuth direction enlargement shift memories 923 and 926 with the azimuth direction shift timing T9, detected image data corresponding to the past detected image data A and B is drawn at a pixel corresponding to the azimuth direction shift timing T9. Also, since no new image data is present on a sweep X10, a new azimuth direction enlargement permitting signal is not output from the azimuth direction enlargement permitting signal calculator 927, and “0” is output from the selectors 921 and 924. With azimuth direction shift timing T11, “0” is written into the azimuth direction enlargement shift memories 923 and 926. Further, since “0” has been written into the azimuth direction enlargement shift memories 923 and 926 with the azimuth direction shift timing T10, signals output from these shift memories are “0”. Thereby, “0” is input into a pixel corresponding to the azimuth direction shift timing T10. In other words, no enlarged image data is drawn. In this manner, detected image data originally indicating a large target is enlarged only by one pixel, so that enlargement is suppressed from being performed more than necessary. Next, data output from the maximum value detecting section 93 is input to the target data detecting section 94 and the maximum value detecting section 96 of the distance direction enlargement section 90b. The target data detecting section 94 has the same configuration as that of the target data detecting section 91 of the azimuth direction enlargement section 90a, and causes data smaller than a predetermined threshold value among the input data to be “0”, and outputs data greater than or equal to the predetermined threshold value directly to the shift register 95a. Specifically, the shift register 95a is composed of a D-/circuit, and delays input data, depending on the cycle of the R clock, and outputs resultant data to the maximum value detecting section 96 and the shift register 95b. The shift register 95b is also composed of a D-F/F circuit, and further delays the data delayed by the shift register 95a, depending on the cycle of the R clock, and outputs resultant data to the maximum value detecting section 96. The maximum value detecting section 96 receives data output from the azimuth direction enlargement section 90a and delayed data a and b delayed by the shift registers 95a and 95b, respectively, and outputs a maximum value of these data. Specifically, data at three adjacent sample points present on the same sweep are compared, and greatest data is output. Thereby, for example, when detected image data is input at a certain time point (sample point), and thereafter, data smaller than the detected image data are input two consecutive times in the sweep distance direction, detected image data at a sample point closest to the center is output three consecutive times from the maximum value detecting section 96 to from a pixel corresponding to the sample point closest to the center to a pixel corresponding to a sample point closest to the periphery. As a result, the detected image data of the pixel corresponding to the sample point closest to the center is enlarged by two pixels in the sweep distance direction and is displayed. An operation of the distance direction enlargement section 90b will be described with reference to FIG. 6. Here, FIG. 6 illustrates data output from the azimuth direction enlargement section, data output from each shift register, and distance direction enlargement resultant data (data output from the distance direction enlargement section), when enlargement is performed in the distance direction. (a) indicates the case where only one pixel of detected image data is present in the distance direction, (b) indicates the case where two consecutive pixels of detected image data are present in the distance direction, (c) indicates the case where three consecutive pixels of detected image data are present in the distance direction, and (d) indicates the case where eight consecutive pixels of detected image data are present in the distance direction. For example, as illustrated in FIG. 6(a), when detected image data is present only at the distance position Y1 of the sweep X1, and no detected image data is present at the distance positions Y2 to Y4, no detected image data is present at the distance position Y2 of the sweep X1, but at this time point, the detected image data at the distance position Y1 has been input from the shift register 95a into the maximum value detecting section 96, and therefore, the maximum value detecting section 96 outputs the detected image data at the distance position Y1 of the sweep X1. Thereby, the same detected image data as that of a pixel corresponding to the distance position Y1 of the sweep X1 is drawn into a pixel corresponding to the distance position Y2 of the sweep X1. Next, also, no detected image data is present at the distance position Y3 of the sweep X1, but at this time point, the detected image data at the distance position Y1 has been input from the shift register 95b into the maximum value detecting section 96, the maximum value detecting section 96 outputs the detected image data at the distance position Y1 of the sweep X1. Thereby, the same detected image data as that of a pixel corresponding to the distance position Y1 of the sweep X1 is drawn into a pixel corresponding to the distance position Y3 of the sweep X1 as well. With such an operation, the detected image data of the pixel corresponding to the distance position Y1 of the sweep X1 can be enlarged by two pixels in the sweep distance direction. Next, an operation of FIG. 6(d) will be described (since operations of FIGS. 6(b), 6(c), and 6(d) are similar to the operation of FIG. 6(a), the operation of FIGS. 6(b) and 6(c) will not be described). In the case of FIG. 6(d), i.e., when detected image data is present at eight sample points adjacent on a sweep in the distance direction, operations at the distance positions Y1 and Y2 are the same as that of FIG. 6(a). In the case of distance positions Y3 to Y8, new detected image data is present, and in addition, detected image data is output from the shift registers 95a and 95b, so that detected image data continues to be output within this range. Next, in the case of a distance position Y9, no new detected image data is input, but delayed detected image data is output from the shift registers 95a and 95b, so that the maximum value detecting section 96 outputs the detected image data. Next, in the case of a distance position Y10, no new detected image data is input, and no detected image data is output from the shift register 95a, but detected image data is output from the shift register 95b, so that the maximum value detecting section 96 outputs the detected image data. Next, in the case of a distance position Y11, no new detected image data is input and no detected image data is output from the shift registers 95a and 95b, so that the maximum value detecting section 96 outputs no detected image data. Thus, in the distance direction enlargement section 90b thus configured, if detected image data is present at a certain distance position of a sweep, the detected image data can be enlarged by two pixels in the sweep distance direction and resultant data can be drawn into the image memory 10. Such a distance direction enlargement operation is also performed with respect to a sweep whose detected image data has been enlarged in the azimuth direction. As a result, detected image data can be enlarged both in the azimuth direction and the distance direction. For example, in the case of FIG. 7, azimuth direction enlargement is performed from the sweep X1, directing toward the sweeps X2 and X3, and distance direction enlargement is performed on each of the sweeps X1, X2, and X3. As a result, as illustrated in FIG. 7, the detected image data of a pixel D(1, 3) is enlarged and drawn into the pixel D(1, 3), pixels D(2, 2) to (2, 4), pixels (3, 2) to (3, 4), a pixel D(4, 2), and a pixel D(4, 3). The above-described operation is performed before drawing detected image data into an image memory. Therefore, even in when enlarged display is performed, the number of times of access to the image memory does not change. With the above-described configuration, a radar apparatus can be configured in which, even when detected image data is small, the detected image data can be enlarged and displayed into a predetermined size, and a rate at which data is drawn from an image memory to a display does not decrease, and like apparatuses thereto can be configured. If a predetermined number or more of pixels of detected image data are present in the sweep azimuth direction, an enlarged amount thereof can be limited. Therefore, a radar apparatus can be configured in which a small image is enlarged, and the enlargement of an originally large image is limited, resulting in excellent visibility and suppressing a reduction in display resolution, and like apparatuses thereto can be configured. Since detected image data is enlarged both in the sweep azimuth direction and the sweep distance direction, it is possible to provide an enlarged image having a shape more similar to original detected image data than when enlargement is performed only in one direction, resulting in visibility for the operator. Note that, in this embodiment, when target detected image data has a size of two pixels or less in the azimuth direction, the data is enlarged into three pixels in the azimuth direction, and when target detected image data has a size of three pixels or more, the data is enlarged by only one pixel. Alternatively, by increasing the number of azimuth direction enlargement shift memories, an image enlarged into a larger number of pixels can be formed. In this embodiment, the amount of enlargement in the azimuth direction is determined, depending on the number of azimuth direction enlargement shift memories provided in the azimuth direction enlargement section 90a. Alternatively, the number of azimuth direction enlargement shift memories used by the control section may be set by the operator setting the enlarged amount using an operation section (not shown). With such a configuration, target detected image data can be enlarged by an enlarged amount which the user prefers, and can be displayed. In this embodiment, two shift registers are provided in the distance direction enlargement section 90b so as to enlarge data by two pixels in the sweep distance direction. Alternatively, by changing the number of shift registers provided, the number of pixels by which data is enlarged can be set, depending on the number of shift registers provided. In this embodiment, detected image data is enlarged in the azimuth direction and the distance direction irrespective of the distance from a sweep center (own ship's position). However, in a peripheral portion farther than a predetermined distance, detected image data having a predetermined number or less of pixels (e.g., only one pixel is present alone) may be set not to be enlarged. In this case, the enlargement process may be switched on/off with the following timing. Timing with which a sweep accesses a pixel in an image memory is counted using a counter or the like, and the enlargement process is not performed on and after the number of counts reaches a predetermined number. In other words, since echo has a spread corresponding to an antenna beam width, echo located at a distance from the center has a size extending over a plurality of pixels in the azimuth direction, and therefore, when only one pixel is detected in the azimuth direction, the detected image data is determined as noise or interference, so that the detected image data is not enlarged. With such a configuration, in a peripheral portion where detected image data with respect to a target originally has a large size in the azimuth direction, it is possible to prevent considerably small detected image data caused by noise from being enlarged. On the other hand, the enlargement process is performed in the vicinity of the center as described above, so that detected image data of a target can be reliably obtained in the vicinity of the center where detected image data with respect to a target is small. Thereby, a radar apparatus having excellent visibility, and like apparatuses thereto, can be configured. INDUSTRIAL APPLICABILITY The present invention can be applied to an apparatus, such as a radar apparatus, a sonar apparatus, or the like, which converts a detected signal received in a polar coordinate system into a rectangular coordinate system and stores resultant data into an image memory, and displays the data on a raster scan type display, and particularly an apparatus which enlarges and displays detected data obtained from the detected signal.

<SOH> BACKGROUND ART <EOH>In raster scan type radar apparatuses, the size of a video of a radar is basically determined based on a horizontal beam width and a transmitted pulse width. The wider the horizontal beam width, the larger the expansion in an azimuth direction of echo, and the longer the transmitted pulse width, the larger the expansion in a distance direction of echo. Therefore, due to the expansion of the horizontal beam width of a transmitted wave beam and a received wave beam formed by an antenna, even the same target which is enlarged in the azimuth direction and displayed at a position distant from a sweep center on a display, becomes smaller as the target approaches near a ship carrying the radar apparatus (near the center). This tendency becomes more significant as the resolution of a display is increased (a smaller size of each pixel). In a display having such a high resolution, a target near the position of the own ship is displayed as having a considerably small size. When a sea surface reflection removing process is performed, the size of a target is further reduced due to an influence of the process, so that the target size reduction near the center becomes more significant, resulting in a significant reduction in visibility. As a radar apparatus which solves such a problem, there is an apparatus which, after drawing an image at a pixel where a target is present, following this write operation, accesses again a pixel adjacent thereto in a direction substantially opposite to a sweep moving direction in a rectangular coordinate system, compares data already stored at the adjacent pixel with the current input data, and writes the greater data into the adjacent pixel (see, for example, Patent Documents 1 and 2). [Patent Document 1] JP No. 2648983 B [Patent Document 2] JP No. 2003-28950 A However, in such a conventional radar apparatus, access (drawing) is performed with respect to the same pixel a plurality of times, so that the number of times of access to an image memory during one cycle of sweeping increases. Therefore, a time required to access the image memory increases with an increase in the number of pixels to be enlarged. Here, when display is performed on a high-resolution display, since each pixel in the image memory also inevitably becomes smaller, the number of pixels to be enlarged increases, so that a time required to write detected image data into the image memory increases. On the other hand, in recent years, some radar apparatuses have an antenna having a high rotational speed so as to support high-speed ships, for example. Therefore, when an attempt is made to perform the above-described enlargement/display process in such a high-speed antenna rotation type radar apparatus, it is highly likely that there is not an enough time to write data into the image memory, so that the entire image memory cannot be updated during one cycle of sweeping. In conventional radar apparatuses, detected image data is enlarged only in the azimuth direction, so that the shape of a target displayed on a display differs from its actual shape, i.e., becomes unnatural. Also in conventional radar apparatuses, detected image data is enlarged irrespective of the size of a target, so that detected image data which does not require enlargement is also enlarged, and therefore, display resolution is reduced more than necessary. An object of the present invention is to provide a radar apparatus in which a rate at which detected image data is written into an image memory, is not reduced, irrespective of the enlarged amount of the detected image data, and like apparatuses thereto. Another object of the present invention is to provide a radar apparatus which can obtain an enlarged image, depending on detected data (detected signal) of a target, by enlarging detected image data in two-dimensional directions, and like apparatuses thereto. Still another object of the present invention is to provide a radar apparatus which can reliably display a target around a ship carrying the radar (own ship) without enlarging detected image data when it is not required, and like apparatuses thereto.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a block diagram illustrating a main portion of a radar apparatus of an embodiment of the present invention. FIG. 2 includes a block diagram illustrating a configuration of a W data generator 9 and a block diagram illustrating target data detecting sections 91 and 94 . FIG. 3 is a block diagram illustrating an azimuth direction data extractor 92 . FIG. 4 is a logic circuit diagram of an azimuth direction enlargement permitting signal calculator 927 . FIG. 5 is a diagram illustrating each piece of detected image data, an azimuth direction enlargement permitting signal, a delayed azimuth direction enlargement permitting signal, and azimuth direction enlargement resultant data, when enlargement is performed in an azimuth direction. FIG. 6 is a diagram illustrating each piece of detected image data, data output from each shift register, and distance direction enlargement resultant data, when enlargement is performed in a distance direction. FIG. 7 is a diagram illustrating an image memory, sample points of sweeps (points where detected image data is present), an enlarged range in the azimuth direction, and an enlarged range in the distance direction. detailed-description description="Detailed Description" end="lead"?

20060512

20100316

20070607

67240.0

G01S1300

PIHULIC, DANIEL T

RADAR APPARATUS

UNDISCOUNTED

ACCEPTED

G01S

ACCEPTED

Organic compounds

Disclosed are δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide compounds of formula (I) and the salts thereof, having renin-inhibiting properties. Also disclosed are pharmaceutical compositions comprising these compounds and methods of administering them for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

1. A δ-amino-γ-hydroxy-(o-aryl-alkanoic acid amide compound of formula (I) wherein R1 is hydrogen, halogen, optionally halogenated alkyl, cycloalkyl, hydroxy, optionally halogenated alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy or free or esterified or amidated carboxy-lower alkoxy or lower alkyl; R2 is hydrogen, halogen, optionally halogenated lower alkyl, hydroxy, cycloalkyl, cycloalkoxy, optionally halogenated lower alkoxy-lower alkyl, optionally substituted lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl; optionally lower alkanoylated, halogenated or sulfonylated hydroxy-lower alkoxy; amino-lower alkyl that is unsubstituted or substituted by lower alkyl, by lower alkanoyl and/or by lower alkoxycarbonyl, optionally hydrogenated heteroaryl-lower alkyl, amino-lower alkoxy that is substituted by lower alkyl, by lower alkanoyl and/or by lower alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, lower alkoxy-lower alkoxy, lower alkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-lower alkenyloxy, lower alkenyloxy-lower alkyl, lower alkanoyl lower alkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, lower alkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkyl, cyano-lower alkoxy, cyano-lower alkyl, free or esterified or amidated carboxy-lower alkoxy or free or esterified or amidated carboxy-lower alkyl; R3 and R4 are independently hydrogen, halogen, optionally halogenated lower alkyl, hydroxy, optionally halogenated lower alkoxy or cycloalkoxy, lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy-lower alkyl, optionally S-oxidised lower alkylthio-lower alkyl, optionally hydrogenated heteroarylthio-lower alkyl, optionally hydrogenated heteroaryl-lower alkyl; amino-lower alkyl that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or N,N-disubstituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, cyano-lower alkyl, free or esterified or amidated carboxy-lower alkyl, cycloalkyl, aryl, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy, aryl-lower alkoxy, optionally halogenated lower alkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated heteroarylthio-lower alkoxy; amino-lower alkoxy that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or substituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, cyano-lower alkoxy or free or esterified or amidated carboxy-lower alkoxy; or R4 together with R3 is lower alkeneoxy, lower alkylenedioxy or a fused-on aryl, optionally hydrogenated heteroaryl or cycloalkyl ring; X is methylene, hydroxymethylene, oxygen, optionally lower alkyl substituted nitrogen, optionally oxidized sulfur; R5 is lower alkyl or cycloalkyl; R6 is hydrogen, lower alkyl, hydroxy, alkoxy or halogen; R7 is unsubstituted or N-mono- or N,N-di-lower alkylated or N-lower alkanoylated amino; R8 is lower alkyl, lower alkenyl, cycloalkyl or aryl-lower alkyl; R9 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-alkyl, cycloalkyl carboxamides, N-mono or N,N-dialkyl substituted cycloalkyl carboxamides, optionally substituted aryl-alkyl, optionally substituted aryloxy-aryl, optionally substituted heteroaryloxy-alkyl, free or aliphatically esterified or etherified hydroxy-lower alkyl; amino-lower alkyl that is unsubstituted or N-lower alkanoylated or N-mono- or N,N-di-lower alkylated or N,N-di-substituted by lower alkylene, by hydroxy-, lower alkoxy- or lower alkanoyloxy-lower alkylene, by unsubstituted or N′-lower alkanoylated or N′-lower alkylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, free or esterified or amidated carboxy-lower alkyl, free or esterified or amidated dicarboxy-lower alkyl, free or esterified or amidated carboxy-(hydroxy)-lower alkyl, free or esterified or amidated carboxycycloalkyl-lower alkyl, cyano-lower alkyl, lower alkanesulfonyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted, or lower alkyl substituted by a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 wherein R9 is lower alkyl, optionally substituted cycloalkyl (alkyl, OH, alkoxy, alkoxy-alkyl, halogens), optionally substituted cycloalkyl-alkyl (OH, alkoxy, alkoxy-alkyl, halogens on cycloalkyl), cycloalkyl carboxamides, N-mono or N,N-dialkyl substituted cycloalkyl carboxamides, optionally substituted aryl-alkyl, free or aliphatically esterified or etherified hydroxy-lower alkyl; amino-lower alkyl that is unsubstituted or N-lower alkanoylated or N-mono- or N,N-di-lower alkylated or N,N-di-substituted by lower alkylene, by hydroxy-, lower alkoxy-or lower alkanoyloxy-lower alkylene, by unsubstituted or N′-lower alkanoylated or N′-lower alkylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, free or esterified or amidated carboxy-lower alkyl, free or esterified or amidated dicarboxy-lower alkyl, free or esterified or amidated carboxy-(hydroxy)-lower alkyl, free or esterified or amidated carboxycycloalkyl-lower alkyl, cyano-lower alkyl, lower alkanesulfonyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted, or lower alkyl substituted by a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2 wherein R1 and R4 are hydrogen; R2 is lower alkoxy-lower alkoxy; R3 is halogen or mono, di or tri-halo-substituted alkyl; or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3 wherein the halogen/halo is fluorine or chlorine; or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 4 wherein R3 is fluorine or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 5 wherein R2 is in the meta position and R3 is in the para position; or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 5 wherein R3 is in the ortho position; or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 5 wherein R3 is in the meta position; or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 2 wherein R2 is in the meta position and is lower alkoxy-lower alkoxy optionally substituted by halogen(s); or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9 wherein the halogen(s) is fluorine or chlorine; or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 10 wherein the halogen(s) is fluorine; or a pharmaceutically acceptable salt thereof. 12. A compound according to claim 9 wherein R3 is lower alkoxy substituted by halogen(s); or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 12 wherein the halogen(s) is fluorine or chlorine; or a pharmaceutically acceptable salt thereof. 14. A compound according to claim 13 wherein the halogen(s) is fluorine; or a pharmaceutically acceptable salt thereof. 15. A compound according to claim 9 wherein R3 is in the para position; or a pharmaceutically acceptable salt thereof. 16. A compound according to claim 15 wherein R3 is methoxy; or a pharmaceutically acceptable salt thereof. 17. A compound according to claim 15 wherein R3 is trifluoro-methoxy; or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 1 wherein R3 is located at the para position and is halogen; or a pharmaceutically acceptable salt thereof. 19. A δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide compound according to claim 1 having formula (Ia) wherein R1 is hydrogen, halogen, optionally halogenated alkyl, cycloalkyl, hydroxy, optionally halogenated alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy or free or esterified or amidated carboxy-lower alkoxy or lower alkyl; R2 is hydrogen, halogen, optionally halogenated lower alkyl, hydroxy, cycloalkyl, cycloalkoxy, optionally halogenated lower alkoxy-lower alkyl, optionally substituted lower alkoxy-lower alkoxy, cycloalkoxy-lower alkyl; optionally lower alkanoylated, halogenated or sulfonylated hydroxy-lower alkoxy; amino-lower alkyl that is unsubstituted or substituted by lower alkyl, by lower alkanoyl and/or by lower alkoxycarbonyl; optionally hydrogenated heteroaryl-lower alkyl; amino-lower alkoxy that is substituted by lower alkyl, by lower alkanoyl and/or by lower alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy, cycloalkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, lower alkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-lower alkenyloxy, lower alkenyloxy-lower alkyl, lower alkanoyl-lower alkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, lower alkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated hetero-aryl-lower alkyl, cyano-lower alkoxy, cyano-lower alkyl, free or esterified or amidated carboxy-lower alkoxy or free or esterified or amidated carboxy-lower alkyl; R3 and R4 are independently hydrogen, halogen, optionally halogenated lower alkyl, hydroxy, optionally halogenated lower alkoxy or cycloalkoxy, lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy-lower alkyl, optionally S-oxidised lower alkylthio-lower alkyl, optionally hydrogenated heteroarylthio-lower alkyl, optionally hydrogenated hetero-aryl-lower alkyl; amino-lower alkyl that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or N,N-disubstituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene; cyano-lower alkyl, free or esterified or amidated carboxy-lower alkyl, cycloalkyl, aryl, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy, aryl-lower alkoxy, optionally halogenated lower alkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated heteroarylthio-lower alkoxy; amino-lower alkoxy that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or substituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxalower alkylene or by optionally S-oxidised thia-lower alkylene; cyano-lower alkoxy or free or esterified or amidated carboxy-lower alkoxy; or R4 together with R3 is lower alkeneoxy, alkylenedioxy or a fused-on aryl, optionally hydrogenated heteroaryl or cycloalkyl ring; X is methylene, hydroxymethylene, oxygen, optionally lower alkyl substituted nitrogen or optionally oxidized sulfur; R5 is lower alkyl or cycloalkyl; R6 is hydrogen, lower alkyl, hydroxy, alkoxy or halogen; R7 is unsubstituted or N-mono- or N,N-di-lower alkylated or N-lower alkanoylated amino; R8 is lower alkyl, lower alkenyl, cycloalkyl or aryl-lower alkyl; R9 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-alkyl, cycloalkyl carboxamides, N-mono or N,N-dialkyl substituted cycloalkyl carboxamides, optionally substituted aryl-alkyl, optionally substituted aryloxy-aryl, optionally substituted heteroaryloxy-alkyl, free or aliphatically esterified or etherified hydroxy-lower alkyl; amino-lower alkyl that is unsubstituted or N-lower alkanoylated or N-mono- or N,N-di-lower alkylated or N,N-di-substituted by lower alkylene, by hydroxy-, lower alkoxy- or lower alkanoyloxy-lower alkylene, by unsubstituted or N′-lower alkanoylated or N′-lower alkylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, free or esterified or amidated carboxy-lower alkyl, free or esterified or amidated dicarboxy-lower alkyl, free or esterified or amidated carboxy-(hydroxy)-lower alkyl, free or esterified or amidated carboxycycloalkyl-lower alkyl, cyano-lower alkyl, lower alkanesulfonyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted, or lower alkyl substituted by a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted; or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 19 wherein R9 is cycloalkyl substituted with alkyl, hydroxy, alkoxy, alkoxy-alkoxy or halogens; cycloalkyl-alkyl optionally substituted with alkyl, hydroxy, alkoxy, alkoxy-alkoxy or halogens on cycloalkyl or halogens on alkyl or halongens on alkoxy; cycloalkyl carboxamides; N-mono or N,N-dialkyl substituted cycloalkyl carboxamides; or optionally substituted aryl-alkyl; or a pharmaceutically acceptable salt thereof. 21. A compound according to claim 19 wherein R9 is hydrogen; halogenated alkyl; optionally substituted aryl-alkyl, optionally substituted aryloxy-alkyl, cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of alkenyl, alkynyl, halo, hydroxy, alkoxy, alkoxy-alkoxy, alkylthio, arylthio, aryl-alkoxy, carbamoyl, sulfamoyl, sulfonyl, optionally substituted amino, cyano, carboxy, alkoxycarbonyl, aryl, aryloxy, heterocyclyl or alkyl optionally substituted by amino, halo, hydroxy, alkoxy, carboxy, alkoxycarbonyl, carbamoyl or heterocyclyl; or optionally substituted cycloalkyl-alkyl; or a pharmaceutically acceptable salt thereof. 22. A compound according to claim 21 wherein R1 is hydrogen; R2 is C1-C4 alkoxy -C1-C4 alkoxy or C1-C4 alkoxy-C1-C4 alkyl; R3 is C1-C4 alkyl or C1-C4 alkoxy; R4 is hydrogen; X is methylene; R5 is lower alkyl; R6 is hydrogen; R7 is unsubstituted amino; R8 is branched C3-C4 alkyl; R9 is optionally substituted cycloalkyl-alkyl; or a pharmaceutically acceptable salt thereof. 23. A compound according to claim 22 wherein R2 is 3-methoxypropyloxy; R3 is methoxy; R5 is isopropyl; R8 is isopropyl; or a pharmaceutically acceptable salt thereof. 24. The compound of claim 21 wherein R1 is hydrogen; R2 is C1-C4 alkoxy-C1-C4 alkoxy or C1-C4 alkoxy-C1-C4 alkyl; R3 is C1-C4 alkyl or C1-C4 alkoxy; R4 is hydrogen; X is methylene; R5 is lower alkyl; R6 is hydrogen; R7 is unsubstituted amino; R8 is branched C3-C4 alkyl; R9 is optionally substituted aryl-alkyl; or a pharmaceutically acceptable salt thereof. 25. A compound according to claim 24 wherein R2 is 3-methoxypropyloxy; R3 is methoxy; R5 is isopropyl; R8 is isopropyl; or a pharmaceutically acceptable salt thereof. 26. The compound of claim 24 wherein aryl-alkyl is alkyl substituted with phenyl; or a pharmaceutically acceptable salt thereof. 27. The compound of claim 26 wherein aryl-alkyl is methyl substituted with phenyl. 28. A compound according to claim 27 wherein R2 is 3-methoxypropyloxy; R3 is methoxy; R5 is isopropyl; R8 is isopropyl; or a pharmaceutically acceptable salt thereof. 29. A method for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders which method comprises administering a therapeutically effective amount of the compound of formula (1) to a warm-blooded animal in need thereof. 30. A pharmaceutical composition comprising the compound of formula (1) and one or more pharmaceutically acceptable excipient(s). 31. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a therapeutically effective amount of an anti-diabetic agent, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent. 32. A pharmaceutical composition according to claim 30 for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders. 33-36. (canceled) 37. A compound according to claim 1, for use as a medicament. 38. A pharmaceutical composition according to claim 31 for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

The invention relates to novel δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides of formula (I) wherein R1 is hydrogen, halogen, optionally halogenated alkyl, cycloalkyl, hydroxy, optionally halogenated alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy or free or esterified or amidated carboxy-lower alkoxy or lower alkyl; R2 is hydrogen, halogen, optionally halogenated lower alkyl, hydroxy, cycloalkyl, cycloalkoxy, optionally halogenated lower alkoxy-lower alkyl, optionally substituted lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl; optionally lower alkanoylated, halogenated or sulfonylated hydroxy-lower alkoxy; amino-lower alkyl that is unsubstituted or substituted by lower alkyl, by lower alkanoyl and/or by lower alkoxycarbonyl, optionally hydrogenated heteroaryl-lower alkyl, amino-lower alkoxy that is substituted by lower alkyl, by lower alkanoyl and/or by lower alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, lower alkoxy-lower alkoxy, lower alkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-lower alkenyloxy, lower alkenyloxy-lower alkyl, lower alkanoyl lower alkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, lower alkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkyl, cyano-lower alkoxy, cyano-lower alkyl, free or esterified or amidated carboxy-lower alkoxy or free or esterified or amidated carboxy-lower alkyl; R3 and R4 are independently hydrogen, halogen, optionally halogenated lower alkyl, hydroxy, optionally halogenated lower alkoxy or cycloalkoxy, lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy-lower alkyl, optionally S-oxidised lower alkylthio-lower alkyl, optionally hydrogenated heteroarylthio-lower alkyl, optionally hydrogenated heteroaryl-lower alkyl; amino-lower alkyl that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or N,N-disubstituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, cyano-lower alkyl, free or esterified or amidated carboxy-lower alkyl, cycloalkyl, aryl, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy, aryl-lower alkoxy, optionally halogenated lower alkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated heteroarylthio-lower alkoxy; amino-lower alkoxy that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or substituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, cyano-lower alkoxy or free or esterified or amidated carboxy-lower alkoxy; or R4 together with R3 is lower alkeneoxy, lower alkylenedioxy or a fused-on aryl, optionally hydrogenated heteroaryl or cycloalkyl ring; X is methylene, hydroxymethylene, oxygen, optionally lower alkyl substituted nitrogen, optionally oxidized sulfur, R5 is lower alkyl or cycloalkyl; R6 is hydrogen, lower alkyl, hydroxy, alkoxy or halogen; R7 is unsubstituted or N-mono- or N,N-di-lower alkylated or N-lower alkanoylated amino; R8 is lower alkyl, lower alkenyl, cycloalkyl or aryl-lower alkyl; R9 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-alkyl, cycloalkyl carboxamides, N-mono or N,N-dialkyl substituted cycloalkyl carboxamides, optionally substituted aryl-alkyl, optionally substituted aryloxy-aryl, optionally substituted heteroaryloxy-alkyl, free or aliphatically esterified or etherified hydroxy-lower alkyl; amino-lower alkyl that is unsubstituted or N-lower alkanoylated or N-mono- or N,N-di-lower alkylated or N,N-di-substituted by lower alkylene, by hydroxy-, lower alkoxy- or lower alkanoyloxy-lower alkylene, by unsubstituted or N′-lower alkanoylated or N′-lower alkylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, free or esterified or amidated carboxy-lower alkyl, free or esterified or amidated dicarboxy-lower alkyl, free or esterified or amidated carboxy-(hydroxy)lower alkyl, free or esterified or amidated carboxycycloalkyl-lower alkyl, cyano-lower alkyl, lower alkanesulfonyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted, or lower alkyl substituted by a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted; and to pharmaceutically acceptable salts thereof, to processes for the preparation of the compounds according to the invention, to pharmaceutical compositions containing them and to their use as medicinal active ingredients. The compounds of the present invention exhibit inhibitory activity on the natural enzyme renin. Thus, compounds of formula (I) may be employed for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders. Listed below are definitions of various terms used to describe the compounds of the present invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group. Aryl and aryl in aryl-alkyl, aryl-lower alkoxy, aryl-lower alkyl and the like is, e.g., phenyl or naphthyl that is unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy optionally substituted with halogens, hydroxy, lower alkylamino, di-lower alkylamino, halogen and/or by trifluoromethyl. Cycloalkoxy and cycloalkoxy in cycloalkoxy-lower alkoxy is, e.g., 3- to 8-membered, preferably 3-, 5 or 6-membered, cycloalkoxy, such as cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, also cyclobutyloxy, cycloheptyloxy or cyclooctyloxy. Cycloalkyl and cycloalkyl in cycloalkyl-alkyl refers, e.g., to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may be optionally substituted by one or more substituents such as alkenyl, alkynyl, halo, hydroxy, alkoxy, alkoxy-alkoxy, alkylthio, arylthio, aryl-alkoxy, carbamoyl, sulfamoyl, sulfonyl, -optionally substituted amino, cyano, carboxy, alkoxycarbonyl, aryl, aryloxy, heterocyclyl or alkyl optionally substituted by amino, halo, hydroxy, alkoxy, carboxy, carbamoyl or heterocyclyl and the like. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groups include adamantyl and the like. Optionally substituted amino refers to a primary or secondary amino group which may optionally be substituted, e.g., by acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, carbamoyl and the like. Carbamoyl refers, e.g., to H2NC(O)—, alkyl-NHC(O)—, (alkyl)2NC(O)—, aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—, alkyl(heteroaryl)-NC(O)—, aralkyl-NHC(O)—, alkyl(aralkyl)-NC(O)— and the like. Sulfamoyl refers, e.g., to H2NS(O)2', alkyl-NHS(O)2—, (alkyl)2NS(O)2—, aryl-NHS(O)2—, alkyl(aryl)-NS(O)2—, (aryl)2NS(O)2—, heteroaryl-NHS(O)2—, aralkyl-NHS(O)2—, heteroaralkyl-NHS(O)2— and the like. Free or esterified or amidated carboxy-lower alkoxy is, e.g., carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy or N-mono- or N,N-di-lower alkylcarbamoyl-lower alkoxy. Optionally substituted lower alkanoylated, halogenated or sulfonylated hydroxy-lower alkoxy is, e.g., lower alkanoyloxy-lower alkyl, hydroxy-lower alkoxy, halo-(hydroxy)-lower alkoxy or lower alkanesulfonyl-(hydroxy)lower alkoxy. Amino-lower alkyl that is unsubstituted or substituted by lower alkyl, lower alkanoyl and/or by lower alkoxycarbonyl is, e.g., amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl or lower alkoxycarbonylamino-lower alkyl. Amino-lower alkoxy that is unsubstituted or substituted by lower alkyl, lower alkanoyl and/or by lower alkoxycarbonyl is, e.g., amino-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy or lower alkoxycarbonylamino-lower alkoxy. Optionally S-oxidised lower alkylthio-lower alkoxy is, e.g., lower alkylthio-lower alkoxy, or lower alkanesulfonyl-lower alkoxy. Optionally hydrogenated heteroaryl-lower alkoxy is, e.g., optionally partially hydrogenated or N-oxidised pyridyl-lower alkoxy, thiazolyl-lower alkoxy or especially morpholino-lower alkoxy. Optionally hydrogenated heteroarylthio-lower alkoxy is, e.g., optionally partially or fully hydrogenareal heteroarylthio-lower alkoxy, such as thiazolylthio-lower alkoxy or thiazolinylthio-lower alkoxy, imidazolylthio-lower alkoxy, optionally N-oxidised pyridlylthio-lower alkoxy or pyrimidinylthio-lower alkoxy. Free or esterified or amidated carboxy-lower alkyl is, e.g., carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl or N-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl. Optionally halogenated lower alkyl is, e.g., lower alkyl or polyhalo-lower alkyl. Optionally halogenated lower alkoxy is, e.g., lower alkoxy or polyhalo-lower alkoxy. Optionally S-oxidised lower alkylthio-lower alkyl is, e.g., lower alkylthio-lower alkyl or lower alkanesulfonyl-lower alkyl. Optionally S-oxidised lower alkylthio-lower alkoxy is, e.g., lower alkylthio-lower alkoxy or lower alkanesulfonyl-lower alkoxy. Optionally hydrogenated heteroaryl-lower alkyl is, e.g., optionally partially hydrogenated or N-oxidised pyridyl-lower alkyl. Optionally hydrogenated heteroarylthio-lower alkyl is, e.g., thiazolylthio-lower alkyl or thiazolinylthio-lower alkyl, imidazolylthio-lower alkyl, optionally N-oxidised pyridylthio-lower alkyl or pyrimidinylthio-lower alkyl. Amino-lower alkyl that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or N,N-disubstituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene; or by optionally S-oxidised thia-lower alkylene is, e.g., amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, lower alkanesulfonylamino-lower alkyl, polyhalo-lower alkanesulfonylamino-lower alkyl, pyrrolidino-lower alkyl, piperidino-lower alkyl, piperazino-, N′-lower alkylpiperazino- or N′-lower alkanoylpiperazino-lower alkyl, morpholino-lower alkyl, thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothiomorpholino-lower alkyl. Optionally S-oxidised lower alkylthio-lower alkoxy is, e.g., lower alkylthio-lower alkoxy or lower alkanesulfonyl-lower alkoxy. Amino-lower alkoxy that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or N,N-disubstituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene is, e.g., amino-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, lower alkanesulfonylamino-lower alkoxy, polyhalo-lower alkanesulfonylamino-lower alkoxy, pyrrolidino-lower alkoxy, piperidino-lower alkoxy, piperazino-, N′-lower alkylpiperazino- or N′-lower alkanoylpiperazino-lower alkoxy, morpholino-lower alkoxy, thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothio-morpholino-lower alkoxy. Unsubstituted or N-mono- or N,N-di-lower alkylated or N-lower alkanoylated amino is, e.g., amino, lower alkylamino, di-lower alkylamino or lower alkanoylamino. Free or aliphatically esterified or etherified hydroxy-lower alkyl is, e.g., hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl or lower alkenyloxy-lower alkyl. Amino-lower alkyl that is unsubstituted or N-lower alkanoylated, N-mono- or N,N-di-lower alkylated or N,N-disubstituted by lower alkylene, by hydroxy-, lower alkoxy- or lower alkanoyloxy-lower alkylene, by unsubstituted or N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene; or by optionally S-oxidised thia-lower alkylene is, e.g., amino-lower alkyl, lower alkanoylamino-lower alkyl, N-mono- or N,N-di-lower alkylamino-lower alkyl, optionally hydroxylated or lower alkoxylated piperidino-lower alkyl, such as piperidino-lower alkyl, hydroxypiperidino-lower alkyl or lower alkoxy-piperidino-lower alkyl, piperazino-, W-lower alkylpiperazino-; or N′-lower alkanoyl-piperazino-lower alkyl, unsubstituted or lower alkylated morpholino-lower alkyl, such as morpholino-lower alkyl or dimethylmorpholino-lower alkyl; or optionally S-oxidised thio-morpholino-lower alkyl, such as thiomorpholino-lower alkyl or S,S-dioxothiomorpholino-lower alkyl. Free or esterified or amidated dicarboxy-lower alkyl is, e.g., dicarboxy-lower alkyl, di-lower alkoxycarbonyl-lower alkyl, dicarbamoyl-lower alkyl or di-(N-mono- or N,N-di-lower alkylcarbamoyl)-lower alkyl. Free or esterified or amidated carboxy-(hydroxy)lower alkyl is, e.g., carboxy-(hydroxy)-lower alkyl, lower alkoxycarbonyl-(hydroxy)-lower alkyl or carbamoyl-(hydroxy)-lower alkyl. Free or esterified or amidated carboxycycloalkyl-lower alkyl is, e.g., 5- or 6-membered carboxycycloalkyl-lower alkyl, lower alkoxycarbonylcycloalkyl-lower alkyl, carbamoylcycloalkyl-lower alkyl or N-mono- or N,N-di-lower alkylcarbamoylcyclo-alkyl-lower alkyl. Unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl is, e.g., sulfamoyl-lower alkyl, lower alkylsulfamoyl-lower alkyl or di-lower alkyl-sulfamoyl-lower alkyl. Unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-lower alkyl is, e.g., thiocarbamoyl-lower alkyl, lower alkylthiocarbamoyl-lower alkyl; or di-lower alkylthiocarbamoyl-lower alkyl, such as N,N-dimethylthiocarbamoylmethyl. Hereinbefore and hereinafter, lower radicals and compounds are to be understood as being, e.g., those having up to and including 7 carbon atoms, preferably up to and including 4 carbon atoms. Five- or 6-membered carboxycycloalkyl-lower alkyl, lower alkoxycarbonylcycloalkyl-lower alkyl, carbamoylcycloalkyl-lower alkyl, N-mono- or N,N-di-lower alkylcarbamoylcyclo-alkyl-lower alkyl is, e.g., ω-(1-carboxycycloalkyl)-C1-C4alkyl, ω-(1-lower alkoxycarbonylcycloalkyl)C1-C4alkyl, ω-(1-carbamoylcycloalkyl)-C1-C4alkyl, ω-(1-lower alkylcarbamoylcycloalkyl)-C1-C4alkyl or ω-(1-di-lower alkylcarbamoylcycloalkyl)-C1-C4alkyl, wherein cycloalkyl is, e.g., cyclopentyl or cyclohexyl; lower alkoxycarbonyl is, e.g., C1-C4alkoxycarbonyl, such as methoxy- or ethoxycarbonyl; lower alkylcarbamoyl is, e.g., C1-C4alkylcarbamoyl, such as methylcarbamoyl; di-lower alkylcarbamoyl is, e.g., di-C1-C4alkylcarbamoyl, such as dimethylcarbamoyl; and lower alkyl is, e.g., C1-C4alkyl, such as methyl, ethyl, propyl or butyl, especially (1-carboxycyclopentyl)methyl. Five- or 6-membered cycloalkoxy-lower alkoxy is, e.g., cyclopentyloxy- or cyclohexyloxy-C1-C4alkoxy, such as cyclopentyloxy- or cyclohexyloxy-methoxy, 2-cyclopentyloxy- or 2-cyclohexyloxy-ethoxy, 2- or 3-cyclopentyloxy- or 2- or 3cyclohexyloxy-propyloxy or 4-cyclopentyloxy- or 4-cyclohexyloxy-butyloxy, especially cyclopentyloxy- or cyclohexyloxy-methoxy. Five- or 6-membered cycloalkoxy-lower alkyl is, e.g., cyclopentyloxy- or cyclohexyloxy-C1-C4alkyl, such as cyclopentyloxy- or cyclohexyloxy-methyl, 2-cyclopentyloxy- or 2-cyclohexyloxy-ethyl, 2- or 3-cyclopentyloxy- or 2- or 3-cyclohexyloxy-propyl, 2-cyclopentyloxy- or 2-cyclohexyloxy-2-methyl-propyl, 2-cyclopentyloxy- or 2-cyclohexyloxy-2-ethyl-butyl or 4-cyclopentyloxy- or 4cyclohexyloxy-butyl, especially cyclopentyloxy- or cyclohexyloxy-methyl. Amino-lower alkoxy is, e.g., amino-C1-C4alkoxy, such as 2-aminoethoxy or 5-aminopentyloxy, also 3-aminopropyloxy or 4-aminobutyloxy. Amino-lower alkyl is, e.g., amino-C1-C4alkyl, such as 2-aminoethyl, 3-aminopropyl or 4-aminobutyl. Carbamoyl-(hydroxy)-lower alkyl is, e.g., carbamoyl-C1-C7(hydroxy)alkyl, such as 1-carbamoyl-2-hydroxyethyl. Carbamoyl-lower alkoxy is, e.g., carbamoyl-C1-C4alkoxy, such as carbamoylmethoxy, 2-carbamoylethoxy, 3-carbamoylpropyloxy or 4-carbamoylbutyloxy, especially carbamoylmethoxy. Carbamoyl-lower alkyl is, e.g., carbamoyl-C1-C7alkyl, such as carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl, 2-(3-carbamoyl)propyl, 2-carbamoylpropyl, 3-(1-carbamoyl)propyl, 2-(2-carbamoyl)propyl, 2-(carbamoyl-2-methyl)propyl, 4-carbamoylbutyl, 1-carbamoylbutyl, 1-(1-carbamoyl-2-methyl)butyl or 3-(4-carbamoyl-2-methyl)butyl. Carboxy-(hydroxy)-lower alkyl is, e.g., carboxy-C1-C7(hydroxy)alkyl, such as 1-carboxy-2-hydroxy-ethyl. Carboxy-lower alkoxy is, e.g., carboxy-C1-C4alkoxy, such as carboxymethoxy, 2-carboxyethoxy, 2- or 3-carboxypropyloxy or 4-carboxybutyloxy, especially carboxy-methoxy. Carboxy-lower alkyl is, e.g., carboxy-C1-C4alkyl, such as carboxymethyl, 2-carboxyethyl, 2- or 3-carboxypropyl, 2-carboxy-2-methyl-propyl, 2-carboxy-2-ethyl-butyl or 4-carboxybutyl, especially carboxymethyl. Cyano-lower alkoxy is, e.g., cyano-C1-C4alkoxy, such as cyanomethoxy, 2-cyano-ethoxy, 2- or 3-cyanopropyloxy or 4-cyanobutyloxy, especially cyanomethoxy. Cyano-lower alkyl is, e.g., cyano-C1-C4alkyl, such as cyanomethyl, 2-cyanoethyl, 2- or 3-cyanopropyl, 2-cyano-2-methyl-propyl, 2-cyano-2-ethyl-butyl or 4-cyanobutyl, especially cyanomethyl. Di-(N-mono- or N,N-di-lower alkylcarbamoyl)-lower alkyl is, e.g., di-(N-mono- or N,N-di-C1-C4alkylcarbamoyl)-C1-C4alkyl, such as 1,2-di-(N-mono- or N,N-di-C1-C4alkylcarbamoyl)ethyl or 1,3-di-(N-mono- or N,N-di-C1-C4alkylcarbamoyl)propyl. Dicarbamoyl-lower alkyl is, e.g., dicarbamoyl-C1-C4alkyl, such as 1,2-dicarbamoylethyl or 1,3-dicarbamoylpropyl. Dicarboxy-lower alkyl is, e.g., dicarboxy-C1-C4alkyl, such as 1,2-dicarboxyethyl or 1,3-dicarboxypropyl. Dimethylmorpholino-lower alkoxy can be N-oxidised and is, e.g., 2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-C1-C4alkoxy, such as 2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-methoxy, 2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)-ethoxy, 3-(2,6-dimethylmorpholino-or 3,5-dimethylmorpholino)-propyloxy, 2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino3-methyl)propyloxy, or 1- or 2-[4-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)]-butyloxy. Dimethylmorpholino-lower alkyl can be N-oxidised and is, e.g., 2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-C1-C4alkyl, such as 2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-methoxy, 2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)-ethoxy, 3-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)-propyl, 2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-3-methyl)-propyl, or 1- or 2-[4-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)]-butyl. Di-lower alkoxycarbonyl-lower alkyl is, e.g., di-lower alkoxycarbonyl-C1-C4alkyl, such as 1,2-dimethoxycarbonylethyl, 1,3-dimethoxycarbonylpropyl, 1,2-dimethoxycarbonylethyl or 1,3-diethoxycarbonylpropyl. Di-lower alkylamino is, e.g., di-C1-C4alkylamino, such as dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-propylamino or N-butyl-N-methylamino. Di-lower alkylamino-lower alkoxy is, e.g., N,N-di-C1-C4alkylamino-C1-C4alkoxy, such as 2-dimethylaminoethoxy, 3-dimethylaminopropyloxy, 4-dimethylaminobutyloxy, 2-diethylaminoethoxy, 2-(N-methyl-N-ethyl-amino)ethoxy or 2-(N-butyl-N-methyl-amino)ethoxy. Di-lower alkylamino-lower alkyl is, e.g., N,N-di-C1-C4alkylamino-C1-C4alkyl, such as 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 2-diethylaminoethyl, 2-(N-methyl-N-ethyl-amino)ethyl or 2-(N-butyl-N-methyl-amino)ethyl. Di-lower alkylcarbamoyl-lower alkoxy is, e.g., N,N-di-C1-C4alkylcarbamoyl-C1-C4alkoxy, such as methyl- or dimethyl-carbamoyl-C1-C4alkoxy, such as N-methyl-, N-butyl- or N,N-dimethyl-carbamoylmethoxy, 2-(N-methylcarbamoyl)ethoxy, 2-(N-butylcarbamoyl)ethoxy, 2-(N,N-dimethylcarbamoyl)ethoxy, 3-(N-methylcarbamoyl)propyloxy, 3-(N-butylcarbamoyl)propyloxy, 3-(N,N-dimethylcarbamoyl)propyloxy or 4-(N-methylcarbamoyl)butyloxy, 4-(N-butylcarbamoyl)butyloxy or 4-(N,N-dimethylcarbamoyl)butyloxy, especially N-methyl-, N-butyl- or N,N-dimethyl-carbamoylmethoxy. Di-lower alkylcarbamoyl-lower alkyl is, e.g., N,N-di-C1-C4alkylcarbamoyl-C1-C4alkyl, such as 2-dimethylcarbamoylethyl, 3-dimethylcarbamoylpropyl, 2-dimethylcarbamoylpropyl, 2-(dimethylcarbamoyl-2-methyl)propyl or 2-(1-dimethylcarbamoyl-3-methyl)butyl. Di-lower alkylsulfamoyl-lower alkyl is, e.g., N,N-di-C1-C4alkylsulfamoyl-C1-C4alkyl, N,N-dimethylsulfamoyl-C1-C4alkyl, such as N,N-dimethylsulfamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl, 3-(N,N-dimethylcarbamoyl)propyl or 4-(N,N-dimethylcarbamoyl)butyl, especially N,N-dimethylcarbamoylmethyl. Unsubstituted or N-lower alkanoylated piperidyl-lower alkyl is, e.g., 1-C1-C7lower alkanoylpiperidin-4-yl-C1-C4alkyl, such as 1-acetylpiperidinylmethyl or 2-(1-acetylpiperidinyl)ethyl. Optionally partially hydrogenated or N-oxidised pyridyl-lower alkoxy is, e.g., optionally partially hydrogenated pyridyl- or N-oxidopyridyl-C1-C4alkoxy, such as pyridyl- or N-oxidopyridyl-methoxy, 2-pyridylethoxy, 2- or 3-pyridylpropyloxy or 4-pyridylbutyloxy, especially 3- or 4-pyridylmethoxy. Optionally partially hydrogenated or N-oxidised pyridyl-lower alkyl is, e.g., optionally partially hydrogenated pyridyl- or N-oxidopyridyl-C1-C4alkyl, such as pyridyl- or N-oxidopyridyl-methyl, 2-pyridylethyl, 2- or 3-pyridylpropyl or 4-pyridylbutyl, especially 3- or 4-pyridylmethyl. Halo-(hydroxy)-lower alkoxy is, e.g., halo-C2-C7(hydroxy)alkoxy, especially halo-C2-C4(hydroxy)alkoxy, such as 3-halo-, such as 3-chloro-2-hydroxy-propyloxy. Hydroxy-lower alkoxy is, e.g., hydroxy-C2-C7alkoxy, especially hydroxy-C2-C4alkoxy, such as 2-hydroxybutyloxy, 3-hydroxypropyloxy or 4-hydroxybutyloxy. Hydroxy-lower alkyl is, e.g., hydroxy-C2-C7alkyl, especially hydroxy-C2-C4alkyl, such as 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl. Hydroxypiperidino-lower alkyl is, e.g., 3- or 4-hydroxypiperidino-C1-C4alkoxy, such as 3- or 4-hydroxypiperidinomethoxy, 2-(3- or 4-hydroxypiperidino)ethoxy, 3-(3- or 4-hydroxypiperidino)propyloxy or 4-(3- or 4-hydroxypiperidino)butyloxy. Imidazolyl-lower alkyl is, e.g., imidazolyl-C1-C4alkyl, such as imidazol4-yl-methyl, 2-(imidazol4-yl)ethyl, 3-(imidazol-4-yl)propyl or 4-(imidazol-4-yl)butyl. Imidazolyl-lower alkoxy is, e.g., imidazolyl-C1-C4alkoxy, such as imidazol-4-yl-methoxy, 2-(imidazol4-yl)ethoxy, 3-(imidazol4-yl)propyloxy or 4-(imidazol4-yl)butyloxy. Imidazolyl-lower alkyl is, e.g., imidazolyl-C1-C4alkyl, such as imidazol-4-yl-methyl, 2-(imidazol4-yl)ethyl, 3-(imidazol4-yl)propyl or 4-(imidazol-4-yl)butyl. Morpholinocarbonyl-lower alkyl is, e.g., morpholinocarbonyl-C1-C4alkyl, such as 1-morpholinocarbonylethyl, 3-morpholinocarbonylpropyl or 1-(morpholinocarbonyl-2-methyl)propyl. Morpholino-lower alkoxy can be N-oxidised and is, e.g., morpholino-C1-C4alkoxy, such as 1-morpholinoethoxy, 3-morpholinopropyloxy or 1-(morpholino-2-methyl)propyloxy. Morpholino-lower alkyl can be N-oxidised and is, e.g., morpholino-C1-C4alkyl, such as morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 1- or 2-(4-morpholino)butyl. Lower alkanoyl is, e.g., C1-C7alkanoyl, especially C2-C6alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl. Lower alkanoylamino is, e.g., N-C1-C7alkanoylamino, such as acetylamino or pivaloylamino. Lower alkanoylamino is, e.g., N-C1-C7alkanoylamino, such as acetylamino or pivaloylamino. Lower alkanoylamino-lower alkyl is, e.g., N-C1-C4alkanoylamino-C1-C4alkyl, such as 2-acetoxyaminoethyl. Lower alkanoylamino-lower alkyl is, e.g., N-C1-C4alkanoylamino-C1-C4alkyl, such as 2-acetoxyaminoethyl. Lower alkanoyl-lower alkoxy (oxo-lower alkoxy) carries the lower alkanoyl group in a position higher than the α-position and is, e.g., C1-C7alkanoyl-C1-C4alkoxy, such as 4-acetylbutoxy. Lower alkanoyloxy-lower alkyl carries the lower alkanoyloxy group in a position higher than the α-position and is, e.g., C1-C7alkanoyloxy-C1-C4alkyl, such as 4-acetoxy-butyl. Lower alkanesulfonyl-(hydroxy)-lower alkoxy is, e.g., C1-C7alkanesulfonyl-C1-C4(hydroxy)alkoxy, such as 3-methanesulfonyl-2-hydroxy-propyloxy. Lower alkanesulfonyl-lower alkoxy is, e.g., C1-C7alkanesulfonyl-C1-C4alkoxy, such as methanesulfonylmethoxy or 3methanesulfonyl-2-hydroxy-propyloxy. Lower alkanesulfonylamino-lower alkoxy is, e.g., C1-C7alkanesulfonylamino-C1-C4alkoxy, such as ethanesulfonylaminomethoxy, 2-ethanesulfonylaminoethoxy, 3-ethanesulfonylaminopropyloxy or 3-(1,1-dimethylethanesulfonylamino)propyloxy. Lower alkanesulfonylamino-lower alkyl is, e.g., C1-C7alkanesulfonylamino-C1-C4alkyl, such as ethanesulfonylaminomethyl, 2-ethanesulfonylaminoethyl, 3-ethanesulfonylaminopropyl or 3-(1,1-dimethylethanesulfonylamino)propyl. Lower alkanesulfonyl-lower alkyl is, e.g., C1-C7alkanesulfonyl-C1-C4alkyl, such as ethanesulfonylmethyl, 2-ethanesulfonylethyl, 3-ethanesulfonylpropyl or 3-(1,1-dimethylethanesulfonyl)propyl. Lower alkenyl is, e.g., C1-C7alkenyl, such as vinyl or allyl. Lower alkenyloxy is, e.g., C1-C7alkenyloxy, such as allyloxy. Lower alkenyloxy-lower alkoxy is, e.g., C1-C7alkenyloxy-C1-C4alkoxy, such as allyloxymethoxy. Lower alkenyloxy-lower alkyl is, e.g., C1-C7alkenyloxy-C1-C4alkyl, such as allyloxymethyl. Lower alkoxy is, e.g., C1-C7alkoxy, preferably C1-C5alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy, tertiary butyloxy, pentyloxy or a hexyloxy or heptyloxy group. Lower alkoxycarbonyl is, e.g., C1-C7alkoxycarbonyl, preferably C1-C5alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, secondary butyloxycarbonyl, tertiary butyloxy, pentyloxycarbonyl or a hexyloxycarbonyl or heptyloxycarbonyl group. Lower alkoxycarbonyl-(hydroxy)-lower alkyl is, e.g., C1-C4alkoxycarbonyl-C1-C7(hydroxy)alkyl, such as 1-methoxycarbonyl- or 1-ethoxycarbonyl-2-hydroxy-ethyl. Lower alkoxycarbonylamino-lower alkoxy is, e.g., C1-C7alkoxycarbonylamino-C2-C7alkoxy, preferably C2-C5alkoxycarbonylamino-C2-C7alkoxy, such as methoxycarbonylamino-C2-C7alkoxy, ethoxycarbonylamino-C2-C7alkoxy, propyloxycarbonylamino-C2-C7alkoxy, isobutyloxycarbonylamino-C2-C7alkoxy, butyloxycarbonylamino-C2-C7alkoxy, isobutyloxycarbonylamino-C2-C7alkoxy, secondary butyloxycarbonylamino-C2-C7alkoxy or tertiary butyloxyamino-C2-C7alkoxy, wherein C2-C7alkoxy is, e.g., methoxy, ethoxy, propyloxy, butyloxy, pentyloxy or hexyloxy. Lower alkoxycarbonylamino-lower alkyl is, e.g., C1-C7alkoxycarbonylamino-C2-C7alkyl, preferably C2-C5alkoxycarbonylamino-C2-C7alkyl, such as methoxycarbonyl-C2-C7alkyl, ethoxycarbonylamino-C2-C7alkyl, propyloxycarbonylamino-C2-C7alkyl isopropyloxycarbonylamino-C2-C7alkyl, butyloxycarbonylamino-C2-C7alkyl, isobutyloxycarbonylamino-C2-C7alkyl, secondary butyloxycarbonylamino-C2-C7alkyl or tertiary butyloxyamino-C2-C7alkyl, wherein C2-C7alkyl is, e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl. Lower alkoxycarbonyl-lower alkoxy is, e.g., C1-C4alkoxycarbonyl-C1-C4alkoxy, such as methoxycarbonyl- or ethoxycarbonyl-methoxy, 2-methoxycarbonyl- or 2-ethoxycarbonyl-ethoxy, 2- or 3-methoxycarbonyl- or 2- or 3-ethoxycarbonyl-propyloxy or 4-methoxycarbonyl- or 4-ethoxycarbonyl-butyloxy, especially methoxycarbonyl- or ethoxycarbonyl-methoxy or 3-methoxycarbonyl- or 3-ethoxycarbonyl-propyloxy. Lower alkoxycarbonyl-lower alkyl is, e.g., C1-C4alkoxycarbonyl-C1-C4alkyl, such as methoxycarbonyl- or ethoxycarbonyl-methoxy, 2-methoxycarbonyl- or 2-ethoxycarbonyl-ethoxy, 3-methoxycarbonyl- or 3-ethoxycarbonyl-propyloxy or 4-ethoxycarbonylbutyloxy. Lower alkoxy-lower alkenyl is, e.g., C1-C4alkoxy-C2-C4alkenyl, such as 4-methoxybut-2-enyl. Lower alkoxy-lower alkoxy is, e.g., C1-C4alkoxy-C2-C4alkoxy, such as 2-methoxy-, 2-ethoxy- or 2-propyloxy-ethoxy, 3-methoxy- or 3-ethoxy-propyloxy or 4-methoxybutyloxy, especially 3-methoxypropyloxy or 4-methoxybutyloxy. Lower alkoxy-lower alkoxy-lower alkyl is, e.g., C1-C4alkoxy-C1-C4alkoxy-C1-C4alkyl, such as 2-methoxy-, 2-ethoxy- or 2-propyloxy-ethoxymethyl, 2-(2-methoxy-, 2-ethoxy- or 2-propyloxy-ethoxy)ethyl, 3-(3-methoxy- or 3-ethoxy-propyloxy)propyl or 4-(2-methoxybutyloxy)butyl, especially 2-(3-methoxypropyloxy)ethyl or 2-(4-methoxybutyloxy)ethyl. Lower alkoxy-lower alkyl is, e.g., C1-C4alkoxy-C1-C4alkyl, such as ethoxymethyl, propyloxymethyl, butyloxymethyl, 2-methoxy-, 2-ethoxy- or 2-propyloxy-ethyl, 3-methoxy- or 3-ethoxy-propyl or 4-methoxybutyl, especially 3-methoxypropyl or 4-methoxybutyl. Lower alkoxypiperidino-lower alkyl is, e.g., piperidino-, hydroxypiperidino- or lower alkoxypiperidino-C1-C4alkyl, such as piperidinomethyl, 4-hydroxypiperidinomethyl or 4-C1-C4alkoxy-, such as 4-methoxy-piperidinomethyl. Lower alkoxypiperidino-lower alkyl is, e.g., C1-C4alkoxypiperidino-C1-C4alkyl, such as 4-C1-C4alkoxy-piperidinomethyl, especially 4-methoxypiperidinomethyl. Lower alkyl may be straight-chained or branched and/or bridged and is, e.g., corresponding C1-C7alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, or a pentyl, hexyl or heptyl group. Lower alkyl R2 or R3 is especially C2-C7alkyl, lower alkyl R5 or R7 is especially branched C3-C7alkyl and lower alkyl R8 or R3 is, e.g., straight-chained, branched or bridged C3-C7alkyl. Lower alkylamino is, e.g., C1-C4alkylamino, such as methylamino, ethylamino, propylamino, butylamino, isobutylamino, secondary butylamino or tertiary butylamino. Lower alkylamino-lower alkoxy is, e.g., C1-C4alkylamino-C1-C4alkoxy, such as propylaminomethoxy, 2-methylamino-, 2-ethylamino-, 2-propylamino- or 2-butylamino-ethoxy, 3-ethylamino- or 3-propylamino-propyloxy or 4-methylaminobutoxy. Lower alkylamino-lower alkyl is, e.g., C1-C4alkylamino-C1-C4alkyl, such as propylaminomethyl, 2-methylamino-, 2-ethylamino-, 2-propylamino- or 2-butylamino-ethyl, 3-ethylamino- or 3-propylamino-propyl or 4-methylaminobutyl. Lower alkylcarbamoyl-lower alkoxy is, e.g., N-C1-C7alkylcarbamoyl-C1-C4alkoxy, such as methyl- or dimethyl-carbamoyl-C1-C4alkoxy, e.g. methylcarbamoylmethoxy, 2-methylcarbamoylethoxy or 3-methylcarbamoylpropyloxy. Lower alkylenedioxy is, e.g., methylenedioxy or ethylenedioxy, but can also be 1,3- or 1,2-propylenedioxy. Lower alkylsulfamoyl-lower alkyl is, e.g., N-C1-C7alkylsulfamoyl-C1-C4alkyl, such as N-methyl-, N-ethyl-, N-propyl- or N-butyl-sulfamoyl-C1-C4alkyl, such as N-methyl-, N-ethyl-, N-propyl- or N-butyl-sulfamoylmethyl, 2-(N-methylsulfamoyl)ethyl, 2-(N-butylsulfamoyl)ethyl, 3-(N-methylsulfamoyl)propyl, 3-(N-butylsulfamoyl)propyl or 4-(N-methylsulfamoyl)butyl, 4-(N-butylsulfamoyl)butyl or 4-(N,N-dimethylsulfamoyl)butyl, especially N-methyl-, N-butyl- or N,N-dimethyl-sulfamoylmethyl. Lower alkylthio-(hydroxy)-lower alkoxy is, e.g., N-C1-C4alkylthio-C1-C4(hydroxy)alkoxy, such as 2-hydroxy-3-methylthiopropyloxy. Oxazolyl-lower alkyl is, e.g., oxazolyl-C1-C4alkyl, such as 2-(1,2,4-oxadiazol-5-yl)ethyl, 3(1,2,4-oxadiazol-5-yl)propyl or 4-(1,2,4-oxadiazol-5-yl)butyl. Lower alkylthio-lower alkoxy is, e.g., N-C1-C4alkylthio-C1-C4alkoxy, such as methylthio-C1-C4alkoxy, e.g., methylthiomethoxy, 2-methylthioethoxy or 3-methylthiopropyloxy. Lower alkylthio-lower alkyl is, e.g., N-C1-C4alkylthio-C1-C4alkyl, such as methylthio-C1-C4alkyl, e.g., methylthiomethyl, 2-methylthioethyl or 3-methylthiopropyl. N′-Lower alkanoylpiperazino-lower alkoxy is, e.g., N′-lower alkanoylpiperazino-C1-C4alkoxy, such as 4-acetylpiperazinomethoxy. N′-Lower alkanoylpiperazino-lower alkyl is, e.g., N′-C2-C7-lower alkanoylpiperazino-C1-C4alkyl, such as 4-acetylpiperazinomethyl. N′-Lower alkylpiperazino-lower alkyl is, e.g., N′-C1-C4alkylpiperazino-C1-C4alkyl, such as 4-methylpiperazinomethyl. Oxo-lower alkoxy is, e.g., oxo-C1-C4alkoxy, such as 3,3-dimethyl-2-oxo-butyloxy. Piperazino-lower alkyl is, e.g., piperazino-C1-C4alkyl, such as piperazinomethyl, 2-piperazinoethyl or 3-piperazinopropyl. Piperidino-lower alkoxy is, e.g., piperidino-C1-C4alkoxy, such as piperidinomethoxy, 2-piperidinoethoxy or 3-piperidinopropyloxy. Piperidino-lower alkyl is, e.g., piperidino-C1-C4alkyl, such as piperidinomethyl, 2-piperidinoethyl or 3-piperidinopropyl. Polyhalo-lower alkanesulfonylamino-lower alkoxy is, e.g., trifluoro-C1-C7alkanesulfonyl-C1-C4alkoxy, such as trifluoromethanesulfonylaminobutyloxy. Polyhalo-lower alkanesulfonylamino-lower alkyl is, e.g., trifluoro-C1-C7alkanesulfonyl-C1-C4alkyl, such as trifluoromethanesulfonylaminobutyl. Pyrimidinyl-lower alkoxy is, e.g., pyrimidinyl-C1-C4alkoxy, such as pyrimidinylmethoxy, 2-pyrimidinylethoxy or 3-pyrimidinylpropyloxy. Pyrimidinyl-lower alkyl is, e.g., pyrimidinyl-C1-C4alkyl, such as pyrimidinylmethyl, 2-pyrimidinylethyl or 3-pyrirnidinylpropyl. Pyrrolidino-lower alkoxy is, e.g., pyrrolidino-C2-C4alkoxy, such as 2-pyrrolidinoethoxy or 3-pyrrolidinopropyloxy. Pyrrolidino-lower alkyl is, e.g., pyrrolidino-C1-C4alkyl, such as pyrrolidinomethyl, 2-pyrrolidinoethyl or 3-pyrrolidinopropyl. S,S-Dioxothiomorpholino-lower alkyl is, e.g., S,S-dioxothiomorpholino-C1-C4alkyl, such as S,S-dioxothiomorpholinomethyl or 2-(S,S-dioxo)thiomorpholinoethyl. S-Oxothiomorpholino-lower alkyl is, e.g., S-oxothiomorpholino-C1-C4alkyl, such as S-oxothiomorpholinomethyl or 2-(S-oxo)thiomorpholinoethyl. Sulfamoyl-lower alkyl is, e.g., sulfamoyl-C1-C4alkyl, such as sulfamoyl-C1-C4alkyl, such as sulfamoylmethyl, 2-sulfamoylethyl, 3-sulfamoylpropyl or 4-sulfamoylbutyl. Tetrazolyl-lower alkyl is, e.g., tetrazolyl-C1-C4alkyl, such as tetrazol-5-ylmethyl, 2-(tetrazol-5-yl)ethyl, 3-(tetrazol-5-yl)propyl or 4-(tetrazol4-yl)butyl. Thiazolinyl-lower alkoxy is, e.g., thiazolinyl-C1-C4alkoxy, such as thiazolinylmethoxy, 2-thiazolinylmethoxy or 3thiazolinylpropyloxy. Thiazolinyl-lower alkyl is, e.g., thiazolinyl-C1-C4alkyl, such as thiazolinylmethyl, 2-thiazolinylethyl or 3-thiazolinylpropyl. Thiazolyl-lower alkoxy is, e.g., thiazolyl-C1-C4alkoxy, such as thiazolylmethoxy, 2-thiazolylethoxy or 3-thiazolylpropyloxy. Thiazolyl-lower alkyl is, e.g., thiazolyl-C1-C4alkyl, such as thiazolylmethyl, 2-thiazolylethyl or 3-thiazolyipropyl. Thiomorpholino-lower alkyl or S,S-dioxothiomorpholino-lower alkyl is, e.g., thiomorpholino-C1-C4alkyl, such as -methyl or -ethyl, or S,S-dioxothiomorpholino-C1-C4alkyl, such as -methyl or -ethyl. Depending on whether asymmetric carbon atoms are present, the compounds of the invention can be present as mixtures of isomers, especially as racemates, or in the form of pure isomers, especially optical antipodes. Salts of compounds having salt-forming groups are especially acid addition salts, salts with bases or, where several salt-forming groups are present, can also be mixed salts or internal salts. Salts are especially the pharmaceutically acceptable or non-toxic salts of compounds of formula (1). Such salts are formed, e.g., by compounds of formula (I) having an acid group, e.g., a carboxy group or a sulfo group, and are, e.g., salts thereof with suitable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb of the Periodic Table of the Elements, e.g., alkali metal salts, especially lithium, sodium or potassium salts; or alkaline earth metal salts, e.g., magnesium or calcium salts; also zinc salts or ammonium salts, as well as salts formed with organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or tri-alkylamines, especially mono-, di- or tri-lower alkylamines; or with quaternary ammonium bases, e.g., with methyl-, ethyl-, diethyl- or triethyl-amine; mono-, his- or tris-(2-hydroxy-lower alkyl)-amines, such as ethanol-, diethanol- or triethanol-amine; tris-(hydroxymethyl)-methylamine or 2-hydroxy-tert-butylamines; N,N-di-lower alkyl-N-(hydroxy-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)-amine or N-methyl-D-glucamine; or quaternary ammonium hydroxides, such as tetrabutylammonium hydroxide. The compounds of formula (I) having a basic group, e.g., an amino group, can form acid addition salts, e.g., with suitable inorganic acids, e.g., hydrohalic acids, such as hydrochloric acid or hydrobromic acid; or sulfuric acid with replacement of one or both protons; phosphoric acid with replacement of one or more protons, e.g., orthophosphoric acid or metaphosphoric acid; or pyrophosphoric acid with replacement of one or more protons; or with organic carboxylic, sulfonic, sulfo or phosphonic acids; or N-substituted sulfamic acids, e.g., acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, as well as with amino acids, such as the α-amino acids mentioned hereinbefore; and with methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate or N-cyclohexylsulfamic acid (forming cyclamates); or with other acidic organic compounds, such as ascorbic acid. Compounds of formula (I) having acid and basic groups can also form internal salts. For isolation and purification purposes it is also possible to use pharmaceutically unacceptable salts. The compounds of the present invention have enzyme-inhibiting properties. In particular, they inhibit the action of the natural enzyme renin. The latter passes from the kidneys into the blood where it effects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensinogen II. The octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume. That increase can be attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I. As a result a smaller amount of angiotensin II is produced. The reduced concentration of that active peptide hormone is the direct cause of the hypotensive effect of renin inhibitors. Thus, the compounds of the present invention may be employed for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders. The groups of compounds mentioned below are not to be regarded as exclusive; rather, e.g., in order to replace general definitions with more specific definitions, parts of those groups of compounds can be interchanged or exchanged for the definitions given above, or omitted, as appropriate. Preferred are the compounds of formula (1), designated as the A group, wherein R9 is lower alkyl, optionally substituted cycloalkyl (alkyl, OH, alkoxy, alkoxy-alkyl, halogens), optionally substituted cycloalkyl-alkyl (OH, alkoxy, alkoxy-alkyl, halogens on cycloalkyl), cycloalkyl carboxamides, N-mono or N,N-dialkyl substituted cycloalkyl carboxamides, optionally substituted aryl-alkyl, free or aliphatically esterified or etherified hydroxy-lower alkyl; amino-lower alkyl that is unsubstituted or N-lower alkanoylated or N-mono- or N,N-di-lower alkylated or N,N-di-substituted by lower alkylene, by hydroxy-, lower alkoxy- or lower alkanoyloxy-lower alkylene, by unsubstituted or N′-lower alkanoylated or N′-lower alkylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, free or esterified or amidated carboxy-lower alkyl, free or esterified or amidated dicarboxy-lower alkyl, free or esterified or amidated carboxy-(hydroxy)-lower alkyl, free or esterified or amidated carboxycycloalkyl-lower alkyl, cyano-lower alkyl, lower alkanesulfonyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted, or lower alkyl substituted by a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted; or a pharmaceutically acceptable salt thereof. Preferred are the compounds in the A group wherein R1 and R4 are hydrogen; R2 is lower alkoxy-lower alkoxy; R3 is halogen or mono, di or tri-halo-substituted alkyl; or a pharmaceutically acceptable salt thereof. Further preferred are the compounds in the A group wherein the halogen/halo is fluorine or chlorine; or a pharmaceutically acceptable salt thereof. More preferred are the compounds in the A group wherein R3 is fluorine or trifluoromethyl; or a pharmaceutically acceptable salt thereof. Most preferred are the compounds in the A group wherein R2 is in the meta position and R3 is in the para position; or a pharmaceutically acceptable salt thereof. Most preferred are also the compounds in the A group wherein R3 is in the ortho position; or a pharmaceutically acceptable salt thereof. Most preferred are also the compounds in the A group wherein R3 is in the meta position; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds in the A group, designated as the B group, wherein R2 is in the meta position and is lower alkoxy-lower alkoxy optionally substituted by halogen(s); or a pharmaceutically acceptable salt thereof. Further preferred are the compounds in the B group wherein the halogen(s) is fluorine or chlorine; or a pharmaceutically acceptable salt thereof. More preferred are the compounds in the B group wherein the halogen(s) is fluorine; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds in the B group, designated as the C group, wherein R3 is lower alkoxy substituted by halogen(s); or a pharmaceutically acceptable salt thereof. Preferred are the compounds in the C group wherein the halogen(s) is fluorine or chlorine; or a pharmaceutically acceptable salt thereof. Further preferred are the compounds in the C group wherein the halogen(s) is fluorine; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds in the B group, designated as the D group, wherein R3 is in the para position; or a pharmaceutically acceptable salt thereof. Further preferred are the compounds in the D group wherein R3 is methoxy; or a pharmaceutically acceptable salt thereof. Further preferred are also the compounds in the D group wherein R3 is trifluoro-methoxy; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds of formula (I) wherein R3 is located at the para position and is halogen; or a pharmaceutically acceptable salt thereof. Preferred are also the δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide compounds of formula (I), designated as the E group, having formula (Ia) wherein R1 is hydrogen, halogen, optionally halogenated alkyl, cycloalkyl, hydroxy, optionally halogenated alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy or free or esterified or amidated carboxy-lower alkoxy or lower alkyl; R2 is hydrogen, halogen, optionally halogenated lower alkyl, hydroxy, cycloalkyl, cycloalkoxy, optionally halogenated lower alkoxy-lower alkyl, optionally substituted lower alkoxy-lower alkoxy, cycloalkoxy-lower alkyl; optionally lower alkanoylated, halogenated or sulfonylated hydroxy-lower alkoxy; amino-lower alkyl that is unsubstituted or substituted by lower alkyl, by lower alkanoyl and/or by lower alkoxy-carbonyl; optionally hydrogenated heteroaryl-lower alkyl; amino-lower alkoxy that is substituted by lower alkyl, by lower alkanoyl and/or by lower alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy, cycloalkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, lower alkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-lower alkenyl-oxy, lower alkenyloxy-lower alkyl, lower alkanoyl-lower alkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, lower alkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkyl, cyano-lower alkoxy, cyano-lower alkyl, free or esterified or amidated carboxy-lower alkoxy or free or esterified or amidated carboxy-lower alkyl; R3 and R4 are independently hydrogen, halogen, optionally halogenated lower alkyl, hydroxy, optionally halogenated lower alkoxy or cycloalkoxy, lower alkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy-lower alkyl, optionally S-oxidised lower alkylthio-lower alkyl, optionally hydrogenated heteroarylthio-lower alkyl, optionally hydrogenated heteroaryl-lower alkyl; amino-lower alkyl that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or N,N-disubstituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene; cyano-lower alkyl, free or esterified or amidated carboxy-lower alkyl, cycloalkyl, aryl, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy, aryl-lower alkoxy, optionally halogenated lower alkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated hetero-arylthio-lower alkoxy; amino-lower alkoxy that is unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-lower alkanesulfonylated or substituted by lower alkylene, by unsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, by oxalower alkylene or by optionally S-oxidised thia-lower alkylene; cyano-lower alkoxy or free or esterified or amidated carboxy-lower alkoxy; or R4 together with R3 is lower alkeneoxy, alkylenedioxy or a fused-on aryl, optionally hydrogenated heteroaryl or cycloalkyl ring; X is methylene, hydroxymethylene, oxygen, optionally lower alkyl substituted nitrogen or optionally oxidized sulfur; R5 is lower alkyl or cycloalkyl; R5 is hydrogen, lower alkyl, hydroxy, alkoxy or halogen; R7 is unsubstituted or N-mono- or N,N-di-lower alkylated or N-lower alkanoylated amino; R8 is lower alkyl, lower alkenyl, cycloalkyl or aryl-lower alkyl; R9 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-alkyl, cycloalkyl carboxamides, N-mono or N,N-dialkyl substituted cycloalkyl carboxamides, optionally substituted aryl-alkyl, optionally substituted aryloxy-aryl, optionally substituted heteroaryloxy-alkyl, free or aliphatically esterified or etherified hydroxy-lower alkyl; amino-lower alkyl that is unsubstituted or N-lower alkanoylated or N-mono- or N,N-di-lower alkylated or N,N-di-substituted by lower alkylene, by hydroxy-, lower alkoxy- or lower alkanoyloxy-lower alkylene, by unsubstituted or N′-lower alkanoylated or N′-lower alkylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, free or esterified or amidated carboxy-lower alkyl, free or esterified or amidated dicarboxy-lower alkyl, free or esterified or amidated carboxy-(hydroxy)-lower alkyl, free or esterified or amidated carboxycycloalkyl-lower alkyl, cyano-lower alkyl, lower alkanesulfonyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted, or lower alkyl substituted by a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted; or a pharmaceutically acceptable salt thereof. Preferred are the compounds in the E group wherein R9 is cycloalkyl substituted with alkyl, hydroxy, alkoxy, alkoxy-alkoxy or halogens; cycloalkyl-alkyl optionally substituted with alkyl, hydroxy, alkoxy, alkoxy-alkoxy or halogens on cycloalkyl or halogens on alkyl or halongens on alkoxy; cycloalkyl carboxamides; N-mono or N,N-dialkyl substituted cycloalkyl carboxamides; or optionally substituted aryl-alkyl; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds in the E group, designated as the F group, wherein R9 is hydrogen; halogenated alkyl; optionally substituted aryl-alkyl, optionally substituted aryloxy-alkyl, cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of alkenyl, alkynyl, halo, hydroxy, alkoxy, alkoxy-alkoxy, alkylthio, arylthio, aryl-alkoxy, carbamoyl, sulfamoyl, sulfonyl, optionally substituted amino, cyano, carboxy, alkoxycarbonyl, aryl, aryloxy, heterocyclyl or alkyl optionally substituted by amino, halo, hydroxy, alkoxy, carboxy, alkoxycarbonyl, carbamoyl or heterocyclyl; or optionally substituted cycloalkyl-alkyl; or a pharmaceutically acceptable salt thereof. Preferred are the compounds in the F group wherein R1 is hydrogen; R2 is C1-C4 alkoxy-C1-C4 alkoxy or C1-C4 alkoxy-C1-C4 alkyl; R3 is C1-C4 alkyl or C1-C4 alkoxy; R4 is hydrogen; X is methylene; R5 is lower alkyl; R6 is hydrogen; R7 is unsubstituted amino; R8 is branched C3-C4 alkyl; R9 is optionally substituted cycloalkyl-alkyl; or a pharmaceutically acceptable salt thereof. Further preferred are the compounds in the F group wherein R2 is 3-methoxypropyloxy; R3 is methoxy; R5 is isopropyl; R8 is isopropyl; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds in the F group, designated as the G group, wherein R1 is hydrogen; R2 is C1-C4 alkoxy-C1-C4 alkoxy or C1-C4 alkoxy-C1-C4 alkyl; R3 is C1-C4 alkyl or C1-C4 alkoxy; R4 is hydrogen; X is methylene; R5 is lower alkyl; R6 is hydrogen; R7 is unsubstituted amino; R8 is branched C1-C4 alkyl; R9 is optionally substituted aryl-alkyl; or a pharmaceutically acceptable salt thereof. Preferred are the compounds in the G group wherein R2 is 3-methoxypropyloxy; R3 is methoxy; R5 is isopropyl; R8 is isopropyl; or a pharmaceutically acceptable salt thereof. Preferred are also the compounds in the G group wherein aryl-alkyl is alkyl substituted with phenyl; or a pharmaceutically acceptable salt thereof. Further preferred are the compounds in the G group wherein aryl-alkyl is methyl substituted with phenyl. More preferred are the compounds in the G group wherein R2 is 3-methoxypropyloxy; R3 is methoxy; R5 is isopropyl; R8 is isopropyl; or a pharmaceutically acceptable salt thereof. As a result of the close relationship between the novel compounds in free form and in the form of their salts, hereinabove and hereinbelow any reference to the free compounds and their salts is to be understood as including also the corresponding salts and free compounds, respectively, as appropriate and expedient. The compounds of the present invention may generally be prepared by those methods disclosed in U.S. Pat. No. 5,559,111, incorporated herein by reference in its entirety as if set forth in full herein. The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a pharmacologically active compound of the instant invention, alone or in combination with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions according to the present invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit renin activity, and for the treatment of conditions associated with renin activity. Such conditions include hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders. Thus, the pharmacologically active compounds of the invention may be employed in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbants, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, preferably about 1-50%, of the active ingredient. Suitable formulations for transdermal application include a therapeutically effective amount of a compound of the invention with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and pre-determined rate over a prolonged period of time, and means to secure the device to the skin. Accordingly, the present invention provides pharmaceutical compositions as described above for the treatment of conditions mediated by renin activity, preferably, hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders. The pharmaceutical compositions may contain a therapeutically effective amount of a compound of the invention as defined above, either alone or in a combination with another therapeutic agent, e.g., each at an effective therapeutic dose as reported in the art. Such therapeutic agents include: a) antidiabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; peroxisome proliferator-activated receptor (PPAR) ligands; protein tyrosine phosphatase-1B (PTP-1B) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN-1 94204; sodium-dependent glucose cotransporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BAY R3401; biguanides such as metformin; alpha-glucosidase inhibitors such as acarbose; GLP-1 (glucagon like peptide-1), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; and DPPIV (dipeptidyl peptidase IV) inhibitors such as LAF237; b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin; c) anti-obesity agents such as orlistat; and d) anti-hypertensive agents, e.g., loop diuretics such as ethacrynic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; β-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors. Other specific anti-diabetic compounds are described by Patel Mona in Expert Opin Investig Drugs, 2003, 12(4), 623-633, in the FIGS. 1to 7, which are herein incorporated by reference. A compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation. The structure of the therapeutic agents identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g., Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Accordingly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of another therapeutic agent, preferably selected from anti-diabetics, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents, most preferably from antidiabetics, anti-hypertensive agents or hypolipidemic agents as described above. The present invention further relates to pharmaceutical compositions as described above for use as a medicament. The present invention further relates to use of pharmaceutical compositions or combinations as described above for the preparation of a medicament for the treatment of conditions mediated by renin activity, preferably, hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders. Thus, the present invention also relates to a compound of formula (I) for use as a medicament, to the use of a compound of formula (I) for the preparation of a pharmaceutical composition for the prevention and/or treatment of conditions mediated by renin activity, and to a pharmaceutical composition for use in conditions mediated by renin activity comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier therefor. The present invention further provides a method for the prevention and/or treatment of conditions mediated by renin activity, which comprises administering a therapeutically effective amount of a compound of the present invention. A unit dosage for a mammal of about 50-70 kg may contain between about 1 mg and 1000 mg, advantageously between about 5-600 mg of the active ingredient. The therapeutically effective dosage of active compound is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, on the form of administration, and on the compound involved. In accordance with the foregoing the present invention also provides a therapeutic combination, e.g., a kit, kit of parts, e.g., for use in any method as defined herein, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, to be used concomitantly or in sequence with at least one pharmaceutical composition comprising at least another therapeutic agent, preferably selected from anti-diabetic agents, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents. The kit may comprise instructions for its administration. Similarly, the present invention provides a kit of parts comprising: (i) a pharmaceutical composition of the invention; and (ii) a pharmaceutical composition comprising a compound selected from an anti-diabetic, a hypolipidemic agent, an anti-obesity agent, an anti-hypertensive agent, or a pharmaceutically acceptable salt thereof, in the form of two separate units of the components (i) to (ii). Likewise, the present invention provides a method as defined above comprising co-administration, e.g., concomitantly or in sequence, of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second drug substance, said second drug substance being an anti-diabetic, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent, e.g., as indicated above. Preferably, a compound of the invention is administered to a mammal in need thereof. Preferably, a compound of the invention is used for the treatment of a disease which responds to modulation of renin activity. Preferably, the condition associated with renin activity is selected from hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders. Finally, the present invention provides a method or use which comprises administering a compound of formula (I) in combination with a therapeutically effective amount of an anti-diabetic agent, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent. Ultimately, the present invention provides a method or use which comprises administering a compound of formula (I) in the form of a pharmaceutical composition as described herein. As used throughout the specification and in the claims, the term “treatment” embraces all the different forms or modes of treatment as known to those of the pertinent art and in particular includes preventive, curative, delay of onset and/or progression, and palliative treatment. The above-cited properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, rabbits, dogs, monkeys or isolated organs, tissues and preparations thereof. Said compounds can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10−3 molar and 10−10 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.001 and 500 mg/kg, preferably between about 0.1 and 100 mg/kg. As described above, the compounds of the present invention have enzyme-inhibiting properties. In particular, they inhibit the action of the natural enzyme renin. Renin passes from the kidneys into the blood where it effects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensin II. The octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume which increase can be attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin lead to a reduction in the formation of angiotensin I, and consequently a smaller amount of angiotensin II is produced. The reduced concentration of that active peptide hormone is the direct cause of the hypotensive effect of renin inhibitors. The action of renin inhibitors may be demonstrated inter alia experimentally by means of in vitro tests, the reduction in the formation of angiotensin I being measured in various systems (human plasma, purified human renin together with synthetic or natural renin substrate). Inter alia the following in vitro tests may be used: An extract of human renin from the kidney (0.5 mGU [milli-Goldblatt units]/mL) is incubated for one h at 37° C. and pH 7.2 in 1 M aqueous 2-N-(tris-hydroxymethylmethyl)-amino-ethanesulfonic acid buffer solution with 23 μg/mL of synthetic renin substrate, the tetradecapeptide H-Asp-Arg-Val-Tyr-Ile-His-ProPhe-His-Leu-Leu-Val-Tyr-Ser-OH. The amount of angiotensin I formed is determined by radioimmunoassay. Each of the inhibitors according to the invention is added to the incubation mixture at different concentrations. The IC50 is defined as the concentration of a particular inhibitor that reduces the formation of angiotensin I by 50%. Recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using standard methods) at 4 nM concentration is incubated with test compound at various concentrations for 1 h at RT in 0.1 M Tris-HCl buffer, pH 7.4, containing 0.05 M NaCl, 0.5 mM EDTA and 0.05% CHAPS. Synthetic peptide substrate Arg-Glu(EDANS)lle-His-Pro-Phe-His-Leu-Val-IIe_His_Thr-Lys(DABCYL)-Arg9 is added to a final concentration of 2 μM and increase in fluorescence is recorded at an excitation wave-length of 340 nm and at an emission wave-length of 485 nm in a microplate spectro-fluorimeter. IC50 values are calculated from percentage of inhibition of renin activity as a function of test compound concentration (Fluorescence Resonance Energy Transfer, FRET, assay). Recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using standard methods) at 1 nM concentration is incubated with test compound at various concentrations for 1.5 h at 37° C. in 0.1 M Tris/HCl pH 7.4 containing 0.05 M NaCl, 0.5 mM EDTA and 0.025% (w/v) CHAPS. Synthetic peptide substrate Ac-IIe-His-Pro-Phe-His-Leu-Val-IIe-His-Asn-Lys-[DY-505-X5] is added to a final concentration of 5 μM. The enzyme reaction is stopped by adding 6 μL of 1.0% TFA The product of the reaction is separated by HPLC and quantified by spectrophotometric measurement at 505 nM wave-length. IC50 values are calculated from percentage of inhibition of renin activity as a function of test compound concentration. Recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using standard methods) at 3.3 nM concentration, 1251-NVP-AJ1891-NX-1 (0.27 μCi/mL) and streptavidin-SPA (0.67 mg/mL) beads are incubated with test compound at various concentrations for 2.0 h at RT in 0.1 M Tris/HCl pH 7.4 containing 0.5M NaCl and 0.5% (wN) Brij35. At the end of the incubation time, the plates are centrifuged (55g, 60 seconds) and counted in a Wallac MicroBeta reader. IC50 values are calculated from percentage of displacement of radioligand binding to renin as a function of test compound concentration. In animals deficient in salt, renin inhibitors bring about a reduction in blood pressure. Human renin may differ from the renin of other species. In order to test inhibitors of human renin, primates, e.g.,marmosets (Callithrix jacchus) may be used, because human renin and primate renin are substantially homologous in the enzymatically active region. Inter alia the following in vivo tests may be used: The test compounds are tested on normotensive marmosets of both sexes having a body weight of approximately 350 g that are conscious, allowed to move freely and in their normal cages. The blood pressure and heart rate are measured via a catheter in the descending aorta and recorded radiometrically. The endogenous release of renin is stimulated by the combination of a 1-week low-salt diet and a single intramuscular injection of furosemide (5-(aminosulfonyl)4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (5 mg/kg). 16 h after the injection of furosemide the test compounds are administered either directly into the femoral artery using an injection cannula or, in the form of a suspension or solution, via an oesophageal tube into the stomach, and their action on the blood pressure and heart rate are evaluated. In the in vivo test described, the compounds of the present invention have hypotensive action at doses of from approximately 0.003 to approximately 1 mg/kg i.v. and at doses of from approximately 0.3 to approximately 100 mg/kg p.o. Alternatively, renin inhibitors may be tested on male normotensive marmosets weighing 250 to 500 g that are conscious, allowed to move freely and in their normal cages. The blood pressure, and heart rate are measured via a catheter placed in the descending aorta and recorded radiometrically. Electrocardiogram are obtained by placing electrodes of transmitter in lead II. The endogenous release of renin is stimulated by two intramuscular injection of furosemide (5-(aminosulfonyl)4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (10 mg/kg) 43 and 19 hours prior compound application. Test compounds are administered either directly into the femoral artery using an injection cannula or, in the form of a suspension or solution, via an oesophageal tube into the stomach, and their action on the blood pressure, heart rate and ECG are evaluated. In the in vivo test described, compounds of the present invention have hypotensive action at doses of from approximately 0.003 to approximately 0.3 mg/kg i.v. and at doses of from approximately 0.31 to approximately 30 mg/kg p.o. The compounds of the present invention also have the property of regulating, especially reducing, intra-ocular pressure. The extent of the reduction in intra-ocular pressure after administration of a pharmaceutical active ingredient of formula (I) according to the present invention can be determined, for example, in animals, for example rabbits or monkeys. Two typical experimental procedures that illustrate the present invention, but are not limited to in any way, are described hereinafter. The in vivo test on a rabbit of the “Fauve de Bourgogne” type to determine the intra-ocular-pressure-reducing activity of topically applied compositions can be designed, for example, as follows: The intra-ocular pressure (IOP) is measured using an aplanation tonometer both before the experiment and at regular intervals of time. After a local anaesthetic has been administered, the suitably formulated test compound is applied topically in a precisely defined concentration (e.g. 0.000001-5% by weight) to one eye of the animal in question. The contralateral eye is treated, for example, with physiological saline. The measured values thus obtained are evaluated statistically. The in vivo tests on monkeys of the species Macaca Fascicularis to determine the intra-ocular-pressure-reducing activity of topically applied compositions can be carried out, e.g., as follows: The suitably formulated test compound is applied in a precisely defined concentration (e.g. 0.000001-5% by weight) to one eye of each monkey. The other eye of the monkey is treated correspondingly, for example with physiological saline. Before the start of the test the animals are anaesthetised with intramuscular injections of, for example, ketamine. At regular intervals of time, the intra-ocular pressure (IOP) is measured. The test is carried out and evaluated in accordance with the rules of “good laboratory practice” (GLP). Illustrative of the invention, the compound of Example 29 demonstrates inhibition of renin activity with an IC50 value of about 0.3 nM in the FRET assay. The following Examples are intended to illustrate the invention and are not to be construed as being limitations thereon. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 10 and 100 mmHg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis, melting point (m.p.) and spectroscopic characteristics, e.g., MS, LC/MS, IR, NMR. In general, abbreviations used are those conventional in the art. EXAMPLE 1 General Procedure (I) a) (2S,4S,5S,7S)-5-tert-Butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid Triethylamine (NEt3) (7.2 mL, 51.6 mmol, 3.0 equiv.) followed by dimethylamino-pyridine (DMAP) (640 mg, 5.2 mmol, 0.3 equiv.) is added to a solution of (2S,4S,5S,7S)-5-tert-butoxycarbonylamino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (9.53 g, 17.2 mmol, 1.0 equiv.) and TBDMSCI (10.3 g, 68.7 mmol, 4.0 equiv.) in dimethylformamide (DMF) (100 mL) at room temperature (RT). The reaction mixture is stirred at RT for 16 hours before water (H2O) is added. Extraction with ethyl acetate (EtOAc), drying [sodium sulphate (Na2SO4)] and evaporation of the solvent affords the crude product. Flash column chromatography [600 g silicon dioxide (SiO2), hexane:EtOAc 5:1] yields the double TBDMS-protected product as a colorless oil. A portion thereof (904 mg, 1.24 mmol, 1.0 equiv.) is dissolved in methyl alcohol (MeOH) (20 mL) and 1 M HCl (2 mL, 2 mmol, 1.6 equiv.) is added. The mixture is stirred at RT for 10 minutes before 1 M sodium hydroxide (NaOH) (2 mL) followed by H2O and a 10% citric acid solution are added for workup. Extraction with EtOAc, drying (Na2SO4) of the combined organic extracts and evaporation of the solvent give the crude product which is purified by flash column chromatography [50 g SiO2, CH2Cl2:MeOH (9:1)] to afford the desired product as a colorless oil. MS (LC-MS): 691.3 [M+Na]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 7.63 minutes. b) ((1S,2S,4S)-4-Benzylcarbamoyl-2-(tert-butyl-dimethyl-silanyloxy)-1-[(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl)-5-methyl-hexyl)-carbamic acid tert-butyl ester HBTU (400 mg, 1.03 mmol, 1.2 equiv.) is added to a solution of (2S,4S,5S,7S)-5-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (575 mg, 0.86 mmol, 1.0 equiv.) in acetonitrile (CH3CN) (15 mL) and DMF (1 mL) at 0° C. After 5 minutes, a solution of benzylamine (94 μL, 0.86 mmol, 1.0 equiv.) and Net3 (1.2 mL, 8.6 mmol, 10 equiv.) in CH3CN (3 mL) is added and the reaction mixture is stirred at room temperature for 5 minutes. For workup EtOAc is added and the organic layer is washed with 1 N HCl, a saturated solution of sodium bicarbonate (NaHCO3) and brine. Drying (Na2SO4) of the organic phase and evaporation of the solvent affords the crude product which is purified by flash column chromatography [50 g SiO2, hexane:EtOAc (4:1)] to afford the desired product as a colorless foam. MS (LC-MS): 780.4 [M+Na]+; Rf [hexane:EtOAc (1:1)]: 0.65 minutes. c) ((1S,2S,4S)-4-Benzylcarbamoyl-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamic acid tert-butyl ester TBAF.3 H2O (302 mg, 0.96 mmol, 1.5 equiv.) is added to a solution of ((1S,2S,4S)-4-benzylcarbamoyl-2-(tert-butyl-dimethyl-silanyloxy)-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamic acid tert-butyl ester (485 mg, 0.64 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (6 mL) at RT. After 1 hour, H2O is added and the mixture is extracted with EtOAc. The combined extracts are dried (Na2SO4) and the solvent is evaporated. Flash column chromatography [50 g SiO2, hexane:EtOAc (3:1)] yields the desired product as a colorless foam. MS (LC-MS): 665.3 [M+Na]+; Rf [hexane:EtOAc (1:1)]: 0.33 minutes. d) (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid benzylamide At 0° C. 4 N HCl/dioxane (7 mL, 28 mmol) is added to ((1S,2S,4S)-4-benzylcarbamoyl-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamic acid tert-butyl ester (214 mg, 0.34 mmol, 1.0 equiv.). The resulting solution is stirred at RT for 15 minutes whereupon a saturated solution of NaHCO3 is carefully added. The mixture is extracted with EtOAc, the combined extracts are dried (Na2SO4) and the solvent is evaporated. Flash column chromatography [20 g SiO2, CH2Cl2:MeOH (9:1) to CH2Cl2:MeOH (9:1) +1% NEt3] affords the product as a colorless oil. MS (LC-MS): 544.3 [M+H]+; Rf [CH2Cl2:MeOH (9:1)]: 0.19 minutes. EXAMPLE 2 General Procedure (II) a) (2S,4S,5S,7S)-5-Azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid Lithium hydroxide (LiOH).H2O (2.18 g, 52.0 mmol) is added to a solution of (3S,5S)-5-{(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one (20.0 9, 43.3 mmol) in dimethoxyethane (DME) (400 mL) and H2O (200 mL) and the resulting solution is stirred at RT for 2 hours. The solvent is co-evaporated with toluene and the resulting solid is dried under high vacuum. This residue is dissolved in DMF (160 mL) and NEt3 (32 mL, 227.6 mmol), TBDMSOTf (41.8 mL, 182.1 mmol) and DMAP (556 mg, 4.6 mmol) are added sequentially. The mixture is stirred at RT for 16 hours. For workup, EtOAc is added and the mixture is quenched by addition of a saturated solution of NaHCO3. The organic phase is separated and the aqueous phase is extracted with EtOAc. Evaporation of the solvent of the combined organic extracts affords bis-TBDMS protected product (32.4 g) while acidification of the basic aqueous layer with 1 N HCl followed by extraction with EtOAc and evaporation of the solvent yields the corresponding mono-silylated free acid (8.8 g). Both isolated products are combined and subjected to flash column chromatography [hexane:EtOAc (4:1) to hexane:EtOAc (1:1)] to give the desired mono-silylated acid as a viscous oil (complete desilylation of the silyl-protected acid during chromatography). MS (LC-MS): 616.0 [M+Na]+; tR (HPLC, C8 column, 20-95% CH3CN/H2O/3.5 minute, 95% CH3CN/1 minute, flow: 0.8 mL/min.): 3.93 minutes. b) (2S,4S,5S,7S)-5-Azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-piperidin-1-yl-ethyl)-amide HBTU (1.20 g, 3.0 mmol) was added to a solution of (2S,4S,5S,7S)-5-azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1.50 g, 2.5 mmol) in CH3CN (50 mL). Then 2-aminoethylpiperidine (324 mg, 2.5 mmol) and NEt3 (3.9 mL) were added and the resulting solution was stirred at RT for 2.5 hours. For workup, EtOAc was added and the organic phase was washed with 1 N HCl, saturated NaHCO3 solution and brine. Drying of the organic phase (Na2SO4) and evaporation of the solvent affords the crude product which is purified by flash column chromatography [CH2Cl2:MeOH (95:5)] to give the desired product as a colorless oil. MS (LC-MS): 705.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 6.82 minutes. c) (2S,4S,5S,7S)-5-Azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-piperidin-1-yl-ethyl)-amide TBAF.3 H2O (1.73 g, 5.5 mmol) is added to a solution of (2S,4S,5S,7S)-5-azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl[-8-methyl-nonanoic acid (2-piperidin-1-yl-ethyl)-amide (1.54 g, 2.2 mmol) in THF (15 mL). The reaction mixture is stirred at RT for 72 hours. For workup, H2O is added and the mixture is extracted with CH2Cl2. The combined organic extracts are dried (Na2SO4) and the solvent is evaporated. Flash column chromatography [CH2Cl2:MeOH (9:1)] yields the desired product as a yellowish oil. MS (LC-MS): 590.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.24 minutes. d) (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-piperidin-1-yl-ethyl)-amide Palladium on carbon (Pd/C) 10% (200 mg) is added to a solution of (2S,4S,5S,7S)-5-azido4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-piperidin-1-yl-ethyl)-amide (780 mg, 1.32 mmol) in MeOH (40 mL) under Ar. Then the reaction suspension is stirred under a atmosphere of hydrogen (H2) for 8 hours. The catalyst is filtered-off over Celite and washed with MeOH. Evaporation of the solvent gives the crude product which is pure according to anaylsis and used without further purification. MS (LC-MS): 564.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.31 minutes. EXAMPLE 3 General Procedure (III) (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid cyclopropylmethyl-amide A solution of (3S,5S)-5-(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one (2.00 g, 4.3 mmol) and cyclopropanemethyl amine (1.9 mL, 21.7 mmol) in acetic acid (0.78 mL) was heated at 100° C. in a sealed tube for 30 minutes. Water was added and the mixture was extracted with CH2Cl2. Drying (Na2SO4) of the combined extracts and evaporation of the solvent afforded the crude product which was used without further purification. Pd/C 10% (1.10 g, 1.0 mmol) was added to a solution of the crude product (2.58 g) in MeOH (16 mL) and the reaction mixture was stirred under a H2 atmosphere for 9 hours. The catalyst was filtered-off over Celite and the solvent was evaporated. Purification of the crude product by flash column chromatography [CH2Cl2 to CH2CL2:MeOH (8:2)] afforded the desired product as a colorless foam. MS (LC-MS): 508.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.91 minutes. EXAMPLE 4 General Procedure (IV) a) 4-Bromo-1-fluoro-2-(3-methoxy-propoxy)-benzene Azodicarbonic acid diisopropylester is added to a solution of 4-bromo-1-fluoro-2-hydroxy-benzene [see Maleczak, Jr., Shi, Holmes and Smith, J Am Chem Soc, Vol. 125, No. 26, pp. 7792-7793 (2003)] (5.52 g, 28.9 mmol, 1 equiv.), triphenylphosphine (8.4 g, 31.8 mmol, 1.1 equiv.) in THF (20 mL) and 3methoxypropanol (3 mL, 31.8 mmol, 1.1 equiv.) in THF at RT and the solution is stirred for 16 hours, before the solvents are evaporated. Flash column chromatography [hexane:EtOAc (9:1) to hexane:EtOAc (4:1)] affords the product as a light yellow oil. MS (LC-MS): 264.9 [M+H]+; Rf [to hexane:EtOAc (4:1)]: 0.6 minutes. b) (3S,5S)-5-((1S,3S)-1-Azido-3-([4-fluoro-3-(3-methoxy-propoxy)-phenyl]-hydroxy-methyl)}-4-methyl-pentyl)-3-isopropyl-dihydro-furan-2-one To a solution of 4-bromo-1-fluoro-2-(3-methoxy-propoxy)-benzene (1.94 g, 13.3 mmol, 1.4 equiv.) and N-methylmorpholine (1.6 mL, 14.7 mmol, 3 equiv.) in THF (20 mL) n-butyl lithium in hexane (1.6 M, 5.5 mL, 8.8 mmol, 1.8 equiv.) is added dropwise at −78° C. The solution is stirred at −78° C. for 1 hour, when a solution of MgBr2 (14.7 mmol) in THF (50 mL), freshly prepared from magnesium (0.36 g, 14.7 mmol, 3 equiv.) and 1,2-dibromoethane (1.3 mL, 14.7 mmol, 3 equiv.), is added dropwise at −78° C. The reaction is stirred at the same temperature for 45 minutes, when (S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-3-methyl-butyraldehyde (1.4 g, 4.9 mmol, 1 equiv.) in THF (14 mL) is added dropwise at −78° C. The reaction mixture is stirred for an additional hour at the same temperature, before it is quenched with satatured aqueous NH4Cl (20 mL) and warmed to RT. The mixture is extracted with EtOAc, the combined extracts are washed with brine, dried over Na2SO4 and the solvent is evaporated. Flash column chromatography [CH2Cl2 to CH2Cl2:acetone (9:1)] affords the product as a light yellow oil. MS (LC-MS): 488[M+Na]+; Rf [CH2Cl2:acetone (98:2)]: 0.25 minutes. The starting material (S)-2-[(S)-2-azido-2-((2S,4S)4-isopropyl-5-oxotetrahydro-furan-2-yl)-ethyl]-3-methyl-butyraldehyde is prepared according to the methods described in EP 0 678 503 B1 and EP 0 678 514 A1. c) (3S,5S)-5-{(1S,3S)-1-Amino-3-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one A solution of isobutyric acid (S-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-1-[4-fluoro-(3methoxy-propoxy)-phenyl]-3-methyl-butyl ester (1.45 g, 2.7 mmol, 1 equiv.), Pd/C (10%, 2,9 g) and ethanolamine (0.17 mL, 2.7 mmol, 1 equiv.) in ethanol (135 mL) were shaken under H2 (1 atmosphere) for 24 hours. The reaction mixture is filtered, before the solvent is evaporated to afford the product as a light grey gum. MS (LC-MS): 424 [M+H]+ d) [(1S,3S)-3-[4-Fluoro-3-(3-methoxy-propoxy)-benzyl]-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-4-methyl-pentyl]-carbamic acid tert-butyl ester A solution of (3S,5S)-5-{(1S,3S)-1-amino-3-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one (1.13 g, 2.7 mmol, 1 equiv.), di-tert-butyldicarbonate (2.1 g, 9.4 mmol) and diisopropylethylamine (1.83 mL, 10.7 mmol, 4 equiv.) in CH2Cl2 (20 mL) is stirred at RT for 164 hours. The solution is washed with aqueous HCl (1 M), saturated aqueous NaHCO3 and brine, dried over Na2SO4 and the solvents are evaporated. Flash column chromatography [CH2Cl2 to CH2Cl2:acetone (95:5)] affords the product as a light yellow oil. MS (LC-MS): 546 [M+Na]+; Rf (CH2Cl2:acetone (95:5)]: 0.71 minutes. e) {(1S,2S,4S)-1-{(S)-2-[4-Fluoro-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-2-hydroxy-4-1(1-hydroxymethyl-cyclopropylmethyl)-carbamoyl]-5-methyl-hexyl}-carbamic acid tert-butyl ester [(1S,3S)-3-[4-Fluoro-3-(3-methoxy-propoxy)-benzyl]-1-((2S,4S)-isopropyl-5-oxo-tetrahydro-furan-2-yl)4-methyl-pentyl]-carbamic acid tert-butyl ester (100 g, 0.19mmol, 1 eq), 3-amino-2,2-dimethylpropanol (0.3 g, 2.8 mmol, 15 eq) and acetic acid (0.11 μL, 0.002 mmol, 0.01 eq) are stirred at 60° C. during 24 hours, when the solvent is evaporated. Flash column chromatography (CH2Cl2/MeOH 95:5 to CH2Cl2/MeOH 9:1) affords the product as an light yellow solid. MS (LC-MS): 627 [M+H]+; Rf (CH2Cl2/MeOH 9:1): 0.25. f) (2S,4S,5S,7S)-5-Amino-7-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-hydroxy-2-isopropyl- 8-methyl-nonanoic acid (1-hydroxymethyl-cyclopropylmethyl)-amide At 5° C. 4N HCl/dioxane (0.97 ml) is added to ((1S,2S,4S)-4-Cyclopropylcarbamoyl-1-{(S-2-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl)-2-hydroxy-5-methyl-hexyl)-carbamic acid tert-butyl ester (89 mg, 0.14 mmol, 1.0 eq) in dioxane (0.8 ml). The resulting solution is stirred at 5° C. for 1 h whereupon it is lyophilised. Flash column chromatography (CH2Cl2/MeOH(10% NH40H) 95:5 to CH2Cl2/MeOH(10% NH4OH) 9:1) affords the product as a light yellow solid. MS (LC-MS): 527.1[M+H]+; Rf (CH2Cl2/MeOH(10% NH4OH) 9:1): 0.16 minutes. EXAMPLE 5 (2S,4S,5S,7S)-5-Amino-7-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-hydroxy-2-isopropyl-8-methyl-nonanoic acid (3-hydroxy-2,2-dimethyl-propyl)-amide The title compound prepared in accordance with General Procedure (IV). MS (LC-MS): 527.1 [M+H]+; Rf [CH2Cl2:MeOH (10% NH3) (9:1)]: 0.16 minutes. EXAMPLE 6 (2S,4S,5S,7S)-5-Amino-7-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-hydroxy-2-isopropyl-8-methyl-nonanoic acid (3-hydroxy-2,2-dimethyl-propyl)-amide The title compound prepared in accordance General Procedure (IV). MS (LC-MS): 606.1 [M+H]+; Rf [CH2Cl2:MeOH (9:1)]: 0.16 minutes. EXAMPLE 7 Cyclopropanecarboxylic acid [1-({(2S,4S,5S,7S)-5-amino-7-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-hydroxy-2-isopropyl-8-methyl-nonanoylamino}-methyl-cyclopropyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 590.1 [M+H]+; Rf [CH2Cl2:MeOH(10NH3) (9:1)]: 0.16 minutes. EXAMPLE 8 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-methoxymethyl-cyclopropylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 551 [M+H]+; Rf [CH2Cl2:MeOH (9:1): 0.16 minutes. EXAMPLE 9 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-hydroxymethyl-cyclopropylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 537 [M+H]+; Rf [CH2Cl2:MeOH (9:1): 0.15 minutes. EXAMPLE 10 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-fluoro-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 499.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.63 minutes. EXAMPLE 11 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2,2-difluoro-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 518.1 [M+]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow. 1.5 mL/min.): 4.75 minutes. EXAMPLE 12 (_b 2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl[-8-methyl-nonanoic acid (3,3,3-trifluoro-propyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 535.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.9 minutes. EXAMPLE 13 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid cyclopropylmethyl-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 508.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.91 minutes. EXAMPLE 14 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-cyclopropyl-1-methyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 536.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.21 minutes. EXAMPLE 15 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((R)-1-cyclopropyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 522.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.95 minutes. EXAMPLE 16 (2S,4S,5S,7S)-5-Amino-4hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((S)-1-cyclopropyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 522.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.93 minutes. EXAMPLE 17 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2,2-dimethyl-cyclopropylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 536.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.81 minutes. EXAMPLE 18 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [(1R,3S)-2,2-dimethyl-3-(2-methyl-propenyl)-cyclopropylmethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MD): 590.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.70 minutes. EXAMPLE 19 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl-8-methyl-nonanoic acid ((R)-1-cyclobutyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 536/1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.12 minutes. EXAMPLE 20 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl-8-methyl-nonanoic acid ((S)-1-cyclobutyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 536.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.15 minutes. EXAMPLE 21 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid cyclopentylmethyl-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 535.4 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.15 minutes. EXAMPLE 22 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((S)-1-cyclopentyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 550.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.25 minutes. EXAMPLE 23 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((R)-1-cyclopentyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 550.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.24 minutes. EXAMPLE 24 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((R)-2,2-dimethyl-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 550.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.) 5.27 minutes. EXAMPLE 25 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((S)-2,2-dimethyl-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 550.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.25 minutes. EXAMPLE 26 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-methyl-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 535.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.08 minutes. EXAMPLE 27 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-fluoro-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 554 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.42 minutes. EXAMPLE 28 (2S,4S,5S,7S)-5-Amino4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid cyclohexylmethyl-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 549.3 [M]+; tR (HPLC, C8 column, 595% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 3.87 minutes. EXAMPLE 29 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((S)-1-cyclohexyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 564.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.36 minutes. EXAMPLE 30 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((R)-1-cyclohexyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 564.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.) 5.38 minutes. EXAMPLE 31 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid cycloheptylmethyl-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 563.2 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.62 minutes. EXAMPLE 32 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 590.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.) 5.71 minutes. EXAMPLE 33 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopropanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 566.0 [M+H]+; tR (HPLC, C8 column, 20-95% CH3CN/H2O/3.5 minutes, 95% CH3CN/1 minute, flow: 0.8 mL/min.): 2.44 minutes. EXAMPLE 34 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-methyl)-cyclobutanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 580.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.11 minutes. EXAMPLE 35 1-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclopentanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 580.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.02 minutes. EXAMPLE 36 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-cyclopentanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 594.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.19 minutes. EXAMPLE 37 1-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 594.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.13 minutes. EXAMPLE 38 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl-cyclohexanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 608.0 [M+H]+; tR (HPLC, C8 column, 20-95% CH3CN/H2O/3.5 minutes, 95% CH3CN/1 minute, flow: 0.8 mL/min.): 2.74 minutes. EXAMPLE 39 (S)-(2S,4S,5S,7S)-5-Amino4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexyl-acetic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 608.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.) 5.26 minutes. EXAMPLE 40 (1S,3R)-3-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclopentanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 580.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.10 minutes. EXAMPLE 41 (1S,3R)-3-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-cyclopentanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 580.0 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.36 minutes. EXAMPLE 42 4-((2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 594.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.08 minutes. EXAMPLE 43 4-((2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexanecarboxylic acid methyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 594.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.01 minutes. EXAMPLE 44 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl-cyclopentanecarboxylic acid The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 579.1 [M+H]+; tR (HPLC, C8 column, 20-95% CH3CN/H2O/3.5 minutes, 95% CH3CN/1 minutes, flow: 0.8 mL/min.): 2.48 minutes. EXAMPLE 45 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 453.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.41 minutes. EXAMPLE 46 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopropanecarboxylic acid amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 550.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.05 minutes. EXAMPLE 47 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclobutanecarboxylic acid amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 564.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.54 minutes. EXAMPLE 48 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopentanecarboxylic acid amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 578.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1minute, flow: 0.5 mL/min.): 4.2 minutes. EXAMPLE 49 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-methyl)-cyclohexanecarboxylic acid amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 592.2 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.02 minutes. EXAMPLE 50 1-(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclopentanecarboxylic acid amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 564.2 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min): 4.66 minutes. EXAMPLE 51 2-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-C3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-cyclopentanecarboxylic acid amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 564.3 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.3 minutes. EXAMPLE 52 2-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-)3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexanecarboxylic acid amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 578.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.84 minutes. EXAMPLE 53 1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopentanecarboxylic acid methylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 592.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.51 minutes. EXAMPLE 54 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-formylamino-cyclopropylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 551 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.41 minutes. EXAMPLE 55 (2S14S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-acetylamino-cyclopropylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 565.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.46 minutes. EXAMPLE 56 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-formylamino-cyclopentylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 579.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.7 minutes. EXAMPLE 57 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2:isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-acetylamino-cyclopentylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 592.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.68 minutes. EXAMPLE 58 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [1-(2,2-dimethyl-propionylamino)-cyclopentylmethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 634.2 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.18 minutes. EXAMPLE 59 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid {1-[(2,2-dimethyl-propionylamino)-methyl]-cyclopentyl}-amide The title prepared in accordance with General Procedure (I). MS (LC-MS): 635.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.34 minutes. EXAMPLE 60 Cyclopropanecarboxylic acid [1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-78 4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopentyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): [M+H]+; Rf [CH2Cl2:MeOH (9:1)]: 0.18 minutes. EXAMPLE 61 [1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-methyl)-cyclopropyl]-carbamic acid tert-butyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 623.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.22 minutes. EXAMPLE 62 [1-({(2S,4S,5S,7S)-5-Amino4-hydroxy-2-isopropyl-7-[4-methoxy-3-3methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-methyl)-cyclopentyl]-carbamic acid tert-butyl ester The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 650.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.43 minutes. EXAMPLE 63 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-amino-cyclopropylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 523.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.33 minutes. EXAMPLE 64 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-amino-cyclopentylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 550.1 [M+H]30 ; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.31 minutes. EXAMPLE 65 (2S,4S,5S,7S)-5 -Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (4-amino-cyclohexyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 550.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.18 minutes. EXAMPLE 66 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (4-amino-cyclohexyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 550.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.14 minutes. EXAMPLE 67 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-dimethylamino-cyclopropylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 551.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.36 minutes. EXAMPLE 68 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-dimethylamino-cyclopentylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 578.2 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.29 minutes. EXAMPLE 69 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-methoxymethyl-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 565.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.11 minutes. EXAMPLE 70 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-methoxy-cyclopentylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 566 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.01 minutes. EXAMPLE 71 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((1S,2S)-2-benzyloxy-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 628.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.38 minutes. EXAMPLE 72 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((1R,2R)-2-benzyloxy-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 628.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.42 minutes. EXAMPLE 73 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (4-methoxy-cyclohexyl)-amide MS (LC-MS): 565.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.59 minutes. EXAMPLE 74 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (4-methoxy-cyclohexyl)-amide MS (LC-MS): 565.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.67 minutes. EXAMPLE 75 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((1S,2S)-2-benzyloxy-cyclohexyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 641.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 6.10 minutes. EXAMPLE 76 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((1R,2R)-2-benzyloxy-cyclohexyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 641.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 6.00 minutes. EXAMPLE 77 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-hydroxy-cyclopropylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 523.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.52 minutes. EXAMPLE 78 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((1R,2R)-2-hydroxy-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 538.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.74 minutes. EXAMPLE 79 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((1S,2S)-2-hydroxy-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 537.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.37 minutes. EXAMPLE 80 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-hydroxymethyl-cyclopentyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 551.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.77 minutes. EXAMPLE 81 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-hydroxy-cyclopentylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 552 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.72 minutes. EXAMPLE 82 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 551.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.62 minutes. EXAMPLE 83 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((1S,2S)-2-hydroxy-cyclohexyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 551.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.41 minutes. EXAMPLE 84 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (4-hydroxy-cyclohexyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 551.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.61 minutes. EXAMPLE 85 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (4-hydroxy-cyclohexyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 552.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.81 minutes. EXAMPLE 86 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-hydroxy-cyclohexylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 565.2 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.07 minutes. EXAMPLE 87 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((R)-1-phenyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 558.3 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.63 minutes. EXAMPLE 88 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((S)-1-phenyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 558.3 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.69 minutes. EXAMPLE 89 (2S,4S,5S,7S)-5-Amino 4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1-methyl-1-phenyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 572.0 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 3.85 minutes. EXAMPLE 90 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (naphthalen-1-ylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 594.5 [M+H]+; Rf [CH2Cl2: MeOH (9:1)]: 0.21 minutes. EXAMPLE 91 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid indan-2-ylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 569.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mLlmin.): 5.16 minutes. EXAMPLE 92 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-methyl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 558.3 [M+H]+; Rf [CH2Cl2:MeOH (9:1)]: 0.17 minutes. EXAMPLE 93 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3-methyl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 558.3 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.28 minutes. EXAMPLE 94 (2S,4S,5S,7S))-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-methyl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 558.3 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 3.76 minutes. EXAMPLE 95 (2S,4$,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((R)-1-p-tolyl-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 571.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): EXAMPLE 96 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid ((S)-1-p-tolyl-ethyl)-amide The title prepared in accordance with General Procedure (I). MS (LC-MS): 571.2 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): EXAMPLE 97 (2S,4S,5S,7S))-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-isopropyl-benzylamide The title prepared in accordance with General Procedure (I). MS (LC-MS): 586.3 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mLlmin.): 4.26 minutes. EXAMPLE 98 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-methoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 573.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.15 minutes. EXAMPLE 99 (2S,4S,5S,7S))-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3-methoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 573.3 [M+H]+; Rf [CH2Cl2:MeOH (9:1)]: 0.17 minutes. EXAMPLE 100 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4methoxy-benzylamide The title prepared in accordance with General Procedure (I). MS (LC-MS); 573.3 [M+H]+; Rf [CH2Cl2:MeOH (9:1)]: 0.14 minutes. EXAMPLE 101 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [(S)-1-(3-methoxy-phenyl)-ethyl]-epared in accordance with General Procedure (I). The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 587.2 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.: 5.10 minutes. EXAMPLE 102 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [(R)-1-(3-methoxy-phenyl)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 587.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.10 minutes. EXAMPLE 103 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [(S)-1-(4-methoxy-phenyl)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 587.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.07 minutes. EXAMPLE 104 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [(R)-1-(4-methoxy-phenyl)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 587.1 [M+H+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mLlmin.): 5.09 minutes. EXAMPLE 105 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-methylsulfanyl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 589.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.10 minutes. EXAMPLE 106 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-methylsulfanyl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 589.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.12 minutes. EXAMPLE 107 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2,5-dimethoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 603.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.13 minutes. EXAMPLE 108 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2,3-dimethoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 603.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.03 minutes. EXAMPLE 109 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2,4-dimethoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 603.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.23 minutes. EXAMPLE 110 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3,4-dimethoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 603.3 [M]+; Rf [CH2Cl2:MeOH (9:1)1:0.18 minutes. EXAMPLE 111 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2,6-dimethoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 603.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.24 minutes. EXAMPLE 112 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3,5-dimethoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 603.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.04 minutes. EXAMPLE 113 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-trifluoromethoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 627.3 [M]+; Rf [CH2Cl2:MeOH (9:1)): 0.31 minutes. EXAMPLE 114 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3-trifluoromethoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 627.2 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.17 minutes. EXAMPLE 115 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-trifluoromethoxy-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 627.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.26 minutes. EXAMPLE 116 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-fluoro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 561.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.03 minutes. EXAMPLE 117 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3-fluoro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 561.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.09 minutes. EXAM 118 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-fluoro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 561.3 [M+H]+; tR (HPLC, C18 column, 10100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.08 minutes. EXAMPLE 119 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 575.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.11 minutes. EXAMPLE 120 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 575.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.09 minutes. EXAMPLE 121 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-chloro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 577.3 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.15 minutes. EXAMPLE 122 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3-chloro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 577.3 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.18 minutes. EXAMPLE 123 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-chloro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 577.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.14 minutes. EXAMPLE 124 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2,5-difluoro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 579.1 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.13 minutes. EXAMPLE 125 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2,4-difluoro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 579.1 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.07 minutes. EXAMPLE 126 (2S,4S,5S,75)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2,6-difluoro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 579.0 [M]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 4.63 minutes. EXAMPLE 127 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3,4-difluoro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LG-MS): 579.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.11 minutes. EXAMPLE 128 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3,5-difluoro-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 579.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.12 minutes. EXAMPLE 129 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-trifluoromethyl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 611.1 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.43 minutes. EXAMPLE 130 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3trifluoromethyl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 611.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.59 minutes. EXAMPLE 131 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-trifluoromethyl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 611.0 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min ): 5.43 minutes. EXAMPLE 132 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-cyano-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 568.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.25 minutes. EXAMPLE 133 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-dimethylamino-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 586.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.26 minutes. EXAMPLE 134 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 601.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.25 minutes. EXAMPLE 135 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 601.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.07 minutes. EXAMPLE 136 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 615.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.07 minutes. EXAMPLE 137 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2,3-dihydro-benzofuran-5-ylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 585.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.07 minutes. EXAMPLE 138 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (benzofuran-4-ylmethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 583.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.11 minutes. EXAMPLE 139 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-piperidin-1-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 626.4 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.58 minutes. EXAMPLE 140 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3-piperidin-1-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 628.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.35 minutes. EXAMPLE 141 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-piperidin-1-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 626.4 [M]+; Rf (CH2Cl2:MeOH (9:1)]: 0.35 minutes. EXAMPLE 142 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-morpholin-4-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 628.4 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.58 minutes. EXAMPLE 143 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3-morpholin4yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 628.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.61 minutes. EXAMPLE 144 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-morpholin-4-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 628.4 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.55 minutes. EXAMPLE 145 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 2-pyrrolidin-1-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 612.4 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.46 minutes. EXAMPLE 146 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3-pyrrolidin-1-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 612.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.66 minutes. EXAMPLE 147 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-pyrrolidin-1-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 612.4 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.37 minutes. EXAMPLE 148 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 3-pyrrol-1-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 608.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.37 minutes. EXAMPLE 149 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-pyrrol-1-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 608.3 [M]+; Rf [CH2Cl2:MeOH (9:1)]: 0.35 minutes. EXAMPLE 150 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid 4-thiophen-3-yl-benzylamide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 625.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.45 minutes. EXAMPLE 151 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid phenethyl-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 557.1 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.18 minutes. EXAMPLE 152 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [1-methyl-1-(1-phenyl-cyclopropyl)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 611.1 [M+H]+; tR (HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 5.6 minutes. EXAMPLE 153 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [2-(2-fluoro-phenyl)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 575.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.12 minutes. EXAMPLE 154 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [2-(3-fluoro-phenyl)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 575.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.11 minutes. EXAMPLE 155 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [2-(4-fluoro-phenyl)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 575.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.06 minutes. EXAMPLE 156 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-phenoxy-ethyl)-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 573.3 [M]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.08 minutes. EXAMPLE 157 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [2-(4-methoxy-phenoxy)-ethyl]-amide The title compound prepared in accordance with General Procedure (I). MS (LC-MS): 603.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 5.09 minutes. EXAMPLE 158 Gelatin solution A sterile-filtered aqueous solution, containing 20% cyclodextrins as solubiliser, of one of the compounds of formula (I), mentioned in the preceding Examples, as active ingredient, is so mixed, with the application of heat and under aseptic conditions, with a sterile gelatin solution containing phenol as preservative, that 1.0 mL of solution has the following composition: active ingredient 3 mg gelatin 150.0 mg phenol 4.7 mg dist. water containing 20% cyclodextrins as solubiliser 1.0 mL EXAMPLE 159 Sterile Dry Substance for Injection Five (5) mg of one of the compounds of formula (I), mentioned in the preceding Examples, as active ingredient, are dissolved in 1 mL of an aqueous solution containing 20 mg of mannitol and 20% cyclodextrins as solubiliser. The solution is sterile-filtered and, under aseptic conditions, introduced into a 2 mL ampoule, deep-frozen and lyophilised. Before being used, the lyophilisate is dissolved in 1 mL of distilled water or 1 mL of physiological saline. The solution is administered intramuscularly or intravenously. The formulation can also be filled into double-chamber disposable syringes. EXAMPLE 160 Nasal Spray Five hundred (500) mg of finely ground (<5.0 gm) powder of one of the compounds of formula (I), mentioned in the preceding Examples, are suspended as active ingredient in a mixture of 3.5 mL of “Myglyol 8 12” and 0.08 g of benzyl alcohol. The suspension is introduced into a container having a metering valve. Five (5.0) g of “Freon 12” are introduced under pressure through the valve into the container. The “Freon” is dissolved in the Myglyolbenzyl alcohol mixture by shaking. The spray container contains approximately 100 single doses which can be administered individually. EXAMPLE 161 Film-Coated Tablets The following constituents are processed for the preparation of 10 000 tablets each containing 100 mg of active ingredient: active ingredient 1000 g corn starch 680 g colloidal silicic acid 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl starch 250 g water quantum satis A mixture of one of the compounds of formula (I), mentioned in the preceding Examples, as active ingredient, 50 g of corn starch and the colloidal silicic acid is processed into a moist mass with starch paste prepared from 250 g of corn starch and 2.2 kg of demineralised water. The mass is forced through a sieve having a mesh size of 3 mm and dried at 45° C. for 30 minutes in a fluidised bed drier. The dried granules are pressed through a sieve having a mesh size of 1 ram, mixed with a previously sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and compressed to form slightly biconvex tablets. Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible without departing from the spirit and scope of the preferred versions contained herein. All references and Patents (U.S. and others) referred to herein are hereby incorporated by reference in their entirety as if set forth in full herein.

20060512

20090901

20070614

86267.0

A61K3144

KUMAR, SHAILENDRA

ORGANIC COMPOUNDS

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Method for Operating Industrial Installations

The method was tackled with picking line for generating strip steel for the automobile industry. The initial conditions to which the tandem-type mill coupled with picking line executed using the installation is exposed. The installation receives an input in the form of human resources, energy, media, raw materials, semifinished product, etc., which is converted by the installation into output. Since the plant is a hot rolling mill, the output is in the form of hot rolled strips. The different components of the input can be assigned to the factor markets that are relevant to the real installation. The different components of the output can further be assigned to the product markets that are relevant to the real installation.

1-18. (canceled) 19. A method for operating an industrial installation, comprising: identifying a plurality of technical measurement variables which co-determine a value retention of a real installation; recording an actual status of the real installation by measuring the identified technical measurement variables; specifying a benchmark; comparing the actual status of the real installation with the specified benchmark to determine a technical measurement variable whose change in value increases the value retention of the real installation, identifying a plurality of structural measures which increase the value retention of the real installation by changing the value of the technical measurement variable; and carrying out the structural measures. 20. The method as claimed in claim 19, wherein the benchmark is specified by recording an actual status on an installation which is similar compared to the real installation to be assessed. 21. The method as claimed in claim 20, wherein the similar installation is an existing installation or an installation which is in a building phase. 22. The method as claimed in claim 20, wherein an installation-specific key component is recorded for specifying the benchmark. 23. The method as claimed in claim 20, wherein an installation-relevant innovation is recorded for specifying the benchmark. 24. The method as claimed in claim 19, wherein the actual status and a significant technical trend are recorded in a factor markets relevant to the real installation, a product markets relevant to the real installation, and a technological environment of the real installation for specifying the benchmark. 25. The method as claimed in claim 19, wherein the method is partially carried out by an external service provider. 26. The method as claimed in claim 19, wherein the actual status of the real installation is partially determined by a software. 27. The method as claimed in claim 19, wherein steps of identifying the technical measurement variables, recording an actual status of the real installation, specifying a benchmark, and comparing the actual status of the real installation with the specified benchmark are carried out more frequently than steps of identifying the structural measures and carrying out the structural measures. 28. The method as claimed in claim 19, wherein an increase of the value retention of the real installation is quantitatively determined. 29. The method as claimed in claim 19, wherein the structural measures are carried out when the actual status of the real installation is at least as good as a setpoint status. 30. The method as claimed in claim 19, wherein the method is for operating a production facility. 31. A system for operating an industrial installation, comprising: an identifier for identifying a plurality of technical measurement variables which co-determine a value retention of a real installation; a recorder for recording an actual status of the real installation by measuring the identified technical measurement variables; an inputting device for inputting a plurality of measured values relating to the identified technical measurement variables; and a comparing device for comparing the actual status of the installation with a benchmark for determining a technical measurement variable whose change in value increases the value retention of the real installation. 32. The system as claimed in claim 31, wherein a plurality of structural measures are identified which increase the value retention of the real installation by changing the value of the determined technical measurement variable. 33. The system as claimed in claim 32, wherein an evaluation is provided by which an increase of the value retention of the real installation is quantitatively determined. 34. A computer program for operating an industrial installation, comprising: a computer sub program for identifying a plurality of technical measurement variables which co-determine a value retention of a real installation; a computer sub program for recording an actual status of the real installation by measuring the identified technical measurement variables; a computer sub program for interrogating a plurality of measured values relating to the identified technical measurement variables; and a computer sub program for comparing the actual status of the real installation with a benchmark for determining a technical measurement variable whose change in value increases the value retention of the real installation. 35. The computer program as claimed in claim 34, wherein a plurality of structural measures are identified which increase the value retention of the real installation by changing the value of the determined technical measurement variable. 36. The computer program as claimed in claim 34, wherein an increase of the value retention of the real installation is quantitatively determined. 37. The computer program as claimed in claim 34, wherein the method is for operating a production facility.

The invention relates to a method for operating industrial installations and industrial processes, and in particular the operation of long-lived industrial production facilities. In this case the operation of the facilities relates in particular to the ongoing maintenance and properly targeted modernization of said facilities. Long-lived industrial installations, for example rolling mills, paper mills or glass manufacturing plants, are built for a specific purpose. At the same time the conditions prevailing in the sales, technology, method and factor markets relevant to the installation at the time of planning and erection are taken into account along with the associated risks, and also projected into the future. In the course of the service life of an installation of said kind there are changes not only in these conditions but also with regard to the integration of the installation into a corporate context. Thus, for example, the products to be produced can be developed further as a result of customer requirements or technological development, and so also can the technology employed in the manufacture of said products. The existing technology is subject to wear and tear or to some other aging process. In the context of software or IT systems this is referred to as obsolescence. Due to these circumstances additional entrepreneurial risks arise over the course of the installation's life. These can manifest themselves for example in a decline in the quality of the products, in production downtimes, in competitors' gaining a lead, or also through missed business opportunities. It is known that over the lifecycle of an installation there is carried out at specific time intervals routine maintenance, event-dependent active maintenance, or at longer time intervals a complete modernization of the installation. In some branches of industry, for example in the automobile industry, it has also proven to be economically feasible to discount the longevity of the installation and for example to build a new production facility in synchronism with each product innovation. The disadvantage of routine maintenance and active maintenance is that with this, in the best case the original status, which is largely determined by the design, can be restored. An improvement or adaptation to new conditions, production factors, products, markets or corporate strategies does not take place. Although complete modernization does not have this disadvantage, for its part it does have the disadvantage that a considerable production outage is always associated with it, and that a financially and technically complicated handling process with not inconsiderable additional risks has to be initiated. Because of the high investment volume and the fiscal depreciation periods associated therewith, it is not possible to sacrifice longevity in the same way in all branches of industry. The invention is based on the technical problem of providing a method for operation of technical installations by means of which structural improvement measures can either be deliberately avoided or else carried out on behalf of the operator in a particularly targeted and efficient manner in terms of an increase in value retention. At the same time the method is also to be realizable by means of a computer program and using a computer system. A further technical problem is to set technical influencing variables of the installation reliably to their setpoint value on a long-term basis. The solution to this technical problem is provided by the features recited in the independent claims. Advantageous developments are reproduced by the features recited in the dependent claims or can be derived from the description in conjunction with the figures. The invention is based on the knowledge that the value retention of an installation can be increased by the reliable setting of technical influencing variables to their setpoint value on a long-term basis. In the present description the value retention of an installation is to be understood as a variable which not only includes the replacement value or current market value of the installation, but also, and quite fundamentally, the economic usefulness of the installation as that capability to generate a profit with the installation at the present time and in the future at the installation site and under the prevailing economic and legal framework conditions. Owing the profit aspect mentioned, the value retention can also be interpreted as the return on fixed capital. The value retention can be expressed in terms of an EBIT (Earnings Before Interest and Taxes) and depends generally on many factors, also including, however, a large number of technical influencing variables. Which influencing variables or measurement variables are important for determining this economic usefulness in the real-world case, i.e. for a real installation or for a real process, depends on the type of the installation and its technological environment. In many cases said variables include the reject rate of the installation, its efficiency, its service lifecycles, its availability, times required for the conversion to a new or different product, its energy and water consumption, the time required for maintenance steps, and many other measurement variables. Experience shows that the technical impact on the economic usefulness of an installation can in many cases be captured by means of approx. 100 to 200 significant technical measurement variables. If those technical measurement variables which co-determine, or at least substantially co-determine, the value retention of a real installation are successfully identified, then it is necessary, in a next step, to specify which measurement methods are to be used to determine the respective measurement variables. In most cases the measurement method for installations of the type to be investigated is known and established across the industry, and to that extent determining the measurement method is not a problem for the person skilled in the art. The result at this intermediate stage of the method is that set of identified technical measurement-variables which determine the economic usefulness of the installation to be investigated. In other words, this set of measurement variables represents the technically related economic condition of the installation. If desired, the identified measurement variables can also be combined into a single variable. In this case it is recorded in a model-based procedure how the aforementioned measurement variables are technically related and how they impact the value retention. The model then yields a computing rule specifying how the aforementioned single variable can be calculated. In the absence of the detailed knowledge required in this case it is also possible to choose a heuristic approach and to weight the measurement variables according to the degree to which they influence the economic usefulness. The factors of this weighting can subsequently be combined to form a single variable. In a suitable normalization of the variable this can be for example a number between 1 and 6, and to that extent stands in the nature of a school mark for the technically related economic condition of the installation. Following the identification of the relevant measurement variables and the associated measurement methods, the actual status of the real installation is recorded by measurement of the identified measurement variables using the specified measurement methods. Once the actual status of the real installation to be investigated has been determined, a benchmark is specified. A benchmark, in this context, is a gauge for the assessment of the previously determined actual status of the installation to be investigated. In order to specify a benchmark, actual statuses are preferably recorded for such installations which are similar when compared with the installation to be assessed. In most cases there are existing installations, for example from the same manufacturer or from a competing manufacturer, or even from the same operator or other operators, which are similar to the installation to be investigated. If this is the case, the actual statuses of such installations are recorded. For the assessment of the actual status of the similar installation, as a general principle the same set of measurement variables is chosen. However, for practical reasons it will often not be possible to measure all the measurement variables in the set of measurement variables on the similar installation, for example because no access to such an installation is granted. In this case there is a smaller number of measured values from the similar installation than is the case on the installation to be investigated. In this case the measurement variables of said similar installation can only be used to a limited extent for purposes of comparison, and the benchmark must be supported by further installations and sources. For example, new installations in the development or building phase which are similar to the installation to be investigated can be used for this purpose. In this case, too, an actual status can be determined in the manner described above. As a rule this will only be possible if the manufacturer of the new installation is the one that is personally practicing the method according to the invention. Installation-specific key components and/or installation-relevant innovations can also be recorded for the purpose of specifying the benchmark. Thus, there are installations in which certain installation components are economically of special significance. An example of this would be a new method for replacing the roller offering significantly faster roller replacement for worn-out rollers in the printing machines sector. A further example would be a new means of regulating the thickness of a product (for example, a protective coating) by the use of new model-based methods based on previously unavailable real-time computing power. Also of particular economic significance would be the possibility, provided for the first time in the real application, to allow a conversion to a new product to proceed fully automatically for the first time. To sum up, key components and installation-relevant innovations of said kind influence the value of the installation to a not inconsiderable degree and are therefore systematically recorded on an industry-specific basis starting from existing installations and used for the benchmark in the manner of a checklist for the degree of expansion of the installation. Similarly, technical innovations which influence the economic usefulness of the installation, and which are also incorporated into the benchmark, can become established in the market relevant to the installation to be investigated. Thus, for example, the economic value of production facilities for traditional, i.e. analog, video recorders or television sets is influenced by the alternative or additional possibilities which digitization brings. The same applies analogously in relation to production facilities for cameras, since digital cameras are becoming increasingly important. For the cases cited, digitization of the product sector is of considerable economic importance, and moreover in particular for such installations which exclusively produce non-digital products of these product types. In order to devise a benchmark it is necessary to study the markets relevant to the installation as well as to record changes in these markets. The markets relevant to the installation are the factor markets and the product markets. Also of importance is, as explained in the foregoing, the technological environment of the installation for the purpose of registering installation-relevant innovations and key components. In a subsequent step of the method according to the invention, the actual status of the real installation is compared with the specified benchmark for the purpose of determining at least one measurement variable whose change in value would increase the value retention of the installation. In this step the current status of the installation to be investigated is thus measured against the benchmark. By this means it is discovered which measurement variable can realistically be improved in its value, with the result being of a qualitative nature. If it is considered, for example, whether the reduction in the reject rate could have an impact on the value retention, then it is possible to establish via the benchmark first what reject rate similar installations have. If the reject rate from the similar installations is less, then it ought to be possible in many cases to reduce the reject rate of the installation to be investigated at reasonable cost. If the reject rate of the real installation is better than in the similar installations, then as a rule there is no need to take action with regard to this measurement variable, since experience has shown that a further improvement in a measurement variable that is in any case good to optimal is associated with a very high overhead. In summary, measuring the status of the installation against the benchmark enables the qualitative conclusion to be made about which measurement variable changes could increase the economic usefulness of the installation at reasonable cost. Following the measurement of the installation status against the benchmark it is optionally possible not only to make a qualitative pronouncement of the aforementioned type, but also to quantify the increase in value retention in a real way and express it for example in the form of an EBIT. This is done by means of an economic costs/benefits calculation and is generally to the person skilled in the art. Once the measurement variables whose change in value would increase the value retention of the installation have been identified, it is subsequently determined which structural measure or which structural measures need to be taken on the installation in order to change the measurement variable in a positive direction, i.e. to change it in such a way that the value retention of the installation is increased. In parallel it is ensured that the measure on this real installation, also when considered in detail, can be technically executed. The achieved result of the method consists in an increase in the value retention of the installation resulting from the optimized setting of the technical influencing variables. An advantage linked with the use of a benchmark is that existing technical weaknesses of the installation are laid bare on a basis that is objectivized to a greater extent and so do not rely on subjective assessments by the operating personnel of the installation operator. The weaknesses of the installations are therefore determined more reliably and more objectively. A further advantage with the use of the benchmark is to be seen in the fact that it can be employed to discover which measurement variables can be improved with an economically justifiable outlay in terms of capital, labor, materials and energy. As a result of the comparison with similar installations it becomes clear whether the measured value associated with the respective measurement variable of the installation is comparatively good or comparatively poor. In this way the situation is avoided whereby the process of optimizing the installation is initiated at points where the technical and at the same time financial overhead is particularly high. In other words, with this approach it is more easily possible to achieve a maximum technical improvement of the installation with minimum effort and resources. In a preferred embodiment the steps involving the capturing of the measurement variables through to the measurement of the installation status against the benchmark, that is to say the steps a) to d) according to claim 1, are performed much more frequently (by a factor of 3 at least) than the following method steps. In this way the installation operator always has an up-to-date benchmark, knows at any given time the current installation status in relation to the status of similar installations, and does not run the risk that the installation to be investigated is being measured against an outdated yardstick. Many of the steps necessary for specifying a benchmark can also be carried out separately and largely independently of a status recording process at an installation. However, the aforementioned revision frequency is to be recommended to ensure the information is up-to-date. A particularly labor-saving procedure is to have the recording of the actual status, and possibly also the comparison of the actual status with the benchmark, execute with software support. During the recording of the actual status the user will specify by means of a selection list the type of installation for which an actual status is to be determined. The program then prompts the user for the measured values relating to the measurement variables of the user's installation. This is possible because installations similar to each other are assessed using the same measurement variables, and the measurement variables relating to the similar installations are stored for the program. Optionally, the program can then also run a comparison of the actual status with the benchmark, assuming the latter is stored in the program. In this case it is also possible for the aforementioned software to be integrated into the installation and possibly linked with the software required for running the installation (e.g. the logic for a CNC machine). At the same time the recording of the measured values for the relevant measurement variables can thus be performed at least partially automatically and in near real-time. An updated benchmark can then be imported into the system at regular intervals by a service provider or the operator of the installation. The recording of the actual status, possibly including comparison of the same with the benchmark, can also (like the overall method itself) be carried out by external service providers, and in this case is objectivized to an even greater extent than if it were carried out by personnel of the installation operator. Usually the process is then also completed particularly quickly and, because of the expert knowledge of the external professionals, also with increased methodical reliability. It is also possible that the actual status is recorded with software support and the comparison with the benchmark performed by the aforementioned external service provider. Following identification of technical measurement variables of the installation which lend themselves to improvement, the method according to the invention also includes the identification of structural measures relating to the installation, by means of which the value of at least one measurement variable will be changed while the value retention of the installation is increased. This method step requires average engineering knowledge and in the present context needs no further explanation. Following identification of the structural measures it is possible to determine quantitatively by how much the economic usefulness of the installation will increase. At the same time the outlay, in financial and technical terms, associated with the structural measures can also be compared with the costs of a complete modernization of the installation. If the method according to the invention is performed by a service provider, it can be contractually agreed with said provider that the service provider will share not only the risk associated with the conversion, but also the risk of a possible non-achievement of the anticipated value retention. A further advantage of the method according to the invention is obtained if the structural measures are carried out at a time when the actual status of the production facility is at least as good as its setpoint status. An attempt to explain this in more detail is shown in FIGS. 3a and 3b. In these, the variable “P” is plotted against time. The continuous straight line shows the setpoint progression of this variable, and the swung curve the actual status. The variable “P” stands for the abstract performance of the installation, which performance is usually synonymous with the return on the capital tied to the installation. The setpoint curve indicates which technically related possibility of return on capital invested in the installation is applicable at a given time. This value is usually positive, as otherwise operation of the installation would be uneconomic. The continuous progression of the setpoint curve is represented in idealized form. Usually the setpoint value is also dependent on non-technical variables, but these are not relevant in the context of the present description. Thus, if the actual curve lies below the setpoint curve, the technical possibilities are not being exploited and the result is an unnecessary relative loss which in the worst case can lead to the installation making an absolute loss. By means of the present invention it is ensured by timely reaction that the period of relative loss is as short as possible and the deviation of the actual curve from the setpoint curve is as small as possible. At the same time it is ensured that the setpoint value itself is adjusted numerically on the basis of changed initial technical conditions. However, since the measurement variables are set in such a way that the value retention of the installation is increased, “P” also stands for every measurement variable which, in terms of the foregoing explanations, has an influence on the economic usefulness of the installation. In other words, an actual curve progression under the setpoint curve is one in which the measurement variable (e.g. the time required for maintenance purposes each week) is worse than the setpoint. If the structural measure is now carried out in a timely manner as proposed, phases are avoided in which the measurement variable falls below its setpoint value. This result is shown in FIG. 3b. In this way it is therefore possible to set measurement variables of the installation to their setpoint value reliably and on a long-term basis. The aforementioned method can be implemented at least in parts by means of a computer system. This system firstly comprises means for identifying those technical measurement variables which co-determine the value retention of a real installation. These means can be a microprocessor which resorts to data in a working memory and/or on hard disk storage in order to carry out the identification. The system also possesses means for inputting measured values relating to the identified measurement variables, for example a keyboard, or a serial or parallel interface, or a USB port. The system further possesses means for comparing the actual status of the installation being studied with a benchmark stored in the system for the purpose of determining at least one measurement variable whose change in value would increase the value retention of the installation. The comparison means also can be a microprocessor in combination with a working memory and/or hard disk storage medium. Optionally the system further has means which enable structural measures to improve the installation to be identified, by means of which measures the value of at least one measurement variable will be changed while the value retention of the installation is increased, and possibly also evaluation means, e.g. a floating point unit of a microprocessor, through the use of which it can be quantitatively determined by how much the value retention of the installation will increase as a result of the structural measure. The method according to the invention can be implemented at least in parts by means of a computer program. This program executes the following steps: a) it identifies those technical measurement variables which co-determine the value retention of a real installation, b) it prompts the user for measured values relating to the identified measurement variables, which values the user enters for example via a keyboard, c) it compares the actual status of the installation with a benchmark stored for the program, and determines at least one measurement variable whose change in value would increase the value retention of the installation. If desired, the program identifies such structural measures to improve the installation by which the value of the at least one measurement variable will be changed while the value retention of the installation will be increased, and establishes quantitatively by how much (e.g. in EUR or another currency) the value retention of the installation will increase as a result of the structural measure. The program can be stored on a data medium such as a CD or a DVD, in a computer memory, or be transferred by means of an electrical carrier signal from computer to computer. The last-mentioned option can be used for example in a network such as a LAN, WLAN or via the Internet. The invention will be explained in more detail below with reference to an exemplary embodiment in conjunction with the figures, in which: FIG. 1 shows the initial conditions to which a hot rolling mill is subject, FIG. 2 shows, in the form of a flowchart, how the method is performed, FIG. 3 shows which result is achieved compared with the prior art, FIG. 4 shows a computer system for implementing the invention Annex 1: Measurement variables of the exemplary embodiment. The practical implementation of the method was tackled on an installation in the shape of a tandem-type mill coupled with pickling line for generating strip steel for the automobile industry. FIG. 1 shows the initial conditions to which the tandem-type mill coupled with pickling line 1 or a method 1′ executed using the installation 1 is exposed. The installation 1 receives an input 2 in the form of human resources, energy, media, raw materials, semifinished product, etc., which is converted by the installation 1 into an output 3. Since the plant is a hot rolling mill, the output 3 is in the form of hot-rolled strips. The different components of the input 2 can be assigned to the factor markets 4 that are relevant to the real installation. The different components of the output 3 can further be assigned to the product markets 5 that are relevant to the real installation 1. In addition to the methods executed by the installation 1 there are available on the market, for example from competitors, competing methods which in their totality form the methods market 6. Relative to the device 1 there are, in competition with it, technically similar systems in the equipment market 7, as well as, at the component level, key components 8 that are relevant to the installation. FIG. 2 shows, in the form of a flowchart, the steps that were applied in the method according to the invention. The letters a) to f) attached to the symbols correspond in this respect to the method steps a) to f) of claim 1. The measurement variables cited in Annex 1 were identified in step a). Since one measurement variable is OEE, the total number of measurement variables overall is very small, and in particular is less than the number of 100 to 200 referred to in the description. These variables were measured in step b). At present a benchmark is being devised for the method from different sources according to step c), which benchmark, upon completion, will permit steps d), e) and f) to be performed. The model calculations according to FIG. 3a and FIG. 3B already explained above shows what results are ultimately to be expected when the method is performed. FIG. 4 shows a computer system according to the invention, comprising a computer 10 whose outputs are displayed on a monitor 12 via a graphics card 11. The computer 10 has a central microprocessor 13 which is linked to the system memory 15 via the system bus 14. The system memory 15 comprises the ROM (Read Only Memory) 16, the BIOS (Basic Input/Output System) 17, and the working memory in the form of a RAM (random Access Memory) 18. The computer 10 further has a hard disk 19, a floppy disk drive 20, a DVD drive 21. The hard disk 19, the floppy disk drive 20 and the DVD drive 21 are connected to the system bus 14 via respective interfaces 19′, 20′ and 21′. The operating system 22, the computer program 23 according to the invention, data 24, and the benchmark 25 are stored on the hard disk 19. When the program 23 is invoked, it is loaded into the working memory 18, where it has a first module 26 for identifying those technical measurement variables which co-determine the value retention of a real installation, a second module 27 for interrogating measured values relating to the identified measurement variables, and a third module 28 for comparing the actual status of the installation with a benchmark 25 in order to determine at least one measurement variable whose change in value would increase the value retention of the installation. Further program modules 29 can also be stored in the RAM, for example a module for identifying structural measures or an evaluation module for calculating by how much (in EUR or another currency) the value retention of an installation can be increased quantitatively by structural modification measures. During execution of the program 23, measured values are interrogated by the system 10. Said values can be typed in by the user via a keyboard 30 with support from a computer mouse 31, whereby the data reaches the working memory 15 via the serial interface 32 and the system bus 14. As alternative to this, the data can be supplied by a server 33. If the computer 10 is part of a LAN, the data reaches the system bus 14 via a network card 34. If the computer 10 is part of a WAN, the data is transferred via a modem or router 35, and via the serial interface 32 to the system bus 14. Annex 1: Measurement Variables a) the OEE Loverall Equipment Efficiency). In this case the OEE includes losses due to inadequate quality of the manufactured products (as a percentage of the number of products manufactured), includes the planned or unplanned downtime of the installation (as a percentage of the weekly working time), includes losses due to reduce speed of the installation (as a percentage of what it would otherwise be possible to manufacture at maximum speed), and includes other losses b) the consumption of hot rolled strip c) the consumption of pickling agents d) the consumption of electricity and other energy e) the consumption of rollers f) the number of man-hours required per ton of steel manufactured g) the number of man-hours required for maintenance purposes by the installation operator's own employees h) the number of man-hours required for maintenance and repairs by external personnel i) the specific spare parts turnover j) the status of the installed equipment (determined via an evaluation matrix) k) the maintenance overhead required to keep the installation in operation l) the information technology configuration level

20070112

20110125

20071018

62201.0

G06F1900

BAHTA, KIDEST

METHOD FOR OPERATING INDUSTRIAL INSTALLATIONS

UNDISCOUNTED

ACCEPTED

G06F

ACCEPTED

Process for the Production of Metal Salts of Trifluoromethane Sulphonic Acid and Their Use as Esterification Catalysts

The subject matter of the invention is a process for the production of metal salts of trifluoromethane sulphonic acid by reacting trifluoromethane sulphonic acid with a metal alcoholate and the use thereof as esterification catalyst and/or transesterification catalyst for the production of hydroxycarboxylic acid esters.

1. Process for the production of metal salts of trifluoromethane sulphonic acid comprising at least one trifluoromethane sulphonic acid group comprising reacting trifluoromethane sulphonic acid (CF3SO3H) with a metal alcoholate, at a temperature of −40° C. to +100° C., the metal being selected from the group consisting of Li, Na, K, Ba, Mg, Ca, Al, In, Sn, Sc, Y, La, Ti, Zr, Fe, Cu, Ag, Zn and mixtures thereof and the alcoholate group(s) of the metal alcoholate comprising independent of each other 1 to 28 carbon atoms as well as optionally hydroxy groups (—OH), ether bonds (C—O—C) and/or more than one alcoholate bond (M—O—). 2. Process according to claim 1 characterised in that the metal salt of the trifluoromethane sulphonic acid is (CF3SO3)mM(OR)n wherein the sum of (m+n) corresponds to the valency of the metal cation and m is at least 1, R is a hydrocarbon moiety with 1 to 6 carbon atoms and, optionally ether bonds (C—O—C) or is hydrogen and R can be different for each n and M is Al. 3. Process according to any one of claims 1, 2, 24, 25 or 26 characterised in that the reaction is conducted in the presence of a solvent selected from the group consisting of alcohols, aliphatic hydrocarbon, aromatic hydrocarbon, ethers having 2 to 32 carbon atoms, ketones having 2 to 32 carbon atoms, water and mixtures thereof. 4. Process according to any one of claims 1, 2, 24, 25 or 26 characterised in that the trifluoromethane sulphonic acid, optionally diluted with a solvent, is added to the metal alcoholate, optionally diluted with a solvent. 5. Process according to any one of claims 1, 2, 24, 25 or 26 characterised in that the metal alcoholate, optionally diluted with a solvent, is added to the trifluoromethane sulphonic acid, optionally diluted with a solvent. 6. A method for producing hydroxycarboxylic acid esters comprising reacting one or more hydroxycarboxylic acids with one or more alcohols in the presence of a metal salt of a trifluoromethane sulphonic acid exhibiting at least one trifluoromethane sulphonic acid group wherein the metal salts of the trifluoromethane sulphonic acid comprise Mg, Ca, Al, Sn, Ti, Zr, Fe, Cu or Zn as metal. 7. The method of claim 6 characterised in that the metal of the metal salt of the trifluoromethane sulphonic acid comprises Al. 8. The method of any one of claims 6 or 7 characterised in that the alcohols exhibit 1 to 28 carbon atoms and, optionally furthermore 1 to 8 ether groups and/or further 1 to 5 hydroxy groups. 9. The method of any one of claims 6 or 7 characterised in that the esterification is carried out at temperatures of 60 to 250° C. and, independently thereof, at pressures of 0.2 to 10 bar. 10. The method of any one of claims 6 or 7 characterised in that the esterification is carried out in the presence of an entrainer and water is removed by azeotropic distillation, the entrainer being preferably an aliphatic hydrocarbon, an aromatic hydrocarbon, a dialkyl ether or an alcohol, preferably the alcohol used for the esterification itself and/or its/their mixture. 11. The method of any one of claims 6 or 7 characterised in that the molar ratio of the alcohol used to the carbonyl groups of the hydroxycarboxylic acid used is from 1:0.5 to 4.0, preferably 1.0 to 2.0. 12. The method of any one of claims 6 or 7 characterised in that the catalyst is used in a quantity of 0.05 to 1.0% by weight, based on the hydroxycarboxylic acid used. 13. The method of any one of claims 6 or 7 characterised in that the esterification is terminated by treating the crude product with metal alcoholates, alkali hydroxides or alkaline earth hydroxides and subsequently worked up by distillation. 14. A method of producing a hydroxycarboxylic acid ester comprising transesterification of a hydroxycarboxylic acid ester with at least one hydroxy group and at least one carboxylic acid ester group (—COO—), optionally having free carboxylic acid groups, with an alcohol and/or another ester, in the presence of a catalyst comprising a metal salt of trifluoromethane sulphonic acid having at least one trifluoromethane sulphonic acid group whereby at least one alcohol is removed from the reaction mixture and wherein the metal of the salts of the trifluoromethane sulphonic acid comprise Mg, Ca, Al, Sn, Ti, Zr, Fe, Cu or Zn. 15. The method of claim 14 characterised in that the metal salts of trifluoromethane sulphonic acid comprises Al. 16. The method of any one of claims 14 or 15 characterised in that the alcohols used comprise 1 to 28 carbon atoms and, optionally 1 to 8 ether groups and/or further 1 to 5 hydroxy groups. 17. The method of any one of claims 14 or 15 characterised in that the transesterification is carried out at temperatures of 60 to 250° C. and, independently thereof, at pressures of 0.05 to 10 bar. 18. The method of any one of claims 14 or 15 characterised in that the molar ratio of the alcohol employed relative to the ester groups of the hydroxycarboxylic acid ester to be converted is from 0.5 to 2.0. 19. The method of any one of claims 14 or 15 characterised in that the catalyst is used in a quantity of 0.02 to 1.0% by weight, based on the hydroxycarboxylic acid ester to be converted. 20. The method of any one of claims 6 or 14 characterised in that the work-up of the hydroxycarboxylic acid ester takes place by distillation at temperatures in the range of 60° C. to 250° C. and pressures of 1 hPa to 1013 hPa or by stripping with a water vapor steam at temperatures of 120° C. to 200° C. and pressures of 1 hPa to 1013 hPa, in particular directly from the crude product or after removal of the catalyst and filtration of the crude product. 21. The method of claim 20 characterised in that the distillative work-up takes place after prior removal of the catalyst with activated carbon, aluminium hydroxide or aluminosilicate. 22. The method of any one of claims 6 or 14 wherein the metal salts of trifluoromethane sulphonic acid are used in the presence of water. 23. The method of claim 22 wherein the metal salts of trifluoromethane sulphonic acid are used in an aqueous environment comprising water, in particular as solvent or diluent, in addition to any water being formed in the course of the reaction. 24. The method of claim 1 wherein said metal is Al. 25. The process of claim 1 wherein said metal is Zr. 26. The process of claim 1 wherein said metal is Ti.

The invention relates to a process for the production of metal salts of trifluoromethane sulphonic acid by reacting trifluoromethane sulphonic acid with a metal alcoholate and their use as esterification catalyst and/or transesterification catalyst for the production of hydroxycarboxylic acid esters. Trifluoromethane sulphonic acid (CF3SO3H) is one of the strongest organic acids. Its protonation power is stronger than that of sulphuric acid. Its metal salts, i.e. metal perfluoromethane sulphonates, also called metal triflates, are available as solids or in solution. The most frequent fields of application of metal compounds of trifluoromethane sulphonic acid are their use as catalyst in the polymerisation of aromatic alkenes, of aromatic monomers, in electrophilic polymerisation of 1,3-pentadiene, the cationic ring opening polymerisation of tetrahydrofuran, in the Michael reaction of O-silylated ketene acetals with alpha,beta-unsaturated esters. Further fields of application are aldol and Friedel-Crafts reactions. From U.S. Pat. No. 4,219,540, the production of metal salts of trifluoromethane sulphonic acid and their use in antiperspirants is known. The aluminium salt of trifluoromethane sulphonic acid is produced by adding trifluoromethane sulphonic acid at room temperature to an aqueous suspension of barium carbonate and stirring the mixture, filtering it and removing water from it at reduced pressure and elevated temperature and drying it. The barium trifluoromethane sulphonate thus obtained is again dissolved in water, stirred and aluminium sulphate dissolved in water is added at room temperature. After heating, filtration is carried out and the filtrate is decolorised with carbon, filtered once more and water is driven off at reduced pressure and elevated temperature, and it is dried. In a similar manner, the corresponding triflates have been produced for the rare earth metals Ce, La and the Nd—Pr alloy didymium [neodymium-praeseodymium-alloy]. A disadvantage is the complicated recovery of the metal triflate and the low yield with respect to the trifluoromethane sulphonic acid used. In comparison with the process described above, the production process according to the invention leads, among other things, to the following improvements: simpler synthesis, high yields, no formation of salts as waste-producing products and higher purity with respect to foreign metal ions since no foreign metal compounds are used for the synthesis. Thus, the following purities are independently of each other obtainable for the aluminium triflates/aluminium alcoholate triflates according to the invention for Na and Fe, less than 100 ppm respectively for Ba, Pb, Ni, Ti, Va and Zn, less than 10 ppm respectively for As, Co, Hg, Mn, Sb, Se, Sn and Ta, less than 1 ppm respectively The object of the invention is achieved by way of a process for the production of metal salts of trifluoromethane sulphonic acid by reacting trifluoromethane sulphonic acid CF3SO3H with a metal alcoholate, if necessary in a solubiliser/diluent at a temperature of −40° C. to +100° C., preferably 0° C. to 80° C., the metal (M) being Li, Na, K, Ba, Mg, Ca, Al, In, Sn, Sc, Y, La, Ti, Zr, Fe, Cu, Ag or Zn, preferably Al, Ti or Zr, and the alcoholate group(s) of the metal alcoholate exhibiting 1 to 28 carbon atoms, preferably 2 to 8 carbon atoms, based on one group, as well as, optionally, furthermore the following: hydroxy groups (C—OH), ether bonds (C—O—C) and/or more than one alcoholate bond (M—O—). According to the invention, metal triflates (metal salts of trifluoromethane sulphonic acid) are compounds which exhibit at least one trifluoromethane sulphonic acid group. Apart from at least one acid group, the metal triflate can also exhibit one alcoholate group with 1 or 2 bonds (2-dentate ligand) with the metal and additionally optionally ether groups and/or free hydroxy groups. Preferably, the metal salt of trifluoromethane sulphonic acid has the following structure (CF3SO3)mM(OR)n wherein (m+n) in total correspond to the valency of the metal cation and m is at least 1, m preferably corresponding to the valency of the metal, R is a hydrocarbon radical with 1 to 28, preferably 2 to 8, carbon atoms which optionally comprises 1 to 8 ether groups, in particular 1 to 3 ether groups and/or 1 to 4 hydroxy groups, is hydrogen, preferably, insofar at least one R is not hydrogen and R can be different for each n and M is Li, Na, K, Ba, Mg, Ca, Al, In, Sn, Sc, Y, La, Ti, Zr, Fe, Cu, Ag or Zn, preferably Al, Ti or Zr. According to the process of the invention, metal triflates of high purity can be produced in a surprisingly simple manner in the dissolved state or as solid pure substance by adding CF3SO3H to metal alkoxides. Alcohol which is released is driven out after or during the addition of the trifluoromethane sulphonic acid. The target substance can be removed from the reaction mixture by extraction with water. In contrast, the metal triflates exhibiting at least one alcohol group are frequently water insoluble in the case of a chain length of more than 4 of the carbon atoms of the alcohol group and can thus be separated from the water-soluble product and/or excess alcohol. Alcohol formed in the hydrolysis or alcohol used as diluent can be separated off by phase separation if water insoluble alcohols are involved (>=C4, preferably >=C5). According to a further object of the invention, the metal triflates, as described above, among other things, can be used as catalysts for the synthesis of hydroxycarboxylic acid esters by conversion of hydroxycarboxylic acids with alcohols and/or transesterification. Numerous routes for producing hydroxycarboxylic acid esters, in particular lactic acid esters, have been described. One variation is the direct esterification of hydroxycarboxylic acid with alcohols at elevated temperature without an addition of catalyst according to EP 0 287 426. In this case, the conversion is carried out at temperatures of 90 to 140° C. using alcohols with up to twelve carbon atoms for the preparation of optically active lactic acid esters. Since this process is merely quasi-continuous, the amount of equipment required is large. Currently, proton-acidic or Lewis-acidic catalysts are used for the esterification process. These catalysts are frequently protonic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, methane sulphonic acid, p-toluene sulphonic acid or acidic ion exchangers. Apart from the protonic acids, which frequently cause problems by corrosion, Lewis acids are also known as esterification catalysts, e.g. using metal halides or strongly acidic styrene resin in combination with the Lewis acid AlCl3. In the case of most esterification processes known from the state of the art, the water formed in the reaction is removed from the reaction mixture by azeotropic distillation by means of an entrainer. For this purpose, aliphatic and aromatic hydrocarbons are usually used. Surprisingly enough, it has been found that hydroxycarboxylic acid esters can be obtained by the direct esterification of hydroxycarboxylic acids with alcohols in the presence of metal triflate catalysts which, moreover, exhibit an unusually high activity. The reaction times are short even when small quantities of catalysts are used. Depending on the alcohol used, the reaction times are usually 5 to 14 hours. According to a further embodiment of the invention, the metal triflates, as described above, are used as catalysts for the transesterification of hydroxycarboxylic acid esters. The metal triflates with at least one trifluoromethane sulphonic acid group are, in this case, brought into contact with hydroxycarboxylic acid esters, preferably with heating, with an alcohol and/or a further hydroxycarboxylic acid ester. As a rule, alcohols are used with a higher boiling point than the alcohol bound in the ester such that the alcohol with a lower boiling point is driven out of the reaction mixture. In this case, Li, Na, K, Ba, Mg, Ca, Al, In, Sn, Sc, Y, La, Ti, Zr, Fe, Cu, Ag or Zn, particularly preferably Al, Ti or Zr are preferably used as metal component of the metal triflates. The alcohols and/or alcoholate groups used for the esterification and transesterification can be branched, straight chain, saturated, unsaturated, aromatic, primary, secondary or tertiary and exhibit preferably 1 to 28 carbon atoms and, if necessary, 1 to 8 ether groups or 1 to 5 further hydroxy groups. The reacted aliphatic and aromatic hydroxycarboxylic acid esters contain at least one hydroxy group (—OH) and one carboxylic acid ester group (—COO—) respectively. The esterification and transesterification can be carried out at temperatures of 60 to 250° C. and pressures of 0.05 to 40 bar. The molar ratio of the alcohol used to the ester groups of the hydroxycarboxylic acid ester used is preferably 0.5 to 2.0 and the catalyst is preferably used in an amount of 0.02 to 1.0% by weight, based on the hydroxycarboxylic acid ester to be reacted. The work-up of the hydroxycarboxylic acid ester produced by transesterification can take place by distillation at temperatures in the region of 60° C. to 250° C. and pressures of 1 hPa to 1013 hPa or by stripping with steam at temperatures of 120° C. to 200° C. and pressures of 1 hPa to 1013 hPa, it being possible for the work-up to take place either directly from the raw product or after removing the catalyst and filtering the raw product. In the case of a work-up by distillation, the catalyst can be removed by adsorption with activated carbon, aluminium hydroxide or aluminosilicate before distillation or remain in the bottom product and be recycled into the process. Catalysts which are used in the esterification reactions can also be used as catalysts for transesterifications. The metal triflates are easy to handle and without problems both in the pure form and in solution. The compounds are stable and pose no particular requirements regarding storage. During handling, the usual measures for handling irritant substances need to be complied with. High yields of hydroxycarboxylic acid esters are achieved with a simultaneously high selectivity, the usual by-products such as the oligo and poly(hydroxycarboxylic acid) esters formed by the reaction of hydroxycarboxylic acids with each other, being formed in much lower proportions compared with the use of conventional catalysts. Moreover, they can be recycled into the reaction in order to be reesterified with an excess of alcohol to form simple hydroxycarboxylic acid esters. A great advantage of the metal triflates compared with the protonic acids as catalyst is the low tendency to corrosion. It is by a factor of >10 lower than that of a reaction mixture with the same proportion of sulphuric acid as catalyst. The metal triflates can be produced in a simple manner as solids or in solution by reacting the acid with a metal alcoholate, as described above. In this respect, it is particularly advantageous that reaction products which have not been purified and contain e.g. suitable alcohols can also be used directly in the esterification reaction. However, other processes are also known according to which aluminium salts or rare earth metal salts of trifluoromethane sulphonates are available, e.g. from the corresponding metal carbonates according to U.S. Pat. No. 4,219,540 already cited above. The metal triflates have a high Lewis acid activity and are stable in aqueous media. They can therefore be considered for use for numerous organic reactions in which water is contained in the starting materials, is formed as reaction product or used as solvent and/or in micro-emulsions. Thus, the metal triflates according to the invention are generally suitable in particular for reactions in protic media. Hydroxycarboxylic acids according to the meaning of this invention are hydroxycarboxylic acids which contain at least one alcohol function (—OH) and one carboxylic acid function (COOH, including COO). For the present invention, the following hydroxycarboxylic acids, are suitable in particular as compounds obtained from raw materials both for the esterification reaction and the transesterification reaction: glycolic acid, lactic acid, β-hydroxy propionic acid, α-hydroxybutyric acid, β-hydroxybutyric acid and γ-hydroxybutyric acid, malic acid, tartaric acid, citric acid, mandelic acid and salicylic acid. These hydroxycarboxylic acids are reacted with primary, secondary and tertiary, straight chain and branched alcohols with a chain length of 1 of 28 carbon atoms. Metal salts of trifluoromethane sulphonic acid (triflates) are used as catalysts. The following are used as metals: Li, Na, K, Ba, Mg, Ca, Al, In, Sn, Sc, Y, La, Ti, Zr, Fe, Cu, Ag and Zn. The hydroxycarboxylic acid esters of the above-mentioned acids have a variety of applications. The esters of lactic acid with ethanol and n-butanol (ethyl lactate and n-butyl lactate) are used, among other things, as environment-friendly additives in solvent formulations for paints and in purifier formulations for the semiconductor industry. In this case, they are used for removing photo resists from templates, for example. In addition, both esters have been approved by the FDA as additives in the food industry. The esters of other alcohols with a higher number of carbon atoms are also used in these fields or in the cosmetics industry. Cetyl lactate, in particular, is used in the U.S.A. in a large number of cosmetic formulations. The esters of citric acid with alcohols and alcohol mixtures, in particular with 4 to 16 carbon atoms, are used mainly as plasticisers for polymers. The esters of other hydroxycarboxylic acids have potentially the same fields of application. EXAMPLE A Production of Metal Triflates The experiments were carried out in a 1000 ml reaction flask of glass equipped with a thermometer, a distillation attachment, dropping funnel and stirrer as well as a vacuum distillation device with cooling traps. To remove the heat of reaction the reaction vessel was cooled by means of an ice bath. Example A1 Production of Aluminium Tristrifluoromethane Sulphonate in Isotridecanol 21.44 g of aluminium triisopropylate and 193.86 g of isotridecanol were introduced into a reaction flask and 45.02 g of trifluoromethane sulphonic acid were metered in at room temperature (25° C.) with vigorous stirring within approximately 1 h by means of a dropping funnel. The reaction vessel was cooled continuously such that the bottom temperature did not exceed 40° C. Subsequently, a vacuum of 100 mbar was applied and the product heated to 110° C. within approximately 45 minutes. At the same time, the pressure was reduced to 50 mbar and the co-product isopropanol was removed by distillation. Aluminium tristrifluoromethane sulphonate (CF3SO3)3Al remained in the flask in solution. Example A2 Production of Aluminium Tristrifluoromethane Sulphonate in Isopropanol 10.72 g of aluminium triisopropylate and 87.93 g of isopropanol were introduced into the reaction flask and 22.5 g of trifluoromethane sulphonic acid were metered in at room temperature (25° C.) with vigorous stirring within 1 h by means of a dropping funnel. The reaction vessel was cooled continuously such that the bottom temperature did not exceed 40° C. Subsequently, the reaction mixture was stirred for 1 h at room temperature. Aluminium tristrifluoromethane sulphonate Al(CF3SO3)3 in isopropanol remained in the flask. Example A3 Production of Zirconium Tetrakistrifluoromethane Sulphonate in Isotridecanol 40.2 g of zirconium tetra-n-butylate and 305.08 g of isotridecanol were introduced into the reaction flask, 60.03 g trifluoromethane sulphonic acid were metered in at room temperature (25° C.) with vigorous stirring within 1 h by means of a dropping funnel. The reaction vessel was cooled continuously such that the bottom temperature did not exceed 40° C. Subsequently, the product was heated under vacuum of 100 mbar to 110° C. within 45 minutes. At the same time, the pressure was reduced to 50 mbar and the co-product n-butanol was removed by distillation. Zirconium tetrakistrifluoromethane sulphonate Zr(CF3SO3) remained in the flask4 in solution. Example A4 Production of Aluminium Tristrifluoromethane Sulphonate, Solvent Free 21.4 g of aluminium triisopropylate and 64.4 g of xylene were introduced into the reaction flask and heated in a rotary evaporator under a vacuum of 500 mbar to 70° C. 45.0 g of trifluoromethane sulphonic acid were added within 60 min. and xylene and the co-product isopropanol were drawn off at 98° C. and 400 mbar. Aluminium tristrifluoromethane sulphonate Al(CF3SO3)3 remained in the flask as a solid. By means of AAS, metal impurities were determined which were below the limit values indicated in the introduction to the description. B Production of Hydroxycarboxylic Acid Using Metal Triflate Catalysis Production of Lactic Acid Esters (Lactates) In the following, it is described how hydroxycarboxylic acids can be obtained be the direct conversion of hydroxycarboxylic acids with alcohols using metal triflates as catalysts. In this process, either the alcohol or the acid was used in excess (up to 100%). The water formed in the reaction was removed from the reaction mixture by azeotropic distillation using an entrainer. Aliphatic and aromatic hydrocarbons or dialkyl ethers were used as entrainers. The reactions for the production of the lactic acid esters were carried out in a 21 glass flask equipped with a column (Sulzer packing of stainless steel), a capillary for the introduction of nitrogen, a dropping funnel and a PT100 heat sensor. At the top of the column was a water separator with a reflux condenser. A heating dome was used for heating. The reaction conditions employed were within a temperature range of 40 to 180° C. and a pressure range of 0.2 to 10 bar, depending on the alcohol used. Example B1 Production of Lactic Acid Ethyl Ester 563.0 g of lactic acid (80% by weight in water, i.e. based on lactic acid and used as an 80% by weight solution in water), 460.7 g of ethanol and 2.3 g Al(OTf)3 (in 9 g of isotridecanol, based on Al(OTf)3 and used as a 20% by weight solution in isotridecanol), were introduced into a reaction flask. The water separator was filled with diisopropyl ether which served as entrainer. A further 300 g of diisopropyl ether were introduced into the flask. The bottom was heated to 80 to 90° C. such that a good reflux was formed and forming water was removed azeotropically at a head temperature of 62° C. The course of the reaction was monitored by way of the acid number. The esterification was carried out up to an acid number of <2 mg KOH/g. This was reached after 12 h, whereby a conversion of more than 99% had been reached for the hydroxycarboxylic acid. The yield of ethyl lactate was more than 88%. The di-lactic acid ethyl ester was formed in a yield of 11%. The crude product was neutralised with Ca(OH)2 to remove the residual acid and the catalyst and filtered. The entrainer and excess alcohol were removed by distillation from the filtrate and the crude product was subjected to fractional distillation at reduced pressure. Example B2 Production of Lactic Acid Ethyl Ester 563.0 g of lactic acid (80% by weight in water) were introduced into a reaction flask and part of the water was removed at reduced pressure at elevated temperature within 30 min such that the lactic acid was present as an approximately 95% solution. 460.7 g of ethanol and 2.3 g of Al(OTf)3 (in 9 g of isotridecanol) were added. The water separator was filled with diisopropyl ether which served as entrainer. A further 300 g of diisopropyl ether were introduced into the flask and the bottom was heated to 80 to 90° C. such that a good reflux was formed and the water generated was removed azeotropically at a head temperature of 62° C. The course of the reaction was monitored by way of the acid number. The esterification was carried out up to an acid number of less than 2 mg KOH/g. This, including drying of the lactic acid, was achieved after 9.5 h. The conversion of lactic acid was more than 99%. The yield of ethyl lactate was more than 87%, the dilactic acid ethyl ester was formed in a 12% yield. The work-up of the crude product was carried our in a manner analogous to example B1. Example B3 Production of Lactic Acid Butyl Ester 563.0 g of lactic acid, based on lactic acid and used as an 80% by weight solution in water, 741.2 g of n-butanol and 2.3 g of Al(OTf)3 (in 9 g isotridecanol) were introduced into the reaction flask. The water separator was filled with diisopropyl ether which served as entrainer. A further 300 g of diisopropyl ether were introduced into the flask. Bottom was heated to 90 to 120° C. such that a good reflux was formed and the water generated was removed azeotropically at a head temperature of 66° C. The course of the reaction was monitored by way of the acid number and the esterification was carried out up to an acid number of less than 2 mg KOH/g. This was reached after 6 h whereby a conversion of more than 99% was reached for the hydroxycarboxylic acid. The yield of ethyl lactate was more than 95%, the dilactic butyl ester was formed in a yield of approximately 4%. The work up of the crude product was carried out in a manner analogous to example B1. Production of Citric Acid Esters (Citrate) The reaction for the production of citric acid esters was carried out in a 21 glass flask equipped with a column (Raschig rings of stainless steel), a capillary for the introduction of nitrogen, a dropping funnel and a PT100 heat sensor. A water separator with a reflux condenser was fitted to the head of the column. A heating dome was used for heating. The reaction temperature was in the range of 80 to 180° C. and a pressure range of 0.2 to 2 bar. Example B4 Production of a Citric Acid Ester with a Mixture of Linear C6/C8 Alcohols, Catalyst Al(OTf)3 384.2 g of citric acid, 1048.4 g of C6/C8 alcohol and 1.2 g of Al(OTf)3 (in 4.5 g of isotridecanol) were introduced into a reaction flask. The alcohol served simultaneously as entrainer for the water. The bottom was heated to 110° C. at reduced pressure such that a good reflux was formed and the water generated was removed azeotropically at a head temperature of 80° C. The course of the reaction was monitored by way of the acid number and esterification was carried out up to an acid number of 0.6 KOH/g which was reached after 9 h. The conversion of citric acid was thus greater than 99%. The reaction mixture was dissolved with an equimolar quantity of NaOH, based on the acid number, neutralised in 1% water (based on the amount weighed in) for 20 min at 40° C. and subsequently dried for 15 to 20 min at reduced pressure and temperature of up to 80° C. To remove the excess alcohol, the crude product was stripped in a laboratory stripping apparatus using steam at 135 to 195° C. Example B5 Production of a Citric Acid Ester with a Mixture of Linear C6/C8 Alcohols, Catalyst, Zr(OTf)4 864.5 g of citric acid, 2358.8 g of C6/C8 alcohol and 1.3 g of Zr(OTf)4 (in 5.1 g of isotridecanol) were introduced into a reaction flask. The alcohol served simultaneously as entrainer. The bottom was heated to 110° C. at reduced pressure such that a good reflux was formed and the water generated was removed azeotropically at a head temperature of 80° C. The course of the reaction was monitored via the acid number and continued up to an acid number of 0.6 mg KOH/g which was reached after 14 h. The conversion of citric acid was thus more than 99%. The work-up was carried out in a manner analogous to example B4. Example B6 Production of a Citric Acid Ester with a Mixture of Linear C6/C8 Alcohols, Catalyst, Sn(OTf)2 384.2 g of citric acid, 1048.4 g of C6/C8 alcohol and 0.1 g of Sn(OTf)2 (in 0.4 g of isotridecanol) were introduced into a reaction flask. The alcohol served simultaneously as entrainer. The bottom was heated to 135° C. at reduced pressure such that a good reflux was formed and the water generated was removed azeotropically at a head temperature of 100° C. The course of the reaction was monitored via the acid number and continued up to an acid number of 0.5 mg KOH/g which was reached after 5 h. The conversion of citric acid was thus >99%. The work-up was carried out in a manner analogous to example B4. The apparatus for the production of the tartaric ester and malic acid ester corresponded to that used for the production of citric acid ester. Example B7 Production of Tartaric Acid Dialky Ester with C6/C8 Alcohol 450.3 g of tartaric acid, 1084.5 g of C6/C8 alcohol and 1.8 g of Al(OTf)3 (in 7.2 g of isotridecanol) were introduced into the flask. The water separator was filled with cyclohexane which served as entrainer. Further cyclohexane was introduced into the flask. The bottom was heated to 80 to 120° C. at reduced pressure and the water generated was removed azeotropically. The course of the reaction was monitored by way of the acid number and continued up to an acid number of <1 mg of KOH/g which was reached after 8 to 10 h, corresponding to a conversion of 99% with respect to the hydroxycarboxylic acid. The work up was carried out in a manner analogous to example B4. Example B8 Production of Malic Acid Dialkyl Ester with C6/C8 Alcohol 402.3 g of malic acid, 1084.5 g of C6/C8 alcohol and 1.6 g of Al(OTf)3 (in 6.4 g of isotridecanol) were introduced into a reaction flask. The water separator was filled with cyclohexane which served as entrainer. Further cyclohexane was introduced into the flask and the bottom was heated to 80 to 120° C. at reduced pressure and the water generated was removed azeotropically. The course of the reaction was monitored by means of the acid number and esterification was carried out up to an acid number of less than 1 mg of KOH/g. This was reached after 8 to 10 h as a result of which a conversion of more than 99% was reached for the hydroxycarboxylic acid. The work up took place in a manner analogous to example B4. Transesterification of Lactic Acid Esters (Lactates) In the following examples, conversions are described according to which hydroxycarboxylic acid esters are reesterified in the presence of metal triflates as catalysts and alcohols. In this process, the alcohol is used in excess (up to 100 mole %). The lower boiling alcohol liberated in the reaction is removed from the reaction mixture by distillation. The reactions for the transesterification of lactic acid esters were carried out in a 11 glass flask equipped with a column (filled with 6 mm Raschig rings) and a column head, a capillary for the introduction of nitrogen and a PT100 heat sensor. A heating dome was used for heating. The reaction conditions used were in a temperature range of 60 to 240° C. and a pressure range of 0.05 to 10 bar. Example C1 Transesterification of Lactic Acid Ethyl Ester with N-butanol and Al(OTf)3 118.1 g (1.0 mole) of ethyl lactate and 148.2 g (2.0 mole) of n-butanol were introduced into the flask and 0.6 g (2.5 mmole) of Al(OTf)3 were added as a 20% solution in n-butanol. The reaction mixture was heated to approximately 120° C. The ethanol formed in the reaction was withdrawn overhead. In the course of the reaction, the bottom temperature was raised stepwise up to approximately 140° C. The increase in the head temperature from the boiling point of pure ethanol to the boiling point of pure n-butanol indicated the end of the reaction. The course of the reaction was additionally monitored by GC. For the work-up of the crude product, the catalyst was removed by means of an adsorption agent and the crude product was filtered. Subsequently, a distillative separation of the excess alcohol and fractional distillation of the reaction product were carried out. Time (h) 1.5 3.0 4.5 6.0 Conversion of ethyl lactate (%) 75.8 97.1 99.8 99.9 Yield of n-butyl lactate (%) 70.9 89.9 90.8 89.5 Yield of oligomeric esters (%) 4.9 7.2 9.0 10.4 Selectivity % 93.5 92.6 91.0 89.5 Example C2 Transesterification of Lactic Acid Ethyl Ester with N-butanol and Zr(OTf)4 118.1 g (1.0 mole) of ethyl lactate and 148.2 g (2.0 mole) of n-butanol were introduced into the flask and 0.6 g (1.8 mmole) of Zr(OTf)4 were added as a 20% solution in n-butanol. The reaction mixture was heated to approximately 120° C. The ethanol formed in the reaction was withdrawn overhead. In the course of the reaction, the bottom temperature was raised stepwise up to approximately 140° C. The increase in the head temperature from the boiling point of pure ethanol to the boiling point of pure n-butanol indicated the end of the reaction. The course of the reaction was additionally monitored by GC. Time (h) 1.0 2.0 3.0 6.0 Conversion of ethyl lactate (%) 50.9 78.4 93.5 99.6 Yield of n-butyl lactate (%) 46.6 73.6 87.7 90.4 Yield of oligomeric esters (%) 4.3 4.8 5.8 9.2 Selectivity % 91.6 93.8 93.8 90.8 Example C3 Transesterification of Lactic Acid Ethyl Ester with Isopropanol Al(OTf)3 118.1 g (1.0 mole) of ethyl lactate and 120.2 g (2.0 mole) of isopropanol were introduced into the flask and 0.6 g (2.5 mmole) of Al(OTf)3 were added in the form of a 20% solution in isopropanol. The reaction mixture was heated to approximately 90° C. The ethanol formed in the reaction was withdrawn overhead. In the course of the reaction, the bottom temperature was raised stepwise up to approximately 105° C. After 6½ hours, the conversion of ethyl lactate was approximately 25%. This lower rate of reaction is attributable above all to the lower reaction temperature and the difficult distillative separation of the ethanol as a result of the slight difference in the boiling point with respect to isopropanol. Example C4 Transesterification of Lactic Acid Isopropyl Ester with N-butanol and Al(OTf)3 132.2 g (1.0 mole) of isopropyl lactate and 148.2 g (2.0 mole) of n-butanol were introduced into the flask and 0.66 g (2.8 mmole) of Al(OTf)3 were added as a 20% solution in n-butanol. The reaction mixture was heated to approximately 125° C. The isopropanol formed in the reaction was withdrawn overhead. In the course of the reaction, the bottom temperature was raised stepwise up to approximately 145° C. The increase in the head temperature from the boiling point of pure isopropanol to the boiling point of the pure n-butanol indicates the end of the reaction. The course of the reaction was additionally monitored by GC. Example C5 Transesterification of Citric Acid Tri-n-butyl Ester with 1-hexanol and Zr(OTf)4 360.5 g of citric acid tri-n-butyl ester, 625.1 g of 1-hexanol and 1.8 g of Al(OTf)3 (20% in isotridecanol) were introduced into the flask. The reaction mixture was heated to approximately 150° C. The n-butanol formed in the reaction was withdrawn overhead. The bottom temperature was increased stepwise in the course of the reaction to as much as approximately 180° C. To remove the excess alcohol, the crude product was stripped in a laboratory stripping device using steam at 135 to 195° C. Example C6 Transesterification of Diisopropyl Tartrate with 1-hexanol and AL(OTf)3 234.3 g (1.0 mole) of diisopropyl tartrate (416.8 g of 1-hexanol (4.0 mole) and 1.17 g of Al(OTf)3 (20% in isotridecanol) were introduced into the flask. The reaction mixture was heated to approximately 100° C. The i-propanol formed in the reaction was withdrawn overhead. The bottom temperature was increased stepwise in the course of the reaction to as much as approximately 120° C. To remove the excess alcohol, the crude product was stripped in a laboratory stripping device using steam at 135 to 195° C.

20070511

20100601

20071101

74217.0

C07C30332

O SULLIVAN, PETER G

PROCESS FOR THE PRODUCTION OF METAL SALTS OF TRIFLUOROMETHANE SULPHONIC ACID AND THEIR USE AS ESTERIFICATION CATALYSTS

UNDISCOUNTED

ACCEPTED

C07C

ACCEPTED

Propulsion cell for a device in an aquatic medium

An electrical cell for the propulsion of a device in an aquatic medium includes a first, second and third chamber forming a housing. The first chamber has an auxiliary electrical cell and a command and control module for the electrical propulsion cell, the second chamber a main electrical cell and members for the controlled admission and regulation of water flow from the aquatic medium in order to form an activation electrolyte for the main cell, and the third chamber a module for triggering the admission by suction of water and the discharge by escape of effluents from an admission valve and an escape valve. The command and control module activates the auxiliary electrical cell to generate electrical energy temporarily and the admission by suction of water from the aquatic medium and the discharge of effluents in order to produce electrical energy from the main electrical cell during a cruise phase.

1. Electrical cell for the propulsion of a device in an aquatic medium, characterized in that it comprises at least, in a sealed cell body: a first chamber forming a housing comprising an auxiliary electrical cell and a command and control module for the electrical propulsion cell; a second chamber forming a housing comprising a main electrical cell of the electrochemical type, said second chamber being provided with members for the controlled admission and the regulation of a flow of water from the aquatic medium into said second chamber, which forms a reservoir, in order to form, after the command to admit water from the aquatic medium, an electrolyte for activating said main electrical cell; a third chamber forming a housing comprising a module for triggering the admission by suction of water from the aquatic medium and the discharge by escape of effluents resulting from the chemical reaction of the main cell into the aquatic medium, from an admission valve and an escape valve, respectively, which are mounted in said third chamber, said command and control module of the electrical propulsion cell permitting the activation of said auxiliary electrical cell in order to generate electrical energy temporarily during a stage of launching said device in an aquatic medium, and the triggering of the admission by suction of water from the aquatic medium and of the discharge by escape of effluents in order to produce electrical energy from said main electrical cell during a cruise phase. 2. Electrical propulsion cell according to claim 1, characterized in that said auxiliary and main electrical cells are controlled sequentially by said command and control module of the electrical propulsion cell and are connected respectively to a main and secondary electrical energy distribution network. 3. Electrical propulsion cell according to claim 1, characterized in that said auxiliary electrical cell is formed by a set of thermal cell elements started up by pyrotechnic ignition. 4. Electrical propulsion cell according to claim 1, characterized in that said members for the controlled admission and the regulation of a flow of water from the aquatic medium into said second chamber comprise at least: a motor-driven pump unit, the suction nozzle of which is connected to said valve for the admission of water from the aquatic medium, and the outlet nozzle of which delivers the water sucked in from the aquatic medium directly into said second chamber forming a reservoir, in order to form said activation electrolyte and to immerse said main electrical cell in the latter; a thermostatic valve connected to said main electrical cell, said thermostatic valve regulating the admission of said activation electrolyte into said main cell in order to trigger the activation of said main electrical cell by electrochemical reaction: a device for the circulation of the activation electrolyte and the separation of the effluents, said device for circulation and separation comprising an inlet nozzle connected to the internal cavity of said main electrical cell, containing the activation electrolyte, a first outlet nozzle connected in the vicinity of the admission nozzle of the motor-driven pump and a second effluent outlet nozzle connected to said discharge valve located in said third chamber. 5. Electrical propulsion cell according to claim 4, characterized in that said second outlet nozzle of said device for circulation and separation is connected to said discharge valve located in said third chamber by means of a mode valve which permits the orientation, in a first position, of the effluents towards the effluent discharge valve when the main electrical cell is started up during the launch phase, and, respectively, in a second position, of the activation electrolyte towards the suction nozzle of the motor-driven pump, in order to generate closed-loop circulation of the activation electrolyte in the main electrical cell during the cruise phase. 6. Electrical cell according to claim 4, characterized in that said thermostatic valve is formed by a three-way valve receiving: a direct flow of activation electrolyte drawn from said second chamber forming a reservoir, a derivative flow of activation electrolyte passing by way of a heat exchanger, the derivative flow being maintained at a substantially constant temperature by said heat exchanger, said thermostatic valve delivering, from said direct flow and said derivative flow at a substantially constant temperature acting as a reference temperature, a flow of thermostatically-controlled activation electrolyte at a substantially constant temperature to the internal cavity of said main electrical cell. 7. Electrical propulsion cell according to claim 4, characterized in that said main electrical cell of the electrochemical type is an AgO—Al cell. 8. Electrical propulsion cell according to claim 7, characterized in that said main electrical cell of the electrochemical type is formed by: an electrochemical block constituted by a stack of AgO—Al electrochemical couples located in the cavity of a sealed module connected, on the one hand, to said thermostatic valve and, on the other hand, to said device for the circulation of the electrolyte; a reserve of anhydrous sodium hydroxide, said electrochemical block and said reserve of anhydrous sodium hydroxide being located in said second chamber forming a reservoir. 9. Electrical propulsion cell according to claim 8, characterized in that said anhydrous sodium hydroxide reserve is constituted by a mixture of micropellets of anhydrous sodium hydroxide and powder-form stannates charged in bulk into said second chamber forming a reservoir. 10. Electrical propulsion cell according to claim 1, characterized in that said sealed cell body is formed by an assembly of elements constituted at least by: a front collar; a front end of the main electrical cell, said front collar and said front end forming said third chamber; a central shell; a rear end, said front end, said central shell and said rear end forming said second chamber; a rear collar, said rear end and said rear collar forming said first chamber. 11. Electrical propulsion cell according to claim 10, characterized in that said central shell at least is constituted by a metal alloy which is a good heat conductor, a portion at least of said central shell which is located in the vicinity of said main electrical cell constituting a heat exchanger with said aquatic medium, to form a heat exchanger for at least a derivative flow of activation electrolyte. 12. Electrical propulsion cell according to claim 10, characterized in that the front collar, the front end of the electrical cell, the central shell, the rear end of the electrical cell and the rear collar are composed of a metal material, the external face thereof which is to be in contact with the aquatic medium being provided with a protective anti-corrosion layer obtained by hard anodic oxidation. 13. Electrical propulsion cell according to (claim 10), characterized in that the internal face of the front end of the electrical cell, of the central shell and of the rear end of the electrical cell constituting said second chamber forming a reservoir comprise a chemical nickel coating for protection against corrosion by the anhydrous sodium hydroxide. 14. Electrical propulsion cell according to claim 11, characterized in that the internal face of said central shell, except for the portion forming the heat exchanger, also comprises a thermally insulating coating at the portion forming a reservoir for the activation electrolyte, in order to reduce the cooling of the stored activation electrolyte by heat exchange with the aquatic medium during the cruise phase. 15. Electrical propulsion cell according to claim 10, characterized in that said sealed cell body is provided with a double sealing barrier with respect to said aquatic medium: a first sealing barrier formed by a seal between the aquatic medium and the first chamber, and the third chamber respectively; a second sealing barrier formed by a seal between the first and second chamber and the second and third chamber, respectively. 16. Electrical propulsion cell according to claim 10, characterized in that it also comprises: a plurality of temperature sensors for the flow of activation electrolyte entering and leaving the main electrical cell, in order to be able to regulate the temperature of the flow of activation electrolyte by means of said thermostatic valve; a plurality of sensors for sensing the relative pressure of the activation electrolyte in the second chamber forming a reservoir, of the activation electrolyte at the inlet of the device for the circulation of the activation electrolyte and for the separation of the effluents, said sensors of relative pressure delivering a relative pressure value with respect to the pressure outside the sealed cell body; a plurality of contacts, a contact for sealing the valve for the admission of water from the aquatic medium, a contact for opening the valve for the admission of water to the sealed cell body. 17. Electrical propulsion cell according to claim 10, characterized in that the front collar, the central shell and the rear collar have a substantially cylindrical cross-section of revolution. 18. Electrical propulsion cell according to claim 17, characterized in that the front collar and the rear collar have a distal end which is open with respect to the front end and the rear end, respectively, of the cell in order to construct said electrical propulsion cell, on the one hand, in the form of an independent module which can be stored as a substantially inert component with its charge of anhydrous sodium hydroxide reserve when the electrical propulsion cell is not mounted with the device, and, on the other hand, in the form of an element integrated directly in the body of the device, the distal end of said front collar being secured mechanically and coupled electrically to an active portion of the device and the distal end of the rear collar being secured mechanically and coupled electrically to the propulsive and control rear portion of the device in order to constitute an electrical propulsion cell which can be activated as soon as the device is launched. 19. Use of an electrical cell for the propulsion of a device in an aquatic medium according to claim 1 for the supply of power to, the propulsion and the control of a device, such as a torpedo, a reconnaissance submarine or a surface device. 20. Electrical propulsion cell according to claim 1, characterized in that said main electrical cell of the electrochemical type is an AgO—Al cell.

The propulsion of devices in an aquatic medium, especially when these devices of the underwater type are moving, at least for a short while in the submerged state, requires the provision of a propulsive energy, such as electrical energy, under conditions of power, duration and modulation by successive ranges which are well determined. This is especially the case with underwater attack, response or observation devices launched from another carrying device, such as a submarine, such launched underwater devices then being subjected to a generally brief launch stage or phase followed by a longer cruise stage or phase. The supply of electrical energy to such launched underwater devices must then meet very specific criteria in respect of electrical power delivered and duration of delivery of this energy, in order to enable the launched underwater devices to fulfil their mission in accordance with a pre-established programme. Under these conditions, the use of conventional electrical energy sources, such as lead accumulator batteries, cannot be accepted owing, on the one hand, to the electrical power required to ensure such a function and, on the other hand, to the inert mass necessary in order to use such conventional sources of electrical energy. The known electrical energy sources of the prior art of the thermal cell type generally enable substantial electrical power to be delivered. However, they require the provision of substantial thermal energy in order consequently to permit the provision of electrical power. Therefore, such sources cannot be used for mission times of aquatic devices, especially underwater devices, exceeding some tens of seconds, owing to the major difficulty encountered in providing such an amount of electrical energy beyond such a time, from thermal sources on board such devices, especially when the latter are submerged. The object of the present invention is to overcome the disadvantages of traditional electrical cells or sources of electrical energy which cannot be considered for immediate use in the context of the operational constraints mentioned above. In particular, the present invention relates to the use of an electrical cell for the propulsion of a device in an aquatic medium, which cell permits the delivery of electrical power necessary and sufficient for the propulsion of this type of device in accordance with a launch phase followed by a cruise phase, over distances which may extend to 10 to 20 kilometres. Furthermore, the present invention relates also to the use of an electrical cell for the propulsion of a device in an aquatic medium, which cell permits the delivery of the above-mentioned electrical power for a period of the order of from 30 to 45 minutes. In addition, the present invention relates also to the use of an electrical cell for the propulsion of a device in an aquatic medium, which cell has a specific structure permitting, on the one hand, the storage of this electrical propulsion cell, which is inert in the absence of any activation, for a long period, for example several months, under optimum safety conditions, then the structural and/or functional integration of this cell in a device, for exploitation in the context of an operational mission, on simple activation when the electrical propulsion cell is immersed in an aquatic medium. Finally, the present invention relates also to the use of an electrical cell for the propulsion of a device in an aquatic medium permitting the execution of missions of a non-destructive nature, the electrical propulsion cell, when the device has returned to its place of origin, being capable not only of being re-used, after reconditioning, but also of being stored under conditions of safety and reliability similar to those of a first use. The electrical cell for the propulsion of a device in an aquatic medium, to which the present invention relates, is noteworthy in that it comprises at least, in a sealed cell body, a first chamber forming a housing comprising an auxiliary electrical cell and a command and control module for the electrical propulsion cell, a second chamber forming a housing comprising a main electrical cell of the electrochemical type, this second chamber being provided with members for the controlled admission and the regulation of a flow of water from the aquatic medium into this second chamber, which forms a reservoir, in order to form, after the command to admit water from the aquatic medium, an electrolyte for activating the main electrical cell, and a third chamber forming a housing comprising a module for triggering the admission by suction of water from the aquatic medium and the discharge by escape of effluents resulting from the chemical reaction of the main cell into the aquatic medium, from an admission valve and an escape valve, respectively, which are mounted in this third chamber, the command and control module of the electrical propulsion cell permitting the activation of the auxiliary electrical cell in order to generate electrical energy temporarily during a stage of launching this device in an aquatic medium, and the triggering of the admission by suction of water from the aquatic medium and of the discharge by escape of effluents in order to produce electrical energy from the main electrical cell during a cruise phase. The electrical cell for the propulsion of a device in an aquatic medium, to which the present invention relates, can be used for the propulsion of devices of any type in an aquatic medium, such as, in particular, a torpedo, a reconnaissance or exploration device or submarine, a surface device, for example. The present invention will be better understood on reading the description and referring to the drawings hereinafter in which: FIG. 1a is, purely by way of illustration, a sectional view, taken on a longitudinal plane of symmetry, of the electrical cell for the propulsion of a device in an aquatic medium, in accordance with the subject-matter of the present invention; FIG. 1b shows purely by way of illustration various signal timing diagrams representing a specific operating mode of the electrical cell for the propulsion of a device in an aquatic medium, to which the present invention relates. A more detailed description of the electrical cell for the propulsion of a device in an aquatic medium according to the subject-matter of the present invention will now be given in conjunction with FIG. 1a and then FIG. 1b. As can be seen in the above-mentioned FIG. 1a, the electrical cell to which the invention relates comprises at least, in a sealed cell body marked 0, a first chamber 1, a second chamber 2 and a third chamber 3, each of the above-mentioned chambers forming a housing. The first chamber 1 comprises an auxiliary electrical cell marked 10 and a command and control module marked 11 for the electrical propulsion cell. The second chamber 2 comprises a main electrical cell marked 211, this main electrical cell advantageously being of the electrochemical type in order to operate under the conditions which will be explained hereinafter. The second chamber 2 is also provided with members for the controlled admission and the regulation of a flow of water from the aquatic medium into the second chamber 2, which forms a reservoir, in order to constitute, after the command to admit water from the aquatic medium into the above-mentioned reservoir, an activation electrolyte marked 20, the function of which is of course to activate the main electrical cell 211. Finally, the third chamber 3 comprises a module for triggering the admission by suction of water from the aquatic medium and the discharge by escape of the effluents resulting from the chemical reaction of the main cell into the aquatic medium, the operations of admission by suction and discharge by escape of the effluents being effected from an admission valve 32 and an escape valve 33, respectively, mounted in the third chamber 3. The triggering module bears the reference 34 in FIG. 1a. It permits the triggering of the admission by suction of water by means of the admission valve 32 and, respectively, the command to discharge the effluents by means of the escape valve 33, as will be described later on in the description. According to a particularly advantageous aspect of the electrical cell for the propulsion of a device in an aquatic medium, to which the present invention relates, the command and control module 11 of the electrical propulsion cell, which module is located in the first chamber 1, permits the activation of the auxiliary electrical cell 10 in order to generate electrical energy temporarily during a stage of launching the device in an aquatic medium and permits the triggering of the admission by suction of water from the aquatic medium and the triggering of the discharge by escape of the effluents in order to produce electrical energy from the main electrical cell 211 during a so-called cruise phase. With reference to FIG. 1a, the auxiliary electrical cell 10 and the main electrical cell 211 are controlled sequentially by the command and control module 11 of the electrical propulsion cell located in the first chamber 1 and are connected respectively to a main and secondary electrical energy distribution network. In a general manner, it is pointed out by way of non-limiting example that the auxiliary cell and the main cell deliver electrical voltages having substantially different nominal values V′N, VN and they can therefore each be connected respectively to a main and secondary electrical energy distribution network, these networks of course being protected and isolated by diode connections, for example. These connections of the conventional type are not shown in the drawings. In addition, the auxiliary electrical cell 10 is advantageously formed by a set of thermal cell elements started up by pyrotechnic ignition, for example. The object of the auxiliary cell 10 is to supply electrical power to the device moving in an aquatic medium during the launch phase in particular, that is to say, at the beginning of the mission of the above-mentioned device, and during a phase in which the device is at a distance from the starting point not exceeding a few hundred metres. The auxiliary cell 10 thus supplies the energy to the engine for the propulsion of the device moving in an aquatic medium under substantially reduced power and also to all the members of the electrical cell for the propulsion of a device in an aquatic medium, in accordance with the subject-matter of the present invention, as will be described later on in the description. Therefore, the auxiliary cell 10 may advantageously be formed by four thermal cells connected in two parallel branches of two cells in series, for example. The two parallel branches are advantageously each isolated by a diode with respect to a reverse voltage which may originate from the main cell or from the other parallel branch constituting the auxiliary cell 10. Each of the thermal cells making up the auxiliary cell 10 is advantageously ignited by double pyrotechnic ignition by means of an ignition box not shown in the drawings. In a non-limiting preferred embodiment, a first thermal cell is started up as soon as the device moving in an aquatic medium is launched, on the basis of a signal delivered externally by a system for launching the device moving in an aquatic medium, for example. The above-mentioned signal, such as a rectangular wave form voltage for a predetermined period, can then enable an electrical capacitance located in the ignition box to be charged. The capacitance is then discharged onto the pyrotechnic igniters of the thermal cell that was subjected to the ignition operation first. The other three thermal cells making up the auxiliary cell 10 are then ignited by the electrical energy supplied by the first thermal cell subjected to the ignition process. This operation is possible as soon as the first thermal cell ignited provides sufficient nominal voltage. In a non-limiting embodiment, the duration of operation of the auxiliary cell 10 does not exceed three seconds. In a non-limiting embodiment, the auxiliary cell 10 permits the delivery of a maximum no-load voltage of the order of 250 V for an average power of 45 kW. The electrical energy delivered by the auxiliary cell 10 is delivered on a main electrical energy distribution network and on a secondary network, which is of course connected in a conventional manner to the device which is to be supplied temporarily by the auxiliary cell 10. As regards the members for the controlled admission and the regulation of a flow of water from the aquatic medium into the second chamber 2, as shown in FIG. 1a, these advantageously comprise a motor-driven pump unit marked 24, the suction nozzle of which is connected to the valve for the admission of water from the aquatic medium, which valve bears the reference 32 in FIG. 1a, and the outlet nozzle of which delivers the water sucked in from the aquatic medium directly into the second chamber 2 forming a reservoir, in order to form the activation electrolyte and to immerse the main electrical cell 211 in the above-mentioned activation electrolyte 20. As is also shown in FIG. 1a, the suction nozzle 25 of the motor-driven pump unit 24 is connected to the admission valve 32 by way of a pipe 21. The connection between the suction nozzle 25 and the valve 32 for the admission of water from the aquatic medium by way of the pipe 21 can be effected directly or by means of a flow regulator bearing the reference 23 in FIG. 1a. The above-mentioned flow regulator 23 enables the rate of admission of water from the aquatic medium into the reservoir formed by the chamber 2 to be regulated in a non-limiting preferred embodiment, as will be described later on in the description. Furthermore, the members for the controlled admission and the regulation of a flow of water from the aquatic medium into the second chamber 2 advantageously comprise, as shown in FIG. 1a, a thermostatic valve 28 connected to the main electrical cell 211. The thermostatic valve 28 regulates the admission of the activation electrolyte 20 into the main cell 211 in order to trigger the activation of the main electrical cell by electrochemical reaction, as will be described later on in the description. Finally, the members for the controlled admission and the regulation of a flow of water from the aquatic medium into the second chamber 2 comprise a device for the circulation of the activation electrolyte and the separation of the effluents thereof. As shown in a non-limiting manner in FIG. 1a, the device for the circulation of the activation electrolyte and the separation of the effluents advantageously comprises an inlet nozzle 271 connected to the internal cavity of the main electrical cell 211, the latter containing, in steady state, the activation electrolyte, a first outlet nozzle 272 connected in the vicinity of the suction nozzle 25 of the motor-driven pump and a second effluent outlet nozzle 273 which is connected by way of a pipe 22 to the discharge valve 33 located in the third chamber 3. In addition, as shown in a non-limiting manner in FIG. 1a, the second outlet nozzle 273 of the device for circulation and separation is connected to the effluent discharge valve 33 located in the third chamber 3 by means of a mode valve marked 26 which permits the orientation, in a first position, of the effluents towards the effluent discharge valve 33, when the main electrical cell is started up during the launch phase, and, respectively, in a second position, of the activation electrolyte towards the suction nozzle 25 of the motor-driven pump, in order to generate closed-loop circulation of the activation electrolyte 20 in the main electrical cell during the cruise phase. Finally, the thermostatic valve 28 is advantageously formed by a three-way valve receiving at least on one of the paths a direct flow FD of activation electrolyte 20 drawn from the second chamber 2 forming a reservoir and on a second path a derivative flow of activation electrolyte passing by way of a heat exchanger 29, the above-mentioned derivative flow Fd of activation electrolyte being maintained at a substantially constant temperature by the heat exchanger. The thermostatic valve 28 delivers on a third path from the direct flow and the derivative flow at a substantially constant temperature acting as a reference temperature a flow of thermostatically-controlled activation-electrolyte marked 210 at a substantially constant temperature to the internal cavity of the main electrical cell 211. The operating mode of the members for the controlled admission and the regulation of a flow of water from the aquatic medium into the second chamber and in particular the device for the circulation and separation of the activation electrolyte and the effluents is as follows: the set of elements making up the above-mentioned members is basically intended to regulate the thermal equilibrium of the main cell 211 and of course to evacuate the effluents. This regulation is effected by the circulation of the activation electrolyte of the main cell, the operation of which is as follows: the motor-driven pump unit 24 pressurizes the reservoir, that is to say, the whole of the second chamber 2 in which the electrolyte is stored. The circulation of the activation electrolyte is then established by means of the thermostatic valve 28 which, thanks to its three-way circuit, enables the direct flow FD coming from the reservoir formed by the chamber 2 and the derivative flow Fd passing by way of the heat exchanger 29 to be mixed. The resulting electrolyte mixture, i.e. the flow of activation electrolyte 210, is then at a substantially constant temperature owing to the operation of the thermostatic valve 28 which enables the reference temperature given by the derivative flow Fd passing through the heat exchanger 29 to be maintained by adjusting the incoming flows. The flow of activation electrolyte 210 is then delivered to the internal members of the main cell 211 of the electrochemical type in order to irrigate the internal members thereof at a rate of flow controlled by the motor-driven pump unit 24. Specifically, the main cell 211 is advantageously constituted by a stack of electrochemical couples irrigated by the flow of thermostatically-controlled activation electrolyte 210 in order to bring about the chemical reaction of the cell which enables the corresponding electrical energy to be generated. On leaving the main cell 211, the activation electrolyte is collected in order to be routed by the inlet nozzle 271 of the effluent separator 27. The effluent separator may advantageously be constituted by a gas separator based on the principle of centrifugation, as a function of the type of electrochemical reaction brought into play in the main cell 211. The gas separator thus separates two phases, a first liquid phase corresponding to the recycled activation electrolyte sent back to the motor-driven pump unit 24 by means of the mode valve 26 and a second gaseous phase which is discharged to the aquatic medium by way of the pipe 22 and the effluent discharge valve 33. It will thus be appreciated that the function of the mode valve 26 is to switch the flow of recycled activation electrolyte either to the motor-driven pump unit 24 during closed-circuit operation of the assembly in the course of the cruise phase, or, where appropriate, to an evacuation to the aquatic medium at the end of the mission, for example, in particular during a mission of a non-destructive nature, by means of the discharge valve 33. It will of course be appreciated that the mode valve 26 is controlled by the command and control module 11 of the electrical propulsion cell, as will be described in more detail later on in the description. A non-limiting preferred embodiment of the assembly of the electrical cell for the propulsion of a device in an aquatic medium, to which the present invention relates, will now be given in conjunction with FIG. 1a and FIG. 1b when the main electrical cell of the electrochemical type is an Ago—Al cell. Under the above-mentioned conditions, the electrical propulsion cell comprises a main electrical cell 211 of the electrochemical type formed by an electrochemical block constituted by a stack of AgO—Al electrochemical couples located in the cavity of a sealed shell module 211a. The above-mentioned sealed module comprises, for example, a plurality of electrochemical couples 211b which are connected in parallel and which of course permit the circulation of the flow of thermostatically-controlled activation electrolyte 210. As shown in FIG. 1a, the sealed module is connected, on the one hand, to the thermostatic valve 28 at the base of the sealed module 211a and, on the other hand, to the device 27 for the circulation of the electrolyte and for the separation of effluents, at the inlet nozzle 271 of the latter. The main electrical cell of the electrochemical type is also formed by a reserve of anhydrous sodium hydroxide, the electrochemical block and the anhydrous sodium hydroxide being located in the second chamber 2 forming a reservoir. In FIG. 1a, the reserve of anhydrous sodium hydroxide has been represented by crystals represented by crosses, which crystals are not completely diluted in the water from the aquatic medium admitted into the chamber 2. On the admission of water from the aquatic medium, the triggering of the activation of the main electrical cell brings into play, with the AgO—Al electrochemical couples, the anhydrous sodium hydroxide and the water, a main electrochemical reaction: 2Al+3AgO+2NaOH+3H2δ3Ag+2NaAl(OH)4+2kCal, a parasitic corrosion reaction: 2Al+2NaOH+2H2δ2NaAlO2+3H2+200 kCal. Under these conditions of electrochemical reaction, the effluents are formed by hydrogen gas H2. In a non-limiting manner, it is pointed out that the anhydrous sodium hydroxide reserve is advantageously constituted by a mixture of micropellets of anhydrous sodium hydroxide and powder-form stannates charged in bulk into the second chamber forming a reservoir. The operating mode of the assembly will now be described taking into account the advantageous, but not indispensable, use of the flow regulator 23. At the time when the cell is activated, that is to say, at the time when the opening of the admission valve 32 is triggered, after the phase of launching the device, the admission valve 32 and the flow regulator 23 for the admission of water from the aquatic medium permit the inflow of water from the aquatic medium towards the reservoir formed by the second chamber 2. By dissolution, this brings about the formation of the activation electrolyte. The flow regulator 23 intervenes in order to control the incoming flow of water, regardless of the activation immersion of the device and of course of the cell for the propulsion of a device in an aquatic medium. The admission valve 32 thus ensures the sealing of the reservoir 2 formed by the second chamber 2 during all of the phases of cell storage, including during the launch phase, as will be described later on in the description. When the whole of the system is started up and the stabilized circulation of the activation electrolyte is established, as described above in the description, the equilibrium of the pressures with respect to the external aquatic medium is the following: the reservoir formed by the second chamber 2 is pressurized by the pump 24; the inlet nozzles of the thermostatic valve 28 and of the heat exchanger 29 are subjected directly to the above-mentioned pressure; the inlet of the main cell or more particularly of the sealed block 211a forming the electrochemical block is pressurized by the output pressure of the thermostatic valve 28, which is equal to the pressure of the chamber 2 forming a reservoir, reduced by the drop in pressure brought about by the thermostatic valve 28. Consequently, the internal cavity of the main cell 211 and of the sealed shell module 211a forming the latter is subjected as a whole externally to a relative pressure at least equal to the pressure drop 2 brought about by the thermostatic valve 28. This condition ensures correct operation of the main electrical cell because the above-mentioned pressure ensures good contact of the stack of electrodes constituting the electrochemical couples, and also good internal electrical conductivity. The input pressure of the gas separator device 27 is reduced by the pressure drop introduced by the stack of electrochemical couples 211b. The second outlet 273 of the effluent or gas separator 27 is at a pressure substantially close to that of the aquatic medium and a non-return valve permits a slight drop in pressure, for example. The outlet nozzle for recycled activation electrolyte 272 of the gas or effluent separator device 27 is at a pressure substantially close to the pressure for the suction of water from the aquatic medium. Passage through the mode valve 26 and also a non-return valve enable a slight drop in pressure to be obtained. At the inlet of the motor-driven pump unit, the connection towards the aquatic medium opened by the admission valve 32 at start-up remains open in order, by drawing in water from the aquatic medium, permanently to balance the variations in the internal volume of the cell, in particular of the chamber 2 forming a reservoir. The above-mentioned variations in internal volume are due in particular to an initial degassing of the system in a purging stage prior to the admission of water from the aquatic medium, and due to the volume compensation brought about by the erosion of the electrodes formed by the electrochemical couples which is caused by the electrochemical reactions. The outlet of the mode valve 26 and the outlet of the flow regulator 23 thus meet at the suction nozzle 25 of the motor-driven pump unit 24. This joining is effected in a connecting region subjected to the immersion pressure in the chamber 2 forming a reservoir. All of the command and control functions of the cell are carried out by means of the command and control module 11 mentioned above in the description. More specifically, the above-mentioned module 11 ensures the following functions: control of the functions of the cell on the basis of the data coming from the control and guide section (not shown) of the device; transmission of the cell operating parameters to the above-mentioned control and guide section; regulation of the motor-driven pump 24 by means of an electronic unit 31 located in the third chamber 3. The above-mentioned operating mode will now be described in conjunction with FIG. 1b at points 1, 2 and 3 thereof, for various members making up the assembly shown in FIG. 1a. In particular, the above-mentioned operating mode is described when the admission valve 32 is provided with which is associated a start-up valve 35 which is itself controlled by a pressure reference formed by a pre-positioning valve 36 and when, in addition, a flow regulator 23 is mounted on the pipe 21 for connecting the admission valve 32 and the suction nozzle 25 of the motor-driven pump unit 24. The admission valve 32 opens the chamber 2 forming a reservoir to the aquatic medium. To be more precise, it permits the entry of water from the aquatic medium into the reservoir, the incoming flow of water being directed towards the flow regulator 23 and then towards the motor-driven pump unit 24. The effluent discharge valve 33 is coupled to the admission valve 32 in order to ensure that the effluent or gas separator device 27 is brought into communication with the aquatic medium. The admission valve 32 and the effluent discharge valve 33 are fixedly joined, being located diametrically opposite each other on the periphery of the cell body 0 in a longitudinal plane of symmetry of the latter, and they advantageously have an identical opening cross-section, so that the forces due to the pressure of immersion in the aquatic medium are balanced out at every instant. The admission valve 32 is controlled by a pyrotechnic activator, for example. It also comprises a start-up valve 35 permitting the opening to the aquatic medium of a duct which enables the flow regulator 23 to be positioned at the immersion pressure. The start-up valve 35 can be controlled by means of a pyrotechnic activator. The pyrotechnic control of the start-up valve 35 and the admission valve 32 is effected by means of the command and control module 11 with a specific time lag. The pyrotechnic control of the admission valve 32 acts on a mechanical device which releases a biasing spring. The assembly formed by the admission valve 32 and the effluent discharge valve 33, which are connected by the synchronized control 34 formed basically by a central rod, moves as far as a mechanical stop. The orifice for the admission of water from the aquatic medium is then open while the orifice for the discharge of the effluents or gases remains closed owing to the action of the external pressure on a valve. The above-mentioned device prevents the entry of water from the aquatic medium via the outlet of the effluent discharge valve 33 during the start-up phase. When the second chamber 2 forming a reservoir has been substantially filled, a protective cover arranged at the inlet to the thermostatically controlled activation electrolyte 210 delivered by the thermostatic valve 28 is then opened, the recycled electrolyte subsequently leaves the effluent or gas separator 27 and an internal pressure occurs in the main cell 211, which pressure is close to that of the water from the aquatic medium. The degassing flap of the effluent discharge valve 33 can then be opened by the action of the spring 330 shown in the drawing. Once open, the flap does not cause any drop in pressure in the degassing circuit. The start-up valve 35 and the admission valve 32 each comprise a limit stop contact which indicates their state of activation. The signals of the above-mentioned limit stop contact are sent back to the command and control module 11 which monitors the whole of the start-up operation. The flow regulator 23 is intended to limit the flow of water from the aquatic medium admitted into the second chamber 2 by adjusting a passage cross-section adapted to the immersion pressure. The operating mode of the above-mentioned regulator consists in obstructing the maximum flow cross-section of the diameter of the duct for supplying water from the aquatic medium by the displacement of a slide valve equipped with calibrated orifices. The above-mentioned flow regulator 23 is installed in the reservoir. It is connected between the admission valve 32 and the suction nozzle 25 of the motor-driven pump 24. The start-up valve 35 applies the immersion pressure to the slide valve of the regulator by way of a duct for an external pressure reference RPE. The above-mentioned slide valve then occupies an equilibrium position imposed by a spring. The displacement of the slide valve is proportional to the pressure applied. The passage cross-section for the water from the aquatic medium is thus partially closed and the flow is then pre-adjusted within a range of values of from 10 to 15 litres/second. At the end of the filling operation, when the pressure in the second chamber 2 forming a reservoir is higher than that of the aquatic medium, the regulator re-assumes a completely open position. This later permits an operation in which it is easy to rinse the cell during the performance of a non-destructive mission, for example. The flow regulation is provided for exterior pressures of the aquatic medium corresponding to immersion depths of from 10 to 350 metres. The adjustment can be carried out for different, lower and/or higher, values. The flow regulator 23 comprises an input pressure tap forming a pressure reference of the exterior aquatic medium RPE for the assembly. The thermostatic valve 28 is located at the lower portion of the sealed shell 211a forming the main cell. It is located in the vicinity of the irrigation orifices of the electrochemical couples 211b constituting the above-mentioned main cell and thus ensures the entry of the flow of thermostatically controlled activation electrolyte 210 at a substantially constant temperature which may be from 80 to 98° C., for example. The thermostatic valve 28 operates on a purely mechanical principle. It uses a thermostatic probe to control the position of a slide. Depending on the position of the latter, the slide uncovers passage holes at the hot inlet and the cold inlet so that the mixture irrigating the probe is constantly at a defined temperature. The above-mentioned thermostatic valve 28 is equipped at the outlet with a protective cover 280 which can be snapped shut at a predetermined pressure value of the order of 3.0 bar, this protective cover keeping the internal cavity of the electrochemical block closed as long as the pressure in the reservoir is not sufficient. The thermostatic valve 28 is equipped with a filter surrounding the hot inlet orifices of the reservoir. Under these conditions, particles of sodium hydroxide having a size greater than a predetermined value of the order of 300 microns are stopped, while the flow leaving the pump permits permanent unclogging of the filter. The thermostatic valve 28 comprises a temperature probe whose measurement is conditioned by the command module of the electrical propulsion cell 11. It also comprises a pressure tap RPBEI at the inlet to the sealed shell 211a a of the main electrical cell, this pressure tap being intended for a pressure sensor CP6 enabling the mode valve 26 to be controlled, as will be described later on in the description. The nominal regulation temperature maintained by the thermostatic valve for operation of the cell at maximum power and for a low immersion pressure, is close to 95° C. while, for a high degree of immersion, the drift of the probe permits operation up to approximately 98° C. The effluent or gas separator 27 collects the activation electrolyte leaving the electrochemical block at the upper portion of the sealed shell 211a forming that block. It separates the gases or effluents by a cyclone effect as soon as the state of electrolyte circulation is established. It is installed in the reservoir formed by the chamber 2 and composed of a metal, such as stainless steel, in order to ensure good heat conduction and that the activation electrolyte subjected to the phenomenon of effluent separation is maintained at a temperature close to that of the activation electrolyte which is contained in the reservoir but which is not subjected to the phenomenon of effluent separation. During the start-up phase, the effluent or gas separator 27 transfers the effluents or gases from the electrochemical block to the effluent discharge valve 33 owing to the position of the mode valve 26 which blocks the normal liquid return from the degasser to the motor-driven pump 24. Connected between the outlet of the electrochemical block and the inlet of the gas effluent separator device 27 is a suction tube which enables the gases that have remained trapped in the second chamber 2 forming a reservoir to be evacuated. This operating mode is permitted owing to the fact that the pressure in the reservoir is higher than that at the inlet to the gas separator device 27. During the cruise phase, this degassing tube provides for leakage inside the system, which leakage is very slight and entirely acceptable, while at the same time ensuring the possible evacuation of gases which may settle in the second chamber 2 forming a reservoir. The outlet nozzle 273 of the gas separator device 27 is connected to the effluent or gas discharge valve 33 through the sealed tube 22 and a valve. The above-mentioned tube enables the cell to be rinsed at a rate of the order of 3 litres/second. The outlet nozzle of the effluent or gas separator device 27 delivering the recycled activation electrolyte in the vicinity of the suction nozzle 25 of the motor-driven pump is connected to the latter by means of the mode valve 26. When the mode valve 26 is in the closed position, that is to say, during start-up and during the rinsing of the electrical cell for the propulsion of a device in an aquatic medium, to which the invention relates, the whole of the flow is oriented in the mode valve 26 towards the effluent or gas outlet. When the mode valve 26 is open, the liquid of the degasser passes through the above-mentioned mode valve and is sucked in by the pump by means of the suction nozzle 25 thereof. The inlet of the gas or effluent separator device 27 also comprises a temperature probe CT7 which is identical to the inlet temperature probe CT8 located on the thermostatic valve 28 and also a pressure tap enabling the output pressure of the electrochemical block, also referred to as RPBEO, to be delivered. This pressure tap enables the operating mode of the cell to be managed by the command module 11. Finally, the mode valve 26 is advantageously constituted by a three-way valve having two stable open and closed positions and comprising a slide controlled by an actuating pressure balanced by a spring. It comprises two simple two-way solenoid valves EV1 and EV2 enabling the application of the actuating pressure to the above-mentioned slide to be managed. The solenoid valve EV1 connects the tap for immersion pressure RPE of the flow regulator 23 to the chamber of the mode valve 26. The solenoid valve EV1 is a valve which is normally open in the absence of electrical power. The solenoid valve EV2 connects the input pressure tap of the electrochemical block, that is to say, the output pressure of the thermostatic valve 28, also referred to as RPVT, to the chamber of the mode valve 26. The solenoid valve EV2 is a valve which is normally closed. The mode valve 26 enables the activation electrolyte leaving the outlet nozzle 272 of the gas effluent separator device 27 to be oriented in accordance with two paths corresponding to operating modes of the cell: in the upper or closed position, no pressure is applied to the mode valve 26. Under these conditions, the mode valve 26 orients the effluent flows towards the gas discharge valve 33. This mode of operation takes place during start-up in order to purge the gases to the aquatic medium, and at the end of the mission, during the rinsing of the cell in the case of a non-destructive mission. in the lower or open position, the mode valve 26 receives the actuating pressure which positions its slide in the lower position and it orients the electrolyte towards the inlet of the motor-driven pump, i.e. the suction nozzle 25, so that the activation electrolyte circulates in a closed loop in the cell. The two solenoid valves EV1 and EV2 are completely controlled by the command module 11. According to the scheme shown at point 3 in FIG. 1b: during the activation phase, that is to say, the phase of launching the device, the valve EV1 is supplied with power and therefore closed, which prevents the input pressure of the flow regulator 23 from acting on the slide of the mode valve 26. On the other hand, the solenoid valve EV2 is not supplied with power and is therefore closed, while waiting for a command signal delivered by the command module 11. Under these conditions, the mode valve 26 is not under stress and remains in the upper or closed position. It will be appreciated that the supply of electrical energy to the solenoid valve EV1 by the auxiliary cell 10 is permitted as of the initial start-up thereof; at the end of the operation of filling the reservoir formed by the second chamber 2, when the pressure conditions are detected, the solenoid valve EV2 is supplied with power, which enables the input pressure of the electrochemical block, that is to say, the input pressure RPVT, to be applied to the slide of the mode valve 26. The slide tilts and therefore enables the recycled activation electrolyte coming from the effluent or gas separation device 27 to pass to the pump 24. The solenoid valve EV1 for its part remains closed. At the end, for example, of a non-destructive mission, the supply of power to the first solenoid valve EV1 is cut, which decompresses the chamber of the mode valve 26 and enables the slide to go back up to the upper position. The activation electrolyte is then evacuated by way of the effluent or gas outlet, that is to say, by way of the effluent discharge valve 33. At the same time, the supply of power to the solenoid valve EV2 is cut, which then prevents the input pressure of the electrochemical block, that is to say, the pressure RPVT, from acting on the slide of the mode valve 26. The solenoid valves EV1 and EV2 are controlled by the above-mentioned command and control module 11 which operates on the basis of the pressure data coming from the pressure taps below: tap for reservoir pressure; tap for immersion pressure RPE; tap for the output pressure RPBEO of the electrochemical block. Two differential pressure sensors which are not shown in the drawing enable the following data to be supplied to the command and control module 11 from the above pressure taps: the difference between the reservoir pressure and the immersion pressure indicates the state of operation of the circulation loop. This difference in pressure must tally with the state of the cell and with the flow control of the pump; the difference between the output pressure of the electrochemical block and the immersion pressure indicates the filling state of the cell. The operating mode and the control of the second solenoid valve EV2 by the command module 11 which brings about the switching of the mode valve 26 are effected on the basis of the following criteria: the difference in pressure between the outlet of the electrochemical block and the aquatic medium; the monitoring of the electrical voltage delivered by the electrochemical block; the monitoring of the output temperature of the electrochemical block; the chronology of start-up. By way of summary, the control logic of the mode valve 26 through the supply of electrical power for controlling the two solenoid valves EV1 and EV2 is given hereinafter in accordance with the following Table: 1. Initial state EV1 = 0 EV2 = 0 2. As soon as the thermal EV1 = 1 EV2 = 0 cell voltage is OK 3. As soon as pressure “output BE-immersion” EV1 = 1 EV2 = 1 is OK 4. As soon as the order to stop reaches EV1 = 0 EV2 = 0 the module 1l In addition, the lower position of the slide of the mode valve 26 is detected by means of a magnetic sensor CM6 and is acquired by the command and control module 11. The operating mode of the assembly is represented with reference to points 1), 2) and 3) of FIG. 1b in which: represented at point 1) are the launch and cruise phases, respectively, of the device; the launch phase may last a few seconds or a few tens of seconds and the cruise phase may last several tens of minutes; represented at point 2) is the graph of the voltages delivered by the auxiliary cell and the main electrical cell, respectively, it being understood that the nominal voltage V′N of the auxiliary cell of the order of 165 V is substantially different from that of the main electrical cell 245 V, for example. Represented at point 3) is the control of the two solenoid valves V1 and V2 constituting the mode valve 26 according to the above Table. As regards the motor-driven pump 24, this pump ensures the circulation and recycling of the activation electrolyte at a variable flow rate. It may be constituted by a centrifugal pump immersed in the electrolyte reservoir and by a likewise immersed motor. The motor is a motor of the type whose speed is controlled as a function of the pumping requirement. The electronic control system of the motor is denoted by the unit 31 and located in the chamber 3, for example. The supply of power to the pump motor is advantageously effected from the main electrical network of the main cell at 400 V while the supply of power to the electronic control system may be effected on the auxiliary circuit of the cell at 200 V. In particular, when the main cell has taken over from the auxiliary cell, the secondary network may be supplied with power from the half-voltage delivered by the main cell. Finally, the motor-driven pump 24 is controlled in terms of speed by the command module 11 by means of a series RS422 connection of the conventional type. The motor-driven pump may be controlled in accordance with discrete operating states with incremental flow. The motor-driven pump 24 provides data relating to: absorbed current; rate of rotation; temperature of the circuits for supplying power to IGBT converters (Insulated Gate Bipolar Transistor); self-test evaluation. The starting of the motor-driven pump 24 is controlled by the command and control module 11 as soon as the latter receives the contact signal provided by the opening of the admission valve 32. A more detailed description of the structure of the electrical cell for the propulsion of a device in an aquatic medium and of a method of using that structure in accordance with the subject-matter of the present invention will now be given hereinafter. As shown in FIG. 1a, the sealed cell body 0 is advantageously formed by an assembly of elements constituted at least by a front collar 01 and a front end 02 of the main electrical cell, the front collar 01 and the front end 02 forming the third chamber 3 mentioned above. The sealed cell body 0 also comprises a central shell 03 and a rear end 04, the front end 02, the central shell 03 and the rear end 04 forming the second chamber 2 constituting the reservoir. Finally, the sealed cell body 0 comprises a rear collar 05, the rear end 04 and the rear collar 05 constituting the first chamber 1. As also shown in FIG. 1a, the central shell 03 at least is constituted by a metal alloy which is a good heat conductor. A portion at least of the central shell 03 which is located in the vicinity of the main electrical cell 211 and in particular of the electrochemical block forming that cell constitutes the heat exchanger with the aquatic medium and in particular the heat exchanger 29 for at least the derivative flow of activation electrolyte. It can be seen in FIG. 1a that the derivative flow of activation electrolyte is generated by the pressure produced by the motor-driven pump 24 in a gap 291 formed at the lower portion of FIG. 1a, between the wall of the central shell 02 and a metal wall fixedly joined to the thermostatic valve 28, and finally to the sealed body 211a forming the electrochemical block 211. The above-mentioned gap 291 permits the generation of the derivative flow of activation electrolyte at a substantially constant temperature acting as the reference temperature for the above-mentioned thermostatic valve 28. Preferably, the front collar 01, the front end 02 of the electrical cell, the central shell 03 and the rear end 04 and also the rear collar 05 are composed of a metal material. The external face thereof which is to be in contact with the aquatic medium is advantageously provided with a protective anti-corrosion layer obtained by hard anodic oxidation. As regards the central shell 03, it should be mentioned that this shell, between the front end and the rear end, is formed in a single piece and has no opening at the periphery in order to ensure that the assembly is sealed during all of the phases of storing the cell for the propulsion of a device in an aquatic medium according to the subject-matter of the present invention. This specific design enables double sealing of the reservoir formed by the second chamber 2 with respect to the external aquatic medium to be put in place at the joints with the front end 02 and the rear end 04. As shown in FIG. 1a, the cell body and, in particular, the second chamber 2, is provided with a double sealing barrier with respect to the external aquatic medium. A first sealing barrier, marked B1, is formed by a seal between the aquatic medium and the first chamber, and the third chamber, respectively, and a second sealing barrier, B2, is formed by a seal between the first and second chamber and the second and third chamber, respectively. The above-mentioned sealing barriers are represented by specific hatching in FIG. 1a. Finally, the internal face of the central shell 03, except for the portion forming the heat exchanger 29, also comprises a thermally insulating coating at the portion forming a reservoir for the activation electrolyte. The purpose of this thermally insulating coating is to reduce the cooling of the stored activation electrolyte by heat exchange with the aquatic medium during the cruise phase. This thermally insulating coating may be constituted by a coating of the epoxy resin type, for example. In addition, the internal face of the front end 02 of the electrical cell of the central shell 03 and of the rear end 04 of the electrical cell constituting the second chamber 2 forming a reservoir comprises a chemical nickel coating for protection against corrosion by the anhydrous sodium hydroxide. The sealing of the second chamber 2 forming a reservoir may then be managed in the following manner: the reservoir is the portion of the electrical cell for the propulsion of a device in an aquatic medium according to the subject-matter of the present invention that comprises the active components of the cell, in particular the sodium hydroxide and the electrochemical block. For this reason, the elements making up the above-mentioned reservoir have been organized in such a manner that, together, they have total sealing in respect of storage in water from the aquatic medium owing to the two sealing barriers B1 and B2 mentioned above which are formed by specific seals. In the case of inadvertent immersion, in particular of the reservoir portion, no electrochemical material is in contact with the water from the aquatic medium. Two water detectors, one located at the front and the other located at the rear, that is to say, in the chambers 1 and 3, for example, are connected by specific wiring, on the one hand, to the command and control module 11 and, on the other hand, to the external launch system, which can thus monitor the safety of the cell before the device is launched. The second sealing barrier B2 ensures the integrity of the reservoir function with respect to the external aquatic medium. A pressure switch, which is not shown in the drawing, may be provided in order to permit permanent control of the sealing of the mode valve 26. The above-mentioned pressure switch is connected between the two seals of the mode valve 26, on the one hand, on the water inlet portion, that is to say, on the outlet nozzle 272 of the effluent or gas separator 27 to which the above-mentioned mode valve 26 is connected, and, on the other hand, on the gas outlet portion 273 of the above-mentioned separator 27. The double sealing barrier B1 and B2 equipped with the above-mentioned water and pressure detectors ensures a high level of reliability in terms of the sealing of the electrical cell for the propulsion of a device in an aquatic medium to which the present invention relates. Finally, the front collar 01 and the rear collar 05 have, as shown in FIG. 1a, a distal end which is open with respect to the front end 02 and the rear end 04, respectively, of the cell. This embodiment enables the electrical propulsion cell to which the invention relates to be constructed in the form of an independent module which can be stored as a substantially inert component with its charge of anhydrous sodium hydroxide reserve when the electrical propulsion cell is not mounted with the device, and also in the form of an element integrated directly in the body of the device in the opposite case. To that end, in a non-limiting embodiment, the front collar 01, the central shell 03 and the rear collar 05 advantageously have a substantially cylindrical cross-section of revolution. The above-mentioned shape is particularly suitable for integration in the body of the device when that device is constituted by a torpedo, for example, or by an underwater observation device. In this situation, the distal end of the front collar is secured mechanically and coupled electrically to the active portion of the device and the distal end of the rear collar is secured mechanically and coupled electrically to the propulsive and control rear portion of the device in order to constitute an electrical propulsion cell which can be activated as soon as the device is launched in the aquatic medium. It will be appreciated in particular that the assembly represented in FIG. 1a comprises wire connections by cables and/or by buses, as mentioned above, between the first chamber 1, the second chamber 2 and the third chamber 3, although these connections as a whole are not all represented in the drawings. Under these conditions, the cell for the propulsion of a device in an aquatic medium according to the subject-matter of the present invention comprises temperature sensors for the flow of activation electrolyte entering and leaving the main electrical cell, in order to be able to regulate the temperature of the flow of activation electrolyte by means of the thermostatic valve 28. The cell also comprises sensors for sensing the relative pressure of the activation electrolyte in the second chamber 2 forming a reservoir for that same activation electrolyte at the inlet of the device 27 for the circulation of the activation electrolyte and for the separation of the effluents, these sensors of relative pressure delivering a relative pressure with respect to the pressure outside the sealed cell body, that is to say, with respect to the pressure reference RPE mentioned above in the description. Finally, the cell comprises a plurality of contacts or of detection of a contact for sealing the valve 32 for the admission of water from the aquatic medium, a contact for opening the valve for the admission of water to the above-mentioned sealed cell body 211a. Of course, all of these sensors and/or contacts are connected by suitable connections provided with sealed bushes in a manner known per se. Sealed electrical power bushes such as shown in FIG. 1a under the references 12 and 13 connect the auxiliary cell 10 to the set of elements contained in the second chamber 2 forming a reservoir and the third chamber 3 or front chamber for supplying electrical power to the electronic module 31 of the motor-driven pump 24, the sealed electrical bush 13 being connected directly to the electrochemical block and in particular to the electrochemical couples in order to deliver the electrical power energy to the propulsion unit of the device carrying the electrical cell for the propulsion of a device in an aquatic medium according to the subject-matter of the present invention. The propulsion energy is supplied by means of a power connector provided with an intensity sensor CI as shown in the drawing of FIG. 1a.

20060710

20120320

20070510

92448.0

B63H2117

CULLEN, SEAN P

PROPULSION CELL FOR A DEVICE IN AN AQUATIC MEDIUM

UNDISCOUNTED

ACCEPTED

B63H

ACCEPTED

Positioning Device for Use in Apparatus for Treating Sudden Cardiac Arrest

A positioning device for use in apparatus for treating sudden cardiac arrest in a patient in supine position by providing chest compressions at the lower end of the sternum prevents the apparatus from moving in a caudal direction. The apparatus comprises a frame enclosing the patient at a sternal transversal plane and a pneumatic compression/decompression means mounted on the frame. The device comprises a flexible strap having a first end, a second end and a tensioning means disposed between the first and second ends. First and second end portions of the strap comprise means for attachment to the apparatus. The flexible strap means has a mounted tensioned length sufficient to extend around the patient's neck. A least one of the end portions is releasably attached.

1. A positioning device for use in an apparatus for treating sudden cardiac arrest in a patient in a supine position by providing chest compressions at the lower end of the sternum, which prevents the apparatus from moving in a caudal direction, the apparatus comprising a frame enclosing the patient at a sternal transversal plane and a pneumatic compression/decompression means mounted on the frame, the device comprising a flexible strap means having a first end, a second end and a tensioning means disposed between the first and second ends, first and second end portions extending from the first and second ends, respectively, comprising means for attachment to the apparatus at first and second positions thereof, respectively, the flexible strap means having a mounted tensioned length sufficient to extend around the patient's neck, with the proviso that at least one of said end portions is releasably attached. 2. The device of claim 1, wherein the tensioning means is integrated with the attachment means. 3. The device of claim 1, wherein the positions of attachment are in an anterior frontal plane. 4. The device of claim 1, wherein the flexible means is any of strap, belt, ribbon, band, wire and the like. 5. The device of claim 4, where the flexible means is of a polymer material such as polypropylene, polyester or polyamide or a mixture of polymer materials. 6. The device of claim 1, wherein the means for attachment comprises a snap connection. 7. The device of claim 6, wherein one member of the snap connection is mounted on the frame and the other member is mounted on an end portion of the flexible strap means. 8. The device of claim 7, wherein the frame comprises two legs disposed on either side of the patient, the one member of the snap connection being mounted on one of the legs. 9. The device of claim 6, where the mounting on the frame is releaseable. 10. The device of claim 8, wherein the mounting on the frame allows said one member of the snap connection to be displaced between a proximal and a distal face of the frame. 11. The device of claim 1, comprising a neck support. 12. The device of claim 11, wherein the neck support is of a compressible material. 13. The device of claim 11, wherein the neck support is slidably displaceable along the flexible strap means. 14. The device of claim 13, comprising means for hindering displacement of the neck support in a loaded state thereof. 15. The device of claim 6, wherein said tensioning means is comprised by the member of the snap connection mounted on an end portion of the flexible strap means.

FIELD OF THE INVENTION The present invention relates to a positioning device for use in apparatus for treating sudden cardiac arrest. BACKGROUND OF THE INVENTION Sudden cardiac arrest is commonly treated mechanically and/or by electrical defibrillation. Mechanical treatment may be given manually or by a chest compression apparatus. The length of a compression/decompression cycle is typically from half a second to one second. A number of chest compression apparatus are known in the art, such as the pneumatically driven LUCAS™ mechanical chest compression/decompression system (“Lucas™ system”; an apparatus for compression and physiological decompression in Cardio-Pulmonary Resuscitation, CPR, manufactured by Jolife AB, Lund, Sweden). Specifically the Lucas™ system comprises a support structure and a compression/decompression unit. The support structure includes a back plate for positioning the patient's back posterior to the patient's heart and a front part for positioning around the patient's chest anterior to the heart. The front part has two legs, each having a first end pivotally connected to at least one hinge of the front part and a second end removably attachable to the back plate. The front part is devised to centrally receive the compression/decompression unit which is arranged to repeatedly compress/decompress the patient's chest when the front part is attached to the back plate. The compression/decompression unit comprises a pneumatic unit arranged to drive and control compression and decompression, an adjustable suspension unit to which a compression/decompression pad is attached, and a means for controlling the position of the pad in respect of the patient's chest. Defibrillation may be provided independently of and concomitantly with mechanical stimulation. In cardiac arrest it is of utmost importance that adequate circulation be re-established as soon as possible, that is within a few minutes from the onset of arrest. Any delay might lead to irreversible tissue damage. By “adequate circulation” is understood a circulation which is sufficient to protect vital organs and tissues from (further) damage, in particular by damage caused by insufficient oxygen supply. Due to this requirement mechanical compression/decompression has to be started on the spot and most often continued during the transport of the patient to the hospital. It is thus important that the apparatus for mechanical compression/decompression can be moved with the patient while continuing with providing mechanical stimulation. A problem with apparatus for treating cardiac arrest known in the art is that due to the vigorous pneumatic or other compression action and the anatomy of the human body, the apparatus has a tendency to move in respect to the patient in a caudal direction. This necessitates monitoring of the apparatus' position by the attending personnel in respect of the patient and to correct it, if needed. In a stressful situation like the one in which the apparatus for treating cardiac arrest is applied, this sort of monitoring may detract the attending personnel from other important duties. The present invention seeks to remedy this problem. Another problem with apparatus for treating cardiac arrest known in the art is that moving them with a patient necessitates the assistance of three persons: Two to lift and carry the patient's body with the apparatus, one to the left and one to the right of the patient holding the apparatus with one hand and supporting the patient's seat with the other, and a third for holding the head to prevent it from falling back. OBJECTS OF THE INVENTION It is an object of the present invention to provide a positioning device for use in apparatus for treating sudden cardiac arrest which prevents the apparatus to move in a caudal direction in respect of the patient. It is a another object of the invention to provide a positioning device for use in an apparatus for treating sudden cardiac arrest that supports the head of the patient so as to allow the patient to be moved with the apparatus by two persons rather than by three. Other objects of the invention are to provide a means for positioning the patient's in a way so as to facilitate ventilation and intubation. Further objects of the invention will be evident from the following summary of the invention, the description of preferred embodiments thereof illustrated in a drawing, and the appended claims. SUMMARY OF THE INVENTION According to the present invention is disclosed a positioning device for use in an apparatus for treating sudden cardiac arrest in a patient in supine position by providing chest compressions at the lower end of the sternum, which prevents the apparatus from moving in a caudal direction, the apparatus comprising a frame enclosing the patient at a sternal transversal plane and a pneumatic compression/decompression means mounted on the frame, the device comprising a flexible strap means having a first end, a second end and a tensioning means disposed between the first and second ends, first and second end portions extending from the first and second ends, respectively, comprising means for attachment to the apparatus at first and second positions thereof, respectively, the flexible strap means having a mounted tensioned length sufficient to extend around the patient's neck, with the proviso that at least one of the end portions is releasably attached. It is preferred for the tensioning means to be integrated with the means for attaching the flexible strap means to the apparatus. It is also preferred for the positions of attachment to be arranged in an anterior frontal plane. The positions of attachment may coincide; in such case, they are preferably arranged in a sagittal plane. The flexible strap means of the invention may be any of strap, belt, ribbon, band, wire and the like, here referred to as a strap, preferably of a woven material, in particular of a polymer material such as polypropylene, polyester or polyamide or a mixture of polymer materials. According to a first preferred aspect of the invention both end portions of the flexible strap means are releasably attached. According to a second preferred aspect of the invention the flexible means of the invention comprises a neck support. It is preferred for the neck support to be displaceable along the flexible means. Preferably the flexible means passes through a passage in the neck support. It is also preferred for the neck support to become locked in a selected position on the flexible strap means by the load of the patient's head exerted on the neck support due to the neck support being made in a compressible material. Thereby the passage through which the flexible strap means extends will be deformed and the flexible strap means will be squeezed between wall portions thereof. The neck support of the invention is designed for supporting the patient's neck and the occipital bone region. Thereby a proper position for (natural) ventilation is provided and intubation is facilitated. Intubation is often required in a situation where heart massage is given, for instance for adducing a breathing gas to the lungs of the patient which is more rich in oxygen than ambient air. The neck support may additionally be designed to prevent the patient's head from excessive turning to either side. Apparatus for treating sudden cardiac arrest are of a type partially or wholly enclosing the patient at a lower sternal sagittal plane. Apparatus wholly enclosing the patient comprise a frame and a pneumatic compression/decompression unit mounted on the frame. The frame may typically comprise a back plate, left and right legs extending upwardly from the back plate and supporting a bridge element on which the pneumatic compression/decompression unit is mounted. Accordingly, the apparatus when applied to a patient can be considered to comprise two sides, a front side facing the head of the patient and a rear side facing the feet. The apparatus may erroneously be wrongly mounted to the patient, that is, with its mounting means for attachment of the flexible means facing the feet of the patient rather than the head. In a life-threatening condition the time available does not allow to dismount an apparatus once mounted. Therefore, according to a third preferred aspect of the invention, the flexible means is capable of being applied to the rear side as well as the front side and, preferably, to be easily displaceable from the front side to the rear side and vice-versa. Preferably the mounting means comprises a belt that can be disposed around a leg of the apparatus and a displacement member comprising a slot through which the belt passes. The displacement member comprises a means for coupling it with one end portion of the belt, such as a male or female member of a snap connection, the end portion of the belt being provided with the corresponding female or male member, respectively. The invention will now be explained in more detail by reference to preferred embodiments illustrated by a rough drawing. DESCRIPTION OF THE FIGURES In the attached drawing, FIG. 1 is a perspective view of first embodiment of the device of the invention mounted at the legs of an apparatus for treating sudden cardiac arrest fully enclosing a patient to which mechanical heart compression/decompression is being provided, in a perspective view; FIG. 2 is a second embodiment of the invention mounted at left and right legs of an apparatus of the aforementioned kind but with the patient omitted, the flexible means of the device disposed in a horizontal plane being shown in a top view but mounting being shown in a sectional view; FIG. 3 is a third embodiment of the invention, in the same view as in FIG. 2; FIG. 4 is a longitudinal section through the neck support of FIG. 3; FIG. 5 is a sectional view of the mounting of a fourth embodiment of the invention, with releasable connection means and an end portion of the flexible strap also being shown, in the same view as in FIG. 2; FIG. 6 is a sectional view of the mounting of a fifth embodiment of the invention, with releasable connection means and an end portion of the flexible strap also being shown, in the same view as in FIG. 2; FIG. 7 is a sectional view of the mounting of a sixth embodiment of the invention, with releasable connection means and an end portion of the flexible strap also being shown, in the same view as in FIG. 2; FIG. 8 is a sectional view of the mounting of the first embodiment shown in FIG. 1, with releasable connection means, tensioning means and an end portion of the flexible strap also being shown, in the same view as in FIG. 2. DESCRIPTION OF PREFERRED EMBODIMENTS FIG. 1 shows a patient in a supine position receiving heart massage by an apparatus for treating cardiac arrest. The apparatus for treating cardiac arrest is only shown to the extent required for illustrating the principles of the present invention. The apparatus, which shares the general design of the Lucas™ system, encloses the patient in the sternum region. The uppermost portion of the enclosure is positioned at a substantial distance above the patient's chest. “Left” and “right” designate positions from the patient's perspective. Curved left 1 and right 2 legs extend from a bottom plate (not shown) at which their first ends are releasably mounted. At their second ends the legs 1, 2 are swivelingly mounted via joints 7, 8, respectively, at a bridge element 3 that carries a central pneumatic compression/decompression unit 4. A plunger extends downwards from the compression/decompression unit 4 and terminates in a suction cup 6. By a reciprocating movement B of the plunger and the suction cup 6 the patient's breast is compressed and decompressed periodically. In its top or apical position the cup 6 abuts the uncompressed breast at the sternum, from which position the compression/decompression cycle starts. The apparatus for treating cardiac arrest allows the depth and rate of compression to be adjusted to suit the individual patient. Due to the anatomy of the chest the apparatus has a tendency to move in a caudal direction A. This movement is restricted by the positioning device of the invention which comprises a flexible but essentially non-elastic strap 10 having two end portions flanking a central strap portion which passes through a neck support 15. The strap is fixed via snap connections 32, 33 at mountings 30, 31 which, in turn are fixed to the left 1 and right legs 2, respectively. The snap connections 32, 33 comprise tensioning means and are shown in greater detail in FIG. 8. A belt 30 of synthetic textile material encloses tightly the right leg 2. At its short side it is connected by stitched seams 39 to the ends of a short piece 37 of same material so as to form an eye which holds a bar 40 of the male member 38 of a snap connection 32 of ordinary make. Its female member 41 comprises buckle means in form of three bars 42, 43, 44 defining two slots in which the flexible strap 10 is mounted and then is folded back. The strap can be tensioned by pulling the back-folded free end portion 34. The device of the invention thus consists of a flexible strap provided with tensioning and, possibly, other means such as neck support means, two mountings releasably or non-releasably fixed to the legs of an apparatus for treating cardiac arrest, and releasable means for connecting left and right free end portions of the strap with the left and right mountings, respectively. FIGS. 2 to 7 illustrate further preferred embodiments of the invention. The person skilled in the art will realize that the connecting, mounting, and tensioning means of the various embodiments are substantially exchangeable. A second preferred embodiment of the invention is shown in FIG. 2, the strap of which comprises a left section 11, a right section 13, and a central section 12. At its left and right end portions the strap is connected to male 22, 23 members of separable connectors 22, 19; 23, 21, the male members of which are provided with eyes or slots 24 and 26, respectively. After passing through the slit 24 of the male member 23 the end portion of the left strap section 11 is folded back to abut a portion of the strap extending from the slit's 24 opposite side at which it is fixed by a rivet 25, thereby forming a loop. Similarly the right strap section 13 passes though slot 26. Its back-folded end portion, which is substantially longer than the back-folded end portion of the left strap section 11, is adjustably fixed to the portion of the right strap section 13 extending from the slit's 26 opposite side by a friction buckle 27 of ordinary make fastened at the strap section 13. A rectangular sleeve 28 holds the free end tongue 29 of the right strap section 13 in place. In FIG. 2 the male members 22, 23 of the left and right separable connectors are shown caught in corresponding female members 19, 21 by a snap mechanism. From the face of the female members 19, 21 facing away from the snap connection extend short flexible sheets 17, 18, the other ends of which are fixed at robust rings 14 and 16, respectively. The flexible sheets 17, 18 are rectangular sheets of a woven material which is embedded in the plastic material (polypropylene, polycarbonate or similar) of the male members 19, 21 and the rings 14, 16. The rings 14 and 16 are mounted at the left 1 and right 2 legs, respectively, of the apparatus by means of circular belts 6 and 9 which enclose the legs 1, 2 and pass through the openings of the rings 14 and 16, respectively. The size of the loop formed by a portion of the right strap section 13 can be adjusted (tensioned) by pulling the strap tongue 29. Thereby the total length of the strap 11, 12, 13 can be adjusted to fit a particular patient. A corresponding tensioning means can be arranged at the left strap portion 11 which then has to be given a length about corresponding to that of the right strap portion 13. In a third embodiment of the invention shown in FIG. 3 a section intermediate between the left 111 and right 113 sections of the strap passes trough a passage 142 in a neck support 115. The neck support 115 has the form of two truncated cones joined at their smaller bases. The neck support 115 is of a compressible polyurethane foam material 140 surrounded by a textile non-woven cover 141 (FIG. 4). When the neck and a portion of the patient's occipital bone region rest on the neck support 115 the polyurethane foam 140 and thus the passage 142 become compressed and squeeze the central portion of the strap, thereby hindering the support 115 from moving sideways. The second embodiment has only one releasable connector 121, 123. As in the first embodiment the male member 123 comprises a slot 126 through which part of the right strap portion 113 extends, as well as a friction buckle 127 and a rectangular sleeve 128 for holding the tongue 129 of the right strap section 113. The free end of the left strap portion 111 is embedded in a sturdy ring 114 fixed at the left leg 101 by means of a circular belt 106. The female member 121 of the separable connector 121, 123 is partially merged with a ring 116 (thus omitting the flexible sheet 18 of the first embodiment) for corresponding fixation at the right leg 102 by means of a circular belt 109. It is also possible to provide the left strap portion 111 with a tensioning means similar to the tensioning means 127 of the right strap portion 113, and to make the left strap section 111 correspondingly longer. Fourth, fifth and sixth preferred embodiments of the invention described below differ from the aforementioned ones in regard of their mountings. The mounting of the fourth preferred embodiment shown in FIG. 5 comprises a ribbon 209 of flexible material partly enclosing an about rectangular leg 202 to which it is fastened by screws 230 and 231 in bores arranged in one long side thereof. The length of the portion of the ribbon 209 extending between screws 230 and 231 is sufficient to allow the female snap member 221 to be moved from one short side of the leg 202 to its other short side. The mounting of the fifth preferred embodiment shown in FIG. 6 comprises a ribbon 309 of flexible material fastened at opposing long sides of a leg 302 close to one of its short sides by means of a twin-head stud 330 arranged in a through bore of leg 302 extending from one of its long sides to the other long side. The length of the ribbon 309 is just sufficient to let it pass through a hemi-circular eye 316 of the female member 321 of a snap connection 321, 323 of which are also shown the male member 323 carrying a slot 326 through which a right strap portion 313 according to the invention extends. This embodiment provides only for connection of the strap at one short side of the leg 302. The mounting of the sixth preferred embodiment shown in FIG. 7 comprises a belt 409, 409′ of a flexible material in a folded state to make its inner faces abut each other. The folded belt 409, 409′ is mounted around a leg 402 so that its two loops nearly fully enclose the leg. The outer loop of the belt is designated 409 and the inner loop 409′. One fold of the belt 409, 409′ encircle a pin 437 of a male member 436 of a snap connection 435, 436. Where the outer and inner loops 409, 409′ meet after encircling the pint 437 they have fixed to each other by sewing 438. The other fold of the belt 109, 109′ encircles the most distant (in relation to the belt 109, 109′) pin 434 of a friction bucket 432, 433, 434 through which the inner loop 109′ passes. The friction bucket 432, 433, 434 pertains to the female member 435 of said snap connection 435, 436. This arrangement allows the mounting to be mounted at a leg 402 with the inner loop 109′ in a tensioned state and the outer loop 109 in a slackened state such that the bar 416 delimiting a slot of a female member 421 of a snap connection 421, 423 can be displaced along the outer loop 109 from one short side of the leg 402 to its other short side. The male member of snap connection 421, 423 is provided with a slot 426 through which a right strap portion 413 passes. The device of the invention is preferably made from suitable polymer materials but also textile materials of natural origin and metal elements may be used for certain parts thereof. For instance, the bar 416 and the friction buckles 27; 127; 433, 434, 435 may, independent of each other, be made from a metal, in particular steel. Similarly, woven flexible straps, belts, and the like, such as strap 11, 12, 13, may be made of natural fibers, such as cotton, or of a blend of natural and synthetic fibers. In rare circumstances a patient under treatment with an apparatus for treating sudden cardiac arrest of the aforementioned kind would also benefit from the apparatus being prevented from moving in an occipital direction. Such circumstances prevail during ambulance or similar transport of the patient with the apparatus. Normally patients are put in an ambulance on a stretcher head-on. The stretcher with the patient is fixed in position by a safety belt. In case of a collision or a rapid application of the brakes the apparatus seeks to move in an occipital direction. Thereby the centre of compression would be displaced in the same direction. The compressions then would be applied incorrectly and the patient risk to be injured as well as not properly treated. Such movement can be prevented by arranging one or several flexible straps fixed at the legs or other suitable part of the apparatus and extending from its rear side to the pubic arch, from there to the gluteal fascia and back to the legs of the apparatus. The flexible strap(s) for securing the apparatus in respect of the patient can be mounted to the leg(s) by means corresponding to those used in the device if the invention for preventing a movement in a caudal direction.

<SOH> BACKGROUND OF THE INVENTION <EOH>Sudden cardiac arrest is commonly treated mechanically and/or by electrical defibrillation. Mechanical treatment may be given manually or by a chest compression apparatus. The length of a compression/decompression cycle is typically from half a second to one second. A number of chest compression apparatus are known in the art, such as the pneumatically driven LUCAS™ mechanical chest compression/decompression system (“Lucas™ system”; an apparatus for compression and physiological decompression in Cardio-Pulmonary Resuscitation, CPR, manufactured by Jolife AB, Lund, Sweden). Specifically the Lucas™ system comprises a support structure and a compression/decompression unit. The support structure includes a back plate for positioning the patient's back posterior to the patient's heart and a front part for positioning around the patient's chest anterior to the heart. The front part has two legs, each having a first end pivotally connected to at least one hinge of the front part and a second end removably attachable to the back plate. The front part is devised to centrally receive the compression/decompression unit which is arranged to repeatedly compress/decompress the patient's chest when the front part is attached to the back plate. The compression/decompression unit comprises a pneumatic unit arranged to drive and control compression and decompression, an adjustable suspension unit to which a compression/decompression pad is attached, and a means for controlling the position of the pad in respect of the patient's chest. Defibrillation may be provided independently of and concomitantly with mechanical stimulation. In cardiac arrest it is of utmost importance that adequate circulation be re-established as soon as possible, that is within a few minutes from the onset of arrest. Any delay might lead to irreversible tissue damage. By “adequate circulation” is understood a circulation which is sufficient to protect vital organs and tissues from (further) damage, in particular by damage caused by insufficient oxygen supply. Due to this requirement mechanical compression/decompression has to be started on the spot and most often continued during the transport of the patient to the hospital. It is thus important that the apparatus for mechanical compression/decompression can be moved with the patient while continuing with providing mechanical stimulation. A problem with apparatus for treating cardiac arrest known in the art is that due to the vigorous pneumatic or other compression action and the anatomy of the human body, the apparatus has a tendency to move in respect to the patient in a caudal direction. This necessitates monitoring of the apparatus' position by the attending personnel in respect of the patient and to correct it, if needed. In a stressful situation like the one in which the apparatus for treating cardiac arrest is applied, this sort of monitoring may detract the attending personnel from other important duties. The present invention seeks to remedy this problem. Another problem with apparatus for treating cardiac arrest known in the art is that moving them with a patient necessitates the assistance of three persons: Two to lift and carry the patient's body with the apparatus, one to the left and one to the right of the patient holding the apparatus with one hand and supporting the patient's seat with the other, and a third for holding the head to prevent it from falling back.

<SOH> SUMMARY OF THE INVENTION <EOH>According to the present invention is disclosed a positioning device for use in an apparatus for treating sudden cardiac arrest in a patient in supine position by providing chest compressions at the lower end of the sternum, which prevents the apparatus from moving in a caudal direction, the apparatus comprising a frame enclosing the patient at a sternal transversal plane and a pneumatic compression/decompression means mounted on the frame, the device comprising a flexible strap means having a first end, a second end and a tensioning means disposed between the first and second ends, first and second end portions extending from the first and second ends, respectively, comprising means for attachment to the apparatus at first and second positions thereof, respectively, the flexible strap means having a mounted tensioned length sufficient to extend around the patient's neck, with the proviso that at least one of the end portions is releasably attached. It is preferred for the tensioning means to be integrated with the means for attaching the flexible strap means to the apparatus. It is also preferred for the positions of attachment to be arranged in an anterior frontal plane. The positions of attachment may coincide; in such case, they are preferably arranged in a sagittal plane. The flexible strap means of the invention may be any of strap, belt, ribbon, band, wire and the like, here referred to as a strap, preferably of a woven material, in particular of a polymer material such as polypropylene, polyester or polyamide or a mixture of polymer materials. According to a first preferred aspect of the invention both end portions of the flexible strap means are releasably attached. According to a second preferred aspect of the invention the flexible means of the invention comprises a neck support. It is preferred for the neck support to be displaceable along the flexible means. Preferably the flexible means passes through a passage in the neck support. It is also preferred for the neck support to become locked in a selected position on the flexible strap means by the load of the patient's head exerted on the neck support due to the neck support being made in a compressible material. Thereby the passage through which the flexible strap means extends will be deformed and the flexible strap means will be squeezed between wall portions thereof. The neck support of the invention is designed for supporting the patient's neck and the occipital bone region. Thereby a proper position for (natural) ventilation is provided and intubation is facilitated. Intubation is often required in a situation where heart massage is given, for instance for adducing a breathing gas to the lungs of the patient which is more rich in oxygen than ambient air. The neck support may additionally be designed to prevent the patient's head from excessive turning to either side. Apparatus for treating sudden cardiac arrest are of a type partially or wholly enclosing the patient at a lower sternal sagittal plane. Apparatus wholly enclosing the patient comprise a frame and a pneumatic compression/decompression unit mounted on the frame. The frame may typically comprise a back plate, left and right legs extending upwardly from the back plate and supporting a bridge element on which the pneumatic compression/decompression unit is mounted. Accordingly, the apparatus when applied to a patient can be considered to comprise two sides, a front side facing the head of the patient and a rear side facing the feet. The apparatus may erroneously be wrongly mounted to the patient, that is, with its mounting means for attachment of the flexible means facing the feet of the patient rather than the head. In a life-threatening condition the time available does not allow to dismount an apparatus once mounted. Therefore, according to a third preferred aspect of the invention, the flexible means is capable of being applied to the rear side as well as the front side and, preferably, to be easily displaceable from the front side to the rear side and vice-versa. Preferably the mounting means comprises a belt that can be disposed around a leg of the apparatus and a displacement member comprising a slot through which the belt passes. The displacement member comprises a means for coupling it with one end portion of the belt, such as a male or female member of a snap connection, the end portion of the belt being provided with the corresponding female or male member, respectively. The invention will now be explained in more detail by reference to preferred embodiments illustrated by a rough drawing.

20070207

20101130

20071129

67041.0

A61H3100

THANH, QUANG D

POSITIONING DEVICE FOR USE IN APPARATUS FOR TREATING SUDDEN CARDIAC ARREST

UNDISCOUNTED

ACCEPTED

A61H

ACCEPTED

Hydraulic control system for mobile equipment

What is disclosed is a hydraulic control system for a mobile equipment, in particular for a wheel or backhoe loader, wherein a shovel is linked to a boom. The angular position of the shovel may be kept constant through the intermediary of an orientation control device during a pivoting movement of the boom relative to the axles of the equipment. In accordance with the invention, the orientation control device is realized such that in the event of a change of a pre-set angular position, a control signal is generated through a pilot control device, whereby a shovel control unit may be controlled in such a manner that the shovel is again returned into its predetermined angular position.

1. Hydraulic control system for a mobile equipment, comprising a shovel retained on a boom which is adapted to be pivoted by means of a boom cylinder, which may be pivoted by means of a shovel cylinder adapted to be controlled by means of a shovel control unit, wherein the shovel position may be fed back via a transmitting member to an orientation control device whereby the shovel cylinder may be controlled, and wherein the orientation control device comprises an actuation head in operative connection with the transmitting member, the position change of said actuation head during a pivoting movement of the shovel being convertable via a control device into a control signal for keeping the shovel in a target angular position, characterized in that a basic position of the actuation head is variable, and in that the transmitting member is connected with the actuation head such that both downward pivoting of the shovel and upward pivoting of the shovel from its target angular position results in a positional change of the actuation head, so that depending on this positional change a control signal for returning the shovel into its target angular position at the shovel cylinder may be emitted, and also the actuation head may be reset in the direction of its pre-set basic position. 2. The control system in accordance with claim 1, wherein the actuation head is a control lever of a pilot control device, the electric or hydraulic control signals of which are supplied to the shovel control unit. 3. The control system in accordance with claim 2, wherein the pilot control device comprises two hydraulic pilot control elements whose control ports are connected via signal lines to control ports of the shovel control unit. 4. The control system in accordance with claim 3, wherein the shovel control unit comprises a shovel pilot control device, the control ports of which are connected via control lines to control chambers of a shovel proportional valve, the signal lines being connected via shuttle valves with the control lines, so that the higher one of the control pressures in the control chambers prevails. 5. The control system in accordance with claim 2, wherein the control lever is connected via a spring assembly with the transmitting member and via another, oppositely acting tensile spring assembly with an actuation lever whereby the target position of the control lever may be adjusted. 6. The control system in accordance with claim 2, wherein the control lever is connected via a lever mechanism with the transmitting member and an actuation lever for adjusting the target position, the lever mechanism being realized such that a target pivotal position of the control lever may be adjusted through the intermediary of the actuation lever, and the control lever may be adjusted when the shovel has been moved from its target angular position. 7. The control system in accordance with claim 5, wherein the end portion of the transmitting member linked to the spring assembly or to the lever mechanism, respectively, is mounted on a frame of the equipment by means of a movable bearing. 8. The control system in accordance with claim 3, wherein a pressure port of the pilot control device is adapted to be connected with a control oil pump or a tank via a switching valve.

The invention concerns a hydraulic control system for a mobile equipment, such as a wheel loader or a backhoe loader, in accordance with the preamble of claim 1. In backhoe loaders or wheel loaders a boom is pivotally linked to a frame. At the end portion of the boom opposite the frame of the wheel/backhoe loader a shovel is mounted which is pivotable relative to the boom through the intermediary of a shovel cylinder. The boom is pivoted by means of a boom cylinder that is linked to the frame of the wheel/backhoe loader. The two afore-mentioned cylinders each have the form of a differential cylinder, the pressure chambers of which are connected via a pilot control device having an associated proportional valve with a variable displacement pump or a tank for extending or retracting the respective differential cylinder. One demand to such constructions is that the relative position of the shovel should be maintained constant relative to the wheel/backhoe loader during raising or lowering of the boom, in order to avoid inadvertent dumping of the material received in the shovel. In the solution known from WO 02/081828 A1, maintaining this relative position (“self-levelling”) is realized through an orientation control device wherein the pivoting movement of the shovel relative to the boom is transmitted via a thrust rod to a rotatably mounted guide member, against the control cam of which a tappet of a control valve is biased. By means of this control valve it is possible to generate a control pressure which is present in a control chamber of the proportional valve associated with the shovel cylinder. The path of the control cam is selected such that the shovel cylinder is controlled during the pivoting movement of the boom in such a way that the shovel maintains the desired position relative to the ground or to the wheel/backhoe loader. The orientation control device of the known solution is, however, realized such that only one desired relative position may be adjusted. Moreover the “self-levelling” in this known solution is possible only in one direction, i.e., in the direction of “upward pivoting” of the shovel. “Self-levelling” may also be achieved by a particular configuration of the loading geometry of the boom and of the shovel. Thus, e.g., the shovel may be linked to the boom by means of parallel links. Such a parallel kinematic is, however, very complex and correspondingly costly. In contrast, the invention is based on the object of furnishing a hydraulic control system for a mobile equipment, in particular a wheel loader or a backhoe loader, wherein such “self-levelling” is achieved at minimum complexity in terms of apparatus. This object is achieved through a hydraulic control system for a mobile equipment, in particular for a backhoe loader or a wheel loader, having the features of claim 1. In accordance with the invention, the shovel linked to a boom is maintained in a predetermined position relative to the ground or to the axles of the backhoe/wheel loader by means of an orientation control device. The orientation control device comprises a transmitting member which transmits the pivoting movement of the shovel to an actuation head, the basic position of which is adjustable. This basic position of the actuation head of the orientation control device corresponds to a position of the shovel relative to the equipment which is to be kept constant. As long as the shovel maintains its pre-adjusted angular position during the pivoting movement of the boom, the actuation head remains in its adjusted basic position. In the event of a change of the angular position, the actuation head is shifted, and in dependence on this shift a control signal is generated which is conducted to a shovel control for adjusting a shovel cylinder in such a way that the shovel resumes its pre-adjusted angular position, and the actuation head is returned correspondingly. In other words, in accordance with the invention a target angular position of the shovel is adjusted with the aid of the adjustable actuation head, and an intervention in the control of the shovel is carried out if the latter moves out of the pre-set angular position. Such a control system allows to set practically any desired angular position as a target value and keep it constant during the pivoting movement of the boom, wherein the complexity in technological terms is extremely low. In the subject matter of WO 02/081828 A1 discussed at the outset, neither the target angular position of the shovel may be adjusted nor could the shovel be adjusted downwardly (tilted) during the pivoting movement of the boom, so that a target position relying on this movement can not be reached by the known solution. In a particularly preferred embodiment, the actuation head of the orientation control device has the form of an actuation lever of a pilot control device, the electric or hydraulic control signals of which are supplied to the shovel control unit. This pilot control device is preferably executed with two hydraulic pilot control elements, the control ports of which are connected with the control ports of the shovel control unit via signal lines. This shovel control unit may in turn be executed with a hydraulic shovel pilot control device, the control ports of which are connected via control lines with control chambers of a proportional valve for controlling the shovel cylinder. The control line of the shovel pilot control device and the signal lines leading to the pilot control device of the orientation control device are interconnected via shuttle valves, so that in the control chambers of the proportional valves the respective higher control pressure is present which is either predetermined by the pilot control device or by the shovel pilot control device in order to adjust an angular position of the shovel. In a variant of the invention, feeding back of the movement of the transmitting member to the control lever takes place through the intermediary of a spring assembly which is acted upon in a direction opposite to the spring assembly by a tensile spring assembly, with the latter in turn acting on an actuation lever, so that it is possible to adjust a target position of the control lever by adjusting this actuation levers. In an alternative variant it is possible to use, instead of the springs attacking on either side of the control lever, a suitable lever mechanism which on the one hand enables the adjustment of a target value and on the other hand transforms a relative movement of the transmitting member into a pivoting movement of the actuation lever. Manufacture of the orientation control device is particularly simple if the transmitting member has the form of a thrust rod which attacks in parallel with the boom at the shovel, wherein the end portion of the thrust rod removed from the shovel is mounted on a frame of the equipment through the intermediary of a movable bearing and is connected with the actuation lever via the afore-mentioned springs or the lever mechanism or means having a similar action. The orientation control device may very easily be deactivated if a pressure port of the control device is adapted to be connected to a control oil pump or a tank via a switching valve. Upon switching to tank pressure it is not possible to output a signal via the pilot control device to supersede the control pressure output by the shovel pilot control device—self-levelling does not take place. Further advantageous developments of the invention are subject matter of further subclaims. In the following, preferred embodiments of the invention are explained by referring to schematic drawings, wherein: FIG. 1 is a diagrammatic view of a control system in accordance with the invention for maintaining a pre-set angular position of a shovel constant; FIG. 2 shows a variant of an orientation control device of the control system of FIG. 2, and FIG. 3 is another embodiment of an orientation control device. FIG. 1 shows a diagrammatic view of a control system of a mobile equipment, e.g., of a wheel loader or of a backhoe loader. The latter comprises a boom 2, to the free end portion of which a shovel 4 is linked by means of a pivoted articulation 6. The other end portion of the boom 2 is linked to a frame 10 of the backhoe loader through the intermediary of a linking mechanism 8. The pivoting movement of the boom 2 is executed by means of a double-acting boom cylinder 12 which may be supplied with pressure medium via a cylinder control unit 14. The boom cylinder 12 is articulatedly supported at the frame 10 and attacks with its piston rod at the boom 2. The pivoting movement of the shovel 4 relative to the boom 2 is executed with the aid of a shovel cylinder 14, the housing of which is linked to the boom 2, and the piston rod of which attacks at the shovel 4. This shovel cylinder 14, too, is realized as a double-action cylinder and is supplied with pressure medium via a shovel control unit 18. In accordance with FIG. 1, a thrust rod 20 is moreover mounted at the shovel 16 by means of a thrust rod articulation 22, said thrust rod extending in the represented angular position in parallel with the boom 2. The end portion of the thrust rod 20 which is removed from the shovel 4 is supported on a frame-side movable bearing 24 adapted to move relative to the boom 2 in the event of a change of the angular position of the shovel 4. At a constant angular position of the shovel 4 relative to the equipment, the boom and the thrust rod 20 as well as the pivoted articulation 6 and the thrust rod bearing 22 on the one hand and the linking mechanism 8 and the movable bearing 24 on the other hand form a parallelogram that changes its geometry during the pivoting movement of the boom 2, however essentially remains a parallelogram (as long as the angular position of the shovel 4 relative to the axles of the backhoe loader remains unchanged). In the embodiment represented in FIG. 1, the thrust rod 20 which is supported at the movable bearing 24 is connected via a spring or spring assembly 26 with an actuation lever 28 of a hydraulic pilot control device 30. The control lever 28 is acted upon in a direction opposite to the spring assembly 26 by a tensile spring assembly 32 having its one end portion removed from the control lever 28 attached to an actuation means 34 which, in the represented embodiment, consists of an actuation lever 36 and a sliding joint 38 connected with the latter either directly or via signal lines, the position of which is variable, and which attacks at the tensile spring assembly 32. By pivoting the actuation levers 36, the sliding joint 38 may be moved indirectly or directly to thus adjust the bias of the tensile spring assembly 32, so that the spring assembly 26 is adjusted, and the control lever 28 may be returned into a desired basic position in accordance with the bias. The hydraulic pilot control device 30 is in a known manner executed with pressure reducing valves which are adapted to be shifted into a regulating position in dependence on the pivoting movement of the actuation lever 28. By means of these pressure reducing valves the pressure at a control oil port P of the pilot control device 30 may be reduced to a desired control pressure which is then present at control ports X, Y of the pilot control device 30. Inside a control oil line 40 connected to the control oil port P an electrically actuated switching valve 42 is arranged which in its spring-biased basic position connects the control oil line 40 with a tank T, and upon energization of a switching solenoid connects the control oil line 40 with a pump line that is connected to a control oil pump. In other words, in the spring-biased basic position the pilot control device 30 does not have an effect as tank pressure prevails at its control oil port P. In the switching position, the control oil port P is connected with the control oil pump, so that control signals may be generated via the pilot control device 30. The two control ports X, Y are connected via signal lines 44, 46 with the shovel control unit 18. The latter comprises a shovel pilot control device 48, and by means of the actuation lever 50 of the latter the control oil pressure furnished by the mentioned control oil pump may be reduced to a desired control pressure. This shovel pilot control device 48 is provided, for example, with four pressure reducing valves, whereby, e.g., the angular position of the shovel relative to the boom 2 and the angular velocity of the pivoting movement may be adjusted. The two control ports X, Y of the shovel pilot control device 48 are each connected via control lines 52, 54 with the inlet of a shuttle valve 56 or 58, respectively, to the other inlet of which the signal line 46 or 44, respectively, is connected. The outlets of the shuttle valves 56, 58 are each connected with control chambers 60, 62 of a shovel proportional valve 64. By means of the latter, the pressure medium flow velocity and pressure medium direction of flow between the pressure chambers of the shovel cylinder 16 and a variable displacement pump or a tank T of the central unit are controlled in a known manner. In its center position, a pressure port P connected with the variable displacement pump and a tank port T connected with the tank are blocked relative to two work ports A, B leading to the pressure chambers of the shovel cylinder 16. In the right-hand (FIG. 1) positions (valve spool to the left, “DUMP”) of the shovel proportional valve 64, the shovel 4 is pivoted downwards from the represented angular position in order to dump material; in the left-hand positions (CROWD), the shovel 4 is pivoted upwards from the represented angular position, e.g., in order to pick up material and hold it in the shovel. The boom control unit 14 has a similar construction as the shovel control unit 18. Pressure medium supply of the boom cylinder 12 takes place via a cylinder proportional valve 66, the control chambers 68, 70 of which may be subjected to a control pressure through the intermediary of a cylinder pilot control device 72 in order to retract the cylinder in the right-hand (view of FIG. 1) positions (LOW), so that the boom 2 is lowered, and to extend the cylinder in the left-hand positions (LIFT) for raising the boom. It shall now be assumed that the boom 2 was pivoted downwards from the represented raised position, and the shovel 4 rests on the ground in the represented angular position. The shovel 4 is filled with material which should not fall out from it when the boom 2 is raised subsequently. It is therefore desired to keep the shovel 4 in the represented angular position or even pivoted upwards more strongly, relative to the ground or to the axles of the vehicle. The control lever 28 is in its represented basic position that corresponds to the mentioned angular position of the shovel 4. In this basic position the control lever 28 is clamped between the tensile spring assembly 32 and the spring assembly 26, with the actuation lever 36 also in its basic position. In order to raise the boom 2, the boom proportional valve 66 is shifted through the intermediary of the boom pilot control device 72 into one of its left-hand positions (LIFT), so that the boom cylinder 12 extends with a corresponding velocity and pivots the boom 2 upwardly about the linking mechanism 8 that is fixed to the frame. If the angular position of the shovel 4 remains constant relative to the ground during this pivoting movement, the position of the control lever 28 also remains unchanged, and no control signal is output by the pilot control device 30. In a change of the angular position of the shovel 4, e.g., pivoting about the pivoted articulation 6 to the left (in a counter-clockwise direction), the thrust rod 20 is moved correspondingly and the movable bearing 24 is shifted to the left, so that the tension of the spring assembly 26 is reduced correspondingly. The position of the sliding joint 38 remains unchanged, and the actuation lever 28 is moved to the left until an equilibrium between the tensile spring assembly 32 and the spring assembly 26 is established. In accordance with this pivoting movement of the control lever 28 a hydraulic control signal is generated by the pilot control device 30, so that the control chambers 60, 62 of the shovel proportional valve 64 are subjected to a corresponding control pressure difference. Owing to this control pressure difference, the shovel proportional valve 64 is taken into one of its right-hand positions (DUMP), so that the shovel 4 is pivoted in a clockwise direction until the basic position pre-selected at the actuation lever 28 is again established. The control pressure in the signal lines 44, 46 is selected such as to be higher than a control pressure in control lines 52, 54, so that this self-levelling is performed even if a control pressure which prevails at the associated inlets of the shuttle valves 56 and 58, respectively, is created through the shovel pilot control device 48 in the control lines 52, 54. The afore-described self-levelling is, however, only possible when the switching valve 42 is taken by means of the switching solenoid into its switching position in which a control oil pressure is present at pressure port P of the pilot control device 30. If the switching valve 42 is de-energized, the shovel position 4 may be adjusted manually through the intermediary of the pilot control device 48. By operating the actuation lever 36 it is possible to pivot the control lever 28 from the represented basic position in order to alter the pre-adjusted angular position of the shovel 4 while self-levelling is activated. This new angular position may be adjusted independently of the adjustment of the shovel pilot control device 48, for its control pressures are overridden. During raising or lowering of the boom 2 this altered angular position of the shovel 4 is then maintained constant through feeding back a movement of the thrust rod 20 to the pilot control device 30 and the resulting application of a control pressure difference on the shovel proportional valve 64. The afore-described regulation of the angular position may be realized at minimum complexity, wherein it is practically possible to adjust any angular position of the shovel 4 that is permitted by the loading geometry. Instead of the hydraulic pilot control devices 30 it is in principle also possible to use an electric pilot control, wherein the electric signals for controlling the correspondingly executed shovel proportional valve 64. Instead of the spring assembly for feeding back a change of the angular position of the shovel 4 to the pilot control device 30 it is, of course, also possible to use other constructions. FIG. 2 shows an embodiment wherein the movable bearing 24 (sliding joint) of the thrust rod 20 is connected via a lever arrangement 74 with the control lever 28 in order to feed back a change of the angular position of the shovel 4 to the pilot control device 30. The lever arrangement represented in FIG. 2 has two slide levers 76, 78 coupled by an end portion at the movable bearing 24 and at the actuation lever 36, respectively, while the two other end portions are articulatedly connected to each other by means of a transverse lever 80. Approximately in the center range of the transverse lever 80, a connecting arm 82 is coupled which is articulatedly connected with the control lever 28. In the case of a constant adjustment of the actuation lever 36 and a movement of the thrust rod 20 along the trajectory of the movable bearing 24, the slide lever 76 is moved accordingly, so that the transverse lever 80 is tilted from its represented vertical position, and the actuation lever 28 is moved accordingly. The actual position must be adjusted by pivoting the actuation lever 36 and correspondingly moving the lower slide lever 78, which in turn results in a pivoting movement of the transverse lever 80 and in an actuation of the control lever 28 into its new basic position. In the embodiment represented in FIG. 3, instead of the U-shaped lever arrangement 74 an approximately z-shaped lever arrangement 84 is used where the slide levers 76, 78 attack in opposite directions at the transverse lever 80. The control lever 28 is linked to the transverse lever 80. During a displacement of the thrust rod 20, the slide lever 76 is driven accordingly, and the transverse lever 80 is pivoted, and the control lever 28 is actuated accordingly. The adjustment of the target pivotal position is effected by means of the actuation lever 36 whereby the slide lever 78 may be displaced, and accordingly the transverse lever 80 may be pivoted. It is essential in the kinematic of these means that a change of the pivotal position of the shovel position 4 may be transposed into an adjustment of the pilot control device 30 wherein the latter outputs a control signal for controlling the shovel proportional valve 64 so as to move the latter into a regulating position in which the shovel 4 may again be returned into the pre-adjusted angular position. What is disclosed is a hydraulic control system for a mobile equipment, in particular for a wheel or backhoe loader, wherein a shovel is linked to a boom. The angular position of the shovel may be kept constant through the intermediary of an orientation control device during a pivoting movement of the boom relative to the axles of the equipment. In accordance with the invention, the orientation control device is realized such that in the event of a change of a pre-set angular position, a control signal is generated through a pilot control device, whereby a shovel control unit may be controlled in such a manner that the shovel is again returned into its predetermined angular position. LIST OF REFERENCE SYMBOLS 2 boom 4 shovel articulation 6 pivoted articulation 8 linking mechanism 10 frame 12 boom cylinder 14 boom control unit 16 shovel cylinder 18 shovel control unit 20 thrust rod 22 thrust rod bearing 24 movable bearing 26 spring assembly 28 control lever 30 pilot control device 32 tensile spring assembly 34 actuation means 36 actuation lever 38 sliding joint 40 control oil line 42 switching valve 44 signal line 46 signal line 48 shovel pilot control device 50 control lever 52 control line 54 control line 56 shuttle valve 58 shuttle valve 60 control chamber 62 control chamber 64 shovel proportional valve 66 boom proportional valve 68 control chamber 70 control chamber 72 boom pilot control device 74 lever arrangement 76 slide lever 78 slide lever 80 transverse lever 82 connecting arm

20060712

20091124

20070517

63074.0

B66C2300

UNDERWOOD, DONALD W

HYDRAULIC CONTROL SYSTEM FOR MOBILE EQUIPMENT

UNDISCOUNTED

ACCEPTED

B66C

ACCEPTED

Vibration suppressing cutting tool

An object is to provide a vibration suppressing cutting tool which is inexpensive and can damp chattering extremely effectively, and which is simple in structure and is applicable to a wide variety of machining diameters and cutting conditions. The shank 2 of the holder 1 is formed with a pocket 4. In the pocket 4, a vibration suppressing piece 5 is received so as to be movable relative to the holder 1 and not protrudable from the pocket 4. Under kinetic energy from the holder during cutting, the vibration suppressing piece 5 alternately knocks against a pair of opposed inner wall surfaces 4a and 4b of the pocket along its surface, along a plurality of lines or on a plurality of points when the holder vibrates during cutting, thereby damping vibrations of the holder.

1-12. (canceled) 13. A vibration suppressing cutting tool comprising a holder having a shank formed with a pocket in which a vibration suppressing piece which is not coupled to said holder is received so as not to be able to come of said pocket, wherein at least portions of the inner wall of said pocket that knock against said vibration suppressing piece or portions of the surface of said vibration suppressing piece that knock against said inner wall of said pocket are flat surfaces, whereby said vibration suppressing piece knock against the inner wall of said pocket along surfaces or at a plurality of portions when the holder vibrates during cutting. 14. The vibration suppressing cutting tool of claim 13 wherein said portions of the inner wall of said pocket that knock against said vibration suppressing piece and said portions of the surface of said vibration suppressing piece that knock against said inner wall of said pocket are both flat surfaces. 15. The vibration suppressing cutting tool of claim 13 wherein said pocket has first and second flat inner wall surfaces opposed to each other, and wherein said vibration suppressing piece has third and fourth flat surfaces and is received in said pocket such that said third and fourth surfaces face said first and second surfaces, respectively, with a clearance defined between said first and second surfaces and said vibration suppressing piece, said first, second, third and fourth surfaces being oriented so as to cross the direction in which said holder vibrates during cutting. 16. The vibration suppressing cutting tool of any of claims 13 to 15 wherein said pocket and said vibration suppressing piece have rectangular sections that are perpendicular to a central axis of said shank, said vibration suppressing piece having surfaces configured to abut said pair of opposed inner wall surfaces of said pocket and each having a greater area than other surfaces of said vibration suppressing piece. 17. The vibration suppressing cutting tool of any of claims 13 to 16 wherein between said vibration suppressing piece and said pair of opposed inner wall surfaces of said pocket, a clearance in the range of 0.01 to 0.5 mm is defined. 18. The vibration suppressing cutting tool of any of claims 13 to 17 wherein said pocket has a section perpendicular to a central axis of said shank and having a width w that is 20 to 100% of the diameter D or width W of said shank, and a height h, which is a distance between said pair of inner wall surfaces, said height h being 5 to 70% of the height H of said shank. 19. The vibration suppressing cutting tool of any of claims 13 to 18 wherein said pocket has an axial length c that is 50 to 250% of the diameter D or height H of said shank, and is displaced toward the front end of said tool. 20. The vibration suppressing cutting tool of any of claims 13 to 19 wherein said vibration suppressing piece is made of a material having a specific gravity that is equal to or greater than the specific gravity of the material forming said shank. 21. The vibration suppressing cutting tool of any of claims 13 to 20 wherein said pair of opposed inner wall surfaces of said pocket extend substantially perpendicular to the direction in which said holder vibrates during cutting. 22. The vibration suppressing cutting tool of any of claims 13 to 21 wherein said vibration suppressing piece comprises a plurality of separate subpieces received in a single pocket or each received in one of a plurality of independent pockets. 23. The vibration suppressing cutting tool of any of claims 13 to 22 wherein said pocket is formed from one side of said holder, said vibration suppressing cutting tool further comprising a piece holding means or sealing means for holding said vibration suppressing piece in said pocket. 24. The vibration suppressing cutting tool of claim 23 wherein said pocket is formed from one side of said holder opposite to the other side of the holder where a cutting edge is located, said pocket being a blind hole that does not reach said other side of said holder. 25. The vibration suppressing cutting tool of any of claims 13 to 24 wherein said holder comprises a shank and a head that is a separate member from said shank, wherein said pocket is open to the front end of said shank, and wherein with said vibration suppressing piece received in said pocket, the opening of said pocket is closed with said head by joining said head to the front end of said shank.

TECHNICAL FIELD This invention relates generally to a cutting tool which has to be kept free of mainly chattering, and particularly a vibration suppressing cutting tool which is simple in structure and inexpensive, and which includes means for effectively suppressing chattering. BACKGROUND ART It is well-known to mount a damper in the holder to suppress chattering utilizing inertia. Particularly in the case of inner diameter machining boring tools, because the size of the holder is restricted by the bore diameter of the workpiece, its protrusion has to be increased while reducing the diameter of the shank. This increases the possibility of chattering. Thus, many of the conventional vibration suppressing tools are boring tools. The following description is therefore mainly made with reference to boring tools. For example, in Patent document 1, a method shown in FIG. 5 is disclosed. In this method, a hole 21 is formed in the holder 1 from its rear end, a damper 22 is received in the hole 21 at its front end near the cutting edge, and a core rod 23 is inserted in the hollow portion of the hole. In Patent document 2, a turning tool is disclosed of which the holder is formed with a deep hole in its central portion into which a viscous fluid and a weight are received. In Patent document 3, a cutting tool is disclosed in which a rod spring is inserted in a hole formed in the tool body, a visco-elastic body is disposed between the rod spring and the hole, a cutting head is provided at the front end of the rod spring, and a frictional vibration suppressing material is provided between the cutting head and the tool body. The cutting tools shown in Patent documents 1 and 2 cancel chattering using the inertia of the damper. The cutting tool disclosed in Patent document 3 reduces vibrations transmitted to the tool body by converting vibration energy to frictional heat. There are also known a boring bar in which a damper made of a different material from the shank is fitted in a hole formed in the shank using tapered surface to damp vibration utilizing the contact friction between the shank and the damper (see Patent document 4), and tools in which a vibration suppressing member for absorbing vibration energy is mounted in the tool body to damp vibration (Patent publications 5 and 6). In the vibration suppressing cutting tools of Patent documents 1 to 3, because the damper is inserted in the deep hole formed in the shank, the hole has to be formed by e.g. a gun drill especially if the tool is an inner diameter machining tool, of which the shank is long and small in diameter, so that the machining cost is high. Also, the hole has a large hollow portion through which the damper is inserted. Such a large hollow portion lowers the rigidity of the holder. Further, the structure is complicated, which also pushes up the cost. Because these holders are complicated in structure, the diameter of the shank is restricted (so that the diameter of the bore that can machined is also restricted in the case of inner diameter machining). This means that in order to sufficiently damp vibration, the cutting conditions are restricted. The tools disclosed in Patent documents 4 and 5 also have the same problems. Also, in order to absorb vibration energy with the vibration suppressing material, it is necessary that the vibration suppressing material be made of a material having a high vibration suppressing ability, such as an Mn—Cu vibration suppressing alloy. But such alloys are expensive and formability of these alloys is not good, either. Thus, it is difficult to manufacture a tool that is both less costly and of high performance. For tools using a vibration suppressing material, if the amount of the vibration suppressing material is reduced to reduce the cost, it is difficult to sufficiently damp vibration. If the amount of the vibration suppressing material is increased, the rigidity and strength of the tool tend to be low, which results in increased deflection and reduced durability of the tool. In the arrangement in which vibration is damped utilizing the contact friction between the shank and the damper, if the friction area is increased in order to increase the vibration suppressing effect, portions that have to be machined increase, thus increasing the cost. If the damper is not in sufficiently close contact with the shank, the rigidity of the tool tends to increase, so that vibration may increase, rather than decrease, during cutting. Patent document 1: JP patent publication 2003-136301A Patent document 2: JP patent publication 6-31507A Patent document 3: JP patent publication 2979823B Patent document 4: JP patent publication 6-31505A Patent document 5: JP patent publication 2001-96403A Patent document 6: JP patent publication 2003-62703A DISCLOSURE OF THE INVENTION Object of the Invention An object of the present invention is to provide a vibration suppressing cutting tool which is free of any of the abovementioned problems of conventional vibration suppressing cutting tools, which is inexpensive and can damp chattering extremely effectively, and which is simple in structure and is applicable to a wide variety of machining diameters and cutting conditions. MEANS TO SOLVE THE PROBLEMS According to the present invention, there is provided a vibration suppressing cutting tool including, as shown in FIGS. 1(a) and 1(b), a holder 1 having a shank 2 formed with a pocket 4 in which a vibration suppressing piece 5 is received so as to be movable relative to the holder 1 and not to be protrudable from the pocket 4. When the holder 1 vibrates during cutting, the inertial force causes the vibration suppressing piece 5 to alternately knock against opposed inner walls of the pocket along surfaces, along a plurality of lines or on a plurality of points, thereby damping the vibration of the holder 1. Preferably, the pocket is defined by opposed first and second inner wall surfaces formed on the shank of the holder, and the vibration suppressing piece has flat surfaces each adapted to oppose one of the first and second inner wall surfaces of the pockets when received in the pocket. The first and second inner wall surfaces of the pocket and thus the flat surfaces of the vibration suppressing piece are arranged so as to extend perpendicular to the direction of vibrations of the holder expected to be produced during cutting. A clearance is present between the first and second inner wall surfaces and the corresponding flat surfaces of the vibration suppressing piece so that the vibration suppressing piece is movable in the pocket within this clearance. Instead of the single vibration suppressing piece 5, a plurality of such vibration suppressing piece 5 may be received in the pocket. Also, such a plurality of vibration suppressing pieces 5 may be each received in one of a plurality of separate pockets 5. The vibration suppressing piece 5 may be adapted to knock against the pocket 4 along a plurality of lines or on a plurality of points. But preferably, the former knocks against the latter along as large a surface of the pocket 4 as possible to effectively damp vibrations. For this purpose, the vibration suppressing piece 5 has a rectangular cross-section (section perpendicular to the axis of the shank) such that its surfaces 5a and 5b to be knocked against the first and second inner wall surfaces 4a and 4b of the pocket have greater surface areas than its other opposed surfaces 5c and 5d. The shape of the vibration suppressing piece 5 as viewed from top of the tool is not particularly limited. The vibration suppressing piece 5 is preferably made of a material that is larger in specific gravity than the material forming the shank 2. For example, if the shank 2 is made of steel, of which the specific gravity is 7.8, the vibration suppressing piece 5 is preferably made of a cemented carbide or a heavy metal of which the specific gravity is higher than 7.8. The vibration suppressing piece may have a specific gravity equal to or smaller than the shank 2. But if the vibration suppressing piece has a higher specific gravity, it is possible to reduce its size in order to obtain required vibration suppressing capability. The clearance between the first and second inner wall surfaces 4a and 4b and the vibration suppressing piece 5 is preferably 0.01 to 0.5 mm. The first and second inner wall surfaces 4a and 4b should be arranged so as cross the direction of vibrations of the holder expected to be produced during cutting, preferably at a right angle. The pocket 4 has a width w which is 20 to 100% of the diameter D or width W of the shank, and a height h which is 5 to 70% of the height H of the shank. The width and height mentioned here and throughout the specification refer to the width and height of a cross-section of the shank. As shown in FIGS. 2(a) and 2(b), the pocket 4 may be a through hole extending from one to the other side of the shank. In this case, the vibration suppressing piece 5 is sealed in the pocket by e.g. piece retaining means or lids 6. Alternatively, as shown in FIGS. 3(a) and 3(b), the pocket may be a blind hole formed from one side 1a of the shank which is opposite to the side 1b of the shank where a cutting edge 7a of a cutting insert 7 is located so as to be closed on the side 1b of the shank. In another alternative embodiment shown in FIGS. 4(a) and 4(b), the shank 2 and the head 3 of the holder are formed separately from each other, the pocket 4 is formed in the front end surface of the shank 2, the vibration suppressing piece 5 is inserted in the pocket 4, and the head 2 is jointed to the front end of the shank to close the opening of the pocket 4. The pocket 4 of any of these embodiments has an axial length c (see FIG. 1(a)) that is 50 to 250% of the diameter D (i.e. height H) of the shank. The pocket 4 is preferably provided axially offset from the axial center of the tool toward its front end. Specifically, the pocket 4 is preferably located such that the distance e (see FIG. 1(a)) between the cutting edge of the cutting insert and the front end of the pocket is about 50 to 250% of the diameter D of the shank. If the tool is a boring tool, the length c of the pocket is more preferably about 100 to 150% of the diameter D of the shank, the distance e between the cutting edge and the pocket is more preferably about 150 to 220% of the diameter D of the shank, though these preferable values vary with e.g. the cutting conditions. If the tool is an inner diameter cutting tool such as a boring tool, the pocket 4 has preferably a width w that is 50 to 100% of the diameter D or width W of the shank, and a height h that is 20 to 40% of the height H of the shank, though according to the size of the tool, good results are obtained even if these values are outside the above ranges. For example, in the case of a boring tool of which the shank has a diameter D exceeding 20 mm, good results were obtained when the pocket 4 had a width w of 0.2D to 0.5D (0.2W to 0.5W) and a height h of 0.2H to 0.5H. For a tool used to cut hard workpieces such as hardened steel, good results were obtained when the pocket 4 had a width w of 0.5D to 1.0D (0.5W to 1.0W) and a height h of 0.4H to 0.7H. For a tool of which the pocket had a width w of 0.2D to 1.0D (0.2W to 1.0W) and a height h of 0.05H to 0.2H, chattering was effectively suppressed during high-speed cutting of carbon steel or cutting of stainless steel. ADVANTAGES OF THE INVENTION When the holder vibrates, the vibration suppressing piece received in the pocket is vibrated by inertia, thus directly knocking the inner wall of the pocket. At this time, the vibration suppressing piece vibrates in reverse phase to the holder, so that the vibration of the holder is canceled by the vibration of the vibration suppressing piece. Chattering of the holder thus decreases. According to the present invention, the vibration suppressing piece knocks the pocket along its surface, along a plurality of lines, or on a plurality of points. Thus, the load of the vibration suppressing piece disperses to a wide range of the inner wall of the pocket, thus making it possible to substantially suppress chattering. By orienting the pocket such that its wall surfaces against which the vibration suppressing piece knocks are perpendicular to the direction of vibration of the holder during cutting, energy from the vibration suppressing piece (energy that serves to cancel vibration of the holder) is transmitted to the shank with a minimum loss, so that it is possible to reduce the size of the vibration-piece and the pocket. This minimizes the reduction in the rigidity of the shank due to the presence of the pocket, thus making it possible to more effectively suppress chattering. According to the present invention, because the pocket can be formed from one side of the holder, the tool can be manufactured easily at a significantly lower cost so that it is possible to provide a less expensive vibration suppressing cutting tool. In the arrangement in which the holder comprises a shank and a head that are formed separately from each other, and the vibration suppressing piece is inserted in the pocket formed in the shank from the front end of the shank, the vibration suppressing piece can most effectively damp chattering, and there is no need to form a cavity for inserting a damper. Thus, it is possible to simplify the structure of the tool, thereby significantly reducing the cost of the tool, while minimizing the reduction in rigidity of the shank due to the presence of the pocket. If the vibration suppressing piece is too small and too lightweight, the vibration suppressing effect tends to be insufficient. If the vibration suppressing piece is too large, a larger pocket is necessary, which reduces the rigidity of the shank. Thus, the dimensions of the pocket are preferably within the above-described ranges. If the length c of the pocket is less than 50% of the diameter D or height H of the shank, the vibration suppressing piece is too small to sufficiently damp vibration. If the length c exceeds 250% of D or H, the rigidity of the shank tends to decrease excessively, so that chattering tends to occur during ordinary cutting, in which the protrusion of the holder (from the support point to the cutting edge) is more than three times the diameter of the shank. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1(a) is a plan view of a tool according to the present invention; FIG. 1(b) is a sectional view taken along line X-X of FIG. 1(a); FIG. 2(a) is a plan view of another tool according to the present invention; FIG. 2(b) is a sectional view taken along line X-X of FIG. 2(a); FIG. 3(a) is a plan view of still another tool according to the present invention; FIG. 3(b) is a sectional view taken along line X-X of FIG. 3(a); FIG. 4(a) is a plan view of yet another tool according to the present invention; FIG. 4(b) is a sectional view taken along line X-X of FIG. 4(a); FIG. 5(a) is a plan view of a conventional vibration suppressing tool, showing its basic structure; FIG. 5(b) is a sectional view taken along line X-X of FIG. 5(a); FIG. 6(a) is a plan view of a tool embodying the present invention; FIG. 6(b) is a sectional view taken along line X-X of FIG. 6(a); FIG. 7(a) is a plan view of the tool of FIG. 6 in which the pocket is inclined by θ°; FIG. 7(b) is a sectional view of the tool of FIG. 6 in which the pocket is inclined by θ°; FIG. 8(a) is a plan view of the tool of FIG. 6 in which the pocket is inclined by θ=90°; FIG. 8(b) is a sectional view of the tool of FIG. 6 in which the pocket is inclined by θ=90°; FIG. 9(a) is a plan view of a tool of another embodiment; FIG. 9(b) is a sectional view taken along line X-X of FIG. 9(a); FIG. 9(c) is a sectional view taken along line Y-Y of FIG. 9(a); FIG. 10 is a comparative view of the amount of deformation according to the shape of the pocket; FIG. 11 is a view showing specifications of tools used in an experiment for confirming effects; FIG. 12 is a view showing the results of the confirmation experiments of the tools shown in FIG. 11; FIG. 13 is a view of the tool of FIG. 9 of which the vibration suppressing piece is replaced with a rectangular parallelepiped vibration suppressing piece; FIG. 14(a) is a plan view of a tool of another embodiment; FIG. 14(b) is a sectional view taken along line X-X of FIG. 14(a); FIG. 15(a) is a plan view of a tool of still another embodiment; FIG. 15(b) is a sectional view taken along line X-X of FIG. 15(a); FIG. 16 is a sectional view of an example in which the pocket is displaced from the axis of the shank; FIG. 17(a) is a plan view of a tool of still another embodiment; FIG. 17(b) is a sectional view taken along line X-X of FIG. 17(a); FIG. 18(a) is a plan view of a tool of yet another embodiment; FIG. 18(b) is a side view of the tool of FIG. 18(a); FIG. 18(c) is a sectional view taken along line X-X of FIG. 18(a); FIG. 19 is a plan view of different pockets and vibration suppressing pieces; FIG. 20 is a sectional view of differently positioned pockets; FIG. 21 is a view showing the results of a test for confirming effects of the tool of FIG. 18; FIG. 22(a) is a plan view of a tool of another embodiment; FIG. 22(b) is a side view of the tool of FIG. 22(a); FIG. 22(c) is a sectional view taken along line X-X of FIG. 22(a); FIG. 23(a) is a plan view of a tool of still another embodiment; FIG. 23(b) is a side view of the tool of FIG. 23(a); FIG. 24(a) is a plan view of a tool of yet another embodiment; FIG. 24(b) is a side view of the tool of FIG. 24(a); FIG. 25 is a view showing the results of a test for confirming effects of the tool of FIG. 22; FIG. 26(a) is a plan view of a tool of another embodiment; FIG. 26(b) is a side view of the tool of FIG. 26(a); FIG. 27(a) is a plan view of a tool of still another embodiment; FIG. 27(b) is a side view of the tool of FIG. 27(a); FIG. 28 is a view showing the results of a test for confirming effects the tool of FIG. 26; FIG. 29 is a perspective view of yet another embodiment; FIG. 30(a) is a view of another vibration suppressing piece having a different sectional shape; FIGS. 30(b) to 30(d) are views of other vibration suppressing pieces having different sectional shapes; FIG. 31 is a sectional view of still another vibration suppressing piece; FIG. 32(a) is a view of a vibration suppressing piece having a different plan shape; and FIG. 32(b) is a view of another vibration suppressing piece having a still different plan shape. DESCRIPTION OF NUMERALS 1 holder 2 shank 3 head 4 pocket 4a first inner wall surface 4b second inner wall surface 5 vibration suppressing piece 5a-5f flat surfaces 6 lid 7 throwaway insert 8 clamp means 9 oil hole 10 mounting hole 11 set pin 12 hole BEST MODE FOR EMBODYING THE INVENTION The vibration suppressing tools according to the embodiments of the present invention are now described with reference to the drawings. Embodiment 1 First, the vibration suppressing tool shown in FIG. 6 is a boring tool which includes a holder 1. A throwaway insert 7 is detachably clamped to the front end of the holder 1 by a clamp means 8. A hole as a pocket 4 is formed in the shank 2 of the holder 1 by e.g. electrical discharge machining so as to extend through the shank 2 from one side thereof to the other side. The pocket 4 is located offset from the axial center of the holder 1 toward its front end. A rectangular parallelepiped vibration suppressing piece 5 made of cemented carbide having a specific gravity of 15.1 is received in the pocket 5. Both open ends of the pocket 4 are closed by lid members 6 to prevent the vibration suppressing pieces 5 from coming out of the pocket 4. The pocket 4 has a rectangular cross-section and includes walls 4a and 4b parallel to each other. The shank 2 of the holder 1 shown has a circular cross-section. But the present invention is applicable to a shank having a polygonal cross-section, too. The vibration suppressing piece 5 has a height a and a width f that are about 0.15 mm smaller than the corresponding height and width of the pocket 4 and has flat surfaces 5a and 5b facing the walls 4a and 4b of the pocket 4 so as to be movable within the range determined by the clearance between the pocket 4 and the vibration suppressing piece 5. According to the present invention, it is essential that the vibration suppressing piece 5 be movable in the pocket 4. If the vibration suppressing piece 5 interfered with the walls of the pocket 4 and were unable to move relative to the shank 2, it would be unable to suppress chattering of the tool. But if the vibration suppressing piece 4 were too small, it would be too lightweight to sufficiently suppress chattering. Based on experiments conducted by the present inventors, it was discovered that if the shank of the holder has a relatively small diameter D, i.e. less than 20 mm, chattering is suppressed effectively if the vibration suppressing piece 5 is smaller in height and width than the pocket 4 by less than about 0.5 mm but the clearance therebetween is large enough for the vibration suppressing piece 5 to be movable in the pocket 4. If the clearance between the vibration suppressing piece 5 and the pocket 4 is smaller than 0.01 mm, the vibration suppressing piece 5 may become immovable in the pocket due to thermal deformation of the holder 1 and/or the vibration suppressing piece 5. Thus, the clearance is preferably in the range of about 0.01 to 0.5 mm. Particularly good results are obtained if the vibration suppressing piece 5 is smaller in height and width than the pocket by about 0.1 to 0.3 mm. But if the shank has a diameter D that is greater than 20 mm, even if the above clearance is large, i.e. the vibration suppressing piece 5 is smaller than the pocket 4 by more than 0.5 mm, the vibration suppressing piece 5 is still sufficiently large and heavyweight, so that it can effectively suppress chattering. If the holder 1 is made of steel, the vibration suppressing piece 5 is preferably made of a material having a specific gravity greater than 7.8, which is the specific gravity of steel. Preferably, the vibration suppressing piece 5 has as large a specific gravity as possible, because by using a vibration suppressing piece having a larger specific gravity, it is possible to effectively suppress chattering without increasing the size of the pocket. Practically, the vibration suppressing piece is preferably made of cemented carbide having a specific gravity of 14 to 16 or a heavy metal having a specific gravity of about 18, because these materials are easily available and are easy to machine. Of course, the vibration suppressing piece may be made of a material having a larger specific gravity if such a material is easily available. Too large a pocket 4 would reduce the rigidity of the holder 1, thereby deteriorating the accuracy of finishing (such as dimensional accuracy or surface roughness) of the tool, or might increase, rather than suppress, chattering. If the pocket 4 is too small, the vibration suppressing piece 5 has to be also correspondingly small, which makes it difficult to effectively suppress chattering. It is especially difficult to form a pocket having a small height h, because to form such a pocket, it is necessary to use a tool such as an end mill having a small diameter. Taking these factors into consideration, the pocket 4 has preferably a width w that is 20 to 100% of the diameter D or width W of the shank, and a height h that is 5 to 70% of the diameter D or height H of the shank. When other factors are further taken into consideration, such as the effect of suppressing chattering, deterioration in machining accuracy resulting from deflection of the holder during machining, and how easy the tool can be manufactured, if the shank has a relatively small diameter, i.e. D=not more than 20 mm, the pocket has preferably a width w that is 50 to 100%, more preferably 70 to 95%, of the diameter D or width W of the shank, and a height h that is 20 to 40%, more preferably 20 to 30%, of the diameter D or height H of the shank. Good results were obtained when the length c of the pocket 4 and the distance e between the front end of the tool and the pocket were both 50 to 250% of the diameter D of the shank. In the case of a boring tool, especially good results were obtained when the length c of the pocket 4 was about 100 to 150% of the diameter D of the shank, and the distance e between the cutting edge and the pocket was about 150 to 220% of the diameter D of the shank. If the diameter D of the shank is greater than 20 mm, even if the pocket is relatively small, vibration suppressing effects are obtainable. That is, even if the pocket 4 has a width w that is about 50% of the diameter D of the shank, good results are obtainable. The inclination angle θ shown in FIG. 7 should be determined according to the direction in which the cutting force acts. For ordinary inner diameter cutting tools, chattering can be suppressed sufficiently by orienting the pocket 4 such that its walls 4a and 4b extend horizontally. If cutting is always performed under the same conditions, good results will be obtained by orienting the pocket 4 such that its inner walls 4a and 4b are inclined within the range of 0 to 45 degrees with respect to a horizontal surface so as to be perpendicular to the direction of the resultant of the main component and thrust component of the cutting force, and inserting the vibration suppressing piece in this pocket. For special machining in which the thrust component is extremely large, it is conceivable to vertically orient the pocket 4 as shown in FIG. 8. But for ordinary inner diameter cutting tools, such a vertically oriented pocket has little effect in suppressing chattering. Embodiment 2 This embodiment, shown in FIG. 9, is preferable when higher machining accuracy is required. While the tool of FIG. 6 can more effectively suppress chattering by increasing the size of the vibration suppressing piece 5, the shank tends to be low in rigidity because the pocket 4 extends through the shank, so that the machining accuracy tends to be low. The vibration suppressing cutting tool of FIG. 9 is free of this problem. The pocket 4 of the vibration suppressing cutting tool of FIG. 9 is formed by an end mill from a side 1a of the shank that is opposite to the side 1b of the shank where the cutting edge 7a is located. Complementary to the contour of the end mill, the pocket 4 has arcuate surfaces at both ends thereof. In order to keep high rigidity of the holder 1, the pocket 4 is a blind hole having a closed end wall having a thickness of about 2 mm on the side 1b of the shank where the cutting edge 7a is located. The opening of the pocket 4 on the side 1a is closed by a lid 6 in the same manner as in Example 1 to prevent the vibration suppressing piece 5 from coming out of the pocket 4. The lid 6 may be made of the same material as the material forming the holder 1. But preferably, the lid 6 is made of cemented carbide and strongly bonded to the holder 1 to minimize the reduction in rigidity of the holder due to the provision of the pocket. The fact that the vibration suppressing tool of FIG. 9 has a blind hole as the pocket 4 is practically important. The inventors of the invention actually manufactured tools as shown in FIG. 6. It was confirmed that chattering was suppressed in these tools very efficiently. However, in these tools, lowering of the rigidity of the holder is unavoidable, which may detrimentally affect the machining accuracy. Accordingly, several differently shaped tool samples, including one having the shape of H beams that are widely used as building materials, were tested for their rigidity. The results are shown in FIG. 10. In columns A to D of FIG. 10, the sections of the shanks of the respective tool samples taken along line X-X of FIG. 1(a) are shown. As is apparent from FIG. 10, the tool sample of FIG. 6 (shown in column A of FIG. 10), which is formed with a through hole as the pocket 4, was about 40% greater in the amount of deformation under loads than conventional inner diameter cutting tools having a steel shank including no vibration suppressing arrangement. In contrast, the tool sample of FIG. 9 (shown in column B of FIG. 10) was only about 9% greater in the amount of deformation under loads than the conventional tool. This means that in the tool sample of FIG. 9, lowering of the rigidity of the holder due to the provision of the pocket is kept to a minimum, so that the machining accuracy is kept stable. As is apparent from FIG. 10, this advantage is not found in any of the other tool samples. In the arrangement of FIG. 9, by forming the lid 6 from cemented carbide and strongly joining such a lid 6 to the shank, it is possible to increase the rigidity of the shank to a level substantially equal to the rigidity of a conventional steel shank having no pocket. The vibration suppressing piece 5 to be inserted in the pocket 4 having arcuate surfaces at both ends as seen from one side of the tool may be a rectangular parallelepiped member as shown in FIG. 13. If such a vibration suppressing piece 5 is sufficiently heavy in spite of the fact that its both ends are flat, the vibration suppressing piece 5 is preferably a rectangular parallelepiped member as shown in FIG. 13 because such a member has no arcuate surfaces at both ends thereof and thus can be formed easily. In order to determine how effectively tools according to the present invention can suppress chattering, tool samples each including a holder having the shape under S12M-STUPR1103 of ISO were prepared and subjected to a cutting experiment. The tool samples each included a shank having a diameter D of 12 mm and formed with a pocket spaced apart from the front end of the tool by a distance e of 21 mm and having a length c of 15 mm, a width w of 8 mm and a height h of 3 mm. The value (w−f) in FIG. 1 was 0.1 mm, and the value t in FIG. 10 was 2 mm. The tool samples subjected to the experiment comprised Examples 1 to 6 of the invention and Comparative Examples 1 to 5 shown in FIG. 11. Examples 1 to 6 of the invention and Comparative Examples 1 and 3 differ from each other in the height and width of the pocket, and the size and material of the vibration suppressing piece. In Comparative Example 2, the clearance between the vibration suppressing piece and the pocket is zero. The holder of Comparative Example 4 comprises a conventional steel shank. The shank of Comparative Example 5 is made of cemented carbide. The shanks of all the examples other than Comparative Example 5 are made of steel. In the cutting experiment, workpieces of ordinary alloy steel SCR420 were cut with a cutting speed of 80 m/min, a depth of cut of 0.2 mm and a feed rate of 0.1 mm/rev, while changing the protruding amount from the tool holder (protruding amount=48 mm, 60 mm, 72 mm and 84 mm). During cutting, each tool sample was observed for any sign of chattering. FIG. 12 shows the results of the experiment, in which the symbol ◯ indicates that the tool sample suffered no chattering, and the symbol X indicates that the tool sample suffered chattering. As will be apparent from these results, chattering was sufficiently suppressed in any of Examples of the invention. Particularly in Examples 1, 3 and 5 of the invention, chattering was more effectively suppressed than in Comparative Example 5, of which the holder was made of cemented carbide. Examples of the invention were also compared with commercially available vibration suppressing boring tools made by several manufacturers for their ability to suppress chattering. When workpieces were cut using the respective tool samples under the same conditions, the commercially available tools all produced noise (metallic sounds) resulting from chattering during cutting. Examples of the invention also produced slight noise in the initial stage of cutting according to the cutting conditions, but such noise soon subsided. Thus, cutting was performed practically silently thereafter. Under other conditions, examples of the invention produced no noise at all from the beginning to end of cutting, so that it was sometimes even impossible to determine whether cutting was being performed. Embodiment 3 FIG. 14 shows still another embodiment. The holder 1 of the vibration suppressing cutting tool of FIG. 14 comprises a shank 2 and a head 3 that are formed separately from each other and joined together. The head 3 may be undetachably joined to the shank 2, or may be detachably connected to the shank 2 so that only the head 3 is replaceable if the head 3 is broken. In this embodiment, the pocket 4 opens at the front end of the shank 2. By joining the head 3 to the shank 2 with the vibration suppressing piece 5 received in the pocket 4, the head 5 serves as a lid for closing the opening of the pocket 4. This eliminates the need for a separate lid. If the pocket 4 is formed by electrical discharge machining, the shank 2 can be made of cemented carbide, so that it is possible to increase the rigidity of the tool and thus dramatically suppress chattering. Embodiment 4 As shown in FIG. 15, the holder of this embodiment is formed with two pockets 4 each formed from one side of the holder 1 and separated from each other by a central wall. In this arrangement, only small vibration suppressing pieces 5 can be used, so that the ability to suppress chattering slightly deteriorates. But with this arrangement, it is possible to supply cutting oil to the cutting edge through an axial oil supply hole formed in the central wall separating the two pockets. Embodiment 5 The vibration suppressing cutting tool of FIG. 16 has its pocket 4 displaced downwardly (or upwardly) from the central axis of the shank 2. In this embodiment, too, an oil supply hole 9 can be formed in the shank at its portion over the pocket 4. Embodiment 6 FIG. 17 shows a different means for preventing the vibration suppressing piece 5 from coming out of the pocket 4. As shown, the vibration suppressing piece 5 is formed with a vertical through hole 10 through which a set pin 11 or the like having a smaller diameter than the through hole 10 extends to prevent the vibration suppressing piece from coming out of the pocket 4 without the need for a lid. Embodiment 7 FIG. 18 shows a vibration suppressing cutting tool of still another embodiment according to the present invention. The tool shown is a boring tool in which the pocket 4 formed in the shank 2 of the holder 1 has a width w and a height h which are both 20 to 50% of the diameter D of the shank. But the tool of this embodiment is not limited to a boring tool, and the dimensions of the pocket are not limited to the above ranges, either. The pocket 4 need not be formed from one side of the shank but may be formed from top (or bottom) of the shank 2 as shown in FIG. 18. The vibration suppressing piece 5 is received in the pocket 4, and the opening of the pocket 4 is closed by a lid 6. The lid 6 is preferably made of cemented carbide to minimize the reduction of the rigidity of the steel shank due to the presence of the pocket. A pocket 4 formed by an end mill has arcuate front and rear ends as shown in FIG. 19. The vibration suppressing piece 5 may have correspondingly arcuate longitudinal ends as shown in FIG. 19(b), or triangular longitudinal ends as shown in FIG. 19(c) to maximize the weight of the vibration suppressing piece. But the vibration suppressing piece may have flat longitudinal end surfaces that are perpendicular to the axis of the tool as shown in FIG. 19(a). The vibration suppressing piece 5 (and thus the pocket 4) is preferably oriented such that its surfaces 5a and 5b are perpendicular to the direction of the cutting force. Thus, the surfaces 5a and 5b are not necessarily horizontal but may be inclined as shown in FIG. 20(a). The vibration suppressing piece 5 does not have to be necessarily square. If the surfaces 5a and 5b, which are oriented so as to be perpendicular to the direction of the cutting force, have a greater area than the surfaces 5c and 5d, which are perpendicular to the surfaces 5a and 5b, vibrations can be more effectively damped. The vibration suppressing piece 5 may be divided into a plurality of subpieces. Even in this case, it can sufficiently damp vibration. The pocket 4 may be displaced from the center of the shank as shown in FIG. 20(b). Such a pocket 4 may be formed more easily and thus at a lower cost. Also, with this arrangement, since the vibration suppressing piece 5 knocks against the wall surfaces of the pocket 5 at positions displaced from the center of the shank, it applies torsional force to the shank. Thus, if the shank is subjected to torsional vibration, this vibration suppressing piece can effectively damp such vibration. Description is now made of the results of a test conducted to confirm the vibration suppressing ability of the tool of Embodiment 7. In the test, Examples 1 and 2 of the invention and Comparative Examples 1 to 3 were used. Examples 1 and 2 of the invention and Comparative Examples 1 and 2 each include a shank of S16RSSKPR09 under ISO (16 mm in diameter) which is formed with a pocket of the size shown in FIG. 21 (its center of gravity is on the center of the shank) in which is received a vibration suppressing piece made of a heavy metal having a specific gravity of 18.1 and having a width and a height that are both smaller by 0.3 mm than the width and height of the pocket, respectively. Comparative Example 3 includes a steel shank having no pocket. Using these tool samples, workpieces were cut under the following conditions 1 and 2. In any of Examples 1 and 2 of the invention, and Comparative Examples 1 and 2, the distance e from the cutting edge to the pocket is 25 mm, and the pocket has a length c of 20 mm. Cutting conditions 1 Insert used: ISO SPMT090304N (with molded chip breaker) Protrusion of the holder: 80 mm Workpiece: SCM415 Cutting speed: V = 120 m/min Feed rate: f = 0.15 mm/rev Depth of cut: d = 0.5 mm/rev Cutting fluid: Water-insoluble cutting oil Cutting conditions 2 Insert used: ISO SPMT090304N (with molded chip breaker) Protrusion of the holder: 80 mm Workpiece: SUJ2 Cutting speed: V = 120 m/min Feed rate: f = 0.1 mm/rev Depth of cut: d = 0.5 mm/rev Cutting fluid: Water-insoluble cutting oil The test results are shown in FIG. 21. The symbols ◯ and X indicate that the respective tools suffered no chattering and suffered chattering, respectively. For Examples 1 and 2 of the invention, good results were obtained both under the cutting conditions 1, which are the cutting conditions when cutting ordinary carbon steel and under the cutting conditions 2, which are the finish cutting conditions when the workpiece has high hardness. Thus, Examples 1 and 2 of the invention can suppress chattering under any conditions. In contrast, for Comparative Examples 1, the results were bad both under the cutting conditions 1 and 2. This is presumably because the vibration suppressing piece was too lightweight. For Comparative Example 2, good results were obtained under the cutting conditions 1 but not under the cutting conditions 2, in which the thrust component is large. For Comparative Example 3, no vibration suppressing effect was observed at all, so that the results were bad both under the cutting conditions 1 and 2. Embodiment 8 FIG. 22 shows a grooving tool to which the concept of the present invention is applied. FIGS. 23 and 24 show outer diameter cutting tools to which the concept of the present invention is applied. Unlike inner diameter cutting tools, dimensions of these tools are not restricted, so that even if the pocket is large, it is possible to keep high rigidity of the shank by increasing the size of the shank. Negative inserts are mainly used for outer diameter cutting tools. In this case, the cutting resistance tends to be high, so that high vibration energy is produced. Thus, a vibration suppressing piece which can cancel such high vibration energy is required. Also in this case, the pocket 4 preferably has the same width as the tool of FIG. 6 (i.e. 50 to 100% of the width W of the shank) and an increased height h, i.e. 40 to 70% of the height H (or diameter D) of the shank. If the size of the shank is not restricted, it is possible to form a pocket having the abovementioned dimensions. FIG. 25 shows the results of a test conducted to confirm the vibration suppressing ability of the tool of Embodiment 8. While forming grooves in workpieces using grooving tools, vibration energy that is as large as the energy produced during outer diameter cutting is produced. Thus, in the test, how chattering was damped was examined when grooves were formed in workpieces using grooving tools as shown in FIG. 22. For the test, Examples 1 and 2 of the invention and Comparative Examples 1 to 4 were prepared. Examples 1 and 2 of the invention and Comparative Examples 1 to 3 each include a holder having a steel shank (25×25 mm) formed with a pocket of the size shown in FIG. 25 in which is inserted a vibration suppressing piece smaller in size by 0.2 mm than the pocket and made of a heavy metal having a specific gravity of 18.1, and a triangular grooving insert (width of the cutting edge: 3 mm) made of K10-PVD-coated cemented carbide and mounted on the holder so as to be used in a vertical position with respect to the workpiece. Comparative Example 4 has a steel shank with no pocket. Cutting was performed using these tool samples under the following cutting conditions. In any of Examples 1 and 2 of the invention, and Comparative Examples 1 to 3, the distance e from the cutting edge to the pocket is 15 mm, and the pocket has a length c of 30 mm. Cutting conditions 1 Workpiece: S45C Cutting speed: V = 100 m/min Feed rate: f = 0.05 mm/rev Cutting fluid: Water-insoluble cutting oil Cutting conditions 2 Workpiece: S45C Cutting speed: V = 200 m/min Feed rate: f = 0.1 mm/rev Cutting fluid: Water-insoluble cutting oil As will be apparent from the test results shown in FIG. 25, Examples 1 and 2 of the invention were free of chattering both under the cutting conditions 1 and 2. In contrast, Comparative Example 1, in which the pocket excessively reduced the rigidity of the shank, produced as large chattering as was produced by Comparative Example 4. Comparative Examples 2 and 3 were effective during light cutting. But during heavy cutting, chattering was not suppressed sufficiently. Embodiment 9 FIG. 26 shows a still different outer diameter cutting tool. During ordinary outer diameter cutting, large chattering accompanying squeaking sounds is less likely to be produced because it is possible to increase the rigidity of the shank. But silent minute chattering is produced, which could cause minute chipping of the cutting edge or peeling of the coating of a coated tool. Such minute chattering can be suppressed by using a vibration suppressing piece that is smaller than those described and shown above. Thus, in the embodiment of FIG. 26, the pocket 4 has a width w that is 20 to 100% of the width W of the shank and a height h that is 5 to 20% of the height H of the shank, and the vibration suppressing piece 5 is sized such that there exists a clearance of 0.03 to 0.5 mm, more preferably 0.03 to 0.1 mm between the vibration suppressing piece 5 and the wall surfaces 4a and 4b of the pocket 4. The opening of the pocket 4 is closed by a lid 6 to prevent the vibration suppressing piece 5 from coming out of the pocket 4. The tool of FIG. 26 is advantageously used for high-speed machining of carbon steel and machining of stainless steel. The vibration suppressing piece 5 suppresses minute chattering, thus reducing the possibility of chipping of the cutting edge and improving the durability of the tool. The shank 2 may comprise upper and lower halves. In this case, after forming the pocket and receiving the vibration suppressing piece in the pocket, the upper and lower halves are fixedly joined together by fitting, screwing, welding or any other suitable method. Thus, the lower half serves as a lid for the pocket. In the case of boring tools, too, if the rigidity of the shank is increased, not large chattering but minute chattering may be produced. Thus, the pocket and the vibration suppressing piece of FIG. 26, which are used for an outer diameter cutting tool, can also be used for boring tools to suppress minute chattering. FIG. 27 shows such an embodiment. FIG. 28 shows the results of a test conducted to confirm the vibration suppressing ability of the tool of Embodiment 9. For the test, Examples 1 and 2 of the invention and Comparative Examples 1 to 3 were prepared. Examples 1 and 2 of the invention and Comparative Examples 1 and 2 are tools of the type shown in FIG. 26 each having a 25 mm square steel shank formed with a pocket of the size shown in FIG. 28 in which is received a vibration suppressing piece 5 smaller in size by 0.2 mm than the pocket and made of a heavy metal having a specific gravity of 18.1. Comparative Example 3 has a steel shank with no pocket. Cutting was performed using these tool samples under the following cutting conditions. In any of Examples 1 and 2 of the invention and Comparative Examples 1 and 2, the distance e from the cutting edge to the pocket is 15 mm, and the pocket has a length c of 30 mm. Cutting conditions Workpiece: SCM435 Insert: TNMG160412 (with molded chip breaker) Cutting speed: V = 300 m/min Feed rate: f = 0.25 mm/rev Depth of cut: 1.5 mm Cutting fluid: Water-insoluble cutting oil Cutting was performed discontinuously under these cutting conditions, and the number of impacts was measured until the cutting edge was broken. This test was conducted ten times. FIG. 28 shows the average thereof. In the test, Comparative Examples 1 and 2 suffered minute chipping on the cutting edge, and accumulation of such minute chipping resulted in major breakage of the cutting edge. In contrast, Examples 1 and 2 of the invention were free of minute chipping and their cutting edges were broken due to wear. As will be apparent from these test results, according to the present invention, it is also possible to suppress minute chattering, which results in minute chipping. The vibration suppressing cutting tool of FIG. 29 has a shank formed with a plurality of through holes (or blind holes) 12 provided near the front end thereof so as to extend in the width direction of the shank and be displaced from each other in the longitudinal direction of the shank. A plurality of vibration suppressing pieces 5 are each received in one of the holes 12 as pockets so as to be movable in the holes 12 but not to come out of the holes 12. In this arrangement, the vibration suppressing pieces 5 contact the holder along a plurality of lines, so that the vibration suppressing ability of this tool is even higher than that of existing vibration suppressing cutting tools provided with a damper. Because this cutting tool has the plurality of holes 12, the rigidity of the holder is higher than the holder with a single pocket. Preferably, the holes 12 are round holes, or the vibration suppressing pieces 5 are round bars so that the holder can be manufactured more easily at a lower cost. The vibration suppressing piece may have a rectangular cross-section (section perpendicular to the axis of the shank) so as to maximize the contact area with the wall surfaces 4a and 4b of the pocket. But instead, the pocket may have a polygonal cross-section as shown in FIG. 30(a) or an oval cross-section as shown in FIG. 30(b). Also, as shown in FIGS. 30(c) and 30(d), protrusions may be formed on the surfaces 5a and 5b so that the vibration suppressing piece 5 contact the wall surfaces 4a and 4b of the pocket along a plurality of lines or on a plurality of points. In the arrangement of FIG. 31, a plurality of independent pockets 4 are formed in the shank 2 of the holder so as to be displaced from each other in the width direction of the shank, and a plurality of vibration suppressing pieces 5 are each received in one of the pockets 4. With this arrangement, too, the vibration suppressing pieces can be brought into contact with the wall surfaces 4a and 4b of the pockets along a plurality of lines, or along a plurality of surfaces. The plan shape of the vibration suppressing piece 5 is not limited and may be square, rectangular, circular (see FIG. 32(a)), or substantially half-oval (see FIG. 32(b)). Even if the plan shape of the vibration suppressing piece is not rectangular, it can be formed so that its cross-section (section perpendicular to the axis of the shank) is rectangular. This invention is applicable to inner diameter cutting tools, grooving tools, threading tools, ordinary outer diameter turning tools, and the like which tend to suffer chattering. This invention is also applicable to boring quills and drills not only for turning but to be mounted on milling machines and machining centers to effectively suppress chattering. The vibration suppressing cutting tool according to this invention is mounted on known boring machines, outer diameter machining lathes, milling machines, machining centers, etc. By using the vibration suppressing cutting tool according to the present invention, it is possible to prevent a reduction in the yield due to poor machining and a reduction in productivity due to re-machining. Workpieces machined by the vibration suppressing cutting tool according to the present invention are free of chatter marks on their cut surfaces.

<SOH> BACKGROUND ART <EOH>It is well-known to mount a damper in the holder to suppress chattering utilizing inertia. Particularly in the case of inner diameter machining boring tools, because the size of the holder is restricted by the bore diameter of the workpiece, its protrusion has to be increased while reducing the diameter of the shank. This increases the possibility of chattering. Thus, many of the conventional vibration suppressing tools are boring tools. The following description is therefore mainly made with reference to boring tools. For example, in Patent document 1, a method shown in FIG. 5 is disclosed. In this method, a hole 21 is formed in the holder 1 from its rear end, a damper 22 is received in the hole 21 at its front end near the cutting edge, and a core rod 23 is inserted in the hollow portion of the hole. In Patent document 2, a turning tool is disclosed of which the holder is formed with a deep hole in its central portion into which a viscous fluid and a weight are received. In Patent document 3, a cutting tool is disclosed in which a rod spring is inserted in a hole formed in the tool body, a visco-elastic body is disposed between the rod spring and the hole, a cutting head is provided at the front end of the rod spring, and a frictional vibration suppressing material is provided between the cutting head and the tool body. The cutting tools shown in Patent documents 1 and 2 cancel chattering using the inertia of the damper. The cutting tool disclosed in Patent document 3 reduces vibrations transmitted to the tool body by converting vibration energy to frictional heat. There are also known a boring bar in which a damper made of a different material from the shank is fitted in a hole formed in the shank using tapered surface to damp vibration utilizing the contact friction between the shank and the damper (see Patent document 4), and tools in which a vibration suppressing member for absorbing vibration energy is mounted in the tool body to damp vibration (Patent publications 5 and 6). In the vibration suppressing cutting tools of Patent documents 1 to 3, because the damper is inserted in the deep hole formed in the shank, the hole has to be formed by e.g. a gun drill especially if the tool is an inner diameter machining tool, of which the shank is long and small in diameter, so that the machining cost is high. Also, the hole has a large hollow portion through which the damper is inserted. Such a large hollow portion lowers the rigidity of the holder. Further, the structure is complicated, which also pushes up the cost. Because these holders are complicated in structure, the diameter of the shank is restricted (so that the diameter of the bore that can machined is also restricted in the case of inner diameter machining). This means that in order to sufficiently damp vibration, the cutting conditions are restricted. The tools disclosed in Patent documents 4 and 5 also have the same problems. Also, in order to absorb vibration energy with the vibration suppressing material, it is necessary that the vibration suppressing material be made of a material having a high vibration suppressing ability, such as an Mn—Cu vibration suppressing alloy. But such alloys are expensive and formability of these alloys is not good, either. Thus, it is difficult to manufacture a tool that is both less costly and of high performance. For tools using a vibration suppressing material, if the amount of the vibration suppressing material is reduced to reduce the cost, it is difficult to sufficiently damp vibration. If the amount of the vibration suppressing material is increased, the rigidity and strength of the tool tend to be low, which results in increased deflection and reduced durability of the tool. In the arrangement in which vibration is damped utilizing the contact friction between the shank and the damper, if the friction area is increased in order to increase the vibration suppressing effect, portions that have to be machined increase, thus increasing the cost. If the damper is not in sufficiently close contact with the shank, the rigidity of the tool tends to increase, so that vibration may increase, rather than decrease, during cutting. Patent document 1: JP patent publication 2003-136301A Patent document 2: JP patent publication 6-31507A Patent document 3: JP patent publication 2979823B Patent document 4: JP patent publication 6-31505A Patent document 5: JP patent publication 2001-96403A Patent document 6: JP patent publication 2003-62703A

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 ( a ) is a plan view of a tool according to the present invention; FIG. 1 ( b ) is a sectional view taken along line X-X of FIG. 1 ( a ); FIG. 2 ( a ) is a plan view of another tool according to the present invention; FIG. 2 ( b ) is a sectional view taken along line X-X of FIG. 2 ( a ); FIG. 3 ( a ) is a plan view of still another tool according to the present invention; FIG. 3 ( b ) is a sectional view taken along line X-X of FIG. 3 ( a ); FIG. 4 ( a ) is a plan view of yet another tool according to the present invention; FIG. 4 ( b ) is a sectional view taken along line X-X of FIG. 4 ( a ); FIG. 5 ( a ) is a plan view of a conventional vibration suppressing tool, showing its basic structure; FIG. 5 ( b ) is a sectional view taken along line X-X of FIG. 5 ( a ); FIG. 6 ( a ) is a plan view of a tool embodying the present invention; FIG. 6 ( b ) is a sectional view taken along line X-X of FIG. 6 ( a ); FIG. 7 ( a ) is a plan view of the tool of FIG. 6 in which the pocket is inclined by θ°; FIG. 7 ( b ) is a sectional view of the tool of FIG. 6 in which the pocket is inclined by θ°; FIG. 8 ( a ) is a plan view of the tool of FIG. 6 in which the pocket is inclined by θ=90°; FIG. 8 ( b ) is a sectional view of the tool of FIG. 6 in which the pocket is inclined by θ=90°; FIG. 9 ( a ) is a plan view of a tool of another embodiment; FIG. 9 ( b ) is a sectional view taken along line X-X of FIG. 9 ( a ); FIG. 9 ( c ) is a sectional view taken along line Y-Y of FIG. 9 ( a ); FIG. 10 is a comparative view of the amount of deformation according to the shape of the pocket; FIG. 11 is a view showing specifications of tools used in an experiment for confirming effects; FIG. 12 is a view showing the results of the confirmation experiments of the tools shown in FIG. 11 ; FIG. 13 is a view of the tool of FIG. 9 of which the vibration suppressing piece is replaced with a rectangular parallelepiped vibration suppressing piece; FIG. 14 ( a ) is a plan view of a tool of another embodiment; FIG. 14 ( b ) is a sectional view taken along line X-X of FIG. 14 ( a ); FIG. 15 ( a ) is a plan view of a tool of still another embodiment; FIG. 15 ( b ) is a sectional view taken along line X-X of FIG. 15 ( a ); FIG. 16 is a sectional view of an example in which the pocket is displaced from the axis of the shank; FIG. 17 ( a ) is a plan view of a tool of still another embodiment; FIG. 17 ( b ) is a sectional view taken along line X-X of FIG. 17 ( a ); FIG. 18 ( a ) is a plan view of a tool of yet another embodiment; FIG. 18 ( b ) is a side view of the tool of FIG. 18 ( a ); FIG. 18 ( c ) is a sectional view taken along line X-X of FIG. 18 ( a ); FIG. 19 is a plan view of different pockets and vibration suppressing pieces; FIG. 20 is a sectional view of differently positioned pockets; FIG. 21 is a view showing the results of a test for confirming effects of the tool of FIG. 18 ; FIG. 22 ( a ) is a plan view of a tool of another embodiment; FIG. 22 ( b ) is a side view of the tool of FIG. 22 ( a ); FIG. 22 ( c ) is a sectional view taken along line X-X of FIG. 22 ( a ); FIG. 23 ( a ) is a plan view of a tool of still another embodiment; FIG. 23 ( b ) is a side view of the tool of FIG. 23 ( a ); FIG. 24 ( a ) is a plan view of a tool of yet another embodiment; FIG. 24 ( b ) is a side view of the tool of FIG. 24 ( a ); FIG. 25 is a view showing the results of a test for confirming effects of the tool of FIG. 22 ; FIG. 26 ( a ) is a plan view of a tool of another embodiment; FIG. 26 ( b ) is a side view of the tool of FIG. 26 ( a ); FIG. 27 ( a ) is a plan view of a tool of still another embodiment; FIG. 27 ( b ) is a side view of the tool of FIG. 27 ( a ); FIG. 28 is a view showing the results of a test for confirming effects the tool of FIG. 26 ; FIG. 29 is a perspective view of yet another embodiment; FIG. 30 ( a ) is a view of another vibration suppressing piece having a different sectional shape; FIGS. 30 ( b ) to 30 ( d ) are views of other vibration suppressing pieces having different sectional shapes; FIG. 31 is a sectional view of still another vibration suppressing piece; FIG. 32 ( a ) is a view of a vibration suppressing piece having a different plan shape; and FIG. 32 ( b ) is a view of another vibration suppressing piece having a still different plan shape. detailed-description description="Detailed Description" end="lead"?

20060526

20090922

20070426

71449.0

B23B4700

ADDISU, SARA

VIBRATION SUPPRESSING CUTTING TOOL

UNDISCOUNTED

ACCEPTED

B23B

ACCEPTED

Base Pad Polishing Pad and Multi-Layer Pad Comprising the Same

Disclosed is a base pad of polishing pad, which is used in conjunction with polishing slurry during a chemical-mechanical polishing or planarizing process, and a multilayer pad using the same. Since the base pad according to the present invention does not have fine pores, it is possible to prevent premeation of polishing slurry and water and to avoid nonuniformity of physical properties. Thereby, it is possible to lengthen the lifetime of the polishing pad.

1. A base pad of a chemical mechanical polishing pad, which does not include fine pores and has hardness of 10-100 Shore D and compressibility of 1-10%. 2. The base pad as set forth in claim 1, wherein the base pad is 500-2500 micrometers in thickness. 3. The base pad as set forth in claim 1, wherein the base pad is made of at least one selected from the group consisting of polyurethane, PVC, polyvinyl alcohol, polyacrylic acid, polyacrylamide, polyethylene oxide, maleic acid copolymer, methylcellulose, and carboxymethylcellulose. 4. The base pad as set forth in claim 1, wherein at least one, which is selected from the group consisting of polyurethane, PVC, polyvinyl alcohol, polyacrylic acid, polyacrylamide, polyethylene oxide, maleic acid copolymer, methylcellulose, and carboxymethylcellulose, is reacted in a first reactor to firstly produce prepolymer, and the prepolymer is reacted with a substance having a polyol reaction group or an ammonia reaction group in a weight ratio of 3:1-2:1 in a second step so as to achieve complete hardening, thereby producing the base pad. 5. A multilayer polishing pad which is produced using a base pad including no fine pores and having hardness of 10-100 Shore D and compressibility of 1-10%. 6. The multilayer polishing pad as set forth in claim 5, comprising a polishing pad having a polishing layer for polishing, and a base pad for supporting the polishing pad. 7. The multilayer polishing pad as set forth in claim 5, wherein the multilayer polishing pad has a thickness of 2000-4000 micrometers, in which the base pad has a thickness of 500-2500 micrometers. 8. The multilayer polishing pad as set forth in claim 5, wherein the base pad is made of at least one selected from the group consisting of polyurethane, PVC, polyvinyl alcohol, polyacrylic acid, polyacrylamide, polyethylene oxide, maleic acid copolymer, methylcellulose, and carboxymethylcellulose. 9. The multilayer polishing pad as set forth in claim 5, wherein the base pad is produced in such a manner that at least one, which is selected from the group consisting of polyurethane, PVC, polyvinyl alcohol, polyacrylic acid, polyacrylamide, polyethylene oxide, maleic acid copolymer, methylcellulose, and carboxymethylcellulose, is reacted in a first reactor to firstly produce prepolymer, and the prepolymer is reacted with a substance having a polyol reaction group or an ammonia reaction group in a weight ratio of 3:1-2:1 in a second step so as to achieve complete hardening.

TECHNICAL FIELD The present invention relates to a base pad of a polishing pad and a multilayer pad using the same. More particularly, the present invention pertains to a base pad of a polishing pad, which is used in a polishing process for planarizing various kinds of substrates in all stages of a semiconductor process, and a multilayer pad produced using the same. BACKGROUND ART A chemical mechanical polishing (hereinafter, referred to as “CMP”) or planarizing process is conducted to planarize various kinds of substrates, that is, substrates on which silicon, silicon oxide, metal (tungsten, copper, or titanium), metal oxide, dielectric, or ceramic is deposited, in all stages of a semiconductor process. This polishing process is one of precision/glossy surface grinding processes, in which polishing slurry is supplied between a polishing pad and a wafer to chemically corrode a surface of the wafer and to mechanically polish the corroded surface. Typically, a polishing pad comprises a polishing pad which has a polishing layer for rubbing an object during a direct polishing process, and a base pad for supporting the polishing pad. A method of producing the polishing pad is disclosed in, for example, Korean Patent Application Nos. 2001-46795, entitled “a method of producing a chemical mechanical polishing pad using a laser”, 2002-45832, entitled “a method of producing a polishing pad using a laser beam and a mask”, and 2002-06309, entitled “a composition for producing a polyurethane elastic body having high hardness and excellent wear resistance”. Generally, micro-cells are formed, or a through hole or a groove is formed in the polishing pad through physical and chemical methods so as to preserve slurry for a long time. With respect to this, the above Korean Patent Application Nos. 2001-46795 and 2002-45832 disclose a method of forming various patterns of micro-holes, grooves and/or through holes on a polishing pad using a laser and a mask, which is adopted instead of a conventional method of forming cells by the insertion of a hollow body or chemical generation of foam, or instead of another conventional method of forming grooves and through holes using mechanical means. Furthermore, the above Korean Patent Application No. 2002-06309 suggests a composition for producing the polyurethane elastic body, which is capable of improving hardness and wear resistance of the polishing pad. As well, the base pad is produced by incorporating sheet or felt, which is formed by foaming polyurethane material, into a polymeric substance. In more detail, the production of a polyurethane pad using typical foaming is achieved through a one-shot process consisting of one stage, in which all raw materials and foam bodies (chemical and mechanical foam) are agitated and reacted with each other at the same time, thereby forming fine pores in the pad. In the method of producing the pad through urethane incorporation, fibers, such as felt, are immersed in (wetted by) liquid polyurethane which is previously produced, thus polyurethane fills gaps between the felts, resulting in the formation of fine pores. Polishing slurry and DI water used during the polishing process may permeate into the fine pores existing in the base pad, and the permeation into the fine pores may negatively affect polishing uniformity of a wafer, which is an indicate of performance of the CMP process. Additionally, the permeation reduces the time for which the polishing pad is used, that is, its lifetime. Furthermore, physical properties of the conventional base pad may be changed by a rotational force between a platen and a wafer and vertical stress during the CMP process. DISCLOSURE OF INVENTION Technical Problem Therefore, the present inventors have conducted extensive studies into the solution of problems occurring in the prior art, resulting in the development of a base pad of a polishing pad and a multilayer pad using the same. In the base pad, excellent polishing uniformity is assured without the permeation of polishing slurry and water during a chemical mechanical polishing or planarizing (CMP) process, thus lengthening the lifetime of the polishing pad. An object of the present invention is to provide a uniform base pad having no internal fine pores, which is controlled in such a way that the fine pores do not exist therein, so as to prevent permeation of polishing slurry and water during a CMP process and to prevent a change in physical properties thereof due to action of forces on a polishing pad during the CMP process. Another object of the present invention is to provide a multilayer pad including the above base pad. TECHNICAL SOLUTION In order to accomplish the above objects, in the present invention, a base pad, which does not have pores but has uniform physical properties, is produced instead of producing a conventional base pad through foaming or the incorporation of felt. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates a base pad of a polishing pad and a multilayer pad using the same according to the present invention; FIG. 2 is a graph comparatively showing non-absorptivities when the base pad of the present invention and a conventional base pad made of felt are exposed to a mixture solution of water and polishing slurry (water:polishing slurry=1:1); and FIG. 3 is a graph comparatively showing the extent of planarization of substrates which are subjected to CMP processes using the base pad of the present invention and a conventional foam-type base pad. BEST MODE FOR CARRYING OUT THE INVENTION In a conventional polymer base pad which is produced by foaming, or in a conventional base pad which is produced by incorporating felt into a polymeric substance, nonuniform pores exist due to characteristics of the production process. This causes absorption of polishing slurry or DI water onto the base pad, and polishing slurry or DI water absorbed onto the base pad causes nonuniformity of a surface of the pad during a practical CMP process. Accordingly, a wafer is nonuniformly polished during the CMP process, which is undesirable in the CMP process. However, a base pad of the present invention, that is to say, the base pad having no pores therein, can assure uniform physical properties because the fine pores which may cause a nonuniform base pad are not formed in the base pad. Since the conventional base pad, which is produced by the foaming or incorporation of felt into the polymeric substance, has fine pores, physical properties of the base pad are changed due to vertical stress and a rotational force between a platen and a wafer during the CMP process, thus uniformity may be reduced during the polishing process. Additionally, if polishing slurry and DI water permeate into the pores of the base pad during the CMP process, polishing uniformity of the wafer is reduced during the polishing process. The permeation of polishing slurry and DI water into the base pad during the polishing process reduces the lifetime of a polishing pad. Hence, in the present invention, the base pad having no fine pores is developed with the aim of preventing deformation of the base pad which may cause degraded physical properties during the polishing process. In the present invention, the base pad does not have pores, thus it is possible to assure consistency of the thickness of the pad during high precision and high integration CMP processes, thereby avoiding problems in highly precisely controlling the thickness of the conventional base pad using a mechanical process. The base pad according to the present invention is made of at least one selected from the group consisting of polyurethane, PVC, polyvinyl alcohol, polyacrylic acid, polyacrylamide, polyethylene oxide, maleic acid copolymer, methylcellulose, and carboxymethylcellulose. A method of producing the base pad according to the present invention employs a two-stage blend process so that the fine pores are not formed in the base pad, unlike the production of the conventional base pad using foaming or felt incorporation. The two-stage blend process is called a pre-polymer process, and a process of producing a base pad having no fine pores. In other words, in order to produce the base pad having desired physical properties, at least one which is selected from the group consisting of polyurethane, PVC, polyvinyl alcohol, polyacrylic acid, polyacrylamide, polyethylene oxide, maleic acid copolymer, methylcellulose, and carboxymethylcellulose, is fed and reacted in a first reactor to firstly produce prepolymer. In a second stage, prepolymer is reacted with a substance having a polyol reaction group or an ammonia reaction group in a weight ratio of 3:1-2:1 so as to achieve complete hardening. Examples of the substance having the polyol reaction group include polyester glycol, such as polyethylene adipate, polybutylene adipate, and polypropylene adipate, polyalkylene ether polyol, such as tetramethyl ether glycol, poly(oxypropylene)triol, poly(oxypropylene)poly(oxyethylene)triol, poly(oxypropylene)poly(oxyethylene)triol, and poly(oxypropylene)poly(oxyethylene)poly(oxypropylene)triol, polyester polyol, polybutadiene polyol, and polymer polyol. Furthermore, polyol is used alone or in a mixture. Examples of the substance having the ammonia-based reaction group include 3,3′-dichlorobenzidine 4,4′-diamino-3,3′-dichlorophenylether, 4,4′-diamino-3,3′-dichlorodiphenylsulfide, 4,4′-diamino-3-chloro-3-bromodiphenylmethane, 4,4′-methylenebis(2-trifluoromethylaniline), 4,4′-methylenebis(2-chloroaniline) (commercial name—MOCA, manufactured by Dupon, Inc.), 4,4′-methylenebis(2-methoxycarbonylaniline), and 4,4′-methylenebis(2,5-dichloroaniline). As well, the substance having the ammonia-based reaction group is exemplified by a p- or m-phenylenediamine-based compound, such as 2,6-dichloro-m-phenylenediamine, 2-chloro-5-isobutoxycarbonyl-m-phenylenediamine, and 2-chloro-5-isopropoxycarbonyl-m-phenylenediamine, an aminobenzoate compound, such as trimethylenebis(p-aminobenzoate), and diethyleneglycolbis(p-aminobenzoate), and an aminophenylsulfide-based compound, such as 1,2-bis(p-aminophenylthio)ethane, and 1,2-bis(o-aminophenylthio)ethane. In addition, the substance having the ammonia-based reaction group is exemplified by 4-chloro-3,5-diamino-isopropylphenylacetate, 4-ethoxy-3,5-diaminotrifluoromethylbenzene, and bis-{2-(o-aminophenylthio)ethyl}terephthalate. Polyamine is used alone or in a mixture. The base pad does not include fine pores, and has hardness of 10-100 Shore D and compressibility of 1-10%. A conventional multilayer or two-layer polishing pad comprises a polishing pad having a hard polishing layer, and a soft base pad at a lower part thereof, thus a polishing speed is not so high during the polishing process. However, if the novel base pad as described above, that is, the base pad having no pores, is used to produce the two-layer or multilayer polishing pad as shown in FIG. 1, it is possible to increase the polishing speed of a wafer. In the present invention, as shown in FIG. 1, a base pad 2 is attached to a polishing pad 1 having a polishing layer using a pressure sensitive adhesive (PSA) 4, thereby producing a two-layer polishing pad. Another base pad 2 may be attached to the two-layer polishing pad using the pressure sensitive adhesive 4 to produce the multilayer polishing pad. Furthermore, the multilayer polishing pad may be attached to a platen 3 in the polishing process using another pressure sensitive adhesive 4′, which is used to conduct the polishing process. The pressure sensitive adhesive may be exemplified by an adhesive, including a polyacryl component, an epoxy component, or a rubber component, typically known in the art. A double-sided pressure sensitive adhesive tape in which a sticky and adhesive substance is applied on both sides of a base (PET film or felt) may be employed. In addition, the lamination of the multilayer pad may be implemented according to a typical method known in the art, for example, the lamination may be conducted through a conveyer method in which it passes between upper and lower rollers which are spaced apart by a predetermined interval. The multilayer polishing pad, which includes the base pad having a thickness of 500-2500 micrometers, has a thickness of 2000-4000 micrometers. Furthermore, the CMP process is conducted using the polishing pad which includes the base pad having no fine pores according to the present invention, thereby increasing the polishing speed and preventing deformation of the base pad and reduced polishing uniformity due to permeation during the polishing process. Thus, it is possible to lengthen the lifetime of the polishing pad which includes the base pad having no fine pores. FIG. 2 is a graph showing a weight as a function of an immersion time for a conventional base pad sample made of felt and a base pad sample according to the present invention. Weights of the conventional base pad and the base pad of the present invention are measured (using Mettler Toledo AX-204 as a laboratory electronic balance) before they are immersed in a mixture solution of polishing slurry and DI water (1:1), and the samples are immersed for 10-172800 sec. The samples are taken out from the solution after different immersion times, air dried for 30 min, and weighed. It can be seen that the base pad of the present invention has a relatively constant weight according to the immersion time in comparison with the conventional pad in which felt is immersed in polyurethane, thus having non-absorptivity. The CMP process is conducted using a conventional foam-type base pad and the base pad of the present invention in IPEC 472, that is, a commercial CMP process device, under conditions such that a flow rate of polishing slurry is 150 ml, a ratio of platen RPM:object head RPM is 46:28, and a ratio of head pressure:back pressure is 7:2.5. Planarization of a substrate is automatically measured using opti-probe which is thickness measuring equipment manufactured by Therma-wave, Inc. Thereby, a removal rate (polishing speed (A/min)) is obtained, and is shown in FIG. 3. From FIG. 3, it can be seen that the wafer polishing amount per unit time is more in the CMP process using the base pad having no fine pores according to the present invention than in the CMP process using the foam-type base pad. Particularly, in terms of the shape of an edge of the wafer, the base pad of the present invention is preferable to the conventional base pad. When the base pad according to the present invention, that is, the multilayer polishing pad which includes the pad produced through a two-stage prepolymer process so that fine pores do not exist in the pad, is applied to the polishing process, the following advantages can be obtained. 1. It is possible to increase a polishing speed of a wafer during the polishing process, 2. Since deformation of the base pad due to vertical stress and rotational force caused by changes in CMP devices and process variables during the polishing process is prevented, polishing uniformity of the wafer is not reduced, 3. Since permeation of polishing slurry or DI water into the base pad does not occur, it is possible to maintain polishing uniformity of the wafer, 4. It is possible to prevent reduction of a lifetime of the polishing pad due to the deformation of the base pad and the permeation, 5. It is possible to assure uniform physical properties of the base pad, and to highly precisely control thickness and conduct a highly precise surface process in the course of processing the pad, thus it is useful in highly precise and integrated CMP process, and 6. In the course of conducting a metal CMP process, the base pad of the present invention has uniform surface and physical properties, thus dishing or erosion, which are caused by a difference between polishing speeds of silicon oxide and metal circuits, can be prevented. INDUSTRIAL APPLICABILITY A CMP process is conducted using a polishing pad which includes a base pad having no fine pores according to the present invention, thus it is possible to increase a polishing speed and to prevent reduction of polishing uniformity due to deformation of the base pad and permeation occurring during the polishing process. Thereby, it is possible to increase the lifetime of the polishing pad that includes a base pad having no fine pores.

<SOH> BACKGROUND ART <EOH>A chemical mechanical polishing (hereinafter, referred to as “CMP”) or planarizing process is conducted to planarize various kinds of substrates, that is, substrates on which silicon, silicon oxide, metal (tungsten, copper, or titanium), metal oxide, dielectric, or ceramic is deposited, in all stages of a semiconductor process. This polishing process is one of precision/glossy surface grinding processes, in which polishing slurry is supplied between a polishing pad and a wafer to chemically corrode a surface of the wafer and to mechanically polish the corroded surface. Typically, a polishing pad comprises a polishing pad which has a polishing layer for rubbing an object during a direct polishing process, and a base pad for supporting the polishing pad. A method of producing the polishing pad is disclosed in, for example, Korean Patent Application Nos. 2001-46795, entitled “a method of producing a chemical mechanical polishing pad using a laser”, 2002-45832, entitled “a method of producing a polishing pad using a laser beam and a mask”, and 2002-06309, entitled “a composition for producing a polyurethane elastic body having high hardness and excellent wear resistance”. Generally, micro-cells are formed, or a through hole or a groove is formed in the polishing pad through physical and chemical methods so as to preserve slurry for a long time. With respect to this, the above Korean Patent Application Nos. 2001-46795 and 2002-45832 disclose a method of forming various patterns of micro-holes, grooves and/or through holes on a polishing pad using a laser and a mask, which is adopted instead of a conventional method of forming cells by the insertion of a hollow body or chemical generation of foam, or instead of another conventional method of forming grooves and through holes using mechanical means. Furthermore, the above Korean Patent Application No. 2002-06309 suggests a composition for producing the polyurethane elastic body, which is capable of improving hardness and wear resistance of the polishing pad. As well, the base pad is produced by incorporating sheet or felt, which is formed by foaming polyurethane material, into a polymeric substance. In more detail, the production of a polyurethane pad using typical foaming is achieved through a one-shot process consisting of one stage, in which all raw materials and foam bodies (chemical and mechanical foam) are agitated and reacted with each other at the same time, thereby forming fine pores in the pad. In the method of producing the pad through urethane incorporation, fibers, such as felt, are immersed in (wetted by) liquid polyurethane which is previously produced, thus polyurethane fills gaps between the felts, resulting in the formation of fine pores. Polishing slurry and DI water used during the polishing process may permeate into the fine pores existing in the base pad, and the permeation into the fine pores may negatively affect polishing uniformity of a wafer, which is an indicate of performance of the CMP process. Additionally, the permeation reduces the time for which the polishing pad is used, that is, its lifetime. Furthermore, physical properties of the conventional base pad may be changed by a rotational force between a platen and a wafer and vertical stress during the CMP process.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 illustrates a base pad of a polishing pad and a multilayer pad using the same according to the present invention; FIG. 2 is a graph comparatively showing non-absorptivities when the base pad of the present invention and a conventional base pad made of felt are exposed to a mixture solution of water and polishing slurry (water:polishing slurry=1:1); and FIG. 3 is a graph comparatively showing the extent of planarization of substrates which are subjected to CMP processes using the base pad of the present invention and a conventional foam-type base pad. detailed-description description="Detailed Description" end="lead"?

20070517

20080603

20071101

62885.0

B24D1100

MORGAN, EILEEN P

BASE PAD POLISHING PAD AND MULTI-LAYER PAD COMPRISING THE SAME

SMALL

ACCEPTED

B24D

ACCEPTED

Transistor circuit, pixel circuit, display device, and driving method therefor

A transistor circuit having the function of correcting variations in the threshold voltage of a thin-film transistor is provided. The transistor circuit includes a plurality of thin-film transistors (Tr1 to Tr3) formed on a substrate and wiring which connects the gate, source, and/or drain of each of the transistors, so as to perform a predetermined operation. During the operation, a forward bias is applied between the gate and source of the thin-film transistor (Tr2) via the wiring repeatedly and/or continuously. A reverse bias is applied between the gate and source of the transistor (Tr2) in such timing that the operation is not disturbed so that the variations in the threshold voltage are suppressed. More specifically, an additional transistor (Tr3) connected in parallel to the transistor (Tr2) is driven complementarily, so as to generate the above-described timing where the operation is not disturbed, and the reverse bias is applied to the transistor (Tr2) in the generated timing.

1. A transistor circuit having a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, so as to perform a predetermined operation, the transistor circuit comprising: at least one thin-film transistor applied with a forward bias between a gate and a source repeatedly and/or continuously via wiring during the operation, and reverse-bias-application means configured to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the operation is not disturbed. 2. A transistor circuit according to claim 1, comprising an additional thin-film transistor connected in parallel to the thin-film transistor and complement means which drives the additional thin-film transistor relative to the thin-film transistor, so as to generate timing where the above-described operation is not disturbed, wherein the reverse-bias-application means applies the reverse bias to the thin-film transistor in the generated timing. 3. A transistor circuit according to claim 2, wherein the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the N-channel type and/or the P-channel type, similarly, and the complement means applies a pulse to a gate of the additional thin-film transistor, the pulse being opposite in phase to a pulse applied to the gate of the thin-film transistor. 4. A transistor circuit according to claim 2, wherein the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the P-channel type and/or the N-channel type, oppositely, and the complement means applies a pulse to the additional thin-film transistor, the pulse being in phase with a pulse applied to the gate of the thin-film transistor. 5. A pixel circuit that is provided at each of intersections of scan lines in rows and scan lines in columns, and that samples a signal from the signal line upon being selected by the scan line and drives a load element according to the sampled signal, the pixel circuit comprising: a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, at least one thin-film transistor applied with a forward bias between a gate and a source repeatedly and/or continuously via wiring while the load element is driven, and reverse-bias-application means configured to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the driven load element is not disturbed. 6. A pixel circuit according to claim 5, comprising an additional thin-film transistor connected in parallel to the thin-film transistor and complement means which operates the additional thin-film transistor complementarily relative to the thin-film transistor and generates timing where the above-described driven load element is not disturbed, wherein the reverse-bias-application means applies the reverse bias to the thin-film transistor in the generated timing. 7. A pixel circuit according to claim 6, wherein the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the N-channel type and/or the P-channel type, similarly, and the complement means applies a pulse to a gate of the additional thin-film transistor, the pulse being opposite in phase to a pulse applied to the gate of the thin-film transistor. 8. A pixel circuit according to claim 6, wherein the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the P-channel type and/or the N-channel type, oppositely, and the complement means applies a pulse to the additional thin-film transistor, the pulse being in phase with a pulse applied to the gate of the thin-film transistor. 9. A pixel circuit according to claim 5, wherein the plurality of thin-film transistors includes a sampling thin-film transistor that is brought into conduction upon being selected by the scan line, and that samples a signal from the signal line and holds the sampled signal in a holding capacitor, a drive thin-film transistor which controls the amount of power applied to the load element according to the potential of the signal held in the holding capacitor, and a switching thin-film transistor which performs on/off control of the amount of power applied to the load element, wherein the reverse-bias-application means applies the reverse bias to at least one of the drive thin-film transistor and the switching thin-film transistor. 10. A pixel circuit according to claim 9, comprising threshold voltage-cancellation means configured to adjust the level of a signal potential applied to a gate of the drive thin-film transistor, so as to cancel a variation in a threshold voltage of the drive thin-film transistor. 11. A pixel circuit according to claim 9, comprising bootstrap means configured to automatically control the level of a signal potential applied to a gate of the drive thin-film transistor, so as to accommodate a variation in the characteristic of the load element. 12. A display device comprising scan lines in rows, scan lines in columns, and pixel circuits provided at intersections of the scan lines, wherein, upon being selected by the scan line, the pixel circuit samples a video signal from the signal line and drives a light-emission element according to the sampled video signal, and wherein the pixel circuit includes a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, at least one thin-film transistor applied with a forward bias between a gate and a source repeatedly and/or continuously via wiring while the light-emission element is driven, and reverse-bias-application means configured to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the driven light-emission element is not disturbed. 13. A display device according to claim 12, comprising an additional thin-film transistor connected in parallel to the thin-film transistor and complement means which operates the additional thin-film transistor complementarily relative to the thin-film transistor and generates timing where the driven light-emission element is not disturbed, wherein the reverse-bias-application means applies the reverse bias to the thin-film transistor in the generated timing. 14. A display device according to claim 13, wherein the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the N-channel type and/or the P-channel type, similarly, and the complement means applies a pulse to a gate of the additional thin-film transistor, the pulse being opposite in phase to a pulse applied to the gate of the thin-film transistor. 15. A display device according to claim 13, wherein the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the P-channel type and/or the N-channel type, oppositely, and the complement means applies a pulse to the additional thin-film transistor, the pulse being in phase with a pulse applied to the gate of the thin-film transistor. 16. A display device according to claim 12, wherein the plurality of thin-film transistors includes a sampling thin-film transistor that is brought into conduction upon being selected by the scan line, and that samples a video signal from the signal line and holds the sampled video signal in a holding capacitor, a drive thin-film transistor which controls the amount of power applied to the light-emission element according to the potential of the signal held in the holding capacitor, and a switching thin-film transistor which performs on/off control of the amount of power applied to the light-emission element, wherein the reverse-bias-application means applies the reverse bias to at least one of the drive thin-film transistor and the switching thin-film transistor. 17. A display device according to claim 16, comprising threshold voltage-cancellation means configured to adjust the level of a signal potential applied to a gate of the drive thin-film transistor, so as to cancel a variation in a threshold voltage of the drive thin-film transistor. 18. A display device according to claim 16, comprising bootstrap means configured to automatically control the level of a signal potential applied to a gate of the drive thin-film transistor, so as to accommodate a variation in the characteristic of the load element. 19. A method of driving a transistor circuit including a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, so as to perform a predetermined operation, the driving method being adapted to perform: a forward bias-application step adapted to apply a forward bias between the gate and the source of at least one of the thin film transistors repeatedly and/or continuously via the wiring during the operation, and a reverse bias-application step adapted to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the operation is not disturbed. 20. A method of driving a transistor circuit according to claim 19, comprising a complement step adapted to drive an additional thin-film transistor connected in parallel to the thin-film transistor complementarily relative to the thin-film transistor, thereby generating timing where the operation is not disturbed, wherein the reverse bias-application step is adapted to apply the reverse bias to the thin-film transistor in the generated timing. 21. A method of driving a pixel circuit that is provided at each of intersections of scan lines in rows and scan lines in columns, and that includes a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, so as to sample a signal from the signal line upon being selected by the scan line and drive a load element according to the sampled signal, the driving method being adapted to perform: a forward bias-application step adapted to apply a forward bias between the gate and the source of at least one of the thin film transistors repeatedly and/or continuously via the wiring while the load element is driven, and a reverse bias-application step adapted to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the driven load element is not disturbed. 22. A method of driving a pixel circuit according to claim 21, comprising a complement step adapted to operate an additional thin-film transistor connected in parallel to the thin-film transistor complementarily relative to the thin-film transistor, thereby generating timing where the driven load element is not disturbed, wherein the reverse bias-application step is adapted to apply the reverse bias to the thin-film transistor in the generated timing. 23. A method of driving a display device comprising scan lines in rows, scan lines in columns, and pixel circuits provided at intersections of the scan lines, wherein, upon being selected by the scan line, the pixel circuit samples a video signal from the signal line and drives a light-emission element according to the sampled video signal, and wherein the pixel circuit includes a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, the driving method being adapted to perform: a forward bias-application step adapted to apply a forward bias between the gate and the source of at least one of the thin-film transistors repeatedly and/or continuously via the wiring while the light-emission element is driven, and a reverse bias-application step adapted to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the driven light-emission element is not disturbed. 24. A method of driving a display device according to claim 23, the driving method comprising a complement step adapted to operate an additional thin-film transistor connected in parallel to the thin-film transistor complementarily relative to the thin-film transistor, thereby generating timing where the driven light-emission element is not disturbed, wherein the reverse bias-application step is adapted to apply the reverse bias to the thin-film transistor in the generated timing.

TECHNICAL FIELD The present invention relates to a transistor circuit including thin-film transistors integrally formed on a substrate. Further, the present invention relates to a pixel circuit which is an example of the transistor circuit. Still further, the present invention relates to a display device including the pixel circuits arranged in matrix. The active-matrix display device includes a flat display panel such as a liquid-crystal display and an organic EL display, for example. BACKGROUND ART The thin-film transistor which is an example field-effect transistor uses an amorphous silicon film and/or a polycrystalline silicon film formed on an insulation substrate including glass or the like, as an element region. In recent years, the thin-film transistor has been actively developed, as a pixel switch of the active-matrix display device. The thin-film transistor includes a gate, a drain, and a source, and passes a current between the source and the drain according to a voltage applied to the gate. When the thin-film transistor operates in a saturation region, a drain current Ids is provided according to the following transistor-characteristic expression. Ids=(½) μ(W/L)Cox(Vgs−Vth)2 Here, Vgs represents the gate voltage with reference to the source, Vth represents a threshold voltage, Cox represents a gate capacitor, W represents a channel width, L represents a channel length, and μ represents the mobility of a semiconductor film. As is clear from the transistor-characteristic expression, when the gate voltage Vgs of the thin-film transistor exceeds the threshold voltage Vth, the drain current Ids is passed. Several thin-film transistors are connected so that a transistor circuit having a predetermined function is formed. In general, the transistor circuit includes a plurality of thin-film-transistors formed on a substrate and wiring adapted to connect the gate, source, and/or drain of each of the transistors, so as to perform a predetermined operation. A pixel circuit is a typical example of the above-described transistor circuit. The pixel circuit is formed at each of intersections of scan lines in rows and signal lines in columns so that the entire pixel circuits form the active-matrix display device. Upon being selected by the scan line, the pixel circuit operates, so as to sample a video signal from the signal line and drive a load element such as an organic EL light-emission element. The above-described active matrix-organic EL-display device including the thin-film transistor, as an active element, is disclosed in Japanese Unexamined Patent Application Publication No. 8-234683, for example. In the saturation region, when the gate voltage exceeds the threshold voltage, the thin-film transistor is turned on and the drain current is passed, as is clear from the above-described transistor-characteristic expression. On the other hand, when the gate voltage becomes lower than the threshold voltage, the thin-film transistor is cut off. However, the threshold voltage Vth of the thin-film transistor is not necessarily constant but varied with time. Due to the variation in the threshold voltage, the cut-off operation is disturbed, which causes the transistor circuit to malfunction. Further, as is clear from the above-described transistor-characteristic expression, the drain current varies as the threshold value varies, even though the gate voltage is maintained constant. In the case of a pixel circuit configured to drive a light-emission element by a current, the drain current is varied due to the variation in the threshold voltage, so that the brightness of the light-emission element is deteriorated. DISCLOSURE OF INVENTION In view of the above-described known technical problems, an object of the present invention is to provide a transistor circuit having the function of correcting variations in the threshold voltage of a thin-film transistor, a pixel circuit, a display device, and a driving method therefor. For achieving the object, the following means is provided. That is to say, a transistor circuit having a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, so as to perform a predetermined operation, is provided. The transistor circuit includes at least one thin-film transistor applied with a forward bias between a gate and a source repeatedly and/or continuously via wiring during the operation, and reverse-bias-application means configured to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the operation is not disturbed. Preferably, an additional thin-film transistor connected in parallel to the thin-film transistor and complement means which drives the additional thin-film transistor relative to the thin-film transistor, so as to generate timing where the above-described operation is not disturbed, are provided, wherein the reverse-bias-application means applies the reverse bias to the thin-film transistor in the generated timing. For example, the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the N-channel type and/or the P-channel type, similarly, and the complement means applies a pulse to a gate of the additional thin-film transistor, the pulse being opposite in phase to a pulse applied to the gate of the thin-film transistor. On the other hand, the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the P-channel type and/or the N-channel type, oppositely, and the complement means applies a pulse to the additional thin-film transistor, the pulse being in phase with a pulse applied to the gate of the thin-film transistor. Further, the present invention provides a pixel circuit that is provided at each of intersections of scan lines in rows and scan lines in columns, and that samples a signal from the signal line upon being selected by the scan line and drives a load element according to the sampled signal. The pixel circuit includes a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source and/or a drain of each of the thin-film transistors, at least one thin-film transistor applied with a forward bias between a gate and a source repeatedly and/or continuously via wiring while the load element is driven, and reverse-bias-application means configured to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the driven load element is not disturbed. Preferably, an additional thin-film transistor connected in parallel to the thin-film transistor and complement means which operates the additional thin-film transistor complementarily relative to the thin-film transistor and generates timing where the above-described driven load element is not disturbed are provided. The reverse-bias-application means applies the reverse bias to the thin-film transistor in the generated timing. For example, the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the N-channel type and/or the P-channel type, similarly, and the complement means applies a pulse to a gate of the additional thin-film transistor, the pulse being opposite in phase to a pulse applied to the gate of the thin-film transistor. On the other hand, the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the P-channel type and/or the N-channel type, oppositely, and the complement means applies a pulse to the additional thin-film transistor, the pulse being in phase with a pulse applied to the gate of the thin-film transistor. Preferably, the plurality of thin-film transistors includes a sampling thin-film transistor that is brought into conduction upon being selected by the scan line, and that samples a signal from the signal line and holds the sampled signal in a holding capacitor, a drive thin-film transistor which controls the amount of power applied to the load element according to the potential of the signal held in the holding capacitor, and a switching thin-film transistor which performs on/off control of the amount of power applied to the load element, wherein the reverse-bias-application means applies the reverse bias to at least one of the drive thin-film transistor and the switching thin-film transistor. Further, threshold voltage-cancellation means is included, the threshold voltage-cancellation means being configured to adjust the level of a signal potential applied to a gate of the drive thin-film transistor, so as to cancel a variation in a threshold voltage of the drive thin-film transistor. Further, bootstrap means is included, the bootstrap means being configured to automatically control the level of a signal potential applied to a gate of the drive thin-film transistor, so as to accommodate a variation in the characteristic of the load element. Further, the present invention provides a display device including scan lines in rows, scan lines in columns, and pixel circuits provided at intersections of the scan lines, wherein, upon being selected by the scan line, the pixel circuit samples a video signal from the signal line and drives a light-emission element according to the sampled video signal. The pixel circuit includes a plurality of thin-film transistors formed on a substrate, wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, at least one thin-film transistor applied with a forward bias between a gate and a source repeatedly and/or continuously via wiring while the light-emission element is driven, and reverse-bias-application means configured to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the driven light-emission element is not disturbed. Preferably, an additional thin-film transistor connected in parallel to the thin-film transistor and complement means are provided, the complement means being configured to operate the additional thin-film transistor complementarily relative to the thin-film transistor and generate timing where the driven light-emission element is not disturbed, wherein the reverse-bias-application means applies the reverse bias to the thin-film transistor in the generated timing. For example, the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the N-channel type and/or the P-channel type, similarly, and the complement means applies a pulse to a gate of the additional thin-film transistor, the pulse being opposite in phase to a pulse applied to the gate of the thin-film transistor. On the other hand, the thin-film transistor is of an N-channel type and/or a P-channel type, the additional thin-film transistor is of the P-channel type and/or the N-channel type, oppositely, and the complement means applies a pulse to the additional thin-film transistor, the pulse being in phase with a pulse applied to the gate of the thin-film transistor. Preferably, the plurality of thin-film transistors includes a sampling thin-film transistor that is brought into conduction upon being selected by the scan line, and that samples a video signal from the signal line and holds the sampled video signal in a holding capacitor, a drive thin-film transistor which controls the amount of power applied to the light-emission element according to the potential of the signal held in the holding capacitor, and a switching thin-film transistor which performs on/off control of the amount of power applied to the light-emission element, wherein the reverse-bias-application means applies the reverse bias to at least one of the drive thin-film transistor and the switching thin-film transistor. Further, threshold voltage-cancellation means is included, the threshold voltage-cancellation means being configured to adjust the level of a signal potential applied to a gate of the drive thin-film transistor, so as to cancel a variation in a threshold voltage of the drive thin-film transistor. Still further, bootstrap means is included, the bootstrap means being configured to automatically control the level of a signal potential applied to a gate of the drive thin-film transistor, so as to accommodate a variation in the characteristic of the load element. Further, the present invention provides a method of driving a transistor circuit including a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, so as to perform a predetermined operation. The driving method is adapted to perform a forward bias-application step adapted to apply a forward bias between the gate and the source of at least one of the thin film transistors repeatedly and/or continuously via the wiring during the operation, and a reverse bias-application step adapted to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the operation is not disturbed. Further, a complement step is included, the complement step being adapted to drive an additional thin-film transistor connected in parallel to the thin-film transistor complementarily relative to the thin-film transistor, thereby generating timing where the operation is not disturbed, wherein the reverse bias-application step is adapted to apply the reverse bias to the thin-film transistor in the generated timing. Further, the present invention provides a method of driving a pixel circuit that is provided at each of intersections of scan lines in rows and scan lines in columns, and that includes a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors, so as to sample a signal from the signal line upon being selected by the scan line and drive a load element according to the sampled signal. The driving method is adapted to perform a forward bias-application step adapted to apply a forward bias between the gate and the source of at least one of the thin film transistors repeatedly and/or continuously via the wiring while the load element is driven, and a reverse bias-application step adapted to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the driven load element is not disturbed. Further, a complement step is included, the complement step being adapted to operate an additional thin-film transistor connected in parallel to the thin-film transistor complementarily relative to the thin-film transistor, thereby generating timing where the driven load element is not disturbed, wherein the reverse bias-application step is adapted to apply the reverse bias to the thin-film transistor in the generated timing. Further, the present invention provides a method of driving a display device comprising scan lines in rows, scan lines in columns, and pixel circuits provided at intersections of the scan lines, wherein, upon being selected by the scan line, the pixel circuit samples a video signal from the signal line and drives a light-emission element according to the sampled video signal, and wherein the pixel circuit includes a plurality of thin-film transistors formed on a substrate and wiring adapted to connect a gate, a source, and/or a drain of each of the thin-film transistors. The driving method is adapted to perform a forward bias-application step adapted to apply a forward bias between the gate and the source of at least one of the thin-film transistors repeatedly and/or continuously via the wiring while the light-emission element is driven, and a reverse bias-application step adapted to suppress a variation in a threshold voltage of the thin-film transistor by applying a reverse bias between the gate and source of the thin-film transistor in such timing that the driven light-emission element is not disturbed. Further, a complement step is included, the complement step being adapted to operate an additional thin-film transistor connected in parallel to the thin-film transistor complementarily relative to the thin-film transistor, thereby generating timing where the driven light-emission element is not disturbed, wherein the reverse bias-application step is adapted to apply the reverse bias to the thin-film transistor in the generated timing. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A to 1C are schematic diagrams showing a transistor circuit according to a first embodiment of the present invention. FIG. 2 is a timing chart provided for illustrating operations of the transistor circuit shown in FIG. 1A. FIG. 3 shows schematic diagrams showing a transistor circuit according to a second embodiment of the present invention. FIGS. 4A and 4B are schematic diagrams showing a transistor circuit according to a third embodiment of the present invention. FIG. 5 is a block diagram showing an overview of an active-matrix display device relating to the present invention and pixel circuits included therein. FIG. 6 is a block diagram showing an example pixel circuit. FIG. 7 is a timing chart provided, so as to illustrate operations of the pixel circuit shown in FIG. 6. FIGS. 8A and 8B are schematic diagrams showing another example pixel circuit. FIG. 9 is a circuit diagram showing a pixel circuit according to a first embodiment of the present invention. FIG. 10 is a timing chart provided, so as to illustrate operations of the pixel circuit shown in FIG. 9. FIG. 11 is a circuit diagram showing a pixel circuit according to a second embodiment of the present invention. FIG. 12 is a timing chart provided, so as to illustrate operations of the pixel circuit shown in FIG. 11. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings. FIGS. 1A to 1C show a transistor circuit according to a first embodiment of the present invention. FIG. 1A is a circuit diagram showing the structure, FIG. 1B is a timing chart showing the operations, and FIG. 1C is a graph showing the principles. As shown in FIGS. 1A, the transistor circuit includes two thin-film transistors Tr1 and Tr2 formed on a substrate, and wiring provided for connecting the gates, sources, and drains of the thin-film transistors Tr1 and Tr2, so as to perform inverter operations. That is to say, the transistor circuit is forms an inverter by using two N-channel transistors Tr1 and Tr2. Since the N-channel thin-film transistor can be produced at low cost by using an amorphous silicon film, as an active layer, the N-channel thin-film transistor has a cost advantage. Here, the inverter is shown, as merely an example, and it is essential only that the transistor circuit relating to the present invention include the thin-film transistors irrespective of the functions and operations thereof. Specifically, according to the circuit configuration, a predetermined gate voltage V1 is applied to the gate of the transistor Tr1, the drain is applied with a power voltage Vcc and the source transmits an output Vout. In the drawing, a load capacity CL is connected to an output end. The output Vout is applied to one end of the load capacity CL and the other end is grounded on Vss. Since the gate voltage V1 is set, so as to be greater than the sum of a threshold voltage of the transistor Tr1 and the power voltage Vcc, the transistor Tr1 is turned on at all times. An input signal Vin is applied to the gate of the transistor Tr2, the source is grounded on Vss, and the drain is connected to the source of the transistor Tr1, whereby an output node is generated. Since the transistor circuit performs an inverter operation, as shown in FIG. 1B, the input signal Vin is reversed and the output signal Vout is obtained. That is to say, when the input signal Vin is at a low level (L), the output signal Vout is at a high level (H). When the input signal Vin is at the level H, the output signal Vout is at the level L. As for the transistor Tr2, when the input signal Vin is at the low level, the transistor Tr2 is turned off so that the output node is detached from the ground potential Vss. Since the transistor Tr1 is turned on at all times, the output node is pulled up to the power voltage Vcc. As a result, the level of the output Vout becomes high (Vcc). Conversely, when the input signal Vin is at the high level, the transistor Tr2 is turned on, and the output node is pulled down toward the ground potential Vss. When the sum of a current discharged from the load capacity CL and a current transmitted from the transistor Tr1 becomes proportional to a current flowing through the transistor Tr2, the output Vout is determined to be at the low level. Usually, the Vout at the low level is a little higher than the ground potential Vss. As is clear from the description above, the input signal Vin at the low level should be lower than the threshold voltage of the transistor Tr2 and is usually set to the ground potential Vss. On the other hand, the input signal Vin at the high level should be sufficiently higher than the threshold voltage of the transistor Tr2. However, according to the above-described ordinary settings, a high-level forward bias is repeatedly applied to the gate of the transistor Tr2, which causes an upward variation in the threshold voltage of the transistor Tr2. If the upward variation is allowed to continue unaddressed, the input signal Vin at the high level may become lower than the threshold voltage which is varied upward, which becomes the cause of a malfunction. Therefore, according to the present invention, the input signal Vin at the low level is applied to the transistor Tr2 at regular time intervals, as a negative potential lower than the ground potential Vss, that is, a reverse bias. The threshold voltage which is shifted upward is revised downward by the reverse bias. As a result, variations in the threshold voltage of the transistor Tr2 can be suppressed. That is to say, according to the first embodiment, the source of the input signal Vin forms reverse-bias application means and applies a reverse bias between the gate and source of the thin-film transistor Tr2 in such timing that the inverter operation is not disturbed (low-level timing in the drawing), so as to suppress the variations in the threshold voltage of the thin-film transistor Tr2. FIG. 1C is a graph showing variations in the threshold voltage of the thin-film transistor Tr2. The horizontal axis shows a gate voltage Vgs relative to the source potential and the vertical axis shows a threshold voltage Vth. When a gate voltage which is always positive (forward bias) is applied repeatedly and/or continuously, the threshold voltage Vth is varied upward. When the upward variation has gone too far, a normal on/off operation cannot be performed. Conversely, when a negative gate voltage (reverse bias) is applied continuously, the threshold voltage Vth is varied downward. The present invention uses the above-described phenomenon, that is to say, the upward-shifted threshold voltage obtained by the continuous application of the forward bias is revised downward by applying the reverse bias in such timing that the operation of the circuit is not disturbed so that the variations in the threshold voltage are suppressed. FIG. 2 is a timing chart showing an input signal Vin and an output signal Vout according to another embodiment, the input signal Vin and the output signal Vout being provided for the transistor circuit shown in FIG. 1A. In this embodiment, the duty of an input pulse Vin deviates from 50%, and a low-level period is short and a high-level period is long. Conversely, in the case of an output pulse Vout obtained by reversing the input pulse Vin, a high-level period is short and a low-level period is long. According to the operation state of a circuit block including the inverter, the above-described input signal Vin may be used. In this embodiment, the reverse bias (low level) is applied during intervals between the forward biases applied to the gate of the transistor Tr2. However, since the reverse-bias application time is short, a sufficient threshold-voltage-variation suppression advantage is not necessarily obtained. That is to say, since the upward variations in the threshold voltage is significant, the upward variations being caused by the continuous change in the forward bias (high level), the downward-revision advantage achieved by using the reverse bias often does not keep up with the upward variations. However, when compared to the case where the reverse bias is not added, it is clear that a predetermined threshold-voltage-variation suppression advantage can be obtained. FIG. 3 is a schematic diagram showing a transistor circuit according to a second embodiment of the present invention. FIG. 3(A) is a circuit diagram showing the configuration and FIG. 3(B) is a timing chart showing the operations. For the sake of clarity, the part corresponding to the first embodiment shown in FIGS. 1A and 1B is designated by the corresponding reference numeral. This embodiment is achieved by improving the embodiment shown in FIG. 1. Particularly, as has been described with reference to FIG. 2, an object of this embodiment is to cope with the case where a sufficient reverse-bias-application time period cannot be ensured. As shown in FIG. 3(A), an additional thin-film transistor Tr3 is connected in parallel to the transistor Tr2 which is a subject. An input signal Vin1 is applied to the gate of the transistor Tr2. As described above, a signal source of the input signal Vin1 forms the reverse-bias-application means at the same time. On the other hand, another input signal Vin2 is applied to the gate of the additional transistor Tr3. The signal source of the input signal Vin2 forms complement means which is a feature element of this embodiment. That is to say, the complement means drives the additional transistor Tr3 complementarily relative to the transistor Tr2 so that the timing where the operations of the transistor Tr2 are not disturbed is forcefully generated. The reverse-bias-application means applies the reverse bias to the thin-film transistor Tr2 in the forcefully generated timing so that the variations in the threshold voltage of the transistor Tr2 are suppressed. In this embodiment, the transistor Tr2 is of the N-channel type and the additional transistor Tr3 is of the same N-channel type. In that case, the complement means applies a signal pulse Vin2 to the gate of the additional transistor Tr3, the signal pulse Vin2 being opposite in phase to the signal pulse Vin1 applied to the transistor Tr2. When the transistors Tr2 and Tr3 are of the P-channel type, the signal pulses Vin1 and Vin2 are opposite in phase to each other. On the other hand, when one of the transistors Tr2 and Tr3 is of the N-channel type and the other is of the P-channel type, the signal pulses Vin1 and Vin2 are in phase. Next, the operations of a transistor circuit shown in FIG. 3(A) will be described with reference to FIG. 3(B). In timing T1, the level of the signal pulse Vin1 becomes low and that of the signal Vin2 also becomes low. At that time, both the transistors Tr2 and Tr3 connected in parallel to each other are turned off. Therefore, the output node is pulled up to the VCC side by the transistor Tr1. As a result, the level of the output signal Vout becomes high. In the next timing T2, the signal pulse Vin1 is shifted so that the level thereof becomes high and the signal pulse Vin2 is maintained at the low level. Since one of the transistors Tr2 and Tr3 that are connected in parallel to each other, that is, the transistor Tr2 is turned on, the output node is pulled down to the Vss side. As a result, the output signal Vout is shifted so that the level thereof becomes low. On the contrary, in the next timing T3, the signal pulse Vin1 is changed so that the level thereof becomes low and the signal pulse Vin2 is changed so that the level thereof becomes high. Subsequently, since one of the transistors Tr2 and Tr3 that are connected in parallel to each other, that is, the transistor Tr3 is turned on, the output node is further pulled down toward the Vss side. Therefore, the output signal Vout is maintained at the low level. Therefore, a single period of input and output signals comes to an end and a change to the next period is made. As is clear from the comparison of the signal pulses Vin1 and Vin2, both the signals are opposite in phase to each other in the timing T2 and the timing T3. Particularly, in timing T3, the transistor Tr2 is turned off and brought to a non-operation state. On the other hand, the transistor Tr3 is turned on and brought to an operation state so that the transistor Tr2 in the non-operation state is place of the transistor Tr2, the output node is further pulled down toward the Vss side and the output signal Vout which is a target can be obtained. The complement function of the transistor Tr3 generates the timing T3 where the operations of the transistor Tr2 are not disturbed. Reverse-bias-application means which is the source of the signal pulse Vin1 applies a reverse bias to the transistor Tr2 in the generated timing T3. As is clear from the timing chart, a time period T2 over which the forward bias is applied is roughly proportional to a time period T1+T3 over which a reverse bias is applied. Therefore, it becomes possible to revise the upward variations in the threshold voltage downward, as required. FIGS. 4A and 4B show a transistor circuit according a third embodiment achieved by improving the second embodiment shown in FIG. 3. FIG. 4A is a circuit diagram showing the configuration of this embodiment and FIG. 4B is a timing chart showing the operations. When the inverter circuit includes the transistors Tr1 and Tr2, both the transistors being of the N-channel type, the transistor Tr1 is kept in an operation state at all times. In other words, the transistor Tr1 is in the state of being applied with a forward bias at all times and the threshold voltage is shifted upward with time. When the upward shift has gone too far, normal operations are often disturbed. Therefore, in this embodiment, a complement transistor Tr4 is also connected in parallel to the transistor Tr1. As shown in FIG. 4B, in the timing T1 and the timing T2, a gate voltage v1 for the transistor Tr1 is at a high level and a gate voltage V2 for the transistor Tr4 is at a low level. On the contrary, in the timing T3 and the timing T4, the gate voltage V1 is changed so that the level thereof becomes low and the level of the gate voltage V2 becomes high. Subsequently, the transistors Tr1 and Tr4 operate complementarily for each other and an entire switch including the pair of the transistors Tr1 and Tr4 is maintained at the on state at all times. At that time, one of the gate voltages, that is, the gate voltage V1 is at the low level in the timing T3 and the timing T4, which makes it possible to apply a reverse bias, so as to correct the threshold value. On the other hand, since the gate voltage V2 is at the low level in the timing T1 and the timing T2, it becomes also possible to apply a reverse bias to the transistor Tr4, so as to suppress variations in the threshold voltage. FIG. 5 is a block diagram schematically showing an active-matrix display device which is an example application for the transistor circuit relating to the present invention and pixel circuits included therein. As shown in the drawing, the active-matrix display device includes a pixel array 1 functioning as main part and a group of peripheral circuits. The peripheral-circuit group includes a horizontal selector 2, a drive scanner 3, a light scanner 4, and so forth. The pixel array 1 includes scan lines WS in rows, signal lines DL in columns, and the pixel circuits 5 arranged in matrix, where the pixel circuits 5 are provided at intersections of the scan lines WS and the signal lines DL. The signal line DL is driven by the horizontal selector 2. The scan line WS is scanned by the light scanner 4. Further, other scan lines DS are also provided, so as to be parallel to the scan lines WS, and scanned by the drive scanner 3. Upon being selected by the scan line WS, the pixel circuit 5 samples a signal from the signal line DL. Further, upon being selected by the scan line DS, the pixel circuit 5 drives a load element according to the sampled signal. The above-described load element includes a current-driven light-emission element formed in each of the pixel circuit 5, for example. FIG. 6 is a reference drawing showing the basic configuration of the pixel circuit 5 shown in FIG. 5. The pixel circuit 5 includes a sampling thin-film transistor (sampling transistor Tr1), a drive thin-film transistor (drive transistor Tr2), a switching thin-film transistor (switching transistor Tr3), a holding capacitor C1, a load element (organic EL light-emission element), and so forth. Upon being selected by the scan line WS, the sampling transistor Tr1 is brought into conduction. Further, the sampling transistor Tr1 samples a video signal from the signal line DL and stores the sampled video signal into the holding capacitor C1. The drive transistor Tr2 controls the amount of power applied to the light-emission element EL according to the potential of the signal held in the holding capacitor C1. The switching transistor Tr3 is controlled by the scan line DS and turns the power applied to the light-emission element EL on/off. That is to say, the drive transistor Tr2 controls the light-emission brightness (luminosity) of the light-emission element EL according to the power amount. On the other hand, the switching transistor Tr3 controls the light-emission time of the light-emission element EL. Due to the above-described control performed by the transistors, the light-emission element EL included in each of the pixel circuits 5 offers the brightness corresponding to the video signal and a desired display image is produced on the pixel array 1. FIG. 7 is a timing chart provided for illustrating operations of the pixel array 1 and the pixel circuits 5 that are shown in FIG. 6. At the head of a single-field period (1f), a selection pulse ws [1] is applied to the pixel circuit 5 of the first row via the scan line WS during a single horizontal period (1H) and the sampling transistor Tr1 is brought into conduction. Subsequently, the video signal is sampled from the signal line DL and written into the holding capacitor C1. One end of the holding capacitor C1 is connected to the gate of the drive transistor Tr2. Therefore, when the video signal is written into the holding capacitor C1, the gate potential of the drive transistor Tr2 increases according to the written signal potential. At that time, a selection pulse ds [1] is applied to the switching transistor Tr3 via another scan line DS. During the application, the light-emission element EL keeps on emitting light. Since the level of the selection pulse ds [1] becomes low in the latter half of the single-field period 1f, the light-emission element EL enters the non-light-emission state. The ratio of the light-emission period and the non-light-emission period can be adjusted by adjusting the duty of the pulse ds [1], so that desired screen brightness can be obtained. When a shift to the next horizontal period is made, signal pulses ws [2] and ds [2] that are used for scanning are applied from the scan lines WS and DS to the second pixel circuit, respectively. Here, returning to FIG. 6, problems of the pixel circuit 5 shown as the reference example will be described. In the pixel circuit 5 shown as the reference example, each of the transistors Tr1 to Tr3 includes a thin-film transistor of the N-channel type so that an amorphous silicon film which is advantageous in terms of cost can be used, as an active layer. However, the drain of the drive transistor Tr2 is connected to the power voltage Vcc, and the source is connected to the anode of the light-emission element EL via the switching transistor Tr3. Subsequently, the transistor Tr2 becomes a so-called source follower, which raises a problem. The signal voltage held in the holding capacitor C1 is applied to the gate of the transistor Tr2 and is maintained constant in principle. However, the source potential varies as the current/voltage characteristic of the light-emission element EL changes over time. In general, the anode potential increases as the light-emission element EL deteriorates over time, so that the source potential also increases. The drive transistor Tr2 operates in a saturation region and a drain current Ids is dependent on the gate potential Vgs relative to the source potential, as shown by the above-described transistor-characteristic expression. Since the transistor Tr2 operates, as the source follower, even though the gate voltage itself is maintained constant, the source potential varies due to the characteristic deterioration of the light-emission element EL and the gate potential Vgs changes corresponding thereto. Therefore, the drain current Ids varies so that the brightness of the light-emission element EL is deteriorated, which raises another problem. Further, the drive transistor Tr2 in itself has variations in the threshold voltage Vth. As is clear from the above-described transistor-characteristic expression, if the gate potential Vgs is maintained constant when the drive transistor Tr2 operates in the saturation region, the drain current IDS changes as the threshold voltage Vth varies, and the brightness of the light-emission element EL changes according to the variation. Particularly, since there are significant variations with time in the threshold voltage of the thin-film transistor including the amorphous silicon film, as the active layer (channel region), it is impossible to control the brightness of the light-emission element correctly without accommodating the variations. FIGS. 8A and 8B show a pixel circuit relating to another reference example obtained by improving the pixel circuit shown in FIG. 6. FIG. 8A is a circuit diagram showing the configuration and FIG. 8B is a timing chart showing the operations. According to the configuration of the improved example, a bootstrap circuit 6 and a threshold-voltage cancellation circuit 7 are added to the pixel circuit shown in FIG. 6, as shown in FIG. 8A. The bootstrap circuit 6 is adapted to automatically control the level of the signal potential applied to a gate (G) of the drive transistor Tr2, so as to accommodate variations in the characteristic of the light-emission element EL. The bootstrap circuit 6 includes a switching transistor Tr4. The scan line WS is connected to the gate of the switching transistor Tr4, the source is connected to the power potential Vss, and the drain is connected to one end of the holding capacitor C1 and connected to the source (S) of the drive transistor Tr2. When a selection pulse is applied to the scan line WS, the sampling transistor Tr1 is turned on and the switching transistor Tr4 is turned on. Accordingly, a video signal Vsig is written into the holding capacitor C1 via a coupling capacitor C2. When the selection pulse is cancelled from the scan line WS, the switching transistor Tr4 is turned off. Subsequently, the holding capacitor C1 is detached from the power potential Vss and coupled to the source. (S) of the drive transistor Tr2. When the selection pulse is applied to the scan line DS after that, the switching transistor Tr3 is turned on and a drive current is transmitted to the light-emission element EL through the drive transistor Tr2. The light-emission element EL starts emitting light, and the anode potential increases according to the current/voltage characteristic thereof so that the source potential of the drive transistor Tr2 increases. At that time, since the holding capacitor C1 is detached from the power potential Vss, the signal potential that had been held increases (bootstraps) as the source potential increases, so that the potential of the gate (G) of the drive transistor Tr2 increases. That is to say, even though the characteristic of the light-emission element EL varies, the gate voltage Vgs of the drive transistor Tr2 agrees with the net signal potential held in the holding capacitor C1 at all times. Due to the above-described bootstrap operations, the drain current of the drive transistor Tr2 is maintained constant at all times by the signal potential held in the holding capacitor C1 and the brightness of the light-emission element EL does not change, even though the characteristic of the light-emission element EL varies. By adding the above-described bootstrap means 6, the drive transistor Tr2 can function, as a constant-current power supply which operates with precision for the light-emission element EL. The threshold-voltage cancellation circuit 7 adjusts the level of the signal potential applied to the gate (G) of the drive transistor Tr2, so as to cancel the variations in the threshold voltage of the drive transistor Tr2, and includes the switching transistors Tr5 and Tr6. The gate of the switching transistor Tr5 is connected to another scan line AZ and the drain/source is connected between the gate and drain of the drive transistor Tr2. The gate of the switching transistor Tr6 is also connected to the scan line AZ, the source is connected to a predetermined off-set voltage Vofs, and the drain is connected to one of electrodes of the coupling capacitor C2. Further, in the drawing, the off-set voltage Vofs, the power potential Vss, and a cathode voltage (GND) may have potentials that are different from one another. However, all of the potentials may be set to a common potential (e.g., GND), as required. When a control pulse is applied to the scan line AZ, the switching transistor Tr5 is brought into conduction and a current flows from the Vcc side toward the gate of the drive transistor Tr2, so that the gate (G) potential increases. Subsequently, a drain current starts flowing into the drive transistor Tr2 and the potential of the source (S) increases. Exactly when the potential difference Vgs between the gate potential (G) and the source potential (S) agrees with the threshold voltage Vth of the drive transistor Tr2, the drain current stops flowing according to the above-described transistor-characteristic expression. The voltage Vgs between the source and the gate at that time is written into the holding capacitor C1, as the threshold voltage Vth of the transistor Tr2. Since the threshold voltage Vth written into the holding capacitor C1 is applied to the gate of the drive transistor Tr2 in addition to the signal potential Vsig, the advantage of the threshold voltage Vth is cancelled. Therefore, even though the threshold voltage Vth of the drive transistor Tr2 varies with time, the threshold-voltage cancellation circuit 7 can cancel the variations. FIG. 8B is a timing chart showing the waveforms of scan pulses applied to the scan lines WS, DS, and AZ and the waveforms of potentials of the gate (G) and the source (S) of the drive transistor Tr2. As shown in the drawing, when in a Vth-cancellation period, the pulse is applied to the scan line AZ, the switching transistor Tr5 is brought into conduction, and the gate potential of the transistor Tr2 increases. After that, since the pulse of the scan line DS falls, the current transmission from the power VCC-side is stopped. Subsequently, the difference between the gate potential and the source potential reduces, and when the difference corresponds to the threshold voltage Vth, the current value becomes zero. As a result, the threshold voltage Vth is written into the holding capacitor C1 connected between the gate and source of the transistor Tr2. Next, when the selection pulse is applied to the next scan line WS, the sampling transistor Tr1 is turned on and the signal Vsig is written into the holding capacitor C1 via the coupling capacitor C2. Subsequently, the signal Vin transmitted to the gate of the drive transistor Tr2 corresponds to the sum of the threshold voltage Vth that had already been written and the Vsig maintained with a predetermined gain. Further, the pulse is applied to the scan line DS and the switching transistor Tr3 is turned on. Subsequently, the drive transistor Tr2 transmits a drain current to the light-emission element EL according to the input-gate signal Vin so that light emission is started. Therefore, the anode potential of the light-emission element EL increases by as much as ΔV, and the above-described ΔV is added to the input signal Vin for the drive transistor Tr2 due to the bootstrap effect. According to the above-described threshold-voltage cancellation function and bootstrap function, even though the threshold voltage of the drive transistor Tr2 and the characteristic of the light-emission element EL vary, it becomes possible to cancel the variations so that the light-emission brightness is maintained constant. By the way, a voltage higher than the source is applied to the gate of the drive transistor Tr2 over the single-field period 1f so that the gate is forward-biased at all time. Since the forward bias is applied to the gate continuously, the threshold voltage Vth of the drive transistor Tr2 varies upward. The threshold-voltage cancellation circuit 7 can cancel the variation. However, when the variation becomes excessively significant the cancel function becomes insufficient to handle the variation, which may change the brightness of the light-emission element EL. Further, the switching transistor Tr3 is turned on and forward-biased during the light-emission period. Subsequently, the threshold voltage of the switching transistor Tr3 varies upward and at the worst, the switching transistor Tr3 may fall into the cut-off state at all times. FIG. 9 shows a pixel circuit according to an embodiment of the present invention. For addressing problems of the pixel circuit shown in FIG. 8A, reverse-bias application means adapted to suppress variations in the threshold voltage is provided for each of the drive transistor Tr2 and the switching transistor Tr3. The reverse-bias application means provided for the drive transistor Tr2 includes a switching transistor Tr7. An additional scan line WS2 is connected to the gate of the transistor Tr7, a negative power Vmb is connected to the source, and the drain is connected to the gate (G) of the drive transistor Tr2. Since the scan timing of the scan line WS2 is different from that of the scan line WS1 connected to the sampling transistor Tr1 and the switching transistor Tr4, the scan lines are divided into the scan lines WS1 and WS2. Here, the potential of the negative power Vmb is set, so as to be lower than the ground potential GND. Therefore, when a selection pulse is applied to the scan line WS2 in such timing that the operation of the pixel circuit is not disturbed, the transistor Tr7 is turned on and the reverse bias (Vmb) can be applied to the gate (G) of the drive transistor Tr2. Subsequently, a forward bias is continuously applied so that the upward-shifted threshold voltage Vth of the transistor Tr2 can be revised downward. The reverse-bias-application means provided for the switching transistor Tr3 is included in the drive scanner 3 (refer to FIG. 5) connected to the scan line DS1. During the light-emission period, the forward bias is applied to the gate of the switching transistor Tr3 via the scan line DS1 and the drain current flows from the power voltage Vcc toward the ground potential GND. When in the non-light-emission period, the potential of the scan line DS1 becomes lower than the ground potential GND and the reverse bias is applied to the switching transistor Tr3. Subsequently, the upward variations in the threshold voltage of the transistor Tr3 can be revised downward. FIG. 10 is a timing chart provided for illustrating operations of the pixel circuit shown in FIG. 9. The pulse applied to the scan line WS1 is represented as ws1, the pulse applied to the scan line WS2 is represented as ws2, the pulse applied to the scan line AZ is represented as az, and the pulse applied to the scan line DS1 is represented as ds1. Further, variations in the gate potential (G), the drain potential (D), and the source potential (S) of the drive transistor Tr2 are superimposed on the level change of the pulse ds1. Further, the drain potential (D) of the drive transistor Tr2 also denotes the source potential of the switching transistor Tr3. During the Vth-cancellation period, the pulse az is applied to the transistors Tr5 and Tr6, and the threshold voltage Vth of the drive transistor Tr2 is detected. The detected threshold voltage Vth is held in the holding capacitor C1, as the difference between the gate potential (G) and source potential (S) of the transistor Tr2. Next, when the pulse ws1 is applied to the sampling transistor Tr1 and the switching transistor Tr4, the video signal Vsig is sampled and written into the holding capacitor C1 via the coupling capacitor C2. The sum of the threshold voltage Vth and the video signal Vsig that are written into-the holding capacitor C1 is shown on the timing chart, as the difference between the gate potential (G) and source potential (S) of the transistor Tr2. Further, when the pulse ds1 is applied to the switching transistor Tr3 in the light-emission period, the drain current flows into the light-emission element EL through the drive transistor Tr2, whereby the source potential (S) increases. However, the difference between the source potential (S) and the gate potential (G) is maintained constant due to the bootstrap function. As the source potential (S) increases, the drain potential (D) also increases. The drain potential (D) denotes the source potential of the switching transistor Tr3. However, since the amplitude of the pulse DS1 is set, so as to be sufficiently higher than the drain potential (D), it becomes possible to apply a forward bias Va necessary for the transistor Tr3, so as to perform an on-operation. After that, when the pixel circuit enters the non-light-emission period, the pulse DS1 is changed so that the level thereof becomes low and the transistor Tr3 is cut off. Since the drain current is interrupted, the drain potential (D) of the drive transistor Tr2 is decreased from the Vcc side to the GND. At that time, since the low-level pulse DS1 is set, so as to be lower than the GND, a reverse bias Vb is applied to the gate of the switching transistor Tr3. Further, during the non-light-emission period, the pulse ws2 is applied to transistor Tr7 is brought into conduction and the reverse bias Vmb is applied to the gate (G) of the drive transistor Tr2. As is clear from the descriptions above, the reverse bias is applied to each of the drive transistor Tr2 and the switching transistor Tr3 in appropriate timing so that variations in the threshold voltage of each of the transistors can be suppressed. However, since the switching transistor Tr3 is susceptible to improvement to some extent, explanations of that matter will be provided. When considering the operation point of the transistor Tr3, the voltage level of the pulse ds1 and the drain voltage (D) of the drive transistor should be considered, as described above. Since the switching transistor Tr3 is turned on during the light-emission period, a potential H of the pulse ds1 is higher than the drain potential (D) by as much as the threshold voltage Vth of the transistor Tr3 and a voltage Va is applied. That is to say, a forward bias is applied between the gate and source of the transistor Tr3 during the light-emission period. After that, when the pixel circuit enters the non-light-emission period, the level L of the pulse DS1 becomes lower than the GND so that a reverse bias is applied. During the reverse-bias period, the drain potential (D) is reduced to the cathode potential (GND) or in the vicinity thereof due to leakage currents or the like. Since the transistor Tr3 is turned off during that period, the reverse bias is applied between the gate and source of the transistor Tr3 by as much as the reverse bias Vb. Therefore, since both the forward bias and the reverse bias are applied to the transistor Tr3, it becomes possible to reduce the variations in the threshold voltage Vth of the transistor Tr3 to a certain extent. However, when the light-emission time included in the single-field period (1f) is increased, the non-light-emission time is squeezed and decreased. Subsequently, the reverse-bias-application time is also decreased, which causes the need for revising the threshold voltage downward with efficiency by as much as the decreased reverse-bias-application time and setting the absolute value of the reverse bias Vb to a high degree. However, when the absolute value of the reverse bias Vb is high, the amplitude of the pulse ds1 increases, which leads to an increased cost. Further, the high absolute value significantly affects the resistance-to-pressure of the transistor Tr3, which affects not only the cost but also the yields. FIG. 11 shows an embodiment achieved by further improving the pixel circuit shown in FIG. 9. For the sake of clarity, parts corresponding to the pixel circuit shown in FIG. 9 are designated by the corresponding reference numbers. As for the improvements, an additional transistor Tr8 is connected in parallel to the problem transistor Tr3 and complement means is connected to the gate of the transistor Tr8 via the scan line DS2. The complement means complementarily drives the additional transistor Tr8 relative to the switching transistor Tr3, so as to generate timing where the operation of the transistor Tr3 is not disturbed. The reverse-bias-application means connected to the switching transistor Tr3 via the scan line DS1 is configured to apply a reverse bias to the transistor Tr3 in the generated timing. FIG. 12 is a timing chart provided for illustrating operations of the pixel circuit shown in FIG. 11. For the sake of clarity, the parts corresponding to the timing chart of the previous embodiment, the timing chart being shown in FIG. 10, are designated by the corresponding reference numbers. As for feature points, the pulse DS1 applied to the gate of the switching transistor Tr3 and the pulse DS2 applied to the gate of the additional transistor Tr8 are opposite to each other in phase. The forward bias Va is applied to the gate of the switching transistor Tr3 during the light-emission period, as is the case with the embodiment shown in FIG. 9. Next, when the pixel circuit enters the non-light-emission period, the pulse DS1 becomes lower than the GND so that the level thereof becomes low and the switching transistor Tr3 is turned off. Since the transistor Tr8 operates complementarily and enters the on state at that time, a current is further transmitted from the power-Vcc side to the drive transistor Tr2. Therefore, the drain potential (D) of the drive transistor Tr2 is not reduced to the cathode potential (GND) and the power potential Vcc and/or a potential in the vicinity thereof can be obtained. Subsequently, during the reverse-bias period included in the non-light-emission period, the absolute value of the voltage between the gate and source of the switching transistor Tr3 is shown as Vcc+Vb so that a significantly high reverse bias can be applied. Therefore, it becomes possible to revise upward variations in the threshold voltage downward with efficiency without applying the pulse DS1 with a large amplitude to the switching transistor Tr3. Thus, since the pixel circuit can accommodate the variations in the threshold voltages of the amorphous silicon thin-film transistor and the polycrystalline silicon thin-film transistor, the brightness of the light-emission element EL is prevented from being deteriorated and a high-quality active-matrix display can be provided. Particularly, since there is no need to increase the amplitude of the pulse applied to the gate of the transistor which performs the on/off control over light emission, a low-cost driver can be achieved. Further, it becomes possible to easily accommodate the variations in the threshold voltage Vth of the switching transistor while accommodating the variations in the threshold voltage Vth of the drive transistor. Industrial Applicability When a positive gate voltage (forward bias) is applied to a thin-film transistor repeatedly and/or continuously, the threshold voltage thereof tends to be shifted in the positive direction. On the contrary, when a negative gate voltage (reverse voltage) is applied to the thin-film transistor repeatedly and/or continuously, the threshold voltage thereof tends to be shifted in the negative direction. A transistor circuit may include a thin-film transistor applied with a forward bias between the gate and source thereof repeatedly and/or continuously via circuit wiring according to the functions and/or operation conditions. Due to the forward bias, the threshold voltage of the thin-film transistor is shifted with time. If the shifted threshold voltage is left unaddressed, cut-off operations of the transistor are disturbed, for example, which may cause the transistor circuit to malfunction. In the present invention, therefore, for the thin-film transistor to which the forward bias has to be applied repeatedly and/or continuously in terms of the operations and/or functions of the transistor circuit, the reverse bias is applied in such timing that the operations are not disturbed. Subsequently, it becomes possible to reset the threshold voltage that had been shifted in the positive direction due to the forward bias in the negative direction, so that the variations in the threshold voltage can be suppressed. In the case of a thin-film transistor to which the forward bias is applied almost continuously, as required, it is often impossible to achieve timing adequate enough to apply the reverse bias. In that case, an additional thin-film transistor is connected in parallel to the thin-film transistor and the additional transistor is driven complementarily relative to the thin-film transistor so that the timing for applying the reverse bias is forcefully generated. Subsequently, in the case of a thin-film transistor of which threshold voltage has to be shifted upward due to continuous forward-bias application, the threshold voltage can be forcefully revised downward by connecting a complementary additional thin-film transistor in parallel to the thin-film transistor.

<SOH> BACKGROUND ART <EOH>The thin-film transistor which is an example field-effect transistor uses an amorphous silicon film and/or a polycrystalline silicon film formed on an insulation substrate including glass or the like, as an element region. In recent years, the thin-film transistor has been actively developed, as a pixel switch of the active-matrix display device. The thin-film transistor includes a gate, a drain, and a source, and passes a current between the source and the drain according to a voltage applied to the gate. When the thin-film transistor operates in a saturation region, a drain current Ids is provided according to the following transistor-characteristic expression. in-line-formulae description="In-line Formulae" end="lead"? Ids =(½) μ( W/L ) Cox ( Vgs−Vth )2 in-line-formulae description="In-line Formulae" end="tail"? Here, Vgs represents the gate voltage with reference to the source, Vth represents a threshold voltage, Cox represents a gate capacitor, W represents a channel width, L represents a channel length, and μ represents the mobility of a semiconductor film. As is clear from the transistor-characteristic expression, when the gate voltage Vgs of the thin-film transistor exceeds the threshold voltage Vth, the drain current Ids is passed. Several thin-film transistors are connected so that a transistor circuit having a predetermined function is formed. In general, the transistor circuit includes a plurality of thin-film-transistors formed on a substrate and wiring adapted to connect the gate, source, and/or drain of each of the transistors, so as to perform a predetermined operation. A pixel circuit is a typical example of the above-described transistor circuit. The pixel circuit is formed at each of intersections of scan lines in rows and signal lines in columns so that the entire pixel circuits form the active-matrix display device. Upon being selected by the scan line, the pixel circuit operates, so as to sample a video signal from the signal line and drive a load element such as an organic EL light-emission element. The above-described active matrix-organic EL-display device including the thin-film transistor, as an active element, is disclosed in Japanese Unexamined Patent Application Publication No. 8-234683, for example. In the saturation region, when the gate voltage exceeds the threshold voltage, the thin-film transistor is turned on and the drain current is passed, as is clear from the above-described transistor-characteristic expression. On the other hand, when the gate voltage becomes lower than the threshold voltage, the thin-film transistor is cut off. However, the threshold voltage Vth of the thin-film transistor is not necessarily constant but varied with time. Due to the variation in the threshold voltage, the cut-off operation is disturbed, which causes the transistor circuit to malfunction. Further, as is clear from the above-described transistor-characteristic expression, the drain current varies as the threshold value varies, even though the gate voltage is maintained constant. In the case of a pixel circuit configured to drive a light-emission element by a current, the drain current is varied due to the variation in the threshold voltage, so that the brightness of the light-emission element is deteriorated.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIGS. 1A to 1 C are schematic diagrams showing a transistor circuit according to a first embodiment of the present invention. FIG. 2 is a timing chart provided for illustrating operations of the transistor circuit shown in FIG. 1A . FIG. 3 shows schematic diagrams showing a transistor circuit according to a second embodiment of the present invention. FIGS. 4A and 4B are schematic diagrams showing a transistor circuit according to a third embodiment of the present invention. FIG. 5 is a block diagram showing an overview of an active-matrix display device relating to the present invention and pixel circuits included therein. FIG. 6 is a block diagram showing an example pixel circuit. FIG. 7 is a timing chart provided, so as to illustrate operations of the pixel circuit shown in FIG. 6 . FIGS. 8A and 8B are schematic diagrams showing another example pixel circuit. FIG. 9 is a circuit diagram showing a pixel circuit according to a first embodiment of the present invention. FIG. 10 is a timing chart provided, so as to illustrate operations of the pixel circuit shown in FIG. 9 . FIG. 11 is a circuit diagram showing a pixel circuit according to a second embodiment of the present invention. FIG. 12 is a timing chart provided, so as to illustrate operations of the pixel circuit shown in FIG. 11 . detailed-description description="Detailed Description" end="lead"?

20060526

20091020

20070426

63462.0

G09G330

LEWIS, DAVID LEE

TRANSISTOR CIRCUIT, PIXEL CIRCUIT, DISPLAY DEVICE, AND DRIVING METHOD THEREFOR

UNDISCOUNTED

ACCEPTED

G09G

ACCEPTED

Method And Apparatus For Providing Quality Of Service To Voip Over 802.11 Wireless Lans

The present invention provides a method and system for providing quality-of-service to VoIP over a wireless local access network by providing periodic, contention-free access to a wireless link for voice packets. This is achieved by coupling Session Initiation Protocol (“SIP”) signaling for call setup with the Point Coordination Function mode of operation of the 802.11 medium access control. The result is that VoIP call signaling via SIP is tied with availability of periodic time-slots on the wireless medium. The periodic time-slots are used to guarantee contention-free access to the wireless link for voice packets. Accordingly, the present invention, in effect, merges two networking technologies: SIP-based VoIP and 802.11-based wireless LANs.

1. A method for providing quality-of-service to VoIP over a wireless local access network comprising: sending an invite message from a calling party to a SIP proxy server; determining whether voice slots are available on an access point; forwarding the invite message from the SIP proxy server to a called party, and if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, adding the calling party to the polling list of the access point, and sending packets to and receiving packets from the called party during a contention-free period of the access point; and 2. The method of claim 1, further comprising if the voice slots are not available on the access point, sending a termination message from the SIP proxy server to the called party. 3. The method of claim 1, wherein sending an invite message to a SIP proxy server comprises sending a SIP INVITE message to the SIP proxy server. 4. The method of claim 3, wherein forwarding the invite message from the SIP proxy server to a called party comprises forwarding the SIP invite message from the SIP proxy server to a called party. 5. The method of claim 1, wherein if the called party sends an acknowledgement message to a calling party in response to receiving the invite message comprises if the called party sends a SIP ACK message to a calling party in response to receiving the invite message. 6. The method of claim 1, wherein sending a termination message from the SIP proxy server to the called party comprises sending a SIP BYE message from the SIP proxy server to the called party. 7. The method of claim 1, wherein adding the calling party to the polling list of the access point comprises sending a MAC management frame from the calling party to the access point requesting the calling party be added to the polling list. 8. The method of claim 7, wherein sending a MAC management frame from the calling party to the access point requesting the calling party to be added to the polling list comprises sending a MAC management frame from the calling party to a point coordinator of the access point. 9. The method of claim 1, further comprising adding the called party to the polling list of the access point. 10. The method of claim 9, wherein adding the called party to the polling list of the access point comprises sending a MAC management frame from the called party to the access point requesting the called party be added to the polling list. 11. The method of claim 10, wherein sending a MAC management frame from the called party to the access point requesting the called party be added to the polling list comprises sending a MAC management frame from the called party to a point coordinator of the access point. 12. The method of claim 1, further comprising adding the called party to the polling list of a new access point. 13. The method of claim 12, wherein adding the called party to the polling list of the new access point comprises sending a MAC management frame from the called party to the new access point requesting the called party be added to the polling list. 14. The method of claim 13, wherein sending a MAC management frame from the called party to the new access point requesting the called party be added to the polling list comprises sending a MAC management frame from the called party to a point coordinator of the new access point. 15. The method of claim 1, further comprising if the voice slots are available on the access point, at least one of sending a termination message from the called party to the calling party and sending a termination message from the calling party to the called party. 16. The method of claim 15, wherein at least one of sending a termination message from the called party to the calling party and sending a termination message from the calling party to the called party comprises at least one of sending a SIP BYE message from the called party to the calling party and sending a termination message from the calling party to the called party. 17. The method of claim 16, further comprising if at least one of the calling party and the called party sends a confirmation message, removing at least one of the calling party and the called party from the polling list of the access point. 18. The method of claim 17, wherein if at least one of the calling party and the called party sends a confirmation message comprises if at least one of the calling party and the called party sends a SIP OK message. 19. The method of claim 17, wherein removing at least one of the calling party and the called party from the polling list of the access point comprises sending a MAC management frame from the at least one of the calling party and the called party to the access point requesting the at least one of the calling party and the called party be removed from the polling list. 20. The method of claim 19, wherein sending a MAC management frame from the at least one of the calling party and the called party to the access point requesting the at least one of the calling party and the called party be removed from the point coordinator of the polling list. 21. The method of claim 1, further comprising if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, moving at least one of the calling party and the called party to a new access point in a same IP subnet, and adding the at least one of the calling party and the called party to the polling list of the new access point. 22. The method of claim 1, further comprising if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, moving at least one of the calling party and the called party to a new access point in a different IP subnet, adding the at least of one of the calling party and the called party to the polling list of the new access point, and sending a re-invite message to at least one of the calling party and the called party. 23. The method of claim 22, wherein sending a re-invite message to at least one of the calling party and the called party comprises sending a SIP RE-INVITE message to at least one of the calling party and the called party. 24. The method of claim 1, wherein sending packets to and receiving packets from the calling party during a contention-free period of the access point comprises sending packets to the access point, wherein the access point forwards the packets to at least one of the called party and the calling party. 25. The method of claim 24, wherein sending packets to the access point further comprises sending packets from the access point to a voice VLAN via a wireline network, wherein the wireline network is a switched network. 26. The method of claim 25, wherein sending packets to the access point further comprises sending packets from the access point to a voice VLAN via a wireline network, wherein the wireline network is a switched ethernet. 27. The method of claim 26, wherein sending packets from the access point to a voice VLAN via a wireline network further comprises sending packets from the access point to a voice VLAN via a wireline network using packet level quality-of-service techniques. 28. The method of claim 27, wherein sending packets from the access point to a voice VLAN via a wireline network using packet level quality-of-service techniques comprises sending packets from the access point to a voice VLAN via a wireline network using Differentiated Services. 29. A machine-readable medium having instructions stored thereon for execution by a processor to perform a method for providing quality-of-service to VoIP over a wireless local access network, comprising: sending an invite message from a calling party to a SIP proxy server; determining whether voice slots are available on an access point; and forwarding the invite message from the SIP proxy server to a called party, and if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, adding the calling party to the polling list of the access point, and sending packets to and receiving packets from the called party during a contention-free period of the access point. 30. The machine-readable medium of claim 29, wherein the method further comprises if the voice slots are not available on the access point, sending a termination message from the SIP proxy server to the called party. 31. An system for providing quality-of-service to VoIP over a wireless local access network, comprising: means for sending an invite message from a calling party to a SIP proxy server; means for determining whether voice slots are available on an access point; means for forwarding the invite message from the SIP proxy server to a called party, and if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, means for adding the calling party to the polling list of the access point, and means for sending packets to and receiving packets from the called party during a contention-free period of the access point. 32. The system of claim 31, further comprising means for sending a termination message from the SIP proxy server to the called party. 33. The system of claim 31, wherein one machine comprises the SIP proxy server and the access point. 34. The system of claim 31, wherein a first machine comprises the SIP proxy server and a second machine comprises the access point. 35. The system of claim 34, further comprising a communication protocol between the first machine and the second machine for allowing the SIP proxy server and the access point to communicate.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to computer networks, and, more particularly, to voice-over-IP networks over wireless local area networks. 2. Description of the Related Art Traditional telephony carriers, which primarily utilize a public-switched telephony network (“PSTN”), are moving towards a packet-based Voice-over-IP (“VoIP”) infrastructure. A key component of a typical telephony infrastructure is “call control.” Call control comprises a call setup and a call teardown. Both the call setup and the call teardown involve an exchange of call control messages between two end users. Either end user may initiate the setup or teardown. The call setup allocates resources for the exchange of voice and/or data between the two end users. In contrast, the call teardown frees up those resources such that other end users may exchange voice and/or data. In VoIP, call control is achieved through Session Initiation Protocol (“SIP”). It should be noted that one of ordinary skill in the are would contemplate achieving call control through any of a variety of other known protocols. In addition to carrier networks, VoIP has been steadily ground in enterprise networks as well. In parallel with the adoption of VoIP, many enterprise networks are in the process of deploying support network access via IEEE 802.11 based wireless local area networks (“LANs”). The 802.11 wireless LAN standard offers a medium access method, called Point Coordination Function (“PCF”), that offers support for near-isochronous (i.e., real-time) services where an “Access Point” periodically polls individual stations for packets to transmit. However, there has been little deployment of VoIP over wireless LANs using PCF. A key reason is that most 802.11 Access Points support a medium access method known as Distributed Coordination Function (“DCF”), that is contention-based, i.e., each wireless station competes for control of the wireless medium. While the DCF method works for data packets, VoIP packets, on the other hand, require timely, periodic access to the wireless medium to maintain acceptable voice quality. With increasing use of wireless LANs in the enterprise, use of IP softphones, for example, on 802.11 enabled laptops and handheld devices to initiate and receive VoIP calls will explode. It is well understood that quality of service (“QoS”) is required for voice traffic in terms of delay, jitter and loss. At the same time, bandwidth on wireless links is far below that of wireline links (e.g., ethernet), and, therefore, uncontrolled access to the wireless medium can introduce unacceptable delay for VoIP traffic. Therefore, to make efficient use of wireless resources and provide real-time services for VoIP packets, a need exists for a method and apparatus to manage the contention resulting from VoIP call signaling on the wireless medium. Without a solution to this problem, voice quality for VoIP calls over wireless LANs will degrade to unacceptable levels as the data/voice traffic on the wireless link increases. In other words, the method and apparatus should provide sufficient QoS to support wireless voice quality comparable to that of wireline links, even in the prospect of reduced wireless bandwidth. SUMMARY OF THE INVENTION In one aspect of the present invention, a method for providing quality-of-service to VoIP over a wireless local access network is provided. The method comprises sending an invite message from a calling party to a SIP proxy server and determining whether voice slots are available on an access point. The method forwards the invite message from the SIP proxy server to a called party, and if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, the method adds the calling party to the polling list of the access point, and sends packets to and receives packets from the called party during a contention-free period of the access point. In another aspect of the present invention, a machine-readable medium having instructions stored thereon for execution by a processor to perform a method for providing quality-of-service to VoIP over a wireless local access network is provided. The medium contains instructions for sending an invite message from a calling party to a SIP proxy server and determining whether voice slots are available on an access point. The medium contains instructions for forwarding the invite message from the SIP proxy server to a called party, and if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, the medium contains instructions for adding the calling party to the polling list of the access point, and sending packets to and receiving packets from the called party during a contention-free period of the access point. In yet another aspect of the present invention, a system for providing quality-of-service to VoIP over a wireless local access network is provided. The system contains means for sending an invite message from a calling party to a SIP proxy server and means for determining whether voice slots are available on an access point. The system contains means for forwarding the invite message from the SIP proxy server to a called party, and if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, the system contains means for adding the calling party to the polling list of the access point, and means for sending packets to and receiving packets from the called party during a contention-free period of the access point. BRIEF DESCRIPTION OF THE DRAWINGS The invention may be understood by reference to the following description taken in conjunction with the accompanying drawings, in which like reference numerals identify like elements, and in which: FIG. 1 is an exemplary SIP configuration, in accordance with one embodiment of the present invention; FIG. 2 is an exemplary operation of a superframe based on the IEEE 802.11 standard, in accordance with one embodiment of the present invention; and FIG. 3 is an exemplary SIP configuration, in accordance with one embodiment of the present invention. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Illustrative embodiments of the invention are described below. In the interest of clarity, not all features of an actual implementation are described in this specification. It will of course be appreciated that in the development of any such actual embodiment, numerous implementation-specific decisions must be made to achieve the developers' specific goals, such as compliance with system-related and business-related constraints, which will vary from one implementation to another. Moreover, it will be appreciated that such a development effort might be complex and time-consuming, but would nevertheless be a outline undertaking for those of ordinary skill in the art having the benefit of this disclosure. While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the description herein of specific embodiments is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims. It is to be understood that the systems and methods described herein may be implemented in various forms of hardware, software, firmware, special purpose processors, or a combination thereof. In particular, the present invention is preferably implemented as an application comprising program instructions that are tangibly embodied on one or more program storage devices (e.g., hard disk, magnetic floppy disk, RAM, ROM, CD ROM, etc.) and executable by any device or machine comprising suitable architecture, such as a general purpose digital computer having a processor, memory, and input/output interfaces. It is to be further understood that, because some of the constituent system components and process steps depicted in the accompanying Figures are preferably implemented in software, the connections between system modules (or the logic flow of method steps) may differ depending upon the manner in which the present invention is programmed. Given the teachers herein, one of ordinary skill in the related art will be able to contemplate these and similar implementations of the present invention. As explained in greater detail in the disclosure herein, the present invention generally provides quality of service (“QoS”) to Voice-over-IP (“VoIP”) over an 802.11 wireless local area network (“LAN”) by providing periodic, contention-free access to a wireless link for voice packets. This is achieved by coupling Session Initiation Protocol (“SIP”) signaling for call setup with the Point Coordination Function (“PCF”) mode of operation of the 802.11 medium access control (“MAC”). The result is that VoIP call signaling via SIP is tied with availability of periodic time-slots on the wireless medium. The periodic time-slots are used to guarantee contention-free access to the wireless link for voice packets. Accordingly, the present invention, in effect, merges two networking technologies: SIP-based VoIP and 802.11-based wireless LANs. A brief overview of both technologies will now be presented. Referring now to FIG. 1, an exemplary SIP configuration 100 is illustrated, in accordance with one embodiment of the present invention. SIP is a signaling protocol for VoIP. SIP comprises call messages for call setup, such as “INVITE,” and for call teardown, such as “BYE.” The call messages are usually sent as UDP/IP packets. An exemplary call setup is described as follows. A first call endpoint (“user agent”) 105 such as an IP Phone or a laptop running an IP softphone, registers with a first SIP Proxy 110 using a SIP REGISTER message (e.g., an INVITE message). The first SIP Proxy is responsible for routing the INVITE message via a second SIP Proxy 115 to a second call endpoint 120. It is understood that although only two SIP Proxies 110, 115 are shown in FIG. 1, any number of SIP Proxies may be used, as is known to those skilled in the art, for routing the INVITE message to the second call endpoint 120. When the second call endpoint 120 receives the INVITE message, the second call endpoint 120 initiates a SIP “200 (OK)” message, which is routed via the SIP Proxies 110, 115 to the first call endpoint 105. When the first call endpoint 110 receives the “200 (OK)” message, the first call endpoint 105 initiates a SIP “ACK” message, which is routed via the SIP Proxies 110, 115 to the second call endpoint 120. When the “ACK” message reaches the first call endpoint 105, the call setup has succeeded. The three SIP messages (i.e., INVITE, 200 (OK), ACK) may carry a Session Description Protocol (“SDP”) payload describing an IP address and associated port numbers of the first call endpoint 105 and the second call endpoint 120. The SDP can also carry one or more media characteristics, such as codec type. Once the call setup succeeds, voice packets may be sent as RTP/UDP/IP packets directly between the first call endpoint 105 and the second call endpoint 120 via the RTP/UDP/IP media path. When it is desired to terminate the call setup (i.e., initiate a call teardown), either the first call endpoint 105 or the second call endpoint 120 sends a “BYE” message to the other endpoint via the SIP Proxies 110, 115. As shown in FIG. 1, the second call endpoint 120 initiates the call teardown by sending a “BYE” message to the first call endpoint 105 via the second SIP Proxy 115 and the first SIP Proxy 110. The call teardown succeeds when the second call endpoint 120 receives the 200 (OK) message. 802.11 wireless LANs (“walls”), when used in infrastructure mode, as is generally the case for enterprise networks, comprise one or more client machines (“stations”) and a central Access Point (“AP”) (not shown). A medium access protocol (“MAC”) specifies which station is to gain access to a wireless link (not shown) to transmit a packet. Two modes of medium access specified for 802.11 include a Distributed Coordination Function (“DCF”) and a Point Coordination Function (“PCF”). In DCF mode, the stations contend with each other to gain channel access. Alternatively, in PCF mode, a central Point Coordinator (“PC”) polls one of the stations (known as a “polled station”) contained in a polling list of the PC. The polled station gains exclusive access to the wireless link for packet transmission/reception. The PC functionality is typically implemented in the AP. That is, the AP runs as the PC during the PCF mode. When polling the station, the PC may send a data packet to the station. Additionally, the PC may provide access to the polled station to transmit another data packet to the PC without contention from unpolled stations. This period of time where the polled station may transmit the data packet is known as a contention-free period (“CFP”). The CFP for a polled station is generally followed and/or preceded by a contention period (“CP”), in which the polled station becomes an unpolled station. That is, in the CP, the station does not have access to transmit the data packet. A “contention repetition interval” comprises a contention-free period and a contention period. The stations express their intent to the PC to be on the polling list by sending MAC management frames (i.e., control messages) to the PC. The MAC management frames comprise, among other requests, an Association Request and a Re-association Request, as is known to those skilled in the art. There are two subfields in the Association Request and the Re-association Request management frames (hereinafter “(re)association management frames”) that allow a station to express its interest to the PC to be included in the polling list. The two subfields are CF-Pollable and CF-Poll Request, which are located in the Capatibility Information field of the (re)association management frames. The (re)association management frames are used to associate or reassociate a station with the AP. If the CF-Pollable subfield is set to 1 and the CF-Poll Request subfield is set to 0, this indicates that the station delivering the message is interested in sending and receiving packets to and from the AP during the CFP. Referring now to FIG. 2, an exemplary operation of a superframe 200 based on the IEEE 802.11 standard is illustrated. The superframe 200 is a logical representation of data/voice packet transmissions between a client and an AP. The superframe 200 comprises one or more time intervals known as a contention repetition interval 205. The contention repetition interval 205 comprises a CFP 210 and a CP 215. During the CFP 210, PCF mode is ideally used. This is because the CFP 210 is generally intended for use by time-critical traffic such as voice packets. While in the CP 215, DCF mode is ideally used. This is because the CP 215 is generally intended for use by data traffic. Current enterprise networks deploy wLANs using only the DCF mode, i.e., stations contend with each other to send packets to the AP. With DCF, there is no arbitration of wireless access by the AP, and the entire operation proceeds solely in CP. If SIP-based VoIP is deployed on DCF network, voice packets from one station may contend for channel access with other packets (voice and data) from other stations. Consequently, due to the nature of contention-based medium access, such as exponential back-off with retry attempts, voice packets may be delayed and not receive adequate QoS. Additionally, because there is no coupling of SIP call control and utilization/load on the wireless link, admitting a new voice call during high utilization of the wireless link leads to lost packets, which leads to poor voice quality. Given the above overview of SIP-based VoIP, wireless LANs, and the problems associated with supporting VoIP over wLANs, the present invention will now be described. In one aspect of the present invention, SIP signaling is coupled with availability of resources on the wireless link using specific MAC mechanisms before a VoIP call is admitted. Core VoIP requires a signaling phase (usually via SIP) prior to media exchange between endpoints. The present invention can ensure that the VoIP call setup signaling succeeds only if a periodic time slot can be allocated on the wireless link using PCF. Instead of treating VoIP call setup and wireless medium access independently, availability of wireless resources is tied with VoIP call setup to ensure that if the call setup goes through, then adequate QoS is available on a wireless link for the VoIP call. The present invention integrates VoIP call control with a specific medium access method on a wLAN link that can offer periodic allocation of bandwidth for VoIP packets in a timely fashion. Referring now to FIG. 3, a SIP configuration 300 is shown, in accordance with one embodiment of the present invention. SIP is a call-signaling protocol for VoIP. Two AP's 305 (a first AP 310 and a second AP 315) support a superframe comprising of CFP and CP periods, as described in greater detail in FIG. 2. As previously stated, PCF mode is generally used during CFP while DCF mode is generally used during CP. Two wLAN enabled SIP clients 320 (e.g., a laptop with a wLAN card and a IP softphone) are shown in FIG. 3: a calling party 325 (associated with the first AP 310) and a called party 330 (associated with the second AP 315). Although only two SIP clients 320 are shown in FIG. 3, it is understood that a typical SIP configuration may comprise any number of SIP clients 320. Further, although in FIG. 3 each SIP client 320 is associated with its own AP 305, one or more SIP clients 320 may be associated with a single AP 305. The calling party 325 sends a SIP INVITE message to an SIP Proxy Server 340 using the CP on a wireless link 345. The SIP Proxy Server 340 has a control connection 350 to the AP 305 for querying the AP 305 of ongoing VoIP calls (i.e., the current calls in progress). The control connection 350 may use any of a variety of communication protocols (e.g., client-server, http, etc.). The control connection 350 is used for sending and/or receiving control protocol messages. Alternatively, the SIP Proxy Server 340 may internally keep track of ongoing (i.e., current) VoIP calls. Information of the current calls in progress in the AP 305 is used to determine the number of available voice slots in the AP 305. Whether voice slots are available given the number of current calls in progress” varies upon implementation of the call itself (e.g., the bit rate of a voice call) and the AP 305, as is known to those skilled in the art. Based on current load on the AP 305 in terms of available voice slots on the superframe 200 of FIG. 2, the SIP Proxy Server 340 can either accept the SIP INVITE message for further processing or deny the call setup request. This ensures that if the call setup request is accepted, the calling party 325 will receive adequate time slots on the superframe to ensure that VoIP packets (i.e., voice packets) sent from the calling party 325 to the first AP 310 are not delayed. The VoIP packets are sent within a wireless coverage 355 of the AP 305. Following a successful call setup, the calling party 325 adds itself to the polling list of the PC (typically implemented in the AP 305) using MAC management frames. It is understood that there may be another SIP Proxy Server (not shown) associated with the called party 330 and the second AP 315. The SIP Proxy Server 340 and the first AP 310 are shown in FIG. 3 as two separate machines. However, it is further understood that the SIP Proxy Server 340 and the first AP 310 may reside on the same machine. In the case of the SIP Proxy Server 340 and the first AP 310 residing on the same machine, it is understood that the communication protocol may not be necessary. When either of the SIP clients 320 (i.e., the calling party 325 and the called party 330) terminates the call by sending a BYE SIP message to the SIP Proxy Server 340 on the wireless link 345, that SIP client 320 will also send a MAC management frame to the SIP Proxy Server 340 to remove itself from the list of stations polled by the PC (typically implemented in the AP 305) in the CFP. As a result, the PC does not waste time during the CFP to poll a station that is not in a voice call. In addition to the calling party 325 adding itself to the polling list of the PC following a successful call setup, a similar action can be taken by the called party 330. The second AP 315 (which is connected to the called party 330) receives a SIP INVITE message sent from the calling party 325 via a router 360. The connections between the two APs 305 and the router 360 is typically a wireline link 362. The second AP 315 forwards the SIP INVITE message to the called party 330. The second AP 315 takes this action only if it can add the called party 330 to the polling list during the CFP. In other words, the AP 305 allows the call setup to go through only if the superframes are able to ensure that the voice packets 355 for this call can be transmitted periodically without contention. Thus, after the called party 330 receives the SIP INVITE and accepts the call by sending an ACK message via the wireless link 345 (as described in FIG. 1), the called party 330 sends a MAC management frame to a PC requesting to be added to the polling list of the PC. It should be noted that the present invention applies when either or both SIP clients 310 are connected to a wireless network. When both SIP clients 310 are on wireless LANs, they each send MAC management frames to their respective APs so that their incoming and outgoing voice traffic is sent on the wireless link in PCF mode. When only one of the SIP clients 310 of a voice call is on a wireless link, then only that SIP client 310 can make use of this invention. In addition to providing QoS on the wireless link, an extension to the scheme described herein is to couple the QoS on the wireless link with QoS on the wireline channel. In enterprise networks, QoS on wireline networks is typically achieved by using separate virtual LANs (“VLANs”) 365 for data and voice. This is because enterprise networks typically use a switched network such as a switched ethernet. Alternatively, enterprise networks may use packet level QoS such as Differentiated Services. The Differentiated Services field of an IP header of the packet (previously known as Type-of-Service or “TOS” field) can be instantiated with different code points (Differentiated Service Code Point or “DSCP”) to tag packets with different levels of QoS. With the present invention, packets on the wireless link that are received at the AP 205 from a wireless client during CFP can automatically be placed on the voice VLAN 365 on the wireline side (if the enterprise network is a switched ethernet) or tagged with an appropriate DCSP codepoint for voice level QoS (if the enterprise network uses Differentiated Services). Thus, the present scheme of prioritizing packets on the wireless link 345 can be coupled with the QoS mechanism being used in the wireline side to provide seamless QoS between the wireless and wireline portions of an enterprise network. An additional aspect of our invention relates to mobility of a wireless station between the different APs (e.g., the first AP 310 and the second AP 315), while a VoIP call is in progress. For example, the calling party 325 could move from the range of the first AP 310 to the range of the second AP 315. There are two scenarios: 1) the APs belong to the same IP subnet and 2) the APs belong to different IP subnets. In the first scenario, MAC management frames are used to forward packets to a wireless station (e.g., the calling partying 325, the called party 330). The IP address of the client remains unchanged. As mentioned earlier, if the wireless station changes its AP while a VoIP call is in progress, it re-associates with the “new” AP using a Re-association Request such that the client is directly added to the polling list at the new AP 105 (implementing the PC). In other words, the wireless station does not do a SIP level call setup before adding itself to the polling list at the new PC. This is because as far as the SIP session is concerned, the IP address of the wireless station is unchanged. That is, the wireless station re-associates with the new PC directly in PCF mode. In the second scenario, the IP address of the wireless station changes. Therefore, the wireless station needs to send a SIP RE-INVITE message to the other wireless station. This message can be sent only after the client has associated itself with the new AP. SIP RE-INVITE is a SIP call setup message after an INVITE message has already been sent. It should be noted that the MAC level management frame that is sent is an Association Request rather than a Re-Association request since the new and the previous APs do not have any association, a new association needs to be created between the wireless station and the new AP. That is, the Association Request is sent to the new AP with the CF-Pollable and CF Poll-Request subfields of the Capability Information field set such that the wireless station is directly added to the polling list of the PC at the new AP. This allows voice packets of the ongoing call to be transmitted on the wireless link without contention. Yet another aspect of present invention relates to how the AP determines which packets of a wireless station should be sent using the PCF mode. When a wireless station is added to the polling list of the PC, it is polled by the PC to check if it has any packet to transmit. It can potentially send either a data packet or a voice packet. Similarly when a particular wireless station's turn is reached in the polling list, the corresponding AP is free to transmit any packet to the wireless client. However, it may be wasteful if the CFP is used to transmit packets (either to or from a wireless station) that do not need QoS (e.g., data packets). Thus, the additional mechanism proposed herein is that when a wireless station is polled by the PC, only voice packets should be transmitted. This is easily achieved for packets on the “uplink” (i.e., from a wireless station to the AP) because the station, as part of the SIP call setup, is aware of the tuple <Source IP Address, Source Port#, Destination IP Address, Destination Port#>, and any packet with a matching 4-tuple belongs to the voice call and is sent during the PCF. Thus, it is easy to identify voice packets from data packets on the wireless station side. As used herein, the term “wireless station side” refers to the period that the wireless station transmits packets to the AP, and the term “AP side” refers to the period that the AP transmits packets to the wireless station. On the AP side, identifying voice packets from data packets is generally not straightforward. However, with the present scheme of integrating the SIP proxy with the wireless AP, either on the same machine or on different machines with a control connection, as described herein, the AP is able to distinguish voice packets from data packets. This is possible because SIP INVITE and ACK messages contain the IP address and port numbers of both endpoints. Thus, when SIP INVITE and ACK messages flow through the SIP Proxy on the AP, it keeps track of the IP address and port# that will be used by each point. This enables the PC to distinguish voice packets from data packets on the “downlink” (i.e., from the AP to a wireless station). Any packet that matches the IP address and port pairs will be sent using the PCF mode. All other packets will be sent using the DCF mode. It should be further noted that the type of client device to which this invention can be applied may include any device with both a wireless LAN connection and a SIP-based IP Phone. The particular embodiments disclosed above are illustrative only, as the invention may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown, other than as described in the claims below. It is therefore evident that the particular embodiments disclosed above may be altered or modified and all such variations are considered within the scope and spirit of the invention. Accordingly, the protection sought herein is as set forth in the claims below.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to computer networks, and, more particularly, to voice-over-IP networks over wireless local area networks. 2. Description of the Related Art Traditional telephony carriers, which primarily utilize a public-switched telephony network (“PSTN”), are moving towards a packet-based Voice-over-IP (“VoIP”) infrastructure. A key component of a typical telephony infrastructure is “call control.” Call control comprises a call setup and a call teardown. Both the call setup and the call teardown involve an exchange of call control messages between two end users. Either end user may initiate the setup or teardown. The call setup allocates resources for the exchange of voice and/or data between the two end users. In contrast, the call teardown frees up those resources such that other end users may exchange voice and/or data. In VoIP, call control is achieved through Session Initiation Protocol (“SIP”). It should be noted that one of ordinary skill in the are would contemplate achieving call control through any of a variety of other known protocols. In addition to carrier networks, VoIP has been steadily ground in enterprise networks as well. In parallel with the adoption of VoIP, many enterprise networks are in the process of deploying support network access via IEEE 802.11 based wireless local area networks (“LANs”). The 802.11 wireless LAN standard offers a medium access method, called Point Coordination Function (“PCF”), that offers support for near-isochronous (i.e., real-time) services where an “Access Point” periodically polls individual stations for packets to transmit. However, there has been little deployment of VoIP over wireless LANs using PCF. A key reason is that most 802.11 Access Points support a medium access method known as Distributed Coordination Function (“DCF”), that is contention-based, i.e., each wireless station competes for control of the wireless medium. While the DCF method works for data packets, VoIP packets, on the other hand, require timely, periodic access to the wireless medium to maintain acceptable voice quality. With increasing use of wireless LANs in the enterprise, use of IP softphones, for example, on 802.11 enabled laptops and handheld devices to initiate and receive VoIP calls will explode. It is well understood that quality of service (“QoS”) is required for voice traffic in terms of delay, jitter and loss. At the same time, bandwidth on wireless links is far below that of wireline links (e.g., ethernet), and, therefore, uncontrolled access to the wireless medium can introduce unacceptable delay for VoIP traffic. Therefore, to make efficient use of wireless resources and provide real-time services for VoIP packets, a need exists for a method and apparatus to manage the contention resulting from VoIP call signaling on the wireless medium. Without a solution to this problem, voice quality for VoIP calls over wireless LANs will degrade to unacceptable levels as the data/voice traffic on the wireless link increases. In other words, the method and apparatus should provide sufficient QoS to support wireless voice quality comparable to that of wireline links, even in the prospect of reduced wireless bandwidth.

<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect of the present invention, a method for providing quality-of-service to VoIP over a wireless local access network is provided. The method comprises sending an invite message from a calling party to a SIP proxy server and determining whether voice slots are available on an access point. The method forwards the invite message from the SIP proxy server to a called party, and if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, the method adds the calling party to the polling list of the access point, and sends packets to and receives packets from the called party during a contention-free period of the access point. In another aspect of the present invention, a machine-readable medium having instructions stored thereon for execution by a processor to perform a method for providing quality-of-service to VoIP over a wireless local access network is provided. The medium contains instructions for sending an invite message from a calling party to a SIP proxy server and determining whether voice slots are available on an access point. The medium contains instructions for forwarding the invite message from the SIP proxy server to a called party, and if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, the medium contains instructions for adding the calling party to the polling list of the access point, and sending packets to and receiving packets from the called party during a contention-free period of the access point. In yet another aspect of the present invention, a system for providing quality-of-service to VoIP over a wireless local access network is provided. The system contains means for sending an invite message from a calling party to a SIP proxy server and means for determining whether voice slots are available on an access point. The system contains means for forwarding the invite message from the SIP proxy server to a called party, and if the called party sends an acknowledgement message to a calling party in response to receiving the invite message, the system contains means for adding the calling party to the polling list of the access point, and means for sending packets to and receiving packets from the called party during a contention-free period of the access point.

20070514

20110201

20070830

57316.0

H04Q724

HO, DUC CHI

METHOD AND APPARATUS FOR PROVIDING QUALITY OF SERVICE TO VOIP OVER 802.11 WIRELESS LANS

UNDISCOUNTED

ACCEPTED

H04Q

ACCEPTED

METHOD FOR THE MULTI-ANTENNA TRANSMISSION OF A LINEARLY-PRECODED SIGNAL, CORRESPONDING DEVICES, SIGNAL AND RECEPTION METHOD

An embodiment of invention relates to a method for the transmission of a signal formed by vectors, each vector comprising N source symbols to be transmitted, using M transmission antennas, wherein M is greater than or equal to 2. The method comprises the following steps: linearly precoding the signal using a matrix product of a source matrix formed by vectors that are organized in successive lines by a linear precoding matrix, delivering a precoded matrix; and successively transmitting precoded vectors corresponding to columns of said precoded matrix, the M symbols of each precoded vector being distributed to the M antennas.

1. A method for the sending of a signal formed by vectors, each vector comprising N source symbols to be sent, and implementing M transmit antennas where M is greater than or equal to 2, the method comprising: linearly precoding said signal, implementing a matrix product of a source matrix, formed by said vectors organized in successive rows, by a linear precoding matrix, delivering a precoded matrix, and sending precoded vectors corresponding to columns of said precoded matrix successively, wherein the M symbols of each precoded vector are distributed over said M antennas. 2. The method according to claim 1, wherein the precoding matrix comprises a block matrix. 3. The method according to claim 1, wherein the precoding matrix comprises a unitary matrix having a size greater than or equal to M. 4. The method according to claim 1, wherein the precoding matrix has the form: Θ L = 2 L · [ Θ L / 2 Θ L / 2 Θ L / 2 - Θ L / 2 ] T with   Θ 2 = ⌊  θ 1  cos   η  θ 2  sin   η -  - θ 2  sin   η  - θ 1  cos   η ⌋ and   η = π 4 + k  π 2 , θ 2 = θ 1 - π 2 , and for i ε[1,2], θ i = π 4 + k ′  π 2 where k, k′ are relative integers. 5. A method for the reception of a signal sent on M transmit antennas where M is greater than or equal to 2, implementing P receiver antennas, where P greater than or equal to 2, wherein the method comprises: receiving reception vectors on said P antennas, which are distributed by columns in a reception matrix, wherein P symbols of each reception vector are distributed on said P antennas, processing said reception matrix, comprising multiplying by a linear de-precoding matrix representing a linear precoding matrix used at sending, so as to obtain a de-precoded matrix by which it is possible to extract an estimation of source symbols sent in the signal. 6. The method according to claim 5, wherein the de-precoding matrix is the conjugate transpose matrix of said precoding matrix. 7. The method according to claim 6, wherein said sent signal is conveyed between said M transmit antennas and said P receiver antennas by a transmission channel, said reception matrix is multiplied, during said processing by a matrix representing the inverse of said transmission channel, so as to obtain a matrix of estimated symbols sent, and wherein said matrix of estimated symbols sent is then multiplied by the de-precoding matrix. 8. The method according to claim 6, wherein the method comprises a preliminary step of detecting said M transmit antennas implementing a successive cancellation algorithm. 9. The method according to claim 5, wherein said sent signal is conveyed between said M transmit antennas and said P receiver antennas by a transmission channel, and said de-precoding matrix is an inverse matrix of a total matrix associating the matrix of said channel and said linear precoding matrix. 10. The method according to claim 9, wherein said de-precoding matrix is determined by implementation of a Cholesky decomposition algorithm. 11. A signal comprising: vectors sent successively on M transmit antennas, where M is greater than or equal to 2, the M symbols of each vector being distributed on said M antennas, wherein the vectors are precoded vectors corresponding to columns of a precoded matrix obtained by a matrix product of a linear precoding matrix and a source matrix, formed by source vectors each comprising N source symbols to be sent, said source vectors being organized in said source matrix in successive rows. 12. A device for sending a signal formed by vectors each comprising N source symbols to be sent, and implementing M transmit antennas, where M is greater than or equal to 2, the device comprising: means of linearly precoding said signal, implementing a matrix product of a source matrix, formed by said vectors organized in successive rows, by a linear precoding matrix, delivering a precoded matrix, and means for successively sending precoded vectors corresponding to columns of said precoded matrix, the M symbols of each precoded vector being distributed over said M antennas. 13. A device for the reception of a signal sent on M transmit antennas, where M is greater than or equal to 2, said device comprising. P receiver antennas, where P is greater than or equal to 2, means of reception, on said P antennas, of reception vectors, and means of distribution by columns of said reception vectors in a reception matrix, the P symbols of a reception vector being distributed on said P antennas, and means of processing of said reception matrix, comprising means of multiplying by a linear de-precoding matrix representing a linear precoding matrix used at sending, so as to obtain a de-precoded matrix by which it is possible to extract an estimation of source symbols sent.

CROSS-REFERENCE TO RELATED APPLICATION This Application is a Section 371 National Stage Application of International Application No. PCT/FR2004/003107, filed Dec. 2, 2004 and published as WO 2005/057838 on Jun. 23, 2005, not in English. FIELD OF THE DISCLOSURE The field of the disclosure is that of wireless digital communications. More specifically, the disclosure relates to the sending/reception of a signal that implements a precoding matrix in a MIMO (“Multiple Input Multiple Output”) type multi-antenna system also called a “BLAST” (Bell Laboratories Layered Space-Time”) system. One or more embodiments of the invention can be applied in the field of radio communications, especially for systems of the third, fourth and subsequent generations. BACKGROUND Several sending/reception systems, comprising multiple antennas are already known. Some of the systems use space-time encoding by which their spatial/temporal diversity can be exploited with the utmost efficiency. However, the spectral efficiency of these space-time codes is limited. Certain research work then led to the study of layered space-time (LST) systems using spatial multiplexing techniques to obtain systems whose capacity increases linearly with the number of transmit and receiver antennas. Thus Foschini, in “Layered Space-Time Architecture for Wireless Communication in a Fading Environment When Using Multiple Antennas” (Bell Laboratories Technical Journal, Vol. 1, No. 2, Autumn, 1996, pp. 41-59) presented a first space multiplexing system aimed at augmenting the capacity of transmission systems. To this end, he described a diagonal “BLAST” structure (known as D-BLAST) in which the coded or non-coded and interleaved symbols of each layer are transmitted successively by each of the transmit antennas. Wolniansky, Foschini, Golden and Valenzuela, in “V-BLAST: An Architecture for Realizing Very High Data Rates Over the Rich-Scattering Wireless Channel” (Proc. ISSSE-98, Pisa, Italy, Sep. 29, 1998), subsequently simplified this technique by modifying the architecture of the initial “BLAST” system into a vertical system (“V-BLAST”) without encoding, and by using an interference cancellation algorithm at reception with a zero forcing (ZF) criterion. This vertical architecture quite simply proceeds from a demultiplexing of the chain of information into sub-chains, each of them being transmitted by its respective antenna. Subsequently, Baro, Bauch, Pavlic and Semmler (“Improving BLAST Performance using Space-Time Block Codes and Turbo Decoding”, Globecom 2000, November 2000) envisaged the combination of the space-time codes and turbo-decoding with codes V-BLAST type systems. Finally, Ma and Giannakis (“Full-Diversity Full-Rate Complex-Field Space-Time Coding”, IEEE Transactions on Signal Processing 2003) presented a technique combining linear precoding with MIMO techniques of spatial multiplexing at the time of sending. In this technique, linear precoding is done by the use of particular precoding matrices based on Vandermonde matrices, the different symbols at the time of sending being sent cyclically. The decoding in reception is done according to a maximum likelihood detector. A first drawback of the “BLAST” technique of spatial multiplexing proposed by Foschini is its decoding complexity. Another drawback of this technique, which was subsequently changed into the “V-BLAST” technique, is that the maximum spatial diversity of the systems is not exploited. As for the technique envisaged by Baro, Bauch, Pavlic and Semmler, which consists in combining the space-time codes with the V-BLAST system, it has the drawback of not exploiting the maximum capacity of the system. Furthermore, the different prior art techniques cannot be used to process correlated channels. These different drawbacks are partially resolved by the technique of Ma and Giannakis, which can be used to exploit both the space-time diversity of the systems, by means of linear precoding, and their maximum capacity. However, a major drawback of this technique is the receiver used, which must be of the maximum likelihood (abbreviated as ML) type. These ML receivers are complex to implement and, owing to their complexity, limit the size of the precoding matrix to the number of transmit antennas of the system. SUMMARY An embodiment of the invention is directed to a method for the sending of a signal formed by vectors, each vector comprising N source symbols to be sent, and implementing M transmit antennas where M is greater than or equal to 2. According to an embodiment of the invention, a linear precoding is performed on said signal, implementing a matrix product of a source matrix, formed by said vectors organized in successive rows, by a linear precoding matrix, delivering a precoded matrix, then precoded vectors corresponding to columns of the precoded matrix are sent successively, the M symbols of each precoded vector being distributed over the M antennas. Thus, an embodiment of the invention relies on a wholly novel and inventive approach to the sending of a signal, implementing linear precoding in a multi-antenna system. More specifically, an embodiment of the invention proposes to carry out a transposed space-time mapping, i.e. it proposes to send the symbols having undergone the same precoding by column on the M antennas. This approach therefore differs sharply from the cyclical sending proposed by Ma and Giannakis, which induced high complexity at reception. The technique of an embodiment of the invention is particularly advantageous because it can be used to exploit the maximum capacity of the MIMO channel, given that it does not use space-time codes, and maximum space-time diversity, through the linear precoding. The number M of transmit antennas corresponds to the number of vectors to be sent, these vectors forming the different rows of the source matrix. Advantageously, the precoding matrix of such a sending method is a block matrix. Preferably, the precoding matrix is a unitary matrix having a size greater than or equal to M. Thus, an embodiment of the invention is distinguished from prior art techniques since the size of the precoding matrix is not always equal to the number M of transmit antennas. As shall be seen here below in this document, this is made possible according to an embodiment of the invention through the implementation of a decoding operation of low complexity that therefore enables simple decoding even with large precoding matrices. This precoding matrix belongs to the group comprising the Hadamard matrices, special unitary matrices sized 2×2, also written as SU(2), Fourier matrices, Vandermonde matrices and, more generally, unitary matrices. In one advantageous embodiment of the invention, the precoding matrix is a block matrix having the form: Θ L = 2 L · [ Θ L / 2 Θ L / 2 Θ L / 2 - Θ L / 2 ] T with   Θ 2 = ⌊  θ 1  cos   η  θ 2  sin   η -  - θ 2  sin   η  - θ 1  cos   η ⌋ and   η = π 4 + k  π 2 , θ 2 = θ 1 - π 2 , and for iε[1,2], θ i = π 4 + k ′  π 2 where k, k′ are relative integers. An embodiment of invention also relates to a method for the reception of a signal sent on M transmit antennas where M is greater than or equal to 2, implementing P receiver antennas, where P greater than or equal to 2. According to an embodiment of the invention, reception vectors are received on the P antennas and are distributed by columns in a reception matrix, the P symbols of a reception vector being distributed on the P antennas. The method then implements an operation for processing the reception matrix, comprising a step of multiplication by a linear de-precoding matrix representing a linear precoding matrix used at sending, so as to obtain a de-precoded matrix by which it is possible to extract an estimation of the source symbols sent. It shall be noted that, for optimal reception, the number P of antennas in reception is greater than or equal to the number M of transmit antennas. Herein and throughout the rest of the document, the term “de-precoding” is understood to mean an operation that is substantially the reverse of the precoding operation performed at the sending stage. In a first embodiment, the de-precoding matrix is the conjugate transpose matrix of the precoding matrix. In this case, with the sent signal being conveyed between the M transmit antennas and the P receiver antennas by a transmission channel, the reception matrix is multiplied, during the processing operation, by a matrix representing the inverse of the transmission channel, so as to obtain a matrix of estimated symbols sent. The matrix of estimated symbols sent is then multiplied by the de-precoding matrix. Indeed, the implementation of a MIMO system, comprising a plurality of transmit antennas and a plurality of receiver antennas, induces the existence of different transmit antenna/receiver antenna paths on which it is possible to transmit the payload information, where these different paths can be schematically represented by a channel matrix. In reception, the channel encoding estimated on the different paths must be inverted in order to retrieve the symbols sent. Assuming that the channel is perfectly known to the receiver, it is enough to carry out an inversion of the channel matrix. The reception method especially comprises a preliminary step of detection of the M transmit antennas implementing a successive cancellation algorithm. In a second embodiment, with the sent signal being conveyed between the M transmit antennas and the P receiver antennas by a transmission channel, the de-precoding matrix is an inverse matrix of a total matrix associating the matrix of the channel and the linear precoding matrix. In this embodiment, the reception method implements a decoding with ordering, which enables a priority decoding of the channels having the best signal-to-noise ratio. In this case, the de-precoding matrix is determined by implementation of a Cholesky decomposition algorithm, which can be used to obtain a decoding method that costs little in computation and is less complex than the prior art techniques. The maximum likelihood type techniques are well known and satisfactory but complex. For the decoding of MIMO systems, the use of a Cholesky decomposition with a minimum mean square error (MMSE) criterion is totally novel and can be used to resolve this drawback of complexity inherent in prior-art techniques. One alternative to the Cholesky decomposition would be to use a QR decomposition with the ZF criterion. This technique also has low complexity but shows less satisfactory results. According to one variant of the invention, with the de-precoding matrix being a block matrix, the reception method carries out a distance minimization by change of symbol in a block. This further improves the decoder of an embodiment of the invention. An embodiment of invention also relates to a signal formed by vectors sent successively on M transmit antennas, where M is greater than or equal to 2, the M symbols of each vector being distributed on the M antennas. According to an embodiment of the invention, the vectors are precoded vectors corresponding to columns of a precoded matrix obtained by taking the matrix product of a linear precoding matrix and a source matrix, formed by source vectors each comprising N source symbols to be sent, the source vectors being organized in said source matrix in successive rows. An embodiment of invention also relates to a device for sending a signal formed by vectors each comprising N source symbols to be sent, and implementing M transmit antennas, where M is greater than or equal to 2, for a sending method as described here above. An embodiment of invention also relates to a device for the reception of a signal sent on M transmit antennas, where M is greater than or equal to 2, the device comprising P receiver antennas, where P is greater than or equal to 2. Other features and advantages shall appear more clearly from the following description of a preferred embodiment, given by way of a simple illustrative and non-exhaustive example and from the appended drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates a four-transmit-antenna system implementing a source matrix X and a precoding matrix Θ according to an embodiment of the invention; FIG. 2A presents a system with four antennas for the reception of a signal sent according to the system of FIG. 1, in a first embodiment of the invention known as an embodiment without ordering (without “sequencing”); FIG. 2B presents a system with four antennas for the reception of a signal sent according to the system of FIG. 1, in a second embodiment of the invention known as an embodiment with ordering (sequencing); FIG. 3 describes the comparative performance of the different systems, namely the prior art system without linear precoding and the system of an embodiment of the invention with linear precoding for a precoding matrix sized four and a precoding matrix sized 256. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The general principle of an embodiment of the invention is based on a novel system of linear precoding, at the time of sending, for a multi-antenna system. A source matrix, formed by vectors to be sent arranged in successive rows is multiplied by a precoding matrix having a size greater than or equal to the number of transmit antennas, to form a precoded matrix. Each of the symbols forming a same column of the precoded matrix is then sent simultaneously on each of the transmit antennas, each antenna sending a different symbol from the column of the precoded matrix. Referring now to FIG. 1, we present a system with four transmit antennas implementing a source matrix X and a precoding matrix Θ according to an embodiment of the invention. For the sake of simplification, the description here and further below in the document is limited to the particular case of a square source matrix X and a square precoding matrix Θ. Those skilled in the art will have no difficulty in extending this teaching to all types of matrices X and Θ, it being understood that the number of columns of X should be equal to the number of rows of Θ, and that X must have M rows, where M is the number of transmit antennas. The source matrix X, which comprises the information to be transmitted, is formed by four vectors X1, X2, X3, X4, forming the rows of the matrix X. Each vector Xi, for i=1 to 4, is formed by four symbols: X1=[x1 x2 x3 x4], X2=[x5 x6 x7 x8], X3=[x9 x10 x11 x12], X4=[x13 x14 x15 x16]. The total number of symbols to be sent is therefore 16. This corresponds to the number of transmit antennas M multiplied by the number L of rows of the precoding matrix Θ. The precoding matrix Θ is sized 4×4. It is a block matrix. According to one particular embodiment, the precoding matrix Θ is the following: Θ L = 2 L · [ Θ L / 2 Θ L / 2 Θ L / 2 - Θ L / 2 ] T with   Θ 2 = ⌊  θ 1  cos   η  θ 2  sin   η -  - θ 2  sin   η  - θ 1  cos   η ⌋ and   η = π 4 + k  π 2 , θ 2 = θ 1 - π 2 , and for iε[1,2], θ i = π 4 + k ′  π 2 where k, k′ are relative integers. After multiplication of the source matrix X by the precoding matrix Θ, a precoded matrix S is obtained (S=X.Θ). The matrix S, sized 4×4, is formed by four vectors Si (i=1 to 4): S1=[s1 s5 s9 s13], S2=[s2 s6 s10 s14], S3=[s3 s7 s11 s15], S4=[s4 s8 s12 s16]. These vectors Si, also called precoded vectors, correspond to the multiplication of the source matrix X by a same column of the precoding matrix Θ. Thus, S1 corresponds to the vector obtained by the multiplication of the source matrix X by the first column of the precoding matrix Θ, S2 corresponds to the vector obtained by the multiplication of the source matrix X by the second column of the precoding matrix Θ, and so on and so forth for the four columns of the matrix Θ. At a given point in time, each of the four transmit antennas 10, 11, 12 and 13 then sends one of the symbols of the same precoded vector Si in the same sending burst. Thus, at an instant T0, the first antenna 10 sends the symbol s1 of the vector S1. Substantially at the same instant T0, the second antenna 11 sends the symbol s5 of the vector S1, the third antenna 12 sends the symbol s9 of the vector S1 and the fourth antenna 13 sends the symbol s13 of the vector S1. The other precoded vectors S2, S3 and S4 are respectively sent in three sending bursts corresponding to the times T1, T2 and T3. Each of the symbols of a same precoded vector corresponding to the multiplication of a source matrix X by a same column of a precoding matrix Θ is then sent on each of the transmit antennas, each antenna sending a different symbol of the precoded vector. In other words, if the matrix S is deemed to be formed by four vectors S1′, S2′, S3′ S4′ organized in successive rows, i.e. S1′=[s1 s2 s3 s4], S2′=[s5 s6 s7 s8], S3′=[s9 s10 s11 s12], S4′=[s13 s14 s15 s16], then: the first symbols of each vector Si′ (for i=1 to 4) are sent on the different transmit antennas simultaneously, s1 on the first antenna and s13 on the last antenna; the second symbols of each vector Si′ are sent on the different transmit antennas simultaneously, s2 on the first antenna and s14 on the last antenna; this operation is repeated until the last symbols of each vector Si′. Finally, the system transmits first of all [s1 s5 s9 s13] at an instant T0, then [s2 s6 s10 s14] at T1, then [s9 s7 s11 s15] at T2, and finally [s4 s8 s12 s16] at T3. Referring now to FIGS. 2A and 2B, we present a system with four receiver antennas. After transmission in the MIMO channel, the received signals are constituted by vectors Ri (for i=1 to 4) organized in successive columns in a reception matrix R, where R1=[r1 r5 r9 r13], R2=[r2 r6 r10 r14], R3=[r3 r7 r11 r15], R4=[r4 r8 r12 r16] Thus, the reception matrix R is formed by symbols [r1 r5 r9 r13] received substantially at the same instant T0′, depending on the lengths each of the transmit antenna/receiver antenna paths, on the four receiver antennas (r1 on the first antenna 20, r5 on the second antenna 21, r9 on the third antenna 22 and r13 on the fourth antenna 23), the symbols [r2 r6 r10; r14] received substantially at the same point in time T1′ on the four receiver antennas as described here above as well as symbols [r3 r7 r11 r15] and [r4 r8 r12 r16] received at the times T2′ and T3′. According to a first embodiment illustrated in FIG. 2A, the procedure is based on the technique known as a technique “without ordering”. The technique starts first of all with the inverting of the coding channel estimated on the different transmit/receiver antenna channels so as to retrieve the estimated sent symbols. Thus, a successive cancellation algorithm is implemented to detect the different transmit antennas. This algorithm is the following: r = sH R r = HH H + σ 2  I a = rH H b = R r - 1  a = sHH H HH H + σ 2  I with: r corresponding to the symbols received on the P receiver antennas, i.e. at the reception matrix R; H being the channel, with size (M×P); σ2 being the mean signal-to-noise ratio of the receiver antennas; Rr the self-correlation matrix; a corresponding to different vectors sized M according to the equation described here above; b corresponding first of all to the estimated values of the different symbol vectors sent [s1 s5 s9 s13], then to the estimates of the symbols sent [s2 s6 s10 s14], then to the estimated values of the symbols sent [s3 s7 s11 s15], and finally then to the estimated values of the symbols sent [s4 s8 s12 s16], the exponent H signifying conjugate transpose. This algorithm is like a V-BLAST decoding as described in “Improving BLAST Performance using Space-Time Block Codes and Turbo Decoding”, Globecom 2000, November 2000 (Baro, Bauch, Pavlic and Semmler) in the sense of the minimum mean square error (MMSE) by which it is possible to retrieve the estimated values Ŝi of the vectors Si sent for i ranging from 1 to 4. This amounts to multiplying the reception matrix R by a matrix representing the inverse of the transmission channel. The vectors received are then re-ordered so as to retrieve the estimated values of the vectors sent S1, S2, S3, S4 or again S1′, S2′, S3′, S4′, these estimated vectors being called Ŝ1=[ŝ1 ŝ2 ŝ3 ŝ4], Ŝ2=[ŝ5 ŝ6 ŝ7 ŝ8], Ŝ3=[ŝ9 ŝ10 ŝ11 ŝ12] and Ŝ4=[ŝ13 ŝ14 ŝ15 ŝ16] and being organized in successive rows in a matrix called a matrix of estimated symbols. The receiver then multiplies the matrix of estimated symbols obtained 3 by a de-precoding matrix, to form a de-precoded matrix {circumflex over (X)} used to extract an estimation of the source symbols sent. The de-precoding matrix corresponds to the conjugate transpose of the precoding matrix Θ used when sending (referenced ΘH in FIG. 2A) Since the precoding matrix Θ is unitary, multiplying the matrix of estimated symbols obtained Ŝ by the transposed and conjugate precoding matrix ΘH amounts to multiplying the matrix Ŝ by the matrix Θ−1 that is the inverse of the precoding matrix Θ:{circumflex over (X)}=Ŝ.ΘH=Ŝ.Θ−1. The de-precoding step ΘH=Θ−1 is therefore performed at the level of each V-BLAST iteration. In a second embodiment shown in FIG. 2B, the inversion of the channel encoding and the de-precoding operation are done in conjunction, in implementing a Cholesky decomposition algorithm. Such an algorithm is described especially by Wei Zha and Steven D. Blostein in “Modified Decorrelating Decision-Feedback Detection of BLAST Space-Time System” (ICC 2002, Vol. 1, pp. 335-339, April-May 2002). This technique is called a technique “with ordering”. In this embodiment, the receiver multiplies the reception matrix R, formed by the vectors R1=[r1 r5 r9 r13], R2=[r2 r6 r10 r14], R3=[r3 r7 r11 r15], R4=[r4 r8 r12 r16] organized in successive columns, by the inverse of a total matrix G, the matrix G corresponding to the association of the channel matrix and the precoding matrix Θ. The inverse of the total matrix G, also called a de-precoding matrix, is obtained by implementing a Cholesky decomposition within which an ordering operation is carried out. The ordering operation makes it possible to take a decision first of all on the symbol of the total matrix G having the highest power. The symbols are thus processed in a decreasing order of power. The Cholesky algorithm is the following: R = X   Θ   H R r = P p  ( Θ   HH H  Θ H + σ 2  I )  P p H R r = LL H R r - 1 = ( L H ) - 1  L - 1 x = RH H  Θ H  P p H y = x  ( L H ) - 1 z = P p  yL - 1 = P p  X   Θ   HH H  Θ H  P p H P p  ( Θ   HH H  Θ H + σ 2  I )  P p H with: r corresponding to the symbols received at the P receive antennas, i.e. to the reception matrix R; X corresponding to the source matrix sent; Θ being the precoding matrix sized 4×4; H the channel matrix sized 4×4; σ2 the mean signal-to-noise ratio of the receiver antennas; Rr the self-correlation matrix; L the lower triangular matrix of the self-correlation matrix Rr; Pp the permutation matrix according to a criterion of maximum power of the desired symbol on the interference of this self-correlation matrix; x and y are vectors sized 16 (the number of transmit antennas multiplied by the number of rows of the precoding matrix Θ). At reception, the Cholesky decomposition algorithm enables the receiver to directly obtain a vector z sized 16 (number of transmit antennas multiplied by the number of rows of the precoding matrix Θ) corresponding to the estimation of the symbols sent by the source matrix X in a de-precoded matrix {circumflex over (X)}. The Cholesky decomposition is a numerically stable decomposition. In this embodiment, the advantage of the precoding is to decorrelate the channels if they are correlated. Since the de-precoding matrix is a block matrix, the reception system may further be improved by using a technique of distance minimization by changing of symbols in a block. Referring now to FIG. 3, we present the performance levels obtained, according to an embodiment of the invention, by using a precoding matrix sized 4×4 and a precoding matrix sized 256×256. More specifically, FIG. 3 illustrates the performance values of an embodiment of the invention according to the first embodiment without ordering, i.e. when the de-precoding matrix corresponds to the conjugate transpose of the precoding matrix: systems that use a linear precoding according to an embodiment of the invention are compared with a prior art system without precoding. A gain of 16.0 dB can be observed between the reference curve, which corresponds to a system without precoding, and the curve with precoding 256, which corresponds to system using a precoding matrix sized 256×256, when the binary error rate (BER) is 104, with a spectral efficiency of 8 bps/Hz, when MMSE type equalizers are used at reception. Thus, an embodiment of the invention improves performance with high signal-to-noise ratio while at the same time maintaining complexity in terms of O(L3), where L is the size of the precoding matrix, or again the number of rows of the precoding matrix if this matrix is not a square matrix. For its part, the prior art approach of Ma and Giannakis (“Full-Diversity Full-Rate Complex-Field Space-Time Coding”, IEEE Transactions on Signal Processing 2003), which also uses precoding matrices, cannot be used to obtain a precoding matrix sized 256 because the method would be far too costly in terms of computation. Indeed, the complexity of this approach is an exponential factor in terms of O(ML), where M corresponds to the size of the modulation. The performance values of an embodiment of the invention are further improved when the second embodiment with ordering is implemented at reception. Indeed, when this embodiment with ordering is implemented, a precoding matrix sized 4×4 gives results substantially identical to those obtained with a precoding matrix sized 256 in the embodiment without ordering, i.e. a gain close to 16.0 dB relative to a reference curve, which corresponds to a system without precoding when the binary error rate (BER) is 104, with a spectral efficiency of 8 bps/Hz. With the performance of the system improving when the size of the precoding increases, very good results are obtained for a system with ordering and a precoding matrix sized 256×256. Thus, an embodiment of the proposed invention enables a decoding that is less complex and less costly than with prior art techniques while at the same time showing improved performance. Furthermore, the technique of an embodiment of the invention is suited to single-carrier modulation systems as well as to multiple-carrier modulation systems (OFDM or MC-CDMA systems for example). It can be applied to any multi-antenna system that gives preference to the exploitation of capacity, achieving this result even if the multi-antenna channels are correlated. An embodiment of the invention provides a technique for the multi-antenna sending and reception of a signal implementing a precoding matrix with better performance than that of prior art precoding systems. An embodiment of the invention implements a technique of this kind having lower complexity and greater numerical stability than prior art techniques. More particularly, an embodiment of the invention provides a technique of this kind that does not necessitate space-time codes. An embodiment of the invention implements a technique of this kind that is adapted to MIMO type multi-antenna systems for both single-carrier and multiple-carrier (OFDM and MC-CDMA) type modulations. An embodiment of the invention provides a technique of this kind by which is possible to use the maximum capacity of the MIMO system and the maximum diversity of the system. An embodiment of the invention implements a technique of this kind having improved binary error rate performance as compared with the prior art, while at the same time proposing a solution of the low complexity at reception. An embodiment of the invention implements a technique of this kind that can be used to process correlated multi-antenna channels while limiting deterioration of performance and while not depending on modulation.

<SOH> BACKGROUND <EOH>Several sending/reception systems, comprising multiple antennas are already known. Some of the systems use space-time encoding by which their spatial/temporal diversity can be exploited with the utmost efficiency. However, the spectral efficiency of these space-time codes is limited. Certain research work then led to the study of layered space-time (LST) systems using spatial multiplexing techniques to obtain systems whose capacity increases linearly with the number of transmit and receiver antennas. Thus Foschini, in “Layered Space-Time Architecture for Wireless Communication in a Fading Environment When Using Multiple Antennas” (Bell Laboratories Technical Journal, Vol. 1, No. 2, Autumn, 1996, pp. 41-59) presented a first space multiplexing system aimed at augmenting the capacity of transmission systems. To this end, he described a diagonal “BLAST” structure (known as D-BLAST) in which the coded or non-coded and interleaved symbols of each layer are transmitted successively by each of the transmit antennas. Wolniansky, Foschini, Golden and Valenzuela, in “V-BLAST: An Architecture for Realizing Very High Data Rates Over the Rich-Scattering Wireless Channel” (Proc. ISSSE-98, Pisa, Italy, Sep. 29, 1998), subsequently simplified this technique by modifying the architecture of the initial “BLAST” system into a vertical system (“V-BLAST”) without encoding, and by using an interference cancellation algorithm at reception with a zero forcing (ZF) criterion. This vertical architecture quite simply proceeds from a demultiplexing of the chain of information into sub-chains, each of them being transmitted by its respective antenna. Subsequently, Baro, Bauch, Pavlic and Semmler (“Improving BLAST Performance using Space-Time Block Codes and Turbo Decoding”, Globecom 2000, November 2000) envisaged the combination of the space-time codes and turbo-decoding with codes V-BLAST type systems. Finally, Ma and Giannakis (“Full-Diversity Full-Rate Complex-Field Space-Time Coding”, IEEE Transactions on Signal Processing 2003) presented a technique combining linear precoding with MIMO techniques of spatial multiplexing at the time of sending. In this technique, linear precoding is done by the use of particular precoding matrices based on Vandermonde matrices, the different symbols at the time of sending being sent cyclically. The decoding in reception is done according to a maximum likelihood detector. A first drawback of the “BLAST” technique of spatial multiplexing proposed by Foschini is its decoding complexity. Another drawback of this technique, which was subsequently changed into the “V-BLAST” technique, is that the maximum spatial diversity of the systems is not exploited. As for the technique envisaged by Baro, Bauch, Pavlic and Semmler, which consists in combining the space-time codes with the V-BLAST system, it has the drawback of not exploiting the maximum capacity of the system. Furthermore, the different prior art techniques cannot be used to process correlated channels. These different drawbacks are partially resolved by the technique of Ma and Giannakis, which can be used to exploit both the space-time diversity of the systems, by means of linear precoding, and their maximum capacity. However, a major drawback of this technique is the receiver used, which must be of the maximum likelihood (abbreviated as ML) type. These ML receivers are complex to implement and, owing to their complexity, limit the size of the precoding matrix to the number of transmit antennas of the system.

<SOH> SUMMARY <EOH>An embodiment of the invention is directed to a method for the sending of a signal formed by vectors, each vector comprising N source symbols to be sent, and implementing M transmit antennas where M is greater than or equal to 2. According to an embodiment of the invention, a linear precoding is performed on said signal, implementing a matrix product of a source matrix, formed by said vectors organized in successive rows, by a linear precoding matrix, delivering a precoded matrix, then precoded vectors corresponding to columns of the precoded matrix are sent successively, the M symbols of each precoded vector being distributed over the M antennas. Thus, an embodiment of the invention relies on a wholly novel and inventive approach to the sending of a signal, implementing linear precoding in a multi-antenna system. More specifically, an embodiment of the invention proposes to carry out a transposed space-time mapping, i.e. it proposes to send the symbols having undergone the same precoding by column on the M antennas. This approach therefore differs sharply from the cyclical sending proposed by Ma and Giannakis, which induced high complexity at reception. The technique of an embodiment of the invention is particularly advantageous because it can be used to exploit the maximum capacity of the MIMO channel, given that it does not use space-time codes, and maximum space-time diversity, through the linear precoding. The number M of transmit antennas corresponds to the number of vectors to be sent, these vectors forming the different rows of the source matrix. Advantageously, the precoding matrix of such a sending method is a block matrix. Preferably, the precoding matrix is a unitary matrix having a size greater than or equal to M. Thus, an embodiment of the invention is distinguished from prior art techniques since the size of the precoding matrix is not always equal to the number M of transmit antennas. As shall be seen here below in this document, this is made possible according to an embodiment of the invention through the implementation of a decoding operation of low complexity that therefore enables simple decoding even with large precoding matrices. This precoding matrix belongs to the group comprising the Hadamard matrices, special unitary matrices sized 2×2, also written as SU(2), Fourier matrices, Vandermonde matrices and, more generally, unitary matrices. In one advantageous embodiment of the invention, the precoding matrix is a block matrix having the form: Θ L = 2 L · [ Θ L / 2 Θ L / 2 Θ L / 2 - Θ L / 2 ] T with   Θ 2 = ⌊  θ 1  cos   η  θ 2  sin   η -  - θ 2  sin   η  - θ 1  cos   η ⌋ and   η = π 4 + k  π 2 , θ 2 = θ 1 - π 2 , and for iε[1,2], θ i = π 4 + k ′  π 2 where k, k′ are relative integers. An embodiment of invention also relates to a method for the reception of a signal sent on M transmit antennas where M is greater than or equal to 2, implementing P receiver antennas, where P greater than or equal to 2. According to an embodiment of the invention, reception vectors are received on the P antennas and are distributed by columns in a reception matrix, the P symbols of a reception vector being distributed on the P antennas. The method then implements an operation for processing the reception matrix, comprising a step of multiplication by a linear de-precoding matrix representing a linear precoding matrix used at sending, so as to obtain a de-precoded matrix by which it is possible to extract an estimation of the source symbols sent. It shall be noted that, for optimal reception, the number P of antennas in reception is greater than or equal to the number M of transmit antennas. Herein and throughout the rest of the document, the term “de-precoding” is understood to mean an operation that is substantially the reverse of the precoding operation performed at the sending stage. In a first embodiment, the de-precoding matrix is the conjugate transpose matrix of the precoding matrix. In this case, with the sent signal being conveyed between the M transmit antennas and the P receiver antennas by a transmission channel, the reception matrix is multiplied, during the processing operation, by a matrix representing the inverse of the transmission channel, so as to obtain a matrix of estimated symbols sent. The matrix of estimated symbols sent is then multiplied by the de-precoding matrix. Indeed, the implementation of a MIMO system, comprising a plurality of transmit antennas and a plurality of receiver antennas, induces the existence of different transmit antenna/receiver antenna paths on which it is possible to transmit the payload information, where these different paths can be schematically represented by a channel matrix. In reception, the channel encoding estimated on the different paths must be inverted in order to retrieve the symbols sent. Assuming that the channel is perfectly known to the receiver, it is enough to carry out an inversion of the channel matrix. The reception method especially comprises a preliminary step of detection of the M transmit antennas implementing a successive cancellation algorithm. In a second embodiment, with the sent signal being conveyed between the M transmit antennas and the P receiver antennas by a transmission channel, the de-precoding matrix is an inverse matrix of a total matrix associating the matrix of the channel and the linear precoding matrix. In this embodiment, the reception method implements a decoding with ordering, which enables a priority decoding of the channels having the best signal-to-noise ratio. In this case, the de-precoding matrix is determined by implementation of a Cholesky decomposition algorithm, which can be used to obtain a decoding method that costs little in computation and is less complex than the prior art techniques. The maximum likelihood type techniques are well known and satisfactory but complex. For the decoding of MIMO systems, the use of a Cholesky decomposition with a minimum mean square error (MMSE) criterion is totally novel and can be used to resolve this drawback of complexity inherent in prior-art techniques. One alternative to the Cholesky decomposition would be to use a QR decomposition with the ZF criterion. This technique also has low complexity but shows less satisfactory results. According to one variant of the invention, with the de-precoding matrix being a block matrix, the reception method carries out a distance minimization by change of symbol in a block. This further improves the decoder of an embodiment of the invention. An embodiment of invention also relates to a signal formed by vectors sent successively on M transmit antennas, where M is greater than or equal to 2, the M symbols of each vector being distributed on the M antennas. According to an embodiment of the invention, the vectors are precoded vectors corresponding to columns of a precoded matrix obtained by taking the matrix product of a linear precoding matrix and a source matrix, formed by source vectors each comprising N source symbols to be sent, the source vectors being organized in said source matrix in successive rows. An embodiment of invention also relates to a device for sending a signal formed by vectors each comprising N source symbols to be sent, and implementing M transmit antennas, where M is greater than or equal to 2, for a sending method as described here above. An embodiment of invention also relates to a device for the reception of a signal sent on M transmit antennas, where M is greater than or equal to 2, the device comprising P receiver antennas, where P is greater than or equal to 2. Other features and advantages shall appear more clearly from the following description of a preferred embodiment, given by way of a simple illustrative and non-exhaustive example and from the appended drawings.

20081224

20110426

20090507

88665.0

H04B702

LE, THANH C

METHOD FOR THE MULTI-ANTENNA TRANSMISSION OF A LINEARLY-PRECODED SIGNAL, CORRESPONDING DEVICES, SIGNAL AND RECEPTION METHOD

UNDISCOUNTED

ACCEPTED

H04B

ACCEPTED

Boot band

The objective of the current invention is to provide a boot-band that can be surely fastened around a member to be clamped without any portion of the band body buckling during fastening, and that can be fastened by a one-step operation for improved fastening workability. A boot-band 30 comprising (1) a band body 31 that is wound like a ring around a member to be clamped, and that has, at its respective ends, an outer-layer portion 32 that is overlaid over an inner-layer portion 33, (2) engagement holes 34, 35 that are formed in the outer-layer portion 32, (3) engagement pawls 36, 37 that are formed on, and that protrude radially outwardly from, the inner-layer portion 33, and that are to be engaged with the corresponding engagement holes 34, 35 so that the band body is held in a fastened state, (4) a first boot-band pawl 41 that is formed on the inner-layer portion 33 at a location nearer to the longitudinal end of the band body than the engagement holes 34, 35 are, (5) a second boot-band pawl 38 that is formed on the inner-layer portion 33 and that is to be engaged with the first boot-band pawl 41, and (6) a pressure-reduction means 45 that is formed in the outer-layer portion 32 in such a manner that the pressure-reduction means 45 reduces the pressure applied on the engagement pawls 36, 37 of the inner-layer portion 33 when the outer-layer portion 32 climbs over the engagement pawls 36, 37 just before the first and the second boot-band pawls are engaged.

1. A boot-band comprising a band body that is wound like a ring around a member to be clamped, and that has an outer-layer portion and an inner-layer portion, respectively, at its two ends, with the outer-layer portion being overlaid over the inner-layer portion, engagement holes that are formed in the outer-layer portion, engagement pawls that are formed on, and that protrude outwardly from, the inner-layer portion and that are to be engaged with their corresponding aforementioned engagement holes so that the band body is held in a fastened state, a first boot-band pawl that is formed on the outer-layer portion nearer to the longitudinally outer end of the band body than are the engagement holes are, a second boot-band pawl that is formed on the inner-layer portion and that is to be engaged with the first boot-band, and a pressure-reduction means that is formed in the outer-layer portion in such a manner that said pressure-reduction means reduces the pressure applied on the engagement pawls of the inner-layer portion when the outer-layer portion climbs over the engagement pawls just before the first and the second boot-band pawls are engaged. 2. A boot-band as described in claim 1, wherein said pressure-reduction means has a structure such that the outer-layer portion rises up from the inner-layer portion when the outer-layer portion climbs over the engagement pawls. 3. A boot-band as described in claim 1, wherein said load-reduction means is structured such that an engagement-hole formation area, which is formed within the outer-layer portion and which contains the engagement holes, is separated—by cut lines along the longitudinal sides of said engagement-hole formation area—from the remaining, surrounding area of the outer-layer portion. 4. A boot-band as described in claim 1, wherein said load-reduction means is structured such that an engagement-hole formation area, which is formed within the outer-layer portion and which contains the engagement holes, is separated, by cut lines along the longitudinal sides of said engagement-hole formation area, from the remaining, surrounding area of said outer-layer portion, and whereby said engagement-hole formation area is elastically flexed toward the inner-layer portion. 5. A boot-band as described in claim 1, wherein said load-reduction means is structured such that an engagement-hole formation area, which is formed within the outer-layer portion and which contains the engagement holes, is separated, by cut lines along the longitudinal sides of engagement-hole formation area, from the remaining, surrounding area of the outer-layer portion, whereby said engagement-hole formation area further has a recoverable elastic sub-area that is connected with the remaining, surrounding area of the outer-layer portion. 6. A boot-band as described in claim 1, wherein said pressure-reduction means are slits that are formed longitudinally in the outer-layer portion in such a manner that parts of the outer-layer portion are elastically raised on both sides of the slits by the engagement pawls that are being climbed over.

FIELD OF THE INVENTION The current invention relates to a boot-band, that fastens a boot, i.e., a tube-like or boot-like member made of rubber, resin, or the like, that is to be clamped to another member. BACKGROUND OF THE INVENTION A boot-band is used both for preventing internal grease and the like from flowing outside a boot and for preventing water or foreign matter from entering inside the boot, by fastening a boot that covers, for example, the power transmission part of an automobile. Because the boot-band is wound around the member to be clamped, the boot-band is usually provided with a pair of boot-band pawls, such that the boot-band can be fastened by applying a fastening tool to the pair of boot-band pawls. FIGS. 15 and 16 show a first conventional boot-band 1 as described in the specification of Patent Document 1, and FIGS. 17 and 18 show a second conventional boot-band 2 as described in Patent Document 2. Both of the boot-bands 1 and 2 are composed of a band-body 3 that is made of a thin metallic plate and that is wound like a ring. Therefore, when the band body 3 is wound (around the member to be clamped), an outer-layer portion 4 of the band body 3 overlaps an inner-layer portion 5 of the band body 3. The boot and the member that is covered by the boot are placed inside of the ring formed by the boot-band before fastening is done. In the first conventional boot-band 1, a first boot-band pawl 6 is formed on the outer-layer portion 4, while a second boot-band pawl 7, which to be paired with the first boot-band pawl 6 is formed on the inner-layer portion 5. Engagement holes 8 and 9 are formed in the outer-layer portion 4 in the area between the first boot-band pawl 6 and the longitudinal end (free end) of the outer-layer portion 4. The engagement hole 8 is longer than the engagement hole 9 is, and it is also used as a tack hole for tacking the band body 3. The second boot-band pawl 7, a tack hook 10, and engagement pawls 11, 12 are sequentially arranged on the inner-layer portion 5 in the lengthwise direction of the band body 3 (in the clockwise direction in FIG. 15) After the boot-band 1 is wound like a ring as shown in FIG. 15, the second boot-band pawl 7 and the tack hook 10 are inserted into the engagement hole 8 of the outer-layer portion 4. Then, by a fastening tool (not illustrated), a pinching force F (see FIG. 16) is applied on the pair of boot-band pawls 6 and 7 in such a manner that the distance between the boot-band pawls 6 and 7 is reduced, which in turn simultaneously reduces the circumference of the boot band and the diameter of the ring formed by the band body. The force F pushes the boot-band pawl 6 into the boot-band pawl 7, simultaneously causing the engagement pawls 11 and 12 to be inserted into, and to be engaged with, the engagement holes 8 and 9, respectively, thus completing the fastening of the boot-band, while firmly maintaining the reduced diameter of the band body. At this time, because the end section (i.e., the section near the engagement hole 9) of the outer-layer portion 4 tends to be pushed outwardly by the protruding engagement pawl 11, the end section must be pressed radially inward by the force shown as G in FIG. 16, in order to engage the engagement pawl 12 with the engagement hole 9 during the final stage of fastening. As shown in FIGS. 17 and 18, in the second conventional boot-band 2, a first boot-band pawl 21 is formed on the top of the outer-layer portion 4 and at a location nearest to the longitudinally outer end of the outer-layer portion 4, and a second boot-band pawl 22 that is to be paired with the first boot-band pawl 21 is formed correspondingly on the inner-layer portion 5. Engagement holes 23, 24, and 25 are sequentially formed in the outer-layer portion 4 following the first boot-band pawl 21, and a second boot-band pawl 22, as well as engagement pawls 26, 27, and 28, respectively corresponding to the engagement holes 23, 24, and 25, are sequentially formed on the inner-layer portion 5. The second boot-band pawl 22 is press-molded in such a manner as to protrude radially outward from the inner-layer portion 5, so that the second boot-band pawl 22 has an opening 22a to receive the first boot-band pawl 21. Also, the first boot-band pawl 21 in the outer-layer portion 4 has a pawl extension 29, which is to be inserted into the opening 22a of the second boot-band pawl 22. As shown in FIG. 18, when the second conventional boot-band 2 is fastened, a pair of tool pawls 15a, 15b of a fastening tool 15 are applied to the boot-band pawls 21 and 22 by a force shown by F, and then the outer-layer and inner-layer portions 4 and 5 are pushed radially inward, resulting in a reduction of the diameter of the ring-like band body 3. At the time of this pushing in, while the pawl extension 29 is inserted into the opening 22a, the engagement pawls 26, 27, and 28 are engaged with their corresponding engagement holes 23, 24, and 25, respectively, and thus the fastening of the boot-band is completed. [Patent Document 1] U.S. Pat. No. Re. No. 33744 [Patent Document 2] Japan Patent No. 3001266 In the first conventional boot-band 1, as is shown in FIGS. 15 and 16, a longitudinal force must be applied continuously to the band body 3 by a fastening tool in order to reduce the diameter of the ring, while an inward force must be applied, at the final stage of fastening only, on the outer-layer portion 4 in order to press the outer-layer portion 4 toward the inner-layer portion 5. Therefore, it is required to simultaneously perform two steps—namely, applying both longitudinal and inward forces—which results in a complex fastening process that involves a long operation time and reduced workability. In contrast, in the second conventional boot-band 2, as is shown in FIGS. 17 and 18, the pawl extension 29 of the first boot-band pawl 21, which is located toward the longitudinally outer end of the outer-layer portion 4, is arranged near to the opening 22a of the second boot-band pawl 22, so that a radially inward-force operation for pressing the outer-layer portion 4 toward the inner-layer portion 5 is not necessary. That is, fastening can be done in one action of pulling in of the boot-band pawls 21 and 22, so that workability is better than that of the first conventional boot-band. However, in the case of the second conventional boot-band 2, there is a problem that the inner-layer portion 5 might buckle during fastening. FIG. 19 illustrates the mechanism that causes the buckling 19. A fastening force is applied on the two boot-band pawls 21 and 22, so that the outer-layer portion 4 slides over the inner-layer portion 5 after the pawl extension 29, which is the longitudinally outer end of the outer-layer portion 4, begins to be inserted into the opening 22a. This sliding makes the outer-layer portion 4 climb over the engagement pawls 26, 27, and 28 of the inner-layer portion 5; that is, the outer-layer portion 4 tries to slide with friction against the engagement pawls, the friction force being the greatest at the engagement pawl 26. In the process of such sliding, the outer-layer portion 4 tends to be locked by the friction force at the protruding part of the engagement pawl 26. As a result of this locking, the force applied to the two boot-band pawls 21 and 22 is in reality applied to the engagement pawl 26 and the boot-band pawl 22, both of which are on the same inner-layer portion 5. As a result, the force for pushing in the outer-layer portion 4 and the inner-layer portion 5—force that should be consumed in the portion of the band body 3 between the two pawls 21 and 22—becomes a force pressing on a small portion of the inner-layer portion 5, between the engagement pawl 26 and the boot-band pawl 22. Then, when the strength of the fastening force exceeds the buckling-resistance limit of that small portion of the inner-layer portion 5, buckling 19 is generated between the engagement pawl 26 and the second boot-band pawl 22 of the inner-layer portion 5. When such buckling 19 occurs, the fastening strength for the member to be clamped becomes unstable and weak, so that the fastening is not secure. DISCLOSURE OF THE INVENTION The current invention has been created in view of the above-mentioned problems in the conventional boot-bands. Therefore, one objective of the current invention is to provide a boot-band that can be securely fastened around the member to be clamped without any portion of the band body being buckled during fastening. In addition, another objective of the current invention is to provide a boot-band that can be fastened by a one-step operation, so as to improve fastening workability. For achieving the above-mentioned objectives, the boot-band described in Claim 1 comprises: a band body that is wound like a ring around a member to be clamped, and that has an outer-layer portion and an inner-layer portion, respectively, at its two ends, with the outer-layer portion being overlaid over the inner-layer portion, engagement holes that are formed in the outer-layer portion, engagement pawls that are formed on, and that protrude outwardly from, the inner-layer portion and that are to be engaged with their corresponding engagement holes in the outer-layer portion so that the band body is maintained in a fastening state, a first boot-band pawl that is formed on the outer-layer portion nearer to the longitudinally outer end of the band body than the engagement holes are, a second boot-band pawl that is formed on the inner-layer portion and that is to be engaged with the first boot-band pawl, and a pressure-reduction means that is formed in the outer-layer portion in such a manner that said pressure-reduction means reduces the pressure applied on the engagement pawls of the inner-layer portion when the outer-layer portion climbs over the engagement pawls just before the first and the second boot-band pawls are engaged. According to the invention of Claim 1, when the outer-layer portion climbs over the inner-layer portion during fastening of the band body, the pressure-reduction means formed in the outer-layer portion reduces the inward pressure on the inner-layer portion at the time of fastening. Therefore the outer-layer portion can slide over the inner-layer portion smoothly without extraordinary concentration of stress, so that problems like buckling of the inner-layer portion are prevented. The invention of Claim 2 is a boot-band as described in Claim 1, and wherein said pressure-reduction means has a structure such that the outer-layer portion is displaced radially outward from the inner-layer portion when the outer-layer portion climbs over the engagement pawls. According to the invention of Claim 2, because the outer-layer portion elastically is displaced radially outward from the inner-layer portion, the inward pressure on the inner-layer portion is reduced, especially on the protruding part such as the engagement pawls that are on the inner-layer portion. Thereby the outer-layer portion can slide over the inner-layer portion with such a limited friction force that locking of the protruding part does not occur, so that the resultant pressing force on the protruding part does not exceed the buckling-resistance limit, as a result of which buckling of the inner-layer portion is prevented. The invention of Claim 3 is a boot-band as described in Claim 1 or 2, and wherein said load-reduction means is structured such that an engagement-hole formation area, which is formed within the outer-layer portion and which contains the engagement holes, is separated—by cut lines along the longitudinal sides of said engagement-hole formation area—from the remaining, surrounding area of the outer-layer portion. According to the invention of Claim 3, because a part of the engagement-hole formation area of the outer-layer portion is separated from its periphery by the aforementioned cut lines, when the outer-layer portion climbs over the engagement pawls of the inner-layer portion and the engagement pawls are brought into contact with the engagement-hole formation area, the engagement-hole formation area is displaced outwardly in such a manner that this displacement of the engagement-hole formation area reduces the inward pressure on the inner-layer portion, so that buckling of the inner-layer portion is prevented. Also, according to the invention of Claim 3, after the engagement-hole formation area displaces outwardly, it moves back inwardly by its own spring-back capability into its original state of moving along the inner-layer portion. Thereby, the engagement holes are automatically engaged with each other, so that such engagement makes the outer-layer portion and the inner-layer portion become mutually interconnected. Accordingly, fastening workability is improved. The invention of Claim 4 is a boot-band as described in Claim 1 or 2, and wherein said load-reduction means is structured such that an engagement-hole formation area, which is formed within the outer-layer portion and which contains the engagement holes, is separated, by cut lines along the longitudinal sides of said engagement-hole formation area, from the remaining, surrounding area of said outer-layer portion, and whereby said engagement-hole formation area is elastically flexed toward the inner-layer portion. According to the invention of Claim 4, the engagement-hole formation area is flexed inwardly. But even with such flexing, at the time that the engagement pawls are brought into contact with the engagement-hole formation area, the engagement-hole formation area is displaced outwardly, so that the inward pressure on the inner-layer portion from the outer-layer portion is reduced, so that buckling of the inner-layer portion is prevented. Also, after the engagement-hole formation area displaces outwardly, because the engagement-hole formation area has initially been elastically flexed inwardly, the engagement-hole formation area automatically returns to its original state and then contacts the inner-layer portion with pressure, so that the engagement holes are surely engaged with the engagement pawls. Accordingly, not only is fastening workability improved, but also the engagement holes can be moderately engaged with the engagement pawls. The invention by Claim 5 is a boot-band as described in Claim 1 or 2, and wherein said load-reduction means is structured such that an engagement-hole formation area, which is formed within the outer-layer portion and which contains the engagement holes, is separated, by cut lines along the longitudinal sides of engagement-hole formation area, from the remaining, surrounding area of the outer-layer portion, whereby said engagement-hole formation area further has a recoverable elastic sub-area that is connected with the remaining, surrounding area of the outer-layer portion. According to the invention of Claim 5, when the outer-layer portion climbs over the engagement pawl of the inner-layer portion, because the engagement-hole formation area is displaced elastically outwardly, the inward pressure on the inner-layer portion from the outer-layer portion is reduced, so that buckling of the inner-layer portion is prevented. At this time, the elastic part that is formed at the connecting location is deformed, aiding the displacement of the engagement-hole formation area, but the engagement-hole formation area is returned to the original state by its recovering force after completing the action of climbing over of the engagement pawl. Such recovery of the elastic part helps the engagement-hole formation area contact the inner-layer portion with additional pressure, so that the engagement pawl is engaged with the engagement hole more surely. Thereby, fastening workability is improved, while moderate engagement can be realized. The invention of Claim 6 is a boot-band as described in Claim 1 or 2, and wherein said pressure-reduction means are slits that are formed longitudinally in the outer-layer portion in such a manner that parts of the outer-layer portion are elastically raised on both sides of the slits by the engagement pawls that are being climbed over. According to the invention of claim 6, when the outer-layer portion climbs over the engagement pawl of the inner-layer portion, the neighboring area of the slits in the outer-layer portion are elastically raised and displaced from the protruding part of the engagement pawl, so that the inward pressure on the inner-layer portion from the outer-layer portion is reduced, with the result that buckling of the inner-layer portion is prevented. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1(a) and (b) are, respectively, a plane view and a sectional view showing Embodiment 1 before fastening. FIGS. 2(a) and (b) are, respectively, a plane view and a sectional view showing Embodiment 1 during fastening. FIG. 3 is an overall sectional view showing Embodiment 1 during fastening. FIGS. 4(a) and (b) are, respectively, a plane view and a sectional view showing Embodiment 1 after fastening is completed. FIG. 5 is an overall sectional view showing Embodiment 1 after fastening is completed. FIGS. 6(a) and (b) are, respectively, a plane view and a sectional view showing Embodiment 2 before fastening. FIGS. 7(a) and (b) are, respectively, a plane view and a sectional view showing of a variation of Embodiment 2 before fastening. FIGS. 8(a) and (b) are, respectively, a plane view and a sectional view showing a state before fastening in. FIGS. 9(a) and (b) are, respectively, a plane view and a sectional view showing Embodiment 3 during fastening. FIG. 10 is an overall sectional view showing Embodiment 3 during fastening. FIGS. 11(a) and (b) are, respectively, a plane view and a sectional view showing Embodiment 3 after fastening is completed. FIGS. 12(a), (b) and (c) are, respectively, a plane view, a sectional view, and an end view showing Embodiment 4 before fastening. FIGS. 13(a), (b) and (c) are, respectively, a plane view, a sectional view, and a transversal sectional view showing Embodiment 4 during fastening. FIGS. 14(a), (b) and (c) are, respectively, a plane view, a sectional view, and a transversal sectional view showing Embodiment 4 after fastening is completed. FIG. 15 is an overall sectional view showing the first conventional boot-band before fastening. FIG. 16 is an overall side view showing the first conventional boot-band during fastening. FIG. 17 is an overall sectional view showing the second conventional boot-band after fastening is completed. FIG. 18 is an overall sectional view showing the second conventional boot-band during fastening. FIG. 19 is a sectional view that illustrates the mechanism that causes buckling of the second conventional boot-band. NUMBERS USED IN THE DRAWINGS 30, 50, 60, 70 Boot-band 31 Band body 32 Outer-layer portion 33 Inner-layer portion 34, 35 Engagement hole 36, 37 Engagement pawl 38 Second boot-band pawl 39 Pawl extension 41 First boot-band pawl 44 Cut line 45 Engagement-hole formation area 47 Fastening-piece area 49 Curved part 51 Elastic part 55 Slit BEST MODES FOR CARRYING OUT THE INVENTION The current invention will now be explained in detail with reference to the drawings of the embodiments. For each embodiment, the corresponding members have the same numbers. Embodiment 1 FIGS. 1 to 5 show a boot-band 30 in Embodiment 1 of the present invention. FIG. 1 shows the boot-band 30 before fastening, FIGS. 2 and 3 show intermediate states during fastening, while FIGS. 4 and 5 show the boot-band 30 after fastening has been completed. The boot-band 30 is formed of a belt-like band body 31. The band body 31 is first formed into a belt-like shape by press-punching and slit-processing a thin metallic plate, then is formed into a ring-like shape by being wound. The band body 31 is used for fastening a member (not illustrated) that is to be clamped to another member. The band body 31 that is wound like a ring has, as its respective ends, an outer-layer portion 32 and an inner-layer portion 33, with the outer-layer portion 32 being overlaid over the inner-layer portion 33. As mentioned below, the outer-layer portion 32 and inner-layer portion 33 are pulled in opposite directions so as to reduce the diameter of the ring, so that the member to be clamped is fastened. A first boot-band pawl 41 is formed on the longitudinally end section (the free end side) of the outer-layer portion 32 of the band body 31 in a manner so as to be raised outwardly in the radial direction. Also, a pawl extension 39 extends longitudinally from the first boot-band pawl 41 toward the end of the outer-layer portion 32. That is to say, the pawl extension 39 is formed so as to face a below-mentioned second boot-band pawl 38 that is formed on the inner-layer portion 33. The pawl extension 39 is formed in a planar shape, so that it can be smoothly inserted into the second boot-band pawl 38. Furthermore, engagement holes 34, 35 are sequentially formed in the outer-layer portion 32 in the longitudinal direction from the end of said outer-layer portion 32. The engagement holes 34, 35 are formed at the approximate width-wise center of the outer-layer portion 32 and are elongated longitudinally. The engagement holes 34, 35 are to be engaged with the below-described engagement pawls 36, 37, so as to maintain the band body 31 in a fastened state. The engagement pawls 36, 37 are formed in the inner-layer portion 33 of the band body 31 in the longitudinal direction, and a second boot-band pawl 38 to be paired with the first boot-band pawl 41 is formed adjacent to these engagement pawls 36, 37. The engagement pawls 36, 37 are formed so as to protrude from the band body 31, slanting so as to face the second boot-band pawl 38. These engagement pawls 36, 37 are to be inserted into, and engaged with, the engagement holes 34, 35 of the outer-layer portion 32. The second boot-band pawl 38 also is formed so as to protrude from the inner-layer portion 33. The second boot-band pawl 38 has an opening 38a and a lid part 38b, as shown in FIGS. 1 and 3. The opening 38a is opened toward the first boot-band pawl 41, into which the above-mentioned pawl extension 39 of the first boot-band pawl 41 is to be inserted. The lid part 38b is connected with the inner-layer portion 33 at the opposite side of the opening 38a, and thus presses the pawl extension 39 inwardly so as to hold the pawl extension 39 when the pawl extension 39 is inserted into the opening 38a. Furthermore, the boot-band 30 is provided with a pressure-reduction means that reduces the pressure on the inner-layer portion 33 when the outer-layer portion 32 climbs over the engagement pawls 36, 37 of the inner-layer portion 33. In this embodiment, the pressure-reduction means is formed by partially separating an engagement-hole formation area from the remaining area of the outer-layer portion 32. Here, the engagement-hole formation area is within the outer-layer portion 32 as an area that has predetermined longitudinal and transversal lengths and that contains the engagement holes 34 and 35. Concretely, the engagement-hole formation area 45 is partially separated from the remaining, surrounding area of the outer-layer portion by cut lines 44, which are formed along the boundary of the engagement-hole formation area 45. In this embodiment, the cut lines run along both longitudinal sides of the boundary and along the front transversal side (the nearest side to the first boot-band pawl 41), thus leaving two fastening-piece areas 47, one on each longitudinal side of the engagement-hole formation area 45. As shown in FIG. 18, when a fastening force F is applied to the first and second boot-band pawls 41 and 38 by a tool like a fastening tool 15, the fastening force is conveyed mainly by the fastening-piece area 47, while the engagement-hole formation area 45 that is separated from the fastening piece part 47 via the cut lines 44 can be displaced outwardly from the inner-layer portion 33. Thus, when the engagement-hole formation area 45 climbs over the engagement pawl 37 of the inner-layer portion 33, such escaping displacement reduces the pressure on the inner-layer portion 33 from the outer-layer portion 32. Therefore, buckling of the inner-layer portion 33 is prevented. Next, the fastening operation of the boot-band 30 in this embodiment will be explained in detail. FIG. 1 shows the state before fastening, in which the boot-band 30 is wound like a ring in a manner so that the outer-layer portion 32 overlies the inner-layer portion 33, surrounding the member to be clamped (not depicted). In this state, a fastening tool (see the fastening tool 15 in FIG. 18) is hooked to both the first boot-band pawl 41 and the second boot-band pawl 38, and is then used to push both the outer-layer portion 32 and the inner-layer portion 33 longitudinally inward. FIGS. 2 and 3 show intermediate states during fastening of the band body 31. When the two ends of the outer-layer portion 32 and inner-layer portion 33 are sufficiently pulled in toward each other, the outer-layer portion 32 climbs over the engagement pawl 36, and then over the engagement pawl 37, of the inner-layer portion 33. At the time of this climbing over, when the engagement pawls 37, 36 (in case of FIGS. 2 and 3, the engagement pawl 37) are brought into contact with the outer-layer portion 32, the engagement-hole formation area 45 of the outer-layer portion 32 is pushed up, i.e., displaced outwardly, by the engagement pawl 37. Such displacement of the engagement-hole formation area 45 reduces the pressure applied on the inner-layer portion 33 from the outer-layer portion 32. Thereby, the pressure that is applied on the inner-layer portion 33 is not strong enough to exceed the buckling-resistance limit of the inner-layer portion 33, and so the inner-layer portion 33 does not buckle. Moreover, the fastening force is conveyed mainly via the fastening-piece area 47, so that fastening of the band body 31 continues, and the outer-layer portion 32 continues to slide over the inner-layer portions 33. By this sliding, the pawl extension 39 on the longitudinally outer end of the first boot-band pawl 41 is inserted into the opening 38a of the second boot-band pawl 38, and is prevented from being detached by the lid part 38b. FIGS. 4 and 5 show the state after fastening is completed. At this final state, the engagement-hole formation area 45 moves back inwardly by its own spring-back capability into a form that conforms to that of the inner-layer portion 33. Thereby, the engagement holes 34, 35 are automatically engaged with the engagement pawls 36, 37, so that the outer-layer portion 32 and the inner-layer portion 33 are fixed to each other. In addition, if the spring-back capability of the engagement-hole formation area 45 is not sufficient, the engagement-hole formation area 45 can be pressed inwardly toward the inner-layer portion 33, getting a fixing of the engagement holes 34, 35 with the engagement pawls 36, 37. In this embodiment, when the outer-layer portion 32 climbs over the engagement pawls 36, 37 due to fastening of the band body 31, the engagement-hole formation area 45 is displaced outwardly (that is, in the radially outward direction), so that the pressure applied on the inner-layer portion 33 from the outer-layer portion 32 is reduced, and thus buckling of the inner-layer portion 33 is prevented. Also, when the band body 31 is fastened, the engagement-hole formation area 45, due to its aforementioned spring-back capability, is in such a form along the inner-layer portion 33 that the engagement holes 34, 35 are automatically engaged with, and kept engaged with, the engagement pawls 36, 37, so that fastening workability is improved. Also, in this embodiment, because the pawl extension 39 on the end of the first boot-band pawl 41 is inserted into the second boot-band pawl 38, the longitudinally outer end of the outer-layer portion 32 take close contact with the inner-layer portion 33. In addition, because the first boot-band pawl 41 is arranged near the pawl extension 39 at the longitudinally outer end of the outer-layer portion 32, and at a position near the second boot-band pawl 38, fastening becomes possible with one pressing action, so that fastening workability is further improved. Embodiment 2 FIG. 6 shows a boot-band 50 in Embodiment 2 of the present invention. In the boot-band 50 according to this embodiment, as is similar to Embodiment 1, the engagement-hole formation area 45 of the outer-layer portion 32 is partially separated from the peripheral, fastening piece part 47 via cut lines 44. In addition, the partially separated, engagement-hole formation area 45 is elastically flexed, slanting radially inwardly (in the direction of the inner-layer portion 33). In such an elastically flexed state, when the band body 31 begins to be fastened, and when the outer-layer portion 32 climbs over the engagement pawls 36, 37 of the inner-layer portion 33, the engagement-hole formation area 45 is displaced outwardly (in the radially outward direction of the band body 31). Therefore, the pressure applied on the inner-layer portion 33 from the outer-layer portion 32 is reduced, so that buckling of the inner-layer portion 33 is prevented. Also, after the fastening is sufficient and the outer-layer portion 32 climbs over the engagement pawls 36, 37, the engagement piece part 45 returns automatically by the spring-back capability of the outer-layer portion 32, so that the engagement holes 34, 35 are engaged with the engagement pawls 36, 37. Thereby, not only is fastening workability improved, but also the engagement holes 34, 35 are moderately engaged with the engagement pawls 36, 37, so that a user can tell that the fastening has been completed. FIG. 7 shows a variation of Embodiment 2. In this variation, as an example of a recoverable elastic sub-area, a curved part 49 that is curved radially outwardly is formed on the rear transversal side (the side farthest from the first boot-band pawl 41) of the engagement-hole formation area 45. The engagement-hole formation area 45 is connected with the remaining area of the outer-layer portion 32 via the curved part 49, so that the curved part 49 gives additional elasticity to the engagement-hole formation area 45, which, as a result, has the merit that during the fastening operation it can be smoothly displaced and can smoothly return inwardly. Embodiment 3 FIGS. 8 to 11 show a boot-band 60 in Embodiment 3 of the present invention. FIG. 8 shows the state before fastening, FIGS. 9 and 10 show intermediate states during fastening, while FIG. 11 shows the state after fastening has been completed. In this embodiment, too, an engagement-hole formation area 45 of the outer-layer portion 32 is separated from the peripheral, fastening piece parts 47 via cut lines 47 on the longitudinal sides. In this embodiment, however, as another example of a recoverable elastic sub-area, elastic parts 51 are formed on the front transversal-side boundary (the side nearest to the first boot-band pawl 41) of the engagement-hole formation area 45, each in a curved form protruding radially outwardly. A pair of elastic parts 51 are formed near the ends of the front transversal-side boundary, while a connection part 52 that is connected with the longitudinally outer-end portion of the outer-layer portion 32, is formed between the pair of elastic parts 51. In this case, the elastic parts 51 are curved outwardly to provide a spring property to them, so that they can return to their original state even when they are deformed. In this embodiment, too, before fastening, the band is wound like a ring so that the outer-layer portion 32 is overlaid over the inner-layer portion 33 on the outside side of the member to be clamped. In this state, the fastening tool is hooked to the first boot-band pawl 41 and the second boot-band pawl 38, and then the outer-layer portion 32 and the inner-layer portion 33 are pushed in the boot-band's diameter-reducing direction for fastening. By such fastening, when the outer-layer portion 32 climbs over the engagement pawl 36, and then over the engagement pawl 37, of the lower overlaid portion 33, the engagement piece part 45 is pushed up by the engagement pawl 37 and is displaced outwardly (in the radially outward direction) as shown in FIGS. 9 and 10. At this time, the elastic parts 51 are deformed in a manner so as to extend from a curved state for storing a return torque. In this manner, when the engagement piece part 45 is displaced in the radially outward direction, the pressure applied on the inner-layer portion 33 from the outer-layer portion 32 is reduced, so that the inner-layer portion 33 does not buckle, because the applied pressure can be controlled so as not to surpass the buckling-resistance limit of the inner-layer portion 33. Thereafter, when the outer-layer portion 32 climbs over the engagement pawls 37, 36, and fastening is sufficient, the elastic parts 51 return to their original state due to their spring property, so that the engagement-hole formation area 45 is closely overlaid along the inner-layer portion 33, as shown in FIG. 11. Thereby, the engagement holes 34, 35 are moderately engaged with the engagement pawls 36, 37, thus firmly fastening the member to be clamped. Also, after fastening, the pawl extension 39 on the longitudinally outer end of the first boot-band pawl 41 is inserted into the opening 38a of the second boot-band pawl 38, and is prevented from disengagement by the lid part 38b. In this embodiment, not only is buckling, which might be generated at the inner-layer portion 33, prevented, but also the engagement holes 34, 35 are automatically engaged with the engagement pawls 36, 37 by elastic returning of the elastic parts 51, so that fastening workability is improved, and moderate engagement results, notifying a user that fastening has been completed. Embodiment 4 FIGS. 12 to 14 show a boot-band 70 in Embodiment 4 of the present invention. FIG. 12 shows the state before fastening, FIG. 13 shows an intermediate state, and FIG. 14 shows the state after fastening has been completed. In the boot-band 70 of this embodiment, the pressure-reduction means is provided by slits 55, which are formed in the outer-layer portion 32. The slits 55, which are formed so as to extend longitudinally along the center of the outer-layer portion 32, consists of a first slit 55a that extends from the engagement hole 34 half-way toward the first boot-band pawl, a second slit 55b that connects the engagement hole 34 and the engagement hole 35, and a third slit 55c that extends from the engagement hole 35 half-way in the rear direction. In this manner, the slits 55 are formed in the outer-layer portion 32, so that the area surrounding the slits 55 in the outer-layer portion 32 can be elastically deformed. In this embodiment, too, the band body 31 starts to be fastened as shown in FIG. 12. When the outer-layer portion 32 climbs over the engagement pawls 37, 36 of the lower overlaid portion 33, as shown in FIG. 13, the peripheral area of the slits 55 acts to deform slanting so as to be displaced from the protruding engagement pawls 36, 37. Such a displacement due to deformation reduces the pressure that the outer-layer portion 32 applies to the inner-layer portion 33. Therefore, the applied pressure can be controlled so as not to surpass the buckling-resistance limit of the inner-layer portion 33, so that the inner-layer portion 33 does not buckle. When fastening is further continued, the outer-layer portion 32 completes climbing over the engagement pawls 36, 37, as shown in FIG. 14, the area surrounding the slits 55 returns to its original form of contacting along the inner-layer portion 33, while the engagement holes 34, 35 are engaged with the engagement pawls 36, 37. Thereby, the member to be clamped can be fastened sufficiently. INDUSTRIAL APPLICABILITY The current invention prevents problems like buckling of the inner-layer portion when the band body is being fastened, and the member to be clamped can be securely and surely fastened. Furthermore, the structure is such that the engagement holes of the outer-layer portion automatically engage with the engagement pawls of the inner-layer portion in a one-step operation, so that fastening workability also is improved.

<SOH> BACKGROUND OF THE INVENTION <EOH>A boot-band is used both for preventing internal grease and the like from flowing outside a boot and for preventing water or foreign matter from entering inside the boot, by fastening a boot that covers, for example, the power transmission part of an automobile. Because the boot-band is wound around the member to be clamped, the boot-band is usually provided with a pair of boot-band pawls, such that the boot-band can be fastened by applying a fastening tool to the pair of boot-band pawls. FIGS. 15 and 16 show a first conventional boot-band 1 as described in the specification of Patent Document 1, and FIGS. 17 and 18 show a second conventional boot-band 2 as described in Patent Document 2. Both of the boot-bands 1 and 2 are composed of a band-body 3 that is made of a thin metallic plate and that is wound like a ring. Therefore, when the band body 3 is wound (around the member to be clamped), an outer-layer portion 4 of the band body 3 overlaps an inner-layer portion 5 of the band body 3 . The boot and the member that is covered by the boot are placed inside of the ring formed by the boot-band before fastening is done. In the first conventional boot-band 1 , a first boot-band pawl 6 is formed on the outer-layer portion 4 , while a second boot-band pawl 7 , which to be paired with the first boot-band pawl 6 is formed on the inner-layer portion 5 . Engagement holes 8 and 9 are formed in the outer-layer portion 4 in the area between the first boot-band pawl 6 and the longitudinal end (free end) of the outer-layer portion 4 . The engagement hole 8 is longer than the engagement hole 9 is, and it is also used as a tack hole for tacking the band body 3 . The second boot-band pawl 7 , a tack hook 10 , and engagement pawls 11 , 12 are sequentially arranged on the inner-layer portion 5 in the lengthwise direction of the band body 3 (in the clockwise direction in FIG. 15 ) After the boot-band 1 is wound like a ring as shown in FIG. 15 , the second boot-band pawl 7 and the tack hook 10 are inserted into the engagement hole 8 of the outer-layer portion 4 . Then, by a fastening tool (not illustrated), a pinching force F (see FIG. 16 ) is applied on the pair of boot-band pawls 6 and 7 in such a manner that the distance between the boot-band pawls 6 and 7 is reduced, which in turn simultaneously reduces the circumference of the boot band and the diameter of the ring formed by the band body. The force F pushes the boot-band pawl 6 into the boot-band pawl 7 , simultaneously causing the engagement pawls 11 and 12 to be inserted into, and to be engaged with, the engagement holes 8 and 9 , respectively, thus completing the fastening of the boot-band, while firmly maintaining the reduced diameter of the band body. At this time, because the end section (i.e., the section near the engagement hole 9 ) of the outer-layer portion 4 tends to be pushed outwardly by the protruding engagement pawl 11 , the end section must be pressed radially inward by the force shown as G in FIG. 16 , in order to engage the engagement pawl 12 with the engagement hole 9 during the final stage of fastening. As shown in FIGS. 17 and 18 , in the second conventional boot-band 2 , a first boot-band pawl 21 is formed on the top of the outer-layer portion 4 and at a location nearest to the longitudinally outer end of the outer-layer portion 4 , and a second boot-band pawl 22 that is to be paired with the first boot-band pawl 21 is formed correspondingly on the inner-layer portion 5 . Engagement holes 23 , 24 , and 25 are sequentially formed in the outer-layer portion 4 following the first boot-band pawl 21 , and a second boot-band pawl 22 , as well as engagement pawls 26 , 27 , and 28 , respectively corresponding to the engagement holes 23 , 24 , and 25 , are sequentially formed on the inner-layer portion 5 . The second boot-band pawl 22 is press-molded in such a manner as to protrude radially outward from the inner-layer portion 5 , so that the second boot-band pawl 22 has an opening 22 a to receive the first boot-band pawl 21 . Also, the first boot-band pawl 21 in the outer-layer portion 4 has a pawl extension 29 , which is to be inserted into the opening 22 a of the second boot-band pawl 22 . As shown in FIG. 18 , when the second conventional boot-band 2 is fastened, a pair of tool pawls 15 a, 15 b of a fastening tool 15 are applied to the boot-band pawls 21 and 22 by a force shown by F, and then the outer-layer and inner-layer portions 4 and 5 are pushed radially inward, resulting in a reduction of the diameter of the ring-like band body 3 . At the time of this pushing in, while the pawl extension 29 is inserted into the opening 22 a, the engagement pawls 26 , 27 , and 28 are engaged with their corresponding engagement holes 23 , 24 , and 25 , respectively, and thus the fastening of the boot-band is completed. [Patent Document 1] U.S. Pat. No. Re. No. 33744 [Patent Document 2] Japan Patent No. 3001266 In the first conventional boot-band 1 , as is shown in FIGS. 15 and 16 , a longitudinal force must be applied continuously to the band body 3 by a fastening tool in order to reduce the diameter of the ring, while an inward force must be applied, at the final stage of fastening only, on the outer-layer portion 4 in order to press the outer-layer portion 4 toward the inner-layer portion 5 . Therefore, it is required to simultaneously perform two steps—namely, applying both longitudinal and inward forces—which results in a complex fastening process that involves a long operation time and reduced workability. In contrast, in the second conventional boot-band 2 , as is shown in FIGS. 17 and 18 , the pawl extension 29 of the first boot-band pawl 21 , which is located toward the longitudinally outer end of the outer-layer portion 4 , is arranged near to the opening 22 a of the second boot-band pawl 22 , so that a radially inward-force operation for pressing the outer-layer portion 4 toward the inner-layer portion 5 is not necessary. That is, fastening can be done in one action of pulling in of the boot-band pawls 21 and 22 , so that workability is better than that of the first conventional boot-band. However, in the case of the second conventional boot-band 2 , there is a problem that the inner-layer portion 5 might buckle during fastening. FIG. 19 illustrates the mechanism that causes the buckling 19 . A fastening force is applied on the two boot-band pawls 21 and 22 , so that the outer-layer portion 4 slides over the inner-layer portion 5 after the pawl extension 29 , which is the longitudinally outer end of the outer-layer portion 4 , begins to be inserted into the opening 22 a. This sliding makes the outer-layer portion 4 climb over the engagement pawls 26 , 27 , and 28 of the inner-layer portion 5 ; that is, the outer-layer portion 4 tries to slide with friction against the engagement pawls, the friction force being the greatest at the engagement pawl 26 . In the process of such sliding, the outer-layer portion 4 tends to be locked by the friction force at the protruding part of the engagement pawl 26 . As a result of this locking, the force applied to the two boot-band pawls 21 and 22 is in reality applied to the engagement pawl 26 and the boot-band pawl 22 , both of which are on the same inner-layer portion 5 . As a result, the force for pushing in the outer-layer portion 4 and the inner-layer portion 5 —force that should be consumed in the portion of the band body 3 between the two pawls 21 and 22 —becomes a force pressing on a small portion of the inner-layer portion 5 , between the engagement pawl 26 and the boot-band pawl 22 . Then, when the strength of the fastening force exceeds the buckling-resistance limit of that small portion of the inner-layer portion 5 , buckling 19 is generated between the engagement pawl 26 and the second boot-band pawl 22 of the inner-layer portion 5 . When such buckling 19 occurs, the fastening strength for the member to be clamped becomes unstable and weak, so that the fastening is not secure.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIGS. 1 ( a ) and ( b ) are, respectively, a plane view and a sectional view showing Embodiment 1 before fastening. FIGS. 2 ( a ) and ( b ) are, respectively, a plane view and a sectional view showing Embodiment 1 during fastening. FIG. 3 is an overall sectional view showing Embodiment 1 during fastening. FIGS. 4 ( a ) and ( b ) are, respectively, a plane view and a sectional view showing Embodiment 1 after fastening is completed. FIG. 5 is an overall sectional view showing Embodiment 1 after fastening is completed. FIGS. 6 ( a ) and ( b ) are, respectively, a plane view and a sectional view showing Embodiment 2 before fastening. FIGS. 7 ( a ) and ( b ) are, respectively, a plane view and a sectional view showing of a variation of Embodiment 2 before fastening. FIGS. 8 ( a ) and ( b ) are, respectively, a plane view and a sectional view showing a state before fastening in. FIGS. 9 ( a ) and ( b ) are, respectively, a plane view and a sectional view showing Embodiment 3 during fastening. FIG. 10 is an overall sectional view showing Embodiment 3 during fastening. FIGS. 11 ( a ) and ( b ) are, respectively, a plane view and a sectional view showing Embodiment 3 after fastening is completed. FIGS. 12 ( a ), ( b ) and ( c ) are, respectively, a plane view, a sectional view, and an end view showing Embodiment 4 before fastening. FIGS. 13 ( a ), ( b ) and ( c ) are, respectively, a plane view, a sectional view, and a transversal sectional view showing Embodiment 4 during fastening. FIGS. 14 ( a ), ( b ) and ( c ) are, respectively, a plane view, a sectional view, and a transversal sectional view showing Embodiment 4 after fastening is completed. FIG. 15 is an overall sectional view showing the first conventional boot-band before fastening. FIG. 16 is an overall side view showing the first conventional boot-band during fastening. FIG. 17 is an overall sectional view showing the second conventional boot-band after fastening is completed. FIG. 18 is an overall sectional view showing the second conventional boot-band during fastening. FIG. 19 is a sectional view that illustrates the mechanism that causes buckling of the second conventional boot-band. detailed-description description="Detailed Description" end="lead"?

20060601

20090623

20070816

97533.0

F16L3300

SANDY, ROBERT JOHN

BOOT BAND

UNDISCOUNTED

ACCEPTED

F16L

ACCEPTED

Simulate usercalling's test system and method which built-in digital spc-exchange

The present invention disclosed a kind of simulate user calling's test system and method which built-in digital SPC exchange, include background processing module, foreground calling control processing module and hardware subsystem, therein: background processing module operation on exchange servicing platform, for supply user setting parameter and display operate interface for test result, foreground calling control processing module is include in the exchange main control module, for control said hardware subsystem execute test process according to designed logical flow and user mount parameter, hardware subsystem composed of loop circuit relay single board, simulation user interface board, interface board control processing unit, multifunction resources process board. Adopt present invention may use few cost to reach the test result which equal to commercial calling device, and may reach more mobility, reach inline test function.

1. A simulated user call test system built in a digital SPC switch, comprising a back process module, a front call control process module and a hardware subsystem for performing a call test, wherein: the back process module runs on a maintaining platform of the switch for providing an operation interface for a user to perform a call test setup, receiving call test result data transmitted by the front call control process module, and performing display and statistic process; the front call control process module is included in a main control module of the switch for receiving call test setup parameters provided by the back process module, controlling the hardware subsystem to perform a call test process according to a flowchart and user parameters set, and reporting a result of call test to the back process module; the hardware subsystem comprises function process units of the digital SPC switch for receiving instructions from the front call control process module, performing test including picking-up or hanging-up phones, detecting signaling tone, dialing, sending test tone, and talking, and reporting test results to the front call control process module. 2. The simulated call test system according to claim 1, wherein the hardware subsystem comprises a loop relay panel, a simulated user interface panel, an interface panel control process element, and a multifunction resource process panel, wherein: the loop relay panel is used for simulating picking-up or hanging-on a phone in a calling or called user terminal and dial function of DP form by the calling user; the multifunction resource process panel comprises: a signal tone detection process module for detecting whether tones, such as the dial tone and busy tone, in the switch are normal or not in the call test process; a signal tone process module for providing playing of signal tones required in the call test process; and a dual tone multiple frequency generator for simulating dial function of user terminal in a DTMF form; the simulated user interface panel connects to the loop relay panel by a user line for providing a simulated user interface in the switch, and initiating a call on the user line when testing; and the interface panel control process element is provided various timers required in the call test, and connected to the loop relay panel, the simulated user interface panel and the multifunction resource process panel with HW wires, on which inter-working and exchanging is completed by a network, and a control between the front call control process module and resources of the hardware subsystem is realized in a message-driven form by such interface. 3. A test method realized based on built-in modules of a digital SPC switch, comprising the following steps of: setting related information for a calling and a called user in a simulated call test through a human-machine interface of a back process module by a tester; transmitting call parameters to a front call control process module through a message channel by the back process module; initiating the call test after the front call control process module obtains related call test process parameters; sending, by the front call control process module, instructions to a hardware subsystem within the switch according to a call test control flowchart set; completing the test process according to the instructions from the front call control process module, and reporting a test result to the front call control process module by the hardware subsystem; processing the call test result, and collecting to the back process module by the front call control process module; and displaying the result by the back process module. 4. The test method according to claim 3, wherein the call test control flowchart comprises the following steps of: (1) first simulating picking-up a phone by a user in an idle state, and entering a state of waiting for dial tone; (2) after detecting the dial tone, preparing for sending the number, and entering a state of dial; (3) sending the number called in a DTMF or DP form according to a setup, after sending the number, initiating a pass detection timer, and entering a state of waiting for pass; (4) receiving the number, analyzing the number, searching for a called user, and feeding ringing back tone by a normal call service system in the switch; (5) if the called user picks up a phone when detecting the ringing, sending a pass test tone and setting the pass detection timer, and entering a state of a pass test; (6) after the calling user receives the pass test tone, sending another pass test tone, and, if the calling user is set first to hang up, setting a talk timer, if not, detecting whether there is a busy tone, and, entering a state of talking; (7) after the called user receives the pass test tone, if the calling user is set first to hang up, detecting whether there is a busy tone, if not, setting a talk timer, and entering a state of talking; (8) when the talk timers of the calling or called users time out or after a busy tone is detected, simulating user hanging up, and releasing the calling and the called users, thereby a call process is completed. 5. The test method according to claim 4, wherein when sending the number, a dial timer is initiated, after the timer times, one digit of the number called is transmitted according to a DP or a DTMF form set, until all digits are transmitted. 6. The test method according to claim 4, wherein in the step (6), if the pass detection timer for the calling user times out, a pass test tone is also transmitted, if the calling user is set first to hang up, a talk timer is set, otherwise, whether there is a busy tone is detected; in the step (7), when the pass detection timer for the called user times out, if the calling user is set first to hang up, whether there is a busy tone is detected, otherwise, a talk timer is set.

TECHNICAL FIELD OF THE INVENTION The present invention relates to the digital stored program control (SPC) switch technique in telecommunication, particularly, to a simulated user call test system built-in digital SPC switch and method thereof. BACKGROUND OF THE INVENTION Currently, the simulated user calling performance test for digital SPC switch mainly employs large traffic call test instruments. In the market, there are a lot of commercial simulated user calling test instruments to be selected. Such test instrument is characterized in simulating the calling process of actual user realistically, in which the test is performed by transmitting and receiving pass detecting tone and judging the pass detecting tone while a call is initiated on an user line, a dial is simulated and the called is communicated, and, therefore, it can realistically reflect the processing on calls by the switch system and its performance on the call processing. However, they are not applied in many institutes because of their high prices. Therefore, in the actual operation of a network, branches of many operators do not buy this kind of equipment, and, consequently, calling tests are very complicated during pass tests of many digital SPC switches. If there is a calling test instrument built-in the switch, the test will be simpler. In the China patent application No. 99116068.1, a simulating caller is disclosed, in which its all parts are installed in a switch. This patent application realized an independent simulated calling test instrument, which can not be built in digital SPC switch system. In actual application, there has already been a kind of switch with a built-in large traffic calling test system, in which it is characterized in that it designs a virtual calling process on a user element processor, simulating the whole process including initiating a call by a user and answering by the called user the call. But the main disadvantage of this kind of system is that it can only realistically test the process of call signaling by the main control system in the tested switch, but not the performances such as the hardware interface performance in the switch and the performance of the switch connection path, and actually, it can not accurately reflect the call process performance of the switch system. SUMMARY OF THE INVENTION The technical problem to be solved by the present invention is to provide a simulated user call test system located within a digital SPC switch, and to provide a test method based on built-in modules of a digital SPC switch, in which equal functions to commercial external call test systems can been realized with a lower cost by using the current hardware and software resources in a digital SPC switch. In order to approach the above object, the present invention provides a simulated user call test system built in a digital SPC switch, which comprises a back process module, a front call control process module and a hardware subsystem for performing a call test, in which: the back process module runs on a maintaining platform of the switch for providing an operation interface for a user to perform a call test setup, receiving call test result data transmitted by the front call control process module, and performing display and statistic process; the front call control process module is included in a main control module of the switch for receiving call test setup parameters provided by the back process module, controlling the hardware subsystem to perform a call test process according to a flowchart and user parameters set, and reporting a call test result to the back process module; the hardware subsystem comprises function process units of the digital SPC switch for receiving instructions from the front call control process module, performing test including picking-up or hanging-up a phone, detecting signaling tone, dialing, sending test tone, and talking, and reporting test results to the front call control process module. In order to realize the above objects, the present invention further provides a test method on the basis of built-in modules of a digital SPC switch, which comprises the following steps of: setting related information for a calling and a called user in a simulated call test through a human-machine interface of a back process module by a tester; transmitting call parameters to a front call control process module through a message channel by the back process module; initiating the call test after the front call control process module obtains related call test process parameters; sending, by the front call control process module, instructions to a hardware subsystem within the switch according to a call test control flowchart set; completing the test process according to the instructions from the front call control process module, and reporting a test result to the front call control process module by the hardware subsystem; processing the call test result, and collecting to the back process module by the front call control process module; displaying the result by the back process module. The above test method is characterized in that the call test control flowchart comprises the following steps of: (1) first simulating picking-up a phone by a user in an idle state, and entering a state of waiting for dial tone; (2) after detecting the dial tone, preparing for sending the number, and entering a state of dial; (3) sending the number called in a DTMF or DP form according to a setup, after sending the number, initiating a pass detection timer, and entering a state of waiting for pass; (4) receiving the number, analyzing the number, searching for a called user, and feeding ringing back tone by a normal call service system in the switch; (5) if the called user picks up a phone when detecting the ringing, sending a pass test tone and setting the pass detection timer, and entering a state of a pass test; (6) after the calling user receives the pass test tone, sending another pass test tone, and, if the calling user is set first to hang up, setting a talk timer, if not, detecting whether there is a busy tone, and, entering a state of talking; (7) after the called user receives the pass test tone, if the calling user is set first to hang up, detecting whether there is a busy tone, if not, setting a talk timer, and entering a state of talking; (8) when the talk timers of the calling or called users time out or after a busy tone is detected, simulating user hanging up, and releasing the calling and the called users, thereby a call process is completed. In the above flowchart, when sending the number, a dial timer is initiated to control the speed of dial, that is, the time interval of digits of the called number, and the time length of the timer can be set. Furthermore, because the procedure is processed based on circuits (one circuit represents one telephone), and each circuit may use a different form to dial (DTMF or DP), after timing out of the timer for each circuit, it first judges the attribute of the circuit before sending the dial, the dial for each time is one digit of the number called. Because the first digit of the number is also transmitted after timing out of the timer, actually, all digits have been judged. In the above flowchart, when the pass detection timer of the calling or called user time out, it continues the next talking step as the same manner as when detecting the pass test tone. Because the pass detection in calling is bi-directional, no-pass to one direction does not mean no-pass to another direction, so that a waiting time can be reserved for the pass detection for another direction, and, further, the failure in pass detection only means no-pass in the calling path, and may have no relation to whether the signaling is normal or not (for example, any failures in hardware in the channel). Therefore, it can continue to go on and the remaining signaling flowchart may be tested in the remaining steps, which results in more accurately locating on the failures. From the above, compared to the prior art, the present invention realizes a test system for simulating user large traffic call built in a digital SPC switch, which has the same function as commercial outside call testers, on the basis of original SPC switch equipments and current resources utilized by adding a call test process and necessary alternative hardware process modules to the switch control process software system. The present invention has the following advantages: (1) the system is wholly built in the switch system, users can obtain such system with less cost when buying a switch system; (2) the call test result is equal to the standard commercial call tester, and easier to use; (3) because the test system is built in a digital switch system, the simulated user call test system can be used as an on-line call test system in a switch system by setting, which helps to find any fault on call function of the system immediately. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view of a built-in simulated user call test system according to the present invention. FIG. 2 is an overall flowchart of a simulated user call test system of the present invention. FIG. 3 is a schematic view of the hardware structure for a built-in simulated user call test system according to one embodiment of the present invention. FIGS. 4A and 4B are a flow chart of a test process at the calling side in the front main control software of the built-in simulated user call test system according to one embodiment of the present invention. FIG. 5 is the flow chart of a test process at the called side in the front main control software of the built-in simulated user call test system according to one embodiment of the present invention. DETAIL DESCRIPTION OF EMBODIMENTS Simulating a user call process mainly includes operations, such as picking up a phone, hanging up the phone, listening to signal tone, dialing the number called, and talking. As a simulated user call test system, its main function is to finish the above operations, and to analysis the result. The present invention accomplishes a simulated user call test system in a digital SPC switch by employing functions, such as simulating user picking up and hanging-up a phone and dialing the number called, of loop relay in the digital SPC switch, by employing functions existing in a switch such as control process and signal tone detection, and by adding certain proper software. The call test system of one embodiment according to the present invention includes the front and back software process modules and hardware subsystem, with a system structure shown in FIG. 1, which comprises the following three parts: The first is the back process module 11, which runs on a maintaining platform of a switch for providing the call test system with a human interface, with its main function as providing user operation interface and displaying call test result. Users can perform call test setup via the human-machine interface. During the call test process and after the end of the call test, the front call control process module transmits the call test result data to the back process module in a real-time manner to display and perform related data statistic process. The second is the front call control process module 12, which presents as a function module in the main control process module of the switch, and in the realization, it is a task having call test process control process for the main control software system of the switch. It receives related call test parameters set by a user through the back platform of the call test system, controls the hardware subsystem for performing a call test, performs call test process according to logic flowchart designed and related parameters set by the user, and reports the result of call test to the back process module of the call test system. The front call control process module is a core of the whole call test system, responsible for managing resources used in the call test. The front platform also has a call service process module of a normal calling, for processing normal service functions of the switch. The third is the hardware subsystem 13 for performing call test, which mainly comprises some function process elements of a digital SPC, and is a key part to accomplish a simulated user call test. The test function of the simulated user call test system is finally realized based on the hardware subsystem. The hardware subsystem receives all instructions from the front call control process module, dispatches hardware resources managed, performs specified test items, and reports the test result to the front call control process module. The whole flow chart of the test method of the present invention is shown in FIG. 2, including the following steps of: step 2100, in which a tester sets related information of simulated call test on the calling and called parties via the human-machine interface of the back process module; these setups include information, such as location of the calling user, the number called, the call interval, the time length of call-holding, dial form, dial interval, the calling user first hanging-up or the called user first hanging-up. step 2101, in which the back process module transmits call parameters to the front call control process module via a message channel; step 2200, in which the front call control module initiates and controls the whole call test process after getting related call test process parameters; the front call control process module is a core process module of the simulated user call test system, with a basic flow chart of the call test shown in FIG. 4A, FIG. 4B and FIG. 5. step 2201, in which the front call control process module transmits a specified instruction to the hardware subsystem; step 2300, in which the hardware subsystem finishes a specified test process according to the instruction from the front call control process module; step 2301, in which the hardware subsystem reports a result of the call test to the front call control process module; step 2400, in which the front call control process module processes the call test result, and collects to the back process module; step 2500, in which the back process module displays the result, and meanwhile the tester may further perform statistic on the related data when desired. The configuration and basic flow chart of the hardware subsystem of the call test according to the present invention will be explained in details below. The configuration of the hardware subsystem of the call test in one embodiment according to the present invention is shown in FIG. 3, comprising loop relay panel 21, simulated user interface panel 22, interface panel control process element 23, and multifunction resource process panel 25. Loop relay interface is used for simulating picking-up or hanging-on a phone in the calling or called user terminal and dial function of a DP form by the calling user; The multifunction resource process panel includes: a signal tone detection process module for detecting whether tones, such as the dial tone and busy tone, in the switch are normal or not in the call test process, in order to perform the next call test process step; a signal tone process module for providing playing of signal tones required in the call test process, for example, sending pass test tone; and a dual tone multiple frequency generator for simulating a dial function of user terminal in a DTMF form; it should be noted that, there are many functions to be applied on the multifunction resource panel, as described above, and busy tone detection and DTMF dial function are not initiated during normal call process, which needs to be initialized before test. Simulated user interface panel connects to loop relay panel by user AB line, for providing simulated user interface in the switch, and initiating call on user line when testing; and interface panel control process element is connected to the loop relay panel, simulated user interface panel and multifunction resource process panel with HW wires, on which inter-working and exchanging is completed by time division switch network LC, and the control between the front call control process module and all hardware above is realized in a message-driven form by the interface. Timers in the process, such as timers for dial, pass detection, and talking, are set on the interface control process element according to the parameters transmitted from the front call control process module, and the parameters can be manually modified via the back process module. The above simulated user interface panel, interface panel control process element, and multifunction resource process panel all are intrinsic parts of a digital SPC switch, and only loop relay panel is the alternative part in the digital SPC switch, but it is a developed part and can be used directly, and, when necessary, it can be added only. All above hardwares support their functions necessary in the test, but their process flow chart in a normal call may not comply with the process flow chart in the test, which needs to modify the software only. It should be noted that, because of continuous development, update and modification on hardware resources in a SPC switch, the present invention does not limit the unit realizing the hardware subsystem to the above specified hardware panel, which is only a preferred embodiment. From the above, it can be seen that the hardware subsystem and software systems of front and back processes in this embodiment of the present invention may be added to the digital SPC switch system in an overlap form, which does not influence original functions of the switch, such as service call. Next, in connection with FIGS. 4A, 4B and 5, it will describe the combination of the front and back call control process modules and hardware resources in the call test system, and the basic service flowchart for processing a call test process. A calling user is in idle state, step 4100; a front call control process module orders a circuit of loop relay panel to simulate picking-up action in the user terminal, step 4101; the loop relay circuit and a signal tone detection circuit on a multifunction resource process panel are connected, step 4102; a state of waiting for (the calling user's) dial tone is entered, step 4200; the multifunction resource process panel detects a dial tone, step 4201; the front call control process module judges whether call dial form of the simulated user manually set is a DTMF form or not, if yes, perform step 4203a, if not, perform step 4203b, and step 4202; a DTMF dial resource on the multifunction resource process panel is applied and initialized, preparing for dial, step 4203a; if the dial form is indicated to be set as a DP form, the loop relay circuit is noticed to be ready for dial, step 4203b; meanwhile, the dial timer is set, step 4204; a dial state is entered, step 4300; when the dial timer times out, step 4301; the front call control process module judges whether the number has been sent, if yes, perform step 4305, if not, perform the next step, step 4302; whether the call dial form set by user is DTMF form or not is judged, if yes, perform step 4-304a, otherwise, perform step 4304b, step 4303; the front call control process module controls a DTMF dialer on the multifunction resource process panel to dial, and returns step 4300, 4304a. the front call control process module controls the circuit of loop relay panel to perform DP dial, and returns step 4300, step 4304b; a pass detection timer is set, step 4305; then, the calling user enters a state of waiting for a pass signal from the called user (which will be introduced continuously below), and a normal call service system of the digital SPC switch receives the number and analyzes it, locates the called user, and feeds ringing back tone to the called user; the following is a control process in a simulated user terminal: the loop relay of a simulated called user detects ringing signal of user line in real time manner, in idle state, step 5100; the ringing signal is detected, step 5101; the front call control process module controls the loop relay panel to simulate user picking-up a phone, step 5102; a pass test tone of 450 Hz is sent to the calling user, step 5103; a pass detection timer is set, step 5104; the caller user is entered a state of pass detection, step 5200; when the called user detects a pass test tone or that the pass detection timer times out, step 5201; whether in the simulated call the called user is set to hanging-up first is judged, if yes, perform step 5203a, if not, perform step 5203b, step 5202; a talking timer of the called user is set, step 5203a; the front call control process module applies for and initializes a busy detection circuit on the multifunction resource process panel, and starts to detect any busy tone in real time, step 5203b; the called user enters a state of talking, step 5300; when a busy tone is detected or the talking timer of the called user times out, step 5301; the front call control process module controls the loop relay panel to simulate the hanging-up the phone by the called user, step 5302; after the simulated user interface panel detects the hanging-up, a normal call service flowchart in the switch releases the called user, step 5303; the called user is entered an idle state, that is, back to step 5100. The control process in the simulated user terminal for the calling user is continuously described below: the calling user is in a state of waiting for pass signal from the called user, step 4400; when the calling user detects the pass signal tone transmitted by the called user or the pass detection timer times out, step 4401; sending 1S pass test tone to the called user, step 4402; whether in the simulated setup the calling user first hangs up is first judged before the talk state is entered, if yes, perform step 4404a, if not, perform step 4404b, step 4403; a talk-holding timer is set for the calling user, step 4404a; the multifunction resource panel is connected, any possible busy tone transmitted from the line is detected, step 4404b; the calling user is entered a talk state, step 4500; when the talk timer for the calling party times out or the multifunction resource detects a busy tone, step 4501; the front call control process module controls the loop relay panel to simulate hanging-up the phone by the calling user, step 4502; after the simulated user interface detects the hanging-up, the front call control process module controls to release the calling user, step 4503, this process is in a normal call service flowchart of the switch; then, the calling user is entered an idle state of step 4100. For any specified setup for a flowchart in the call test process, the present invention does not limit to the above embodiments and various modifications can be performed by system resources of the present invention. INDUSTRIAL APPLICABLE After a user buys the SPC switch equipment, the user can get a call test instrument built in the switch without paying any additional cost or with adding very low cost; This built-in simulated user call test system can really simulate various testes by current standard commercial user simulating callers, and its result is equal to the test result of standard commercial user simulating callers. First, their principles are same, all perform a test by initiating a call on a user line, simulating dial and talking with the called party, and by transmitting pass detection tone, receiving and judging the form of the pass detection tone. Because of the same principle, the test results are comparable. Second, both can manually set related parameters, such as a dial interval, time-length of talking, first hanging-up by the calling or called party, interval between two calls. Further, both can perform statistical process on call test results in details, for example, overall times of initiation, success times of initiation, failure times, and reasons for failures, which can help to analyze and locate any possible problems in the system. When the test call is in a large number, a setup may be set freely, in which the biggest initiation call user number may be only limited by an user number permitted for simultaneous initiation by the switch; any on-line test can be conveniently performed, which helps to find any failure in the system in time, and obtains much more detailed statistics on reasons of the failures than commercial call testers, and facilitates testing and locating failuares; and a visible image interface may be used as a human-machine interface, and it is designed in a software module with a flexible configuration, directly displaying results, and more flexibility and operability.

<SOH> BACKGROUND OF THE INVENTION <EOH>Currently, the simulated user calling performance test for digital SPC switch mainly employs large traffic call test instruments. In the market, there are a lot of commercial simulated user calling test instruments to be selected. Such test instrument is characterized in simulating the calling process of actual user realistically, in which the test is performed by transmitting and receiving pass detecting tone and judging the pass detecting tone while a call is initiated on an user line, a dial is simulated and the called is communicated, and, therefore, it can realistically reflect the processing on calls by the switch system and its performance on the call processing. However, they are not applied in many institutes because of their high prices. Therefore, in the actual operation of a network, branches of many operators do not buy this kind of equipment, and, consequently, calling tests are very complicated during pass tests of many digital SPC switches. If there is a calling test instrument built-in the switch, the test will be simpler. In the China patent application No. 99116068.1, a simulating caller is disclosed, in which its all parts are installed in a switch. This patent application realized an independent simulated calling test instrument, which can not be built in digital SPC switch system. In actual application, there has already been a kind of switch with a built-in large traffic calling test system, in which it is characterized in that it designs a virtual calling process on a user element processor, simulating the whole process including initiating a call by a user and answering by the called user the call. But the main disadvantage of this kind of system is that it can only realistically test the process of call signaling by the main control system in the tested switch, but not the performances such as the hardware interface performance in the switch and the performance of the switch connection path, and actually, it can not accurately reflect the call process performance of the switch system.

<SOH> SUMMARY OF THE INVENTION <EOH>The technical problem to be solved by the present invention is to provide a simulated user call test system located within a digital SPC switch, and to provide a test method based on built-in modules of a digital SPC switch, in which equal functions to commercial external call test systems can been realized with a lower cost by using the current hardware and software resources in a digital SPC switch. In order to approach the above object, the present invention provides a simulated user call test system built in a digital SPC switch, which comprises a back process module, a front call control process module and a hardware subsystem for performing a call test, in which: the back process module runs on a maintaining platform of the switch for providing an operation interface for a user to perform a call test setup, receiving call test result data transmitted by the front call control process module, and performing display and statistic process; the front call control process module is included in a main control module of the switch for receiving call test setup parameters provided by the back process module, controlling the hardware subsystem to perform a call test process according to a flowchart and user parameters set, and reporting a call test result to the back process module; the hardware subsystem comprises function process units of the digital SPC switch for receiving instructions from the front call control process module, performing test including picking-up or hanging-up a phone, detecting signaling tone, dialing, sending test tone, and talking, and reporting test results to the front call control process module. In order to realize the above objects, the present invention further provides a test method on the basis of built-in modules of a digital SPC switch, which comprises the following steps of: setting related information for a calling and a called user in a simulated call test through a human-machine interface of a back process module by a tester; transmitting call parameters to a front call control process module through a message channel by the back process module; initiating the call test after the front call control process module obtains related call test process parameters; sending, by the front call control process module, instructions to a hardware subsystem within the switch according to a call test control flowchart set; completing the test process according to the instructions from the front call control process module, and reporting a test result to the front call control process module by the hardware subsystem; processing the call test result, and collecting to the back process module by the front call control process module; displaying the result by the back process module. The above test method is characterized in that the call test control flowchart comprises the following steps of: (1) first simulating picking-up a phone by a user in an idle state, and entering a state of waiting for dial tone; (2) after detecting the dial tone, preparing for sending the number, and entering a state of dial; (3) sending the number called in a DTMF or DP form according to a setup, after sending the number, initiating a pass detection timer, and entering a state of waiting for pass; (4) receiving the number, analyzing the number, searching for a called user, and feeding ringing back tone by a normal call service system in the switch; (5) if the called user picks up a phone when detecting the ringing, sending a pass test tone and setting the pass detection timer, and entering a state of a pass test; (6) after the calling user receives the pass test tone, sending another pass test tone, and, if the calling user is set first to hang up, setting a talk timer, if not, detecting whether there is a busy tone, and, entering a state of talking; (7) after the called user receives the pass test tone, if the calling user is set first to hang up, detecting whether there is a busy tone, if not, setting a talk timer, and entering a state of talking; (8) when the talk timers of the calling or called users time out or after a busy tone is detected, simulating user hanging up, and releasing the calling and the called users, thereby a call process is completed. In the above flowchart, when sending the number, a dial timer is initiated to control the speed of dial, that is, the time interval of digits of the called number, and the time length of the timer can be set. Furthermore, because the procedure is processed based on circuits (one circuit represents one telephone), and each circuit may use a different form to dial (DTMF or DP), after timing out of the timer for each circuit, it first judges the attribute of the circuit before sending the dial, the dial for each time is one digit of the number called. Because the first digit of the number is also transmitted after timing out of the timer, actually, all digits have been judged. In the above flowchart, when the pass detection timer of the calling or called user time out, it continues the next talking step as the same manner as when detecting the pass test tone. Because the pass detection in calling is bi-directional, no-pass to one direction does not mean no-pass to another direction, so that a waiting time can be reserved for the pass detection for another direction, and, further, the failure in pass detection only means no-pass in the calling path, and may have no relation to whether the signaling is normal or not (for example, any failures in hardware in the channel). Therefore, it can continue to go on and the remaining signaling flowchart may be tested in the remaining steps, which results in more accurately locating on the failures. From the above, compared to the prior art, the present invention realizes a test system for simulating user large traffic call built in a digital SPC switch, which has the same function as commercial outside call testers, on the basis of original SPC switch equipments and current resources utilized by adding a call test process and necessary alternative hardware process modules to the switch control process software system. The present invention has the following advantages: (1) the system is wholly built in the switch system, users can obtain such system with less cost when buying a switch system; (2) the call test result is equal to the standard commercial call tester, and easier to use; (3) because the test system is built in a digital switch system, the simulated user call test system can be used as an on-line call test system in a switch system by setting, which helps to find any fault on call function of the system immediately.

20060601

20100223

20070524

59133.0

H04M308

TRAN, QUOC DUC

SIMULATED USER CALLING TEST SYSTEM AND METHOD WITH BUILT-IN DIGITAL SPC-EXCHANGE

UNDISCOUNTED

ACCEPTED

H04M

ACCEPTED

Method And Device For Division Of A Biological Sample By Magnetic Effect

A method for dividing an analyte present in a solution and that is fixed on magnetic particles, and devices to be used in the method and systems for implementing the method. The method includes sedimentation of the magnetic particles together with separation into a plurality of residues. One implementation: forms at least a residue of magnetic particles in a first receptacle; and displaces the at least the residues towards a plurality of second receptacles, preferably by relative translation of a magnetic system. The second receptacle is connected to the first receptacle through a fluid channel.

1-36. (canceled) 37. A method for dividing an analyte present in a solution in a first receptacle into plural second receptacles, the analyte being fixed on magnetic particles, the method comprising: sedimentation of the magnetic particles by a first magnetic mechanism; and formation of a plurality of residues in the second receptacles. 38. A method according to claim 37, further comprising sedimentation of magnetic particles in a form of at least a first residue in the first receptacle and transport of the at least first residue to the second receptacles, each second receptacle being connected to the first receptacle through at least one fluid channel. 39. A method according to claim 38, in which the at least first residue transported to the second receptacles is by relative displacement of a magnetic field created by a second magnetic mechanism with respect to the fluid channels. 40. A method according to claim 39, in which each fluid channel is parallel to other fluid channels, and in which relative displacement of the magnetic field generated by the second magnetic mechanism is parallel to a direction of the channels. 41. A method according to claim 39, in which the first and second magnetic mechanisms are coincident in a single entity. 42. A method according to claim 39, in which the at least first residue is a single and linear-shaped residue, dividing the first receptacle into two parts. 43. A method according to claim 42, in which each fluid channel is located on a same side of the residue in a direction of displacement of the field generated by the second magnetic mechanism. 44. A method according to claim 42, in which the second magnetic mechanism includes a long magnet that moves relatively to the fluid channels. 45. A method according to claim 44, in which the magnet is displaced relative to the fluid channels, the length of the magnet being such that the projection onto the magnet of the segment defined by the intersection of the plane orthogonal to the displacement containing the magnet and the bottom of the first receptacle on which the residue lies, along this plane orthogonal to the displacement containing the magnet, is included within the segment delimited by the magnet, at all times during the relative displacement of the magnet. 46. A method according to claim 39, in which the second magnetic mechanism forms a single residue in front of each fluid channel. 47. A method according to claim 46, in which all the residues are subjected to a simultaneous displacement along the direction of each fluid channel. 48. A method according to claim 47, in which the second magnetic mechanism includes a magnetic structure with single or multiple projections, free to move relative to the fluid channels. 49. A method according to claim 38, in which the at least first residue is moved as far as the second receptacles. 50. A method according to claim 38, in which each fluid channel includes a ferromagnetic strip, and in which the at least first residue is moved and guided along this strip. 51. A method according to claim 38, in which each second receptacle is connected to the first receptacle through a single fluid channel including a capillary. 52. A method according to claim 37, in which sedimentation of the magnetic particles forms a plurality of residues directly in the second receptacles. 53. A method according to claim 37, in which the analyte quantity is equal in each second receptacle. 54. A method according to claim 37, further comprising a previous fixing of the analyte on the particles and adding the solution containing the analytes fixed on the particles in the first receptacle. 55. A device for dividing an analyte present in a liquid and fixed on magnetic particles, comprising: a first receptacle configured to contain a liquid; and a plurality of second receptacles each connected to the first receptacle through a fluid channel. 56. A device according to claim 55, in which each fluid channel includes a capillary. 57. A device according to claim 55, in which each fluid channel is connected to the first receptacle through a neck. 58. A device according to claim 55, in which the first receptacle is connected to means for adding a solution. 59. A device according to claim 55, in which each second receptacle is fitted with fluid inlet-outlet channels. 60. A device according to claim 55, further comprising a support including the first receptacle, the second receptacles, and the fluid channels. 61. A device according to claim 60, in which each fluid channel is identical and in which a pitch separating two adjacent fluid channels is constant. 62. A device according to claim 55, further comprising a magnetic track for each fluid channel, to guide displacement of a residue of magnetic particles. 63. A set of devices for dividing an analyte, comprising a plurality of devices according to claim 55. 64. A set of devices according to claim 63 such that the first receptacles in each device have a similar size and shape. 65. A system for dividing an analyte fixed on magnetic particles present in a liquid, comprising: a device according to claim 55 and magnetic means. 66. A system according to claim 65, in which the magnetic means comprises magnetic means free to move relative to the channels, thus enabling displacement of the magnetic particles on which the analyte is fixed, from the first receptacle to the second receptacles through the fluid channels. 67. A system according to claim 66, in which the magnetic means is suitable to move in translation with respect to the channel. 68. A system according to claim 66, in which the magnetic means includes a long magnet. 69. A system according to claim 68, in which the length of the magnet is such that any projection of the width of the first receptacle onto the magnet along a plane orthogonal to the displacement and containing the magnet, is included in the magnet, the width of the first receptacle being defined by the segment derived from intersection of the plane perpendicular to the displacement and the bottom of the first receptacle. 70. A system according to claim 65, in which each fluid channel is located on a same side of the first receptacle, along the magnet displacement direction. 71. A system according to claim 65, in which the magnetic means is structured with single or multiple projections. 72. A system according to claim 65, in which the magnetic means includes a set of magnetic elements capable of creating a magnetic field free to move in translation with respect to the channels.

TECHNICAL FIELD This invention relates to a method for equitable or non-equitable division of an analyte present in a sample, and to a device and a system for implementation of this method. More particularly, the invention relates to the use of magnetic means to divide the analyte that was previously fixed on magnetic particles. STATE OF PRIOR ART An analyte means all or part of a corpuscle or molecule to be isolated and/or to be moved into another medium so that it can be used and/or demonstrated, such as a micro-organism, a bacteria, a fungus, a virus, an eukaryote cell; a chemical compound; a molecule such as a peptide, a protein, an enzyme, a polysaccharide, a lipid, a lipoprotein, a lipopolysaccharide, a nucleic acid, a hormone, an antigen, an antibody, a growth factor, a hapten; a cell such as a tumoral cell, etc. This invention is applicable to all fields in which there is a need for making treatments in parallel on a single sample, for example in the case in which treatments are mutually exclusive or have to be done in solutions incompatible with each other. Thus, in some in vitro diagnostic tests, it is desirable to carry out a number of PCR type amplifications on an initial sample; these different amplifications frequently require different primers, different thermal conditions and different buffer components to optimise the amplification. Similarly, during immunological tests, a number of different ligands have to be tested with an initial protein; a single species present in the sample is subjected to a number of reactions for antibody/antigen recognition. It should be noted that these applications require a division which is equitable or non-equitable of a phase of the medium, rather than separation of this medium into several phases. One of the simplest solutions for dividing a sample present in the liquid phase into a number of sub-samples consists of taking a sub-volume of the initial volume and adding it into a receptacle in which one of several specific reactions to be carried out on the analyte will be done. This solution has an obvious limitation in terms of the smallest manipulable volume of the order of a few micro-litres, with a precision of the order of 1%. For lower contents, liquid is lost, and therefore analyte is lost by transporting it in “large” receptacles such as pipette cones, flasks, etc. Other problems that arise are evaporation and adsorption problems on receptacle walls during these manipulations. This solution also requires manual or automatic liquid transfers leading to an inevitable reduction in the quantity of analysable analyte and a dilution of the analyte until a division quite different from the initial planned division is made; in the case of a weak concentration of analyte in the initial sample, this can cause total disappearance of the analyte or a reduction of its quantity such that it becomes undetectable. Another solution consists of filling a single receptacle containing a switching device provided with valves, leading to the sub-receptacles. Placement of these valves becomes complex and occupies a considerable amount of space whenever the number of sub-receptacles exceeds a few units. Therefore there is a real need for a method and a device for equitably or non-equitably dividing an analyte to transport it from an initial receptacle into a number of second receptacles without fluid manipulation and with good efficiency. For the purposes of this invention, transport of the analyte means displacement of the analyte from one receptacle to another, with or without the liquid medium in which it is present. SUMMARY OF THE INVENTION This invention satisfies this need, among other advantages. According to one of its aspects, the invention relates to a method for division of an analyte present in a solution in a first receptacle, and fixed onto magnetic particles. Particles are settled by first magnetic means and the analyte is distributed into several residues located in second receptacles. According to one embodiment, the magnetic particles are settled into at least one residue in the first receptacle, a derived residue being displaced to second receptacles by second magnetic means. Advantageously, the second magnetic means, and/or the magnetic field created by these second magnetic means, is displaced relative to the first receptacle. Preferably, the same magnetic means are used to settle and to displace the residue, in other words the first and second magnetic means are coincident in a single entity. The second receptacles are connected to the first receptacle, each through a fluid channel, and are filled with a solution that may be identical or not, and that is similar or not to the solution in the first receptacle. Therefore, the division method avoids any pipetting and displacement of the solution as such; this enables greater precision making it possible to work on smaller volumes. The method also provides a means of making the division at the same time as the analyte is transferred from the initial solution to another solution necessary for the analyses, if this is the case. Advantageously, each second receptacle is connected to the first receptacle through a single fluid channel, but it is possible that the second receptacles are connected to each other through a different number of channels. The control over the layout of the channels determines the quantity of analyte in each second receptacle. Thus, the arrangement of identical channels in parallel with exactly the same spacing between each channel makes it easy to have an equitable division method. According to one preferred variant of this embodiment, a single linear residue is formed, the size of which is identical to the size of the first receptacle that it therefore passes through; one possibility is to use a long magnet or an elongated induction coil, for example. The residue is then moved, possibly by relative displacement of the coil or the magnet with respect to the device. Therefore, the relative translation of the linear residue and possibly the magnet, “scavenges” the first receptacle and breaks the residue into sub-units depending on the inlet area to the fluid channels; for example, if all channels are identical and are located on the same side of the centre line along which the residue is formed, the division will be equitable. Advantageously, the magnet or the induction coil are larger than the first receptacle such that they “project beyond” the surface of the first receptacle, thus enabling complete and uniform transport of magnetic particles and fast magnetic sedimentation. In preference, these magnetic means move perpendicular to the channels. One alternative is displacement of the magnetic field without physical displacement of the magnetic means, for example with magnetic means comprising successive coils. The main advantages of this variant in which a division of a formed residue takes place, are the simplicity of its use and that no precise alignment between the magnetic structure and the fluid structure is necessary. According to another variant of the same embodiment, a residue with smaller dimensions is formed facing each channel. For example, a multi-tip magnetic structure could be used, which translates each residue into the corresponding channel. Advantageously, the fluid channels are connected to the first receptacle through a neck that enables a transition for the flow of magnetic particles and better control over the transported quantity. For an equitable division, the necks are identical for each channel. The channels may be capillaries. One or more magnetic tracks could also be created to guide the magnetic particles. Advantageously, for small samples, magnetic tracks can replace the channels. Magnetic particles may be transported as far as the second receptacles, where a process to release the analyte takes place, or the release can occur before arrival of the analyte in the second receptacles, subsequent transport of the analyte possibly being made by liquid displacement. According to another embodiment, the sedimentation of magnetic particles coupled to analytes and present in solution in the first receptacle is done directly in a plurality of second receptacles. In this case, the second receptacles may be formed entirely with the first receptacle, advantageously without an area (such as a plane surface) in which the particles could be immobilised outside the second receptacles. The analyte can be fixed on magnetic particles before the solution is added into the first receptacle, or the solution can be added and fixation can be done in the receptacle. The invention also relates to a device for division of an analyte fixed on magnetic particles, comprising several second receptacles connected to a first receptacle, for example through fluid channels. Preferably, the entire fluid circuit will be in one support that may be either the base or the cover of the device. Advantageously, inlet means are connected to the support. These devices may form part of systems according to the invention that include magnetic means, possibly movable and particularly capable of being subjected to a relative translation with respect to a transport or division device, and that entrain magnetic particles from the first receptacle to the second receptacles of the device. One alternative relates to means that can generate a mobile field. Preferred embodiments of devices and systems are a direct result of the corresponding advantages compared with division methods. BRIEF DESCRIPTION OF THE DRAWINGS Other characteristics and advantages will become clear after reading the following examples that are obviously given for illustrative purposes and are in no way limitative, with reference to the attached figures. FIG. 1 shows a perspective and exploded diagrammatic view with a partial section through a first embodiment of a device according to this invention. FIG. 2 shows a diagrammatic view of the formation of a residue according to a first embodiment of the division system according to this invention. FIG. 3 shows a diagrammatic view of the division method according to one embodiment of this invention. FIG. 4 shows a diagrammatic view of a second device according to this invention. FIG. 5 shows a diagrammatic view of a multi-tip magnetic structure and its action. FIG. 6 shows another embodiment of the division device according to the invention. FIGS. 7a to 7d illustrate devices used when carrying out the tests. In these Figures, identical references refer to identical elements. DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS The general architecture of a device 1 according to a first embodiment of the invention is shown in FIG. 1. It is composed of a base 2, possibly prolonged by inlet means 4 and a cover 6. An inlet chamber (or first receptacle) 10 is located on the base 2 and is connected to reaction chambers (or second receptacles) 12 through fluid channels 14 provided with a neck 16, in this case in the form of capillaries. The bottom of the fluid channels 14 may be covered by a ferromagnetic strip. The particular shapes of the chambers 10, 12 are given as example; the receptacles and the capillaries may have other shapes and/or sizes and may be different from each other depending on the application or the technology used for manufacturing the device 1. Similarly, there may be several fluid channels 14 connecting the first chamber 10 to a single reaction chamber 12. Furthermore, other elements necessary for the reactions can be included within the fluid circuit; for example, it is possible to include bubble valves 8 along capillaries 14 or on the second receptacles 12. FIG. 1 suggests a manufacturing method by which the device 1 is made by etching the receptacles 10, 12 and fluid channels 14 in a plane material acting as a base 2, and then assembling the cover 6 by gluing or any other attachment means. This is one possible manufacturing method, but the invention is not dependent on it. Any other technology for making an inlet chamber 10 connected to several reaction chambers 12 through one or several fluid channels 14 could be envisaged. In particular, possible methods that could be envisaged for integration of the fluid circuit onto a support include etching on silicon or glass, micro-injection, hot stamping, plasma etching techniques, techniques similar to the “LIGA” technique using lithography, galvanoplasty and plastic moulding. Etching is preferable for depths of the order of 100 μm. It is also possible to etch the cover 6 instead of the base 2. It may be advantageous to not use “physical” channels 14, but simply ferromagnetic strips deposited on the bottom of the base 2 that will guide the magnetic particles like etched channels. This provides greater freedom in the trajectory of the residue, the particles being guided by the ferromagnetic tracks; furthermore, the presence of magnetic strips eliminates surface condition problems in fluid chambers. These two techniques (“physical” channels and magnetic guide channels) can also be combined, and a magnetic strip can be deposited at the bottom of each “physical” fluid channel 14, depending on how the device is used. A vent 18 is used for evacuation of fluids (air or liquid) when liquids are filled or transferred in receptacles. It may be used when the device is being filled to evacuate the gases present, as well as in the final step to recover the analyte solutions, but a vent is not essential. The sample and the different reagents or buffers can be added into the devices in different ways. For example, in a first variant shown in FIG. 1, the cover 6 of the device is fitted with inlet means in the form of a conical dish 4; it is obvious that this shape is only given as an example. For example, by applying a pipette or a syringe end piece onto this conical dish, the buffer or a reagent can be “pushed” inside the device by applying a pressure on the liquid. Air or any other fluid (liquid or gas) present in the device will be evacuated from the device through the vents 18. In this case, these vents open up into the reaction chambers 12, but they could be placed in other locations of the device 1 depending on the case. Another variant (not shown) for adding liquid into the device would consist of adding it through a channel or capillary similar to the vents 18 opening up into the first chamber 10, and itself connected to the outside of the device through an interface. The first step in using the device 1 is to prepare a homogenous solution containing the analyte according to known techniques; for example, the analyte is extracted from the sample in which it is contained, or “pure” analyte is directly diluted in solution. The analyte is then fixed on magnetic particles. The size of magnetic particles is appropriate for the analyte to be isolated and the solution volume. For example, they may be sub-micrometric in size when the analyte is a molecule. The quantity of particles used depends particularly on the nature and quantity of analyte to be fixed, and is preferably provided in sufficient numbers to fix the entire analyte. In general, appropriate magnetic particles are conventionally used in molecular and cellular biology. If possible, in particular they must be superparamagnetic so that they can be spontaneously rediffused after the magnetic field has been cancelled. These particles form part of the magnetic colloids family and are polymerised and functionalised by the bond with a number of antibodies. Fixation methods are known to those skilled in the art; adsorption, coalescence, capture by nucleotides present on the particle surface, thermosensitivity. It is preferable that this fixation should be reversible; it may be necessary to release the analyte so that it can access chemical reagents or detection means more easily, or be more easily accessible to them. Those skilled in the art are familiar with release of the analyte, or elution. The fixation step may precede the addition of the solution into the first receptacle 10, but it may also take place in this receptacle; the solution is then added into the receptacle in which magnetic particles are also present. Before the analyte is added, the device 1 is filled with buffer without the analyte searched for and without magnetic particles. This buffer may be added by pouring the necessary quantity into the inlet means 4, and by applying a pneumatic pressure on it. Once the device has been filled, the excess buffer present in the inlet means 4 may be removed, for example using a pipette. The second receptacles 12 can be filled with a solution different from the buffer in the inlet chamber 4, 10, and even a different solution can be used in each chamber 12 depending on how the device is used and on the planned analyses. The sample, composed of a given quantity of buffer in which interesting analytes have previously been fixed on magnetic particles, is deposited in the first receptacle 10. This sample is considered as being single phase; the analyte to be transported and divided is present in a one phase. As described above, magnetic particles can be placed in the first receptacle, and analytes in solution can then be added into the buffer to fix them on the particles. In this first embodiment, the magnetic particles are then attracted to the bottom of the inlet chamber 10 in the sedimentation step. Preferably, sedimentation is done using (first) magnetic means; particles are generally micrometric or even nanometric in size, and the magnetic means can increase the sedimentation rate compared with a natural sediment. The sedimentation rate of fixed size magnetic particles depends on the distance of the particles from the top face of a magnetic block located under the receptacle containing the particle solution, and also the volume of the block. In the context of the embodiment presented in the following figures, the residue is formed using the first magnetic means represented by the magnet 20 that will also be used for displacement of the residue 22, and which is in the shape indicated in FIG. 2. It is positioned under the device 1, vertically below with the conical dish 4 in the case illustrated. The magnetic particles are then collected in a linear residue 22 passing through the first chamber 10, along a line AA. However, and as already described, the first magnetic means may have been used only to settle particles in an initial residue, possibly the same shape as this residue 22, the displacement being achieved by second different magnetic means. In this case, the second magnetic means 20 may have rearranged the first residue. According to one preferred embodiment, the residue 22 is displaced by the relative displacement of the first magnetic means, coincident with the second magnetic means as will be described in detail later; a relative displacement of this type can control displacement of the residue and uniformity of the applied magnetic field. However, other solutions could be envisaged, for example a powerful fixed magnet located in the direction of the second receptacles and attracting the residue 22. If a coil is used instead of the magnet, the displacement of the coil may thus be replaced by switching between successive coils in an assembly provided for this purpose; there is then a relatively displacement of the magnetic field, with the physical magnetic means remaining in position. Combinations are possible. Advantageously, this long magnet 20 “projects beyond” from the first receptacle 10. During the movement, the magnet 20 thus scavenges the entire receptacle 10 located at its right, in other words in the direction of the movement (arrow). In fact it is preferable if it is longer than the linear residue 22, and if possible as long as the displacement. Therefore in general, it is desirable that the length of the magnet 20 should be such that, at all times during the relative displacement of the magnet, projection of the width of the first receptacle onto a plane containing the magnet (for example in this case the horizontal plane) and along the plane orthogonal to the displacement (in this case the vertical plane passing through the AA axis) is included within the magnet, or the segment represented by the magnet; the width of the receptacle 10 is defined by the widest segment derived from intersection of the vertical axis and the linear residue 22 that passes through the first receptacle 10. It should also be noted the lack of a neck 16 in FIG. 2; the “comb” shaped structure may be advantageous to better control the division. FIG. 3 represents the division of the residue and therefore the analyte by displacement of the residue 22 from the first receptacle 10 to the second receptacles 12. FIG. 3a shows the configuration of FIG. 2 and therefore describes a linear residue 22, this residue being the result of rearrangement of particles by second magnetic means. It is desirable in this embodiment that all fluid channels should be located on the same side of the AA axis shown by the residue 22. Otherwise, as will be better understood after reading the following, translation of the residue would imply non-filling of the reaction chambers 12 located on the other side of the translation direction. The initial residue is “guided” to fluid channels 14 due to relative displacement, in this case in translation, of the magnet 20 towards the second chambers 12; see FIG. 3b. Relative displacement means either physical displacement of the magnet 20 (or the generated field) that can be moved by any mechanism whatsoever, or manual movement under the support 2-6 or displacement of the support 2-6, for example along a rail above the magnet 20. For example, it is worth mentioning the use of a stepping motor or a pneumatic jack as translation means, but any displacement means known to those skilled in the art could be envisaged depending on the case. Due to the relative translation of the magnetic means or the magnetic field, it is found that the residue maintains its linear structure during its displacement. The residue 22 thus reaches the inlet of fluid channels 14, in which the function of the walls is to separate it into segments (see FIG. 3c). Translation of the residue 22 continues along the fluid channels 14 (FIG. 3d) so that the samples reach the second receptacles (or reaction chambers) 12 (FIG. 3e). In the example shown in FIG. 3, the fluid channels 14 are parallel to each other and perpendicular to the axis of the residue 22, the relative displacement of the magnet being parallel to the direction of the channels. These two elements are preferred since control of the location of the analyte in the channels and the reaction chambers is easier. However, other possibilities could be envisaged (oblique magnet and/or divergent channels, and/or oblique displacement, etc.). Furthermore, the division presented in FIG. 3 is equitable, in other words each of the second receptacles 12 receives the same quantity of analyte, and the initial analyte was divided into equal parts, in this case eight parts. In particular, the pitch between the channels 14 is constant and the necks 16 have exactly the same size. However, a modification of the layout of fluid channels provides a means of making non-equitable but controlled divisions. FIG. 4 shows such an example in which the second receptacles 12a-h do not each contain one eighth of the quantity of the initial analyte; the chamber 12a will receive almost a third of the analyte quantity, which is three times more than chambers 12d-f for example, separated by a constant pitch, in which the contents will be identical in each. Another variable relates to the number of fluid channels opening up in a single reaction chamber 12; for a channel layout similar to that shown in FIG. 3, if two channels join each other in a first chamber 12 while each of the others opens up in an independent chamber, this first chamber 12 will receive twice the amount of analyte as the others. Therefore, the method according to the invention enables controlled non-equitable divisions, before the liquid itself is manipulated. For example, it would be possible to create kits in which reagents are already placed in the reaction chambers 12 by any known means, and for which the layout of the channels 14 and therefore the division coefficients have been defined as a function of reaction sensitivities. Such kits could also be created for equitable divisions. Instead of using a long magnet and a linear residue for the displacement, according to another variant, it would be possible to directly reform a number of residues corresponding to the number of fluid channels 14. For example, a magnetic structure with multiple projections 24 could replace the long magnet 20 for a device like that shown in FIG. 2. A device with multiple projections 24 consists of a magnetic block 26 for which the top face is preferably cut, so as to obtain “tip” or pyramid shaped projections 28; see FIG. 5. It would also be possible to add a polar part made of a ferromagnetic material (iron, iron-chromium alloy such as the AFK502 alloy by Imphy SA) comprising tips preferably machined in the form of pyramids 28 on the plane surface of a magnetic block. The role of the tips 28 is to curve the trajectory of the magnetic particles at the end of their sedimentation; the influence of the block 26 is overriding until particles in solution are separated from the tips by two to three times the height of the tips, and sedimentation is uniform. Then, as the particles become closer to the bottom of the first receptacle 10 and therefore to the surface of the magnetic block 26, there is an increase in the relative influence on them due to the magnetised protuberances materialized by the tips 28. Therefore the residues 30 themselves are located above the tips 28. In FIG. 5, only a few separate tips are shown for convenience, but it is quite clear that they could also form a denser network. Similarly, although in this case they are aligned along a BB axis, in some applications it would be possible to form a “checkerboard” network, for example, with several projecting lines BB or any other appropriate geometry. Although a reduction in scale does not theoretically affect the magnetic properties (the value of the field is kept), however magnetic forces proportional to the gradient of the magnetic field are modified; since they are applied in a small volume, they are increased in a ratio inverse to the dimensions. Therefore the choice of dimensions and material for the magnetic system depends on usage conditions. There is no limitation in the production of large magnetic blocks; up to a few tens of centimetres, for example with 13 tips at a pitch of 5 mm over a length of 65 mm. Since the sedimentation rate depends on the volume of the magnetic block, a uniform sedimentation can be obtained by advantageously using a block 26 with a surface area greater than the surface area of the first receptacle 10 of the analyte solution. Another example embodiment is a 15×40×25 mm NdFeB block with 6 pyramids with a square cross-section with a 5 mm side and height of 2 mm. This model has excellent performances, particularly with a liquid height in the first receptacle 2 equal to 5 mm. In particular, for a first receptacle 10 with a 3 mm section and a 4 mm depth, one of the preferred embodiments consists of having a distance equal to about 1 mm between the bottom of the first receptacle and the top of the magnetic block, in other words between the residue of magnetic particles 30 and the top of the tip(s) 28. In practice, the dimension of the magnetic block 26 may homothetically reduced with no difficulty to areas as small as the order of 100 square millimetres. For smaller dimensions, the tips should be machined from a soft magnetic material with a strong magnetisation at saturation, such as pure iron or an Fe50Co50 alloy. For even smaller areas (with sides of the order of 100 μm), microelectronic processes such as surface nickel plating are used; the parallelepiped shaped block can be used to magnetise (polarise) the deposits. This embodiment in particular may be combined with the use of magnetic tracks; the shape of the deposits may for example consist of concentration pads connected to the reaction chambers 12 through tracks, the deposited materials preferably being coated with a protection layer. Like the long magnet 20, the magnetic means with projection(s) 24 enable transport of residues 30, by relative displacement, for example a relative translation along the channels, in this case small residues, in each channel. Unless this variant is combined with magnetic tracks, it is suited more particularly for operation with larger devices with a pitch between residues 30, and therefore between channels, of more than one millimetre. In this way, a fairly accurate alignment can be achieved between the magnetic structure and the fluid structure. However, it can be used to divide an initial solution with a lower concentration, depending on the density of tips 28. Moreover, since the separation is made in the absence of the mechanical separation device, the magnetic particles are not likely to be collected on a wall of the separator. Another embodiment of a device 40 by which it is possible to proceed according to the invention is shown in FIG. 6. As can be seen in this case, the fluid channels actually correspond to communications enabling the fluid to pass; the second receptacles 42 appear as direct prolongations of the first receptacle 44. The device 40 may actually be a single part including a wall 46 that may be moulded or stamped, etc., to create the second receptacles 42; this wall 46 may also be added onto a composed receptacle. Although it is not essential, it is desirable that the transition should take place gradually due through necks 48; it is also possible that each of the second receptacles 42 should be composed of a cone. In particular, it is preferable that there are no plane areas on the wall 46 of the first receptacle 44 on which the projections are arranged representing the second receptacles 42. The division can then take place directly during sedimentation; the first magnetic means 50 located under the surface 46 attract the magnetic particles in solution into the first receptacle 44, and residues are formed in each of the second receptacles 42, consequently leading to a division of analytes present in the initial sample. For this embodiment, the force of the magnet 50 is homogenous if possible, at the second receptacles 42. The manufacture of the device 40 and control mechanism of the magnet 50 are simpler than in the embodiments described above. FIG. 6 shows an embodiment in which the magnet is located under the device 40. This embodiment is preferred because it uses gravity in parallel, but it is possible to have a similar device for which the surface 48 provided with projections forming the second receptacles 42 is not located on the base. Similarly, the arrangement shown is only illustrative, and sedimentation can be done with a magnet with a shape different from the block 50 (for example projections under each second receptacle 42). As described above, sedimentation into several residues in the second receptacles 42 may also be followed by transport of the analyte from these second receptacles along a fluid path (not shown) in order to make an analysis. Therefore according to the invention, the division of the phase containing the analyte is done without any liquid transfer other than the addition of the initial solution, and particularly without pipetting, which is always a source of inaccuracies, which furthermore are cumulative. No valves are necessary, and the device 1, 40 is simpler to manufacture, without considering the increase in precision inherent to the elimination of mechanical parts. The system according to the invention may be designed with different sizes of receptacles and devices, varying from a few micrometers up to several centimetres. For example, for a device similar to that shown in FIG. 1, we could have: Volume of first receptacle 10: 0.6 μl Dimensions of the first receptacle 10: 4 mm×1.5 mm×0.1 mm Volume of the second receptacles 12: 40 nl Dimensions of the second receptacles 12: 0.4 mm×1 mm×0.1 mm Size of the connecting capillaries 14: 2 mm×0.1 mm×0.1 mm Pitch between chambers: 500 μm Total size of base 2: 6 mm×6 mm Size of the magnet base: 8 mm×8 mm Another possibility for a base 2 with dimensions 8 mm×8 mm would be to have a magnet in which the dimensions of the main block are slightly larger than 8×8 mm. Similarly, as described above, it is possible to have different sizes and shapes of magnets. Long magnets themselves may have different shapes, for example a parallelepiped shaped block, or a block with a pentagon shaped cross-section, or a triangle above a rectangle, and the triangle possibly being truncated. The division device could form part of a wider assembly; it would then be possible to consider successive divisions of the initial sample, in which a second receptacle of a device is itself a first receptacle for another device following it, possibly with treatment of the sample between different successive divisions. Finally, the same magnetic means can be used to control the division for a large number and a very large variety of devices 1, 40. For example for the first embodiment, any set of supports 2-6 with identical shape and size and for which the inlet chamber 10 is similar but for which the fluid circuits 14 are different, may be controlled by the same magnet. Example of Use A NASBA amplification with real time detection by a molecular marker can be installed in each reaction chamber 12. In this method of detection/analysis of nucleic targets present in solution, the sample has to be divided into several channels so as to be able to carry out a maximum number of tests in parallel. The procedure then takes place as follows: i. Targets to be amplified are captured on magnetic particles using conventional techniques; the number of capture probes fixed on the particles will be the same as the number of targets to be amplified, and complementary to these targets. ii. A device like that shown diagrammatically in FIG. 1 is filled with an appropriate buffer, for example TE lM NaCl or Triton X100 0.05%, at a temperature of about 30° C. During filling, air trapping chambers 8 present along capillaries 14 remain full of air. iii. The sample is deposited in an inlet cone 4 of the device as shown in FIG. 1. iv. Magnetic sedimentation, division and transport according to the invention are carried out, transport of the analyte displacing the analyte into the second chambers 12. v. The amplification mix containing enzymes and specific primers is injected into each chamber, for example using syringe pumps. This injection is done through the end opposite the end in which the sample is added, in other words through the vents 18. vi. The temperature of the device is then increased up to 42° C., and the system is allowed to incubate for 1 to 2 h, the fluorescence of the markers being read at regular time intervals for each reaction chamber 12. Comparative Tests Four types of device 60 were made as shown diagrammatically in FIGS. 7a-7d. Chip types 60a, 60b and 60c shown in FIGS. 7a and 7b were made using the same deep etching in silicon technology followed by a thermal oxidation step. Chips 60a and 60b are identical, the only difference being the design of the division comb, which is provided with teeth with rounded and pointed ends respectively. Chip type 60c has the same geometries, but with smaller dimensions, the surface of the receptacle 62 in which the magnetic residues are formed being divided by a factor of 3. In particular, the width of the teeth of the comb (in other words the pitch between the channels 64) is smaller, of the order of 500 μm for devices 60c compared with 900 μm for devices 60a and 60b. Devices 60d in FIG. 7d are made by anisotropic etching in a bath of KOH that forms dishes 66 with inclined sides. Magnetic division experiments were carried out using devices 60 on which a PDMS cover 70 was glued. The shape of the cover was designed to be sufficiently thick to contain a 25 μl sample volume, in other words for example, particularly for devices 60a-60c, a plane cover 70 with uniform thickness except for a protuberance 72 located at the first receptacle (see FIG. 7c). The area 74 for injection of the sample was then opened with a scalpel blade so as to make a cut to prevent debris from being collected in the channels 64. The magnetic particles were marked with fluorescent particles using a marking protocol using 605 Qdots (cat. #1000-1 by Quantum Dots Corp.) on Immunicon magnetic particles (No. F-3106) with a concentration of 7.5×106 Immunicon particles/μl with 10 Qdot/Immunicon in a 10 mM Tris buffer (pH=8: 1M NaCl, Triton X100 0.05%, salmon DNA 0.14 mg/ml) so that the division could be quantified. Depending on the geometry of the devices, the solution containing particles had different characteristics; for a component 60a with eight channels 64, 8 μl of solution containing particles and 17 μl of buffer were used; for a component 60d with 25 dishes, 25 μl of solution containing particles without any added buffer were used. All measurements were made using a Zeiss Axioplan II microscope fitted with its type HBO 100/1007-980 illumination system comprising a mercury arc lamp type HBO 100W/2 and its power supply ebq 100. The 5×/0, 13HD-442924 and 10×/0, 20HD-442934 lenses and the fluorescein cube (optical filter assemblies) are used particularly for observation in black background and in epi-fluorescence. For imagery, the microscope was coupled to a Hamamatsu type ORCA Ergs HPF-C4742-80-12-AG camera, with its HPF-COMPX-SIMPLE-PCI acquisition software. All images were processed on the same AnalySIS software. The Rolin magnet was used for devices 60a to 60c. A turned over APIS type magnet was used for device 60d, so as to obtain a uniform magnetic field with a plane base. The operating method consisted of: Pre-filling with buffer (devices 60a, 60b, 60c were placed in a vacuum chamber) Placement and alignment of the magnet under the microscope. Lower the magnet. Put the device into place. Fluorescence images of the bottom of each receptacle. Injection of particles (8 residues in 25 μl buffer). Reach equilibrium on some experiments. Raise the magnet. Monitor sedimentation in black light (for chip 60d, a microscope slide is placed on the component to prevent light reflection due to the meniscus). Displacement of the device with respect to the magnet, and magnetic division. Fluorescence images of each receptacle. The fluorescence intensity for each residue is an integral intensity on a surface broadly encompassing the residue; it is obtained by subtraction of the intensity obtained before division from the intensity obtained after division, and therefore only represents the fluorescence intensity generated by marked magnetic particles. Coefficients of variation (CV) were calculated starting from the set of measurements (on the eight channels of devices 60a-60c), removing aberrant points if necessary (for example large external pollution particle). The following table resumes the CVs obtained and the CV obtained on fluorescence measurements in channels filled with buffer only. CV before CV after division division device (%) (%) 60b 1 15 60c round 1 13 60c pointed 1 36 60c round 2.4 5 60c pointed 1.2 13 60c round 1.2 5 60c pointed 2 12 60a 2 13 60d (9 dishes) 0.6 38 Sedimentation 60c round 1 4 for 5 minutes 60c round 2 5 60c pointed 3 5 60c round 5 3 60c pointed 2 5 60c round 1 5 60d (9 dishes) 4 5 60d (25 dishes) 16 20 60d (9 dishes) 3 10 60d (25 dishes) 10 18 60d (rows of 8 dishes) 13 10 It should be noted that CVs on fluorescence measurements in components filled with buffer before the division are less than 5%, except for type 60d components with 25 dishes. CVs on fluorescence measurements after division are less than 5% on type 60c components when an equilibrium time is respected before sedimentation. This excellent result was obtained with chips for which the covers 70 (and particularly the opening 74 for injection of the sample) were cut out very approximately. Consequently, the geometric shape of the opening in the cover is not a critical parameter for making a good quality magnetic division with type 60c components. In the case of vertical sedimentation (type 60d components), the results are encouraging for matrices of 9 dishes (CV<10%). Furthermore, fluorescence intensity profiles along the eight channels in type 60a-60c devices were studied; no effect due to the geometry of the injection area into the cover was noted. No drop in the global fluorescence intensity was noted during a sequence including steps consisting of sedimentation, division, return of residues into the first receptacle, dispersion of the residue, sedimentation, division, regardless of the device 60; therefore there were no particle losses during the passage on the division comb. On the other hand, during these steps, the CV was degraded for type 60c components with a pointed comb, while it remained less than 5% for the rounded comb. Having seen these results, it is quite obvious that the division method is efficient for equitable distribution of a set of magnetic particles into sub-sets. The main conclusions to be remembered are: An equitable division between channels with a CV of less than 5% is achieved. The loss of particles during division is negligible. Division combs (60a, 60b, 60c) give better results than components for division by sedimentation in dishes (60d). The geometry of the sample injection area has no significant influence. A Brownian distribution step is preferable before sedimentation of particles.

<SOH> TECHNICAL FIELD <EOH>This invention relates to a method for equitable or non-equitable division of an analyte present in a sample, and to a device and a system for implementation of this method. More particularly, the invention relates to the use of magnetic means to divide the analyte that was previously fixed on magnetic particles.

<SOH> SUMMARY OF THE INVENTION <EOH>This invention satisfies this need, among other advantages. According to one of its aspects, the invention relates to a method for division of an analyte present in a solution in a first receptacle, and fixed onto magnetic particles. Particles are settled by first magnetic means and the analyte is distributed into several residues located in second receptacles. According to one embodiment, the magnetic particles are settled into at least one residue in the first receptacle, a derived residue being displaced to second receptacles by second magnetic means. Advantageously, the second magnetic means, and/or the magnetic field created by these second magnetic means, is displaced relative to the first receptacle. Preferably, the same magnetic means are used to settle and to displace the residue, in other words the first and second magnetic means are coincident in a single entity. The second receptacles are connected to the first receptacle, each through a fluid channel, and are filled with a solution that may be identical or not, and that is similar or not to the solution in the first receptacle. Therefore, the division method avoids any pipetting and displacement of the solution as such; this enables greater precision making it possible to work on smaller volumes. The method also provides a means of making the division at the same time as the analyte is transferred from the initial solution to another solution necessary for the analyses, if this is the case. Advantageously, each second receptacle is connected to the first receptacle through a single fluid channel, but it is possible that the second receptacles are connected to each other through a different number of channels. The control over the layout of the channels determines the quantity of analyte in each second receptacle. Thus, the arrangement of identical channels in parallel with exactly the same spacing between each channel makes it easy to have an equitable division method. According to one preferred variant of this embodiment, a single linear residue is formed, the size of which is identical to the size of the first receptacle that it therefore passes through; one possibility is to use a long magnet or an elongated induction coil, for example. The residue is then moved, possibly by relative displacement of the coil or the magnet with respect to the device. Therefore, the relative translation of the linear residue and possibly the magnet, “scavenges” the first receptacle and breaks the residue into sub-units depending on the inlet area to the fluid channels; for example, if all channels are identical and are located on the same side of the centre line along which the residue is formed, the division will be equitable. Advantageously, the magnet or the induction coil are larger than the first receptacle such that they “project beyond” the surface of the first receptacle, thus enabling complete and uniform transport of magnetic particles and fast magnetic sedimentation. In preference, these magnetic means move perpendicular to the channels. One alternative is displacement of the magnetic field without physical displacement of the magnetic means, for example with magnetic means comprising successive coils. The main advantages of this variant in which a division of a formed residue takes place, are the simplicity of its use and that no precise alignment between the magnetic structure and the fluid structure is necessary. According to another variant of the same embodiment, a residue with smaller dimensions is formed facing each channel. For example, a multi-tip magnetic structure could be used, which translates each residue into the corresponding channel. Advantageously, the fluid channels are connected to the first receptacle through a neck that enables a transition for the flow of magnetic particles and better control over the transported quantity. For an equitable division, the necks are identical for each channel. The channels may be capillaries. One or more magnetic tracks could also be created to guide the magnetic particles. Advantageously, for small samples, magnetic tracks can replace the channels. Magnetic particles may be transported as far as the second receptacles, where a process to release the analyte takes place, or the release can occur before arrival of the analyte in the second receptacles, subsequent transport of the analyte possibly being made by liquid displacement. According to another embodiment, the sedimentation of magnetic particles coupled to analytes and present in solution in the first receptacle is done directly in a plurality of second receptacles. In this case, the second receptacles may be formed entirely with the first receptacle, advantageously without an area (such as a plane surface) in which the particles could be immobilised outside the second receptacles. The analyte can be fixed on magnetic particles before the solution is added into the first receptacle, or the solution can be added and fixation can be done in the receptacle. The invention also relates to a device for division of an analyte fixed on magnetic particles, comprising several second receptacles connected to a first receptacle, for example through fluid channels. Preferably, the entire fluid circuit will be in one support that may be either the base or the cover of the device. Advantageously, inlet means are connected to the support. These devices may form part of systems according to the invention that include magnetic means, possibly movable and particularly capable of being subjected to a relative translation with respect to a transport or division device, and that entrain magnetic particles from the first receptacle to the second receptacles of the device. One alternative relates to means that can generate a mobile field. Preferred embodiments of devices and systems are a direct result of the corresponding advantages compared with division methods.

20060602

20140318

20070830

61659.0

C02F148

MELLON, DAVID C

METHOD AND DEVICE FOR DIVISION OF A BIOLOGICAL SAMPLE BY MAGNETIC EFFECT

UNDISCOUNTED

ACCEPTED

C02F

ACCEPTED

Medicine containing genetically modified antibody against chemokine receptor ccr4

A medicament having a higher therapeutic effect than that provided by administration of a recombinant antibody against human CC chemokine receptor 4 or an antibody fragment thereof or an agent alone is provided.

1. A medicament comprising a combination of a recombinant antibody which specifically binds to human CC chemokine receptor 4 (CCR4) or an antibody fragment thereof and at least one pharmaceutically active agents together with a pharmaceutically acceptable carrier. 2. (canceled) 3. A kit, comprising a recombinant antibody which specifically binds to CCR4 or an antibody fragment thereof, and at least one pharmaceutically active agent. 4. The medicament according to claim 1, wherein the pharmaceutically active agent is an antitumor drug. 5. A process of treating tumor in which CCR4 is expressed comprising administering the medicament according to any one of claims 4 or 7-20 to a patient in need thereof. 6. The process according to the claim 5, wherein the tumor is a hematopoietic organ tumor. 7. The medicament according to claim 4, wherein the recombinant antibody which specifically binds to CCR4 or the antibody fragment thereof is an antibody which specifically binds to an extracellular region of CCR4 and does not show a reactivity to a human platelet. 8. The medicament according to the claim 7, wherein the recombinant antibody which specifically binds to the extracellular region of CCR4 or the antibody fragment thereof does not have an activity of inhibiting binding of TARC or MDC as a CCR4 ligand to CCR4. 9. The medicament according to claim 8, wherein the extracellular region is an extracellular region selected from the group consisting of 1 to 39, 98 to 112, 176 to 206 and 271 to 284 of an amino acid sequence represented by SEQ ID No. 1. 10. The medicament according to claim 8, wherein the extracellular region is an epitope existing at positions 2 to 29 of the amino acid sequence represented by SEQ ID No. 1. 11. The medicament according to claim 8, wherein the extracellular region is an epitope existing at positions 13 to 29 of the amino acid sequence represented by SEQ ID No. 1. 12. The medicament according to claim 8, wherein the extracellular region is an epitope existing at positions 13 to 25 of the amino acid sequence represented by SEQ ID No. 1. 13. The medicament according to the claim 12, wherein in the recombinant antibody which specifically binds to CCR4 or the antibody fragment thereof, a binding activity to a peptide comprising 13 to 25 of the amino acid sequence represented by SEQ ID No. 1 in which at least one of tyrosine residues 16, 19, 20 and 22 is sulfated is lower than a binding activity to a peptide comprising 13 to 25 of the amino acid sequence represented by SEQ ID No. 1. 14. The medicament according to claim 13, wherein the recombinant antibody which specifically binds to the extracellular region of CCR4 or the antibody fragment thereof is an antibody which specifically reacts with an epitope recognized by a monoclonal antibody which hybridoma KM 2160 (FERM BP-10090) produces or an antibody fragment thereof. 15. The medicament according to claim 13, wherein the human recombinant antibody is a human chimeric antibody or a human CDR-grafted antibody. 16. The medicament according to the claim 15, wherein the human chimeric antibody comprises complementarity determining regions (CDRs) of a heavy chain (H chain) variable region (V region) and a light chain (L chain) V region of a monoclonal antibody which specifically binds to CCR4. 17. The medicament according to claim 16, wherein the human chimeric antibody comprises CDR1, CDR2 and CDR3 of a heavy chain (H chain) variable region (V region) of an antibody comprising amino acid sequences represented by SEQ ID Nos. 5, 6 and 7, respectively and/or CDR1, CDR2 and CDR3 of a light chain (L chain) variable region (V region) of an antibody comprising amino acid sequences represented by SEQ ID Nos. 8, 9 and 10, respectively. 18. The medicament according to claim 17, wherein the human chimeric antibody comprises a heavy chain (H chain) variable region (V region) of an antibody molecule comprising an amino acid sequence represented by SEQ ID No. 11 and/or a light chain (L chain) V region of an antibody molecule represented by SEQ ID No. 12. 19. The medicament according to the claim 15, wherein the human CDR-grafted antibody comprises complementarity determining regions (CDRs) of a heavy chain (H chain) variable region (V region) and a light chain (L chain) V region of a monoclonal antibody which specifically binds to CCR4. 20. The medicament according to claim 19, wherein the human CDR-grafted antibody comprises CDR1, CDR2 and CDR3 of a heavy chain (H chain) variable region (V region) of an antibody comprising amino acid sequences represented by SEQ. ID Nos. 5, 6 and 7, respectively and/or CDR1, CDR2 and CDR3 of a light chain (L chain) V region comprising amino acid sequences represented by SEQ ID Nos. 8, 9 and 10, respectively. 21. The medicament according to any one of the claims 15, 18 and 20, wherein the human CDR-grafted antibody comprises a heavy chain (H chain) variable region (V region) of an antibody molecule comprising an amino acid sequence represented by SEQ ID No. 16 or 17 and/or a light chain (L chain) V region of an antibody molecule represented by SEQ ID No. 18. 22. The medicament according to claim 21, wherein the agent is a protein or an agent having low-molecular weight. 23. The medicament according to the claim 22, wherein the protein is a cytokine or an antibody. 24. The medicament according to the claim 23, wherein the cytokine is a cytokine selected from G-CSF, M-CSF, interferon-α, IL-2 and IL-15. 25. The medicament according to claim 24, wherein the agent having low-molecular weight is a chemotherapeutic agent or a hormone therapeutic agent. 26. The medicament according to the claim 25, wherein the chemotherapeutic agent is an agent selected from vincristine, cyclophosphamide, etoposide and Methotrexate.

TECHNICAL FIELD The present invention relates to a medicament comprising a combination of a recombinant antibody which specifically binds to human CC chemokine receptor 4 (CCR4) or an antibody fragment thereof and at least one agent. BACKGROUND ART When a ligand is bound to a chemokine receptor, migration of leukocytes is induced. Human CC chemokine receptor 4 (hereinafter referred to as CCR4) which is mainly expressed on a Th2-type CD4-positive helper T cell in a normal tissue is one type of a chemokine receptor family [Int. Immunol., 11, 81 (1999)]. CCR4 binds specifically to TARC (thymus and activation-regulated chemokine) or MDC (macrophage-derived chemokine). The Th2-type CD4-positive helper T cell which controls humoral immunity is considered to play an important role in allergic diseases or autoimmune diseases. In T cell-type leukemia/lymphoma cells described above, various chemokine receptors are expressed, and there is a relation between subtypes of T cell leukemia/lymphoma and types of receptors expressed in cells. It was reported that CCR4 is expressed at high frequency in leukemia/lymphoma cells [Blood, 96, 685 (2000)]. Since CCR4 is expressed at high frequency in ALK-positive anaplastic large-cell lymphoma and mycosis fungoides, a possibility of CCR4 being a tumor marker having quite a high selectivity in specific carcinomas was suggested [Blood, 96, 685 (2000), Mod. Pathol., 15, 838 (2002), J. Invest. Dermatol., 119, 1405 (2002)]. It was reported that CCR4 is expressed at quite a high frequency also in adult T-cell leukemia (hereinafter referred to as ATL) caused by infection with human T-cell leukemiavirus type I) [Blood, 99, 1505 (2002)]. Regarding the expression of CCR4 in ATL, the expression of CCR4 significantly correlates with bad prognosis [Clin. Cancer Res., 9, 3625 (2003)]. Further, CCR4 is selectively expressed in cells of chronic T cell lymphoma (hereinafter referred to CTL) [J. Invest. Dermatol., 119, 1405 (2002)]. Method for treating leukemia/lymphoma is mainly chemotherapy using a combination of plural low-molecular anticancer agents. However, chemotherapy that provides satisfactory therapeutic effects has been so far unknown [Gan to Kagaku Ryoho, 26, Supplement I, 165-172 (1999)]. Among the CCR4-positive leukemia/lymphoma described above, prognosis of ATL is poor in particular. Concerning patients who suffer from acute or lymphatic leukemia occupying more than 70% of total ATL and have experienced common CHOP therapy (therapy using cyclophosphamide, vincristine, doxorubicin and prednisone in combination), 4-year survival rate is approximately 5% [British J. Haematol., 79, 428-437 (1991)]. In usual chemotherapy, it is sometimes difficult to induce remission because of advent of drug-resistant tumor cells or the like. However, excellent therapeutic results are sometimes obtained by combination of chemotherapy and an antibody. Anti-HER2/neu humanized antibody rhuMAb HER2 (Herceptin/trastuzumab, Roche) exhibited an outstanding effect against breast cancer in combination therapy with a taxane anticancer agent [Clinical Therapeutics, 21, 309 (1999)]. Anti-CD20 human chimeric antibody IDEC-C2B8 (Rituxan/rituximab, IDEC) exhibited an outstanding effect against B cell lymphoma by combination therapy with multiple drug therapy [J. Clin. Oncol., 17, 268 (1999)]. Combination therapy using an antibody and a cytokine is also expected as new immunotherapy against tumors. A cytokine is a general term for various humoral factors that control intracellular interaction in an immune reaction. An antibody-dependent cell-mediated cytotoxic activity (hereinafter referred to as ADCC), one of cytotoxic activities, is induced by binding an antibody to an effector cell such as a mononuclear cell, a macrophage or an NK cell [J. Immunol., 138, 1992 (1987)]. For the purpose of activating an effector cell, combination therapy using a combination of an antibody and a cytokine has been attempted. With respect to B cell leukemia/lymphoma, a clinical test administrating IDEC-C2B8 and interleukin (IL)-2 [British J. Haematol., 117, 828-834 (2002)] or IDEC-C2B8 and granulocyte-colony stimulating factor [Leukemia, 17, 1658-1664 (2003)] in combination has been conducted. However, an outstanding therapeutic effect has not been observed in comparison with use of the antibody alone. Anti-CCR4 antibody KM2760 has been known as a therapeutic agent against the CCR4-positive leukemia/lymphoma that selectively reduces tumor cells via ADCC (WO 03/18635). Combined use of an anti-CCR4 antibody and a chemotherapeutic agent or a cytokine has been unknown so far. In treatment of cancers, especially, leukemia and lymphoma, a therapeutic method that brings forth satisfactory effects has been unknown so far. DISCLOSURE OF THE INVENTION The object of the present invention is to provide a medicament comprising a combination of anti-CCR4 recombinant antibody or an antibody fragment thereof and at least one agent. The present invention relates to the following (1) to (26). (1) A medicament comprising a combination of a recombinant antibody which specifically binds to human CC chemokine receptor 4 (CCR4) or an antibody fragment thereof and at least one agent. (2) A medicament for administering a combination of a recombinant antibody which specifically binds to CCR4 or an antibody fragment thereof and at least one agent. (3) A medicament for administering a recombinant antibody which specifically binds to CCR4 or an antibody fragment thereof and at least one agent either simultaneously or successively. (4) The medicament according to any one of the above (1) to (3), which is an antitumor drug. (5) The medicament according to the above (4), wherein the tumor is a tumor in which CCR4 is expressed. (6) The medicament according to the above (5), wherein the tumor in which CCR4 is expressed is a hematopoietic organ tumor. (7) The medicament according to any one of the above (1) to (6), wherein the recombinant antibody which specifically binds to CCR4 or the antibody fragment thereof is an antibody which specifically binds to an extracellular region of CCR4 and does not show a reactivity to a human platelet. (8) The medicament according to the above (7), wherein the recombinant antibody which specifically binds to the extracellular region of CCR4 or the antibody fragment thereof does not have an activity of inhibiting binding of TARC (thymus and activation-regulated chemokine) or MDC (macrophage-derived chemokine) as a CCR4 ligand to CCR4. (9) The medicament according to the above (7) or (8), wherein the extracellular region is an extracellular region selected from the group consisting of 1 to 39, 98 to 112, 176 to 206 and 271 to 284 of an amino acid sequence represented by SEQ ID No. 1. (10) The medicament according to any one of the above (7) to (9), wherein the extracellular region is an epitope existing at positions 2 to 29 of the amino acid sequence represented by SEQ ID No. 1. (11) The medicament according to any one of the above (7) to (10), wherein the extracellular region is an epitope existing at positions 13 to 29 of the amino acid sequence represented by SEQ ID No. 1. (12) The medicament according to any one of the above (7) to (11), wherein the extracellular region is an epitope existing at positions 13 to 25 of the amino acid sequence represented by SEQ ID No. 1. (13) The medicament according to the above (12), wherein in the recombinant antibody which specifically binds to CCR4 or the antibody fragment thereof, a binding activity to a peptide comprising 13 to 25 of the amino acid sequence represented by SEQ ID No. 1 in which at least one of tyrosine residues 16, 19, 20 and 22 is sulfated is lower than a binding activity to a peptide comprising 13 to 25 of the amino acid sequence represented by SEQ ID No. 1. (14) The medicament according to any one of the above (1) to (13), wherein the recombinant antibody which specifically binds to the extracellular region of CCR4 or the antibody fragment thereof is an antibody which specifically reacts with an epitope recognized by a monoclonal antibody which hybridoma KM2160 (FERMBP-10090) produces or an antibody fragment thereof. (15) The medicament according to any one of the above (1) to (14), wherein the human recombinant antibody is a human chimeric antibody or a human CDR-grafted antibody. (16) The medicament according to the above (15), wherein the human chimeric antibody comprises complementarity determining regions (CDRs) of a heavy chain (H chain) variable region (V region) and a light chain (L chain) V region of a monoclonal antibody which specifically binds to CCR4. (17) The medicament according to the above (15) or (16), wherein the human chimeric antibody comprises CDR1, CDR2 and CDR3 of a heavy chain (H chain) variable region (V region) of an antibody comprising amino acid sequences represented by SEQ ID Nos. 5, 6 and 7 and/or CDR1, CDR2 and CDR3 of a light chain (L chain) variable region (V region) of an antibody comprising amino acid sequences represented by SEQ ID Nos. 8, 9 and 10, respectively. (18) The medicament according to the above (15) to (17), wherein the human chimeric antibody comprises a heavy chain (H chain) variable, region (V region) of an antibody molecule comprising an amino acid sequence represented by SEQ ID No. 11 and/or a light chain (L chain) V region of an antibody molecule represented by SEQ ID No. 12. (19) The medicament according to the above (15), wherein the human CDR-grafted antibody comprises complementarity determining regions (CDRS) of a heavy chain (H chain) variable region (V region) and a light chain (L chain) V region of a monoclonal antibody which specifically binds to CCR4. (20) The medicament according to the above (15) or (19), wherein the human CDR-grafted antibody comprises CDR1, CDR2 and CDR3 of a heavy chain (H chain) variable region (V region) of an antibody comprising amino acid sequences represented by SEQ. ID Nos. 5, 6 and 7 and/or CDR1, CDR2 and CDR3 of a light chain (L chain) V region comprising amino acid sequences represented by SEQ ID Nos. 8, 9 and 10, respectively. (21) The medicament according to any one of the above (15), (18) and (20), wherein the human CDR-grafted antibody comprises a heavy chain (H chain) variable region (V region) of an antibody molecule comprising an amino acid sequence represented by SEQ ID No. 16 or 17 and/or a light chain (L chain) V region of an antibody molecule represented by SEQ ID No. 18. (22) The medicament according to any one of the above (1) to (21), wherein the agent is a protein or an agent having low-molecular weight. (23) The medicament according to the above (22), wherein the protein is a cytokine or an antibody. (24) The medicament according to the above (23), wherein the cytokine is a cytokine selected from G-CSF, M-CSF, interferon-α, IL-2 and IL-15. (25) The medicament according to any one of the above (1) to (24), wherein the agent having low-molecular weight is a chemotherapeutic agent or a hormone therapeutic agent. (26) The medicament according to the above (25), wherein the chemotherapeutic agent is an agent selected from vincristine, cyclophosphamide, etoposide and Methotrexate. Examples of the medicament in the invention include a medicament comprising a combination of the recombinant antibody which specifically reacts with CCR4 or the antibody fragment thereof and at least one agent, a medicament for administering the recombinant antibody which specifically reacts with CCR4 or the antibody fragment thereof and at least one agent in combination, and a medicament for administering the recombinant antibody which specifically reacts with CCR4 or the antibody fragment thereof and at least one agent either simultaneously or successively. The medicament comprising a combination refers to a medicament in which the recombinant antibody which specifically binds to CCR4 or the antibody fragment thereof and at least one agent are prepared separately and these are administered in combination either simultaneously or successively or a mixed medicament obtained by mixing each ingredient. The mixed medicament obtained by mixing each ingredient includes a fusion antibody obtained by binding at least one agent to the recombinant antibody which specifically binds to CCR4 or the antibody fragment thereof, and the like. The recombinant antibody which specifically binds to CCR4 and the antibody fragment thereof in the invention (both of which are sometimes referred to as an antibody of the invention) include a recombinant antibody which specifically reacts with an extracellular region of human CCR4 and an antibody fragment thereof. A recombinant antibody which does not show a reactivity to a human platelet or an antibody fragment thereof, a recombinant antibody having high ADCC or an antibody fragment thereof, and the like are preferable. That an antibody does not show a reactivity to a human platelet as here referred to means that an antibody does not substantially reactive with a human platelet. Specifically, it means that a reactivity is not shown by the measurement with a flow cytometer. Further, the antibody of the present invention include an antibody which specifically reacts with the region comprising positions 1 to 39, 98 to 112, 176 to 206 or 271 to 284 in the amino acid sequence represented by SEQ ID NO:1; an antibody which specifically reacts with positions 2 to 29 (SEQ ID NO:2) in the amino acid sequence represented by SEQ ID NO: 1 is preferred, an antibody which specifically reacts with and positions 12 to 29 (SEQ ID NO:3) in the amino acid sequence represented by SEQ ID NO: 1 is more preferred and an antibody which specifically reacts with positions 13 to 25 (SEQ ID NO:4) in the amino acid sequence represented by SEQ ID NO:1 is most preferred. The antibody also includes an antibody which specifically reacts with an epitope recognized by a monoclonal antibody binding to CCR4 produced by hybidoma KM 2160 (FERM BP-10090). The hybridoma KM 2160 has been deposited with International Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, on Aug. 12, 2004 with accession No. FERM BP-10090. The antibody in the present invention is preferably an antibody low binding activity to a peptide in which at least one tyrosine residues at positions 16, 19, 20 and 22 is sulfated in the peptide comprising positions 13 to 25 of the amino acid sequence represented by SEQ ID NO.1 than a binding activity to a peptide comprising 13 to 25 of the amino acid sequence represented by SEQ ID No. 1. The antibody in the invention also includes an antibody produced by lectin-resistant cells recognizing a sugar chain structure in which 1-position of fucose is bound to 6-position of N-acetylglucosamine in the reducing end through α-bond in a complex type N-glycoside-linked sugar chain (WO 02/31140, WO 03/85118 and WO 03/85107). A recombinant antibody of the present invention includes a humanized antibody, human antibody, and the like. Examples of the humanized antibody are a human chimeric antibody, a human CDR-grafted antibody, and the like. The human chimeric antibody refers to an antibody comprising H chain V region (hereinafter also referred to as HV or VH) of an antibody of a non-human animal, and L chain V region (herein after also referred to as LV or VL) of an antibody, and CH of human antibody and L chain C region (hereinafter also referred to as CL) of a human antibody. As the non-human animal, any animal can be used so long as hybridomas can be prepared from the animal. Suitable animals include mouse, rat, hamster, rabbit and the like. The human chimeric antibody of the present invention can be produced by obtaining cDNAs encoding VH and VL from a hybridoma capable of producing a monoclonal antibody derived from non-human animal which specifically reacts with CCR4, inserting them into an expression vector for animal cell having genes encoding human antibody CH and human antibody CL to thereby construct a vector for expression of human chimeric antibody, and then introducing the vector into a host cell to express the antibody. Any CH of a human chimeric antibody can be used, so long as it belongs to human immunoglobulin (hereinafter referred to as hIg), but those of IgG class are preferred, and any one of subclasses further belonging to IgG such as γ1, γ2, γ3 and γ4 can be used. Also, as CL of a human chimeric antibody, those of κ class or λ class can be used. The human chimeric antibody of the present invention is a human chimeric antibody which comprises CDR1, CDR2 and CDR3 of VH comprising the amino acid sequences represented by SEQ ID NOs:5, 6 and 7, respectively, and CDR1, CDR2 and CDR3 of VL comprising the amino acid sequences represented by SEQ ID NOs:8, 9 and 10, respectively. Specifically, it includes a human chimeric antibody which comprises VH and VL comprising the amino acid sequences represented by SEQ ID NOs:11 and 12, respectively. More specifically, it includes a human chimeric antibody wherein the VH of the antibody consists of the amino acid sequence represented by SEQ ID NO: 11, the H chain C region of the human antibody consists of an amino acid sequence of the hIgG1 subclass, the L chain V region consists of the amino acid sequence represented by SEQ ID NO:12, and the L chain C region of the human antibody consists of an amino acid sequence of the κ class. An example includes anti-CCR4 human chimeric antibody KM 2760 disclosed in WO01/64754. The human CDR-grafted antibody refers to an antibody in which CDRs of VH and VL of an antibody derived from a non-human animal which specifically binds to CCR4 are grafted into appropriate sites in VH and VL of a human antibody. The human CDR-grafted antibody of the present invention can be produced by constructing cDNAs encoding V regions in which CDRs of VH and VL of a non-human animal-derived antibody which specifically binds to CCR4 are grafted into FR of VH and VL of an arbitrary human antibody, inserting the resulting cDNAs into an expression vector for animal cells which has DNAs encoding the CH and the H chain C region (hereinafter referred to as CL) of a human antibody, respectively, to construct a human CDR-grafted antibody expression vector, and introducing the expression vector into an animal cell to induce expression. As the method for selecting the amino acid sequences of frameworks (hereinafter referred to as FR) of VH and VL of a human antibody, any of those derived from human antibodies can be used. Suitable sequences include the amino acid sequences of FRs of VH and VL of human antibodies registered in databases such as Protein Data Bank, and the amino acid sequences common to each subgroup of FRs of VH and VL of human antibodies (Sequences of Proteins of Immunological Interest, U.S. Dept. Health and Human Services, 1991). As the CH for the antibody of the present invention, any CH of antibodies can be used, so long as it belongs to human immunoglobulin (hereinafter referred to as hIg), but those of IgG class are preferred, and any one of subclasses further belonging to IgG such as γ1, γ2, γ3 and γ4 can be used. Also, as CL of a human chimeric antibody, those of κ class or λ class can be used. An example of the human CDR-grafted antibody of the present invention is a human CDR-grafted antibody or antibody fragment comprising CDR1, CDR2 and CDR3 of VH of the antibody consisting of the amino acid sequences represented by SEQ ID NOs: 5, 6 and 7, respectively; and/or CDR1, CDR2 and CDR3 of VL of the antibody consisting of the amino acid sequences represented by SEQ ID NOs:8, 9 and 10, respectively. Preferred examples include a human CDR-grafted antibody, wherein the VH of the antibody comprises the amino acid sequence represented by SEQ ID NO: 13 or 14, and/or VL of the antibody comprises the amino acid sequence represented by SEQ ID NO: 15. More Preferable examples include: a human CDR-grafted antibody which comprises VH of the antibody comprising an amino acid sequence in which at least one or more amino acid residue selected from Ala at position 40, Gly at position 42, Lys at position 43, Gly at position 44, Lys at position 76 and Ala at position 97 in the amino acid sequence represented by SEQ ID NO.13 is replaced with another amino acid residue; a human CDR-grafted antibody which comprises VH of the antibody comprising an amino acid sequence in which at least one or more amino acid residue selected from Thr at position 28 and Ala at position 97 in the amino acid sequence represented by SEQ ID NO. 14 is replaced with another amino acid residue; a human CDR-grafted antibody which comprises VL of the antibody comprising an amino acid sequence in which at least one or more amino acid residue selected from Ile at position 2, Val at position 3, Gln at position 50 and Val at position 88 in the amino acid sequence represented by SEQ ID NO. 15 is replaced with another amino acid residue; a human CDR-grafted antibody which comprises VH of the antibody comprising an amino acid sequence in which at least one or more amino acid residue selected from Ala at position 40, Gly at position 42, Lys at position 43, Gly at position 44, Lys at position 76, and Ala at position 97 is replaced with another amino acid residue in the amino acid sequence represented by SEQ ID NO.13, and VL of the antibody comprising an amino acid sequence in which at least one or more amino acid residue selected from Ile at position 2, Val at position 3, Gln at position 50 and Val at position 88 in the amino acid sequence represented by SEQ ID NO. 15 is replaced with another amino acid residue; and A human CDR-grafted antibody which comprises VH of the antibody comprising an amino acid sequence in which at least one or more amino acid residue selected from Thr at position 28 and Ala at position 97 in the amino acid sequence represented by SEQ ID NO. 14 is replaced with another amino acid residue, and VL of the antibody comprising an amino acid sequence in which at least one or more amino acid residue selected from Ile at position 2, Val at position 3, Gln at position 50 and Val at position 88 in the amino acid sequence represented by SEQ ID NO.15 is replaced with another amino acid residue. Still more preferable examples include a CDR-grafted antibody which comprises the heavy chain (H chain) variable region (V region) of the antibody comprising the amino acid sequence represented by SEQ ID NO:16 or 17 and the light chain (L chain) V region of the antibody molecule comprising the amino acid sequence represented by SEQ ID NO: 18, and the like. Also included within the scope of the present invention are antibodies or antibody fragments which specifically react with CCR4 and consist of amino acid sequences wherein one or more amino acid residues are deleted, added, substituted or inserted in the above amino acid sequences. The expression “one or more amino acid residues are deleted, substituted, inserted or added in the amino acid sequence in the present invention” means that one or more amino acids are deleted, substituted, inserted, or added at single or plural arbitrary position (s) in the amino acid sequence. Deletion, substitution, insertion and addition may be caused in the same amino acid sequence simultaneously and amino acid residues to be substituted, inserted or added may be either natural or non-natural. Examples of the natural amino acid residues are L-alanine, L-asparagine, L-aspartic acid, L-glutamine, L-glutamic acid, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine and L-cysteine. The followings are preferred examples of the amino acid residues capable of mutual substitution. The amino acid residues in the same group shown below can be mutually substituted. Group A: leucine, isoleucine, norleucine, valine, norvaline, alanine, 2-aminobutanoic acid, methionine, O-methylserine, t-butylglycine, t-butylalanine, cyclohexylalanine Group B: aspartic acid, glutamic acid, isoaspartic acid, isoglutamic acid, 2-aminoadipic acid, 2-aminosuberic acid Group C: asparagine, glutamine Group D: lysine, arginine, ornithine, 2,4-diaminobutanoic acid, 2,3-diaminopropionic acid Group E: proline, 3-hydroxyproline, 4-hydroxyproline Group F: serine, threonine, homoserine Group G: phenylalanine, tyrosine Specific examples of the human CDR-grafted antibody in the invention include a human CDR-grafted antibody described in WO 03/18635, a human CDR-grafted antibody prepared from monoclonal antibody 1G1, 2B10 or 10E4 as described in WO 00/42074, a human CDR-grafted antibody prepared from a humanized antibody or monoclonal antibody 252Y or 252Z as described in WO 99/15666, a human CDR-grafted antibody prepared from a monoclonal antibody as described in U.S. Pat. No. 6,245,332. The human antibody originally means an antibody naturally existing in the human body. However, it also includes antibodies obtained from a human antibody phage library and human antibody-producing transgenic animals prepared by the recent advance in genetic engineering, cell engineering and developmental engineering techniques, and the like. With respect to the antibody naturally existing in the human body, for example, human peripheral blood lymphocytes are isolated, infected with EB virus or the like for immortalization and cloning, whereby lymphocytes producing the antibody can be cultured, and the antibody can be purified from the cultures. The human antibody phage library is a library in which an antibody gene prepared from a human B cell is inserted into a phage gene to express an antibody fragment such as Fab or scFv on the surface of the phage. A library in which mutation is artificially introduced can be used to develop the library. From the library, a phage having a desired antigen binding activity can be recovered using a binding activity to a substrate having an antigen immobilized thereon as an index. The antibody fragment can further be converted to a human antibody molecule comprising two full length H chains and two full length L chains by a protein engineering method. The human antibody-producing transgenic animal means an animal in which a human antibody gene is incorporated into cells. Specifically, a human antibody-producing transgenic mouse prepared by introducing a human antibody gene into a mouse ES cell, grafting the ES cell on an early embryo of the mouse and developing the same, and the like are mentioned. Regarding the method for preparing a human antibody from the human antibody-producing transgenic animal, the human antibody can be produced and accumulated in a culture supernatant by culturing a human antibody-producing hybridoma obtained by a hybridoma preparation method generally carried out in cell fusion method. Examples of transgenic non-human animals include cattle, sheep, goats, pigs, horses, mice, rats, chickens, monkeys, rabbits and the like. An antibody fragment of the present invention includes Fab, Fab′, F(ab′)2, scFv, Diabody, dsFv, and a peptide comprising CDR. An Fab is an antibody fragment having a molecular weight of about 50,000 and having an antigen-binding activity, in which about a half of the N-terminal side of H chain and the full length L chain, among fragments obtained by treating an IgG type antibody molecule with a protease, papain (cleaving at the amino acid residue at position 224 of the H chain), are bound together through a disulfide bond (S—S bond). The Fab of the present invention can be obtained by treating the human CDR-grafted antibody of the present invention which specifically reacts with human CCR4, with the protease, papain. Alternatively, the Fab may be produced by inserting DNA encoding the Fab of the antibody into an expression vector for prokaryote or eukaryote, and introducing the vector into a prokaryote or eukaryote to induce expression. An F(ab′)2 is an antibody fragment having a molecular weight of about 100,000 and having an antigen-binding activity, which is slightly larger than the Fab bound via a S—S bond at the hinge region, among fragments obtained by treating an IgG-type antibody molecule with a protease, pepsin (cleaving at the amino acid residue at position 234 of the H chain). The F(ab′)2 of the present invention can be obtained by treating the human CDR-grafted antibody of the present invention which specifically reacts with human CCR4 with the protease, pepsin. Alternatively, the F(ab′)2 may be prepared by binding Fab′ fragments described below by a thioether bond or a S—S bond. An Fab′ is an antibody fragment with a molecular weight of approximately 50,000 having antigen-binding activity, which is obtained by cleaving S—S bond at the hinge region of the above F(ab′)2. The Fab′ of the present invention can be obtained by treating the F(ab′)2 of the present invention which specifically binds to human CCR4 with a reducing agent, dithiothreitol. Alternatively, the Fab′ may be produced by inserting DNA encoding the Fab′ of the human CDR-grafted antibody which specifically reacts with CCR4 into an expression vector for prokaryote or eukaryote, and introducing the vector into a prokaryote or eukaryote to induce expression. An scFv is a VH-P-VL or VL-P-VH polypeptide in which one chain VH and one chain VL are linked by using an appropriate peptide linker (P) of 12 or more amino acid residues and which has an antigen-binding activity. The scFv of the present invention can be produced by obtaining cDNAs encoding the VH and VL of the human CDR-grafted antibody which specifically binds to CCR4, constructing DNA encoding the scFv, inserting the DNA into an expression vector for prokaryote or eukaryote, and introducing the expression vector into a prokaryote or eukaryote to induce expression. A diabody is an antibody fragment in which scFv having the same or different antigen binding specificity forms a dimer, and has an divalent antigen binding activity to the same antigen or two specific antigen binding activity to different antigens. The diabody of the present invention, for example, a divalent diabody which specifically binds to CCR4, can be produced by obtaining cDNAs encoding VH and VL of the human CCR4-grafted antibody which binds specifically to CCR4, constructing DNA encoding scFv having a polypeptide linker of 3 to 10 amino acid residues, inserting the DNA into an expression vector for prokaryote or an expression vector for eukaryote; and then introducing the expression vector into a prokaryote or eukaryote to express the diabody. A dsFV is an antibody fragment which is obtained by binding polypeptides in which one amino acid residue of each of VH and VL is substituted with a cysteine residue and those cysteine residues are bound via a S—S bond between the cysteine residues. The amino acid residue which is substituted with a cysteine residue can be selected based on a three-dimensional structure estimation of the antibody in accordance with the method shown by Reiter et al. (Protein Engineering, 7, 697 (1994)). The dsFv of the present invention can be produced by obtaining cDNAs encoding VH and VL of the human CCR4-grafted antibody which specifically binds to CCR4, constructing DNA encoding dsFv, inserting the DNA into an expression vector for prokaryote or an expression vector for eukaryote, and then introducing the expression vector into a prokaryote or eukaryote to express the dsFv. A peptide comprising CDR comprises one or more region of CDRs of VH and VL. The peptide comprising plural CDRs can be produced by binding directly to or via an appropriate peptide linker. The peptide comprising CDR of the present invention can be produced by constructing cDNAs encoding CDR of VH and VL of the human CCR4-grafted antibody which specifically binds to CCR4, inserting the cDNAs into an expression vector for prokaryote or an expression vector for eukaryote, and then by introducing the expression vector into a prokaryote or eukaryote to express the peptide. Also, the peptide comprising CDR can be produced by a chemical synthesis method such as an Fmoc method (fluorenylmethoxycarbonyl method), a tBoc method (t-butyloxycarbonyl method), or the like. Agents used in the present invention include protein, agent having low molecular weight, and the like. Examples of proteins include cytokines, antibodies and the like. The cytokines include cytokines which activate the effector cells such as NK cells, macrophages, monocytes, granulocytes, which are immunocompetent cells. Specific examples of the cytokines include interleukin 2 (IL-2), IFN-α, IFN-γ, IL-12, IL-15, IL-18, IL-21, fractalkine, M-CSF, GM-CSF, G-CSF, TNF-α, TNF-β, IL-1α, IL-1β, and the like. Examples of antibodies include antibody, antibody fragment and fusion antibody which specifically react with surface markers of T cell. Specific antibodies include anti-CD3 antibody (Orthoclone), anti-CD4 antibody, anti-CD5 antibody, anti-CD8 antibody, anti-CD30 antibody, anti-CD2 antibody, anti-CD25 antibody (Zenapax, Hoffmann-La Roche Inc.), anti-CD52 antibody (Campath, Ilex Oncology, Inc.), and the like. Examples of the agent having low molecular weight of the present invention include amifostine (ethyol), cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), doxorubicin lipo (doxil), gemcitabine (gemzar), daunorubicin, daunorubicin lipo (daunoxome), procarbazine, mitomycin, cytarabine, etoposide, Methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, paclitaxel (taxol), docetaxel (taxotere), aldesleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, CPT-11, 10-hydroxy-7-ethyl-camptothecin (SN38), floxuridine, fludarabine, hydroxyurea, ifosfamide, idarubicin, mesna, irinotecan, mitoxantrone, topotecan, leuprolide, megestrol, melpharan, mercaptopurine, plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, streptozocin, tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil, prednisolone, vindesine, nimstine, semustin, capecitabine, tomudex, azacytidine, UFT, oxaloplatin, gefitinib (Iressa), imatinib (STI571), amsacrine, all-trans retinoic acid, thalidomide, bexarotene (targretin), dexamethasone, anastrozole (Alimidex), leuplin or combined use thereof. Preferable examples include vincristine, cyclophosphamide, etoposide, Methotrexate or combined use thereof. When the above agent is administered in vivo solely at a high dose, fear of possible side effect may arose. However, in the present invention, the above agent can be used at a low dose by being combined with the recombinant antibody which specifically binds to CCR4 or the antibody fragment thereof. Accordingly, in addition to the satisfactory therapeutic effect, the side effect can be reduced. The medicament of the invention can be used against cells in which CCR4 is expressed. Tumor cells are preferable. Specifically, a hematopoietic organ tumor is mentioned as the tumor. The hematopoietic organ tumor includes acute leukemia, chronic leukemia, Hodgkin's disease, non-Hodgkin's disease and the like. Examples of the acute leukemia include acute lymphatic leukemia and the like, and examples of the acute lymphatic leukemia include pre-T cell acute lymphatic leukemia and the like. The chronic leukemia includes chronic lymphatic leukemia. Examples of the chronic lymphatic leukemia include T cell chronic lymphatic leukemia, T cell pre-lymphatic leukemia, adult T cell leukemic lymphoma (ATL), Sezary syndrome and the like. The non-Hodgkin's disease includes T/NK cell lymphoma. Examples of the T/NK cell lymphoma include pre-T lymphoblast lymphoma/leukemia, mature T cell tumor and the like. Examples of the mature T cell tumor include T cell pre-lymphocyte leukemia, T cell large granular lymphocyte leukemia, Sezary syndrome, mycosis fungoides, primary skin undifferentiated large cell lymphoma, subcutaneous phlegmon-like T cell lymphoma, intestinal disease-type bowel T cell lymphoma, liver/spleen yb T cell lymphoma, angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma, undifferentiated large cell lymphoma, adult T cell leukemia/lymphoma and the like. The effect of the medicament of the present invention can be measured by an in vitro cytotoxic activity measuring method. As the in vitro cytotoxic activity measuring method, an ADCC measuring system is mentioned. ADCC can be measured by contacting target cells expressing CCR4 as an antigen with effector cells such as peripheral blood mononuclear cells, monocytes, macrophages or granulocytes collected from humans or other animals, detecting a degree of damaged target cells, and determining the same. The degree of damaged target cells can be detected by a 51Cr release method, a method for detecting an enzyme activity of target cells, a detecting method using a flow cytometer, or the like. The effect of the medicament of the present invention in the ADCC measuring system can be measured by adding the agent to the ADCC measuring system or exposing these agents to the target cells or the effector cells or both of them for a prescribed period of time and observing influences exerted on ADCC. The effect of the medicament of the present invention may be examined by measuring an in vivo antitumor activity using animal models. Examples of the animal models include xenograft models obtained by grafting a culture cell line derived from a human cancer tissue in immunodeficient mice such as nude mice, isograft models obtained by grafting a cultured mouse cancer cell line in wild-type mice having a normal immune system, and the like. The xenograft models can be prepared by grafting a human cancer cell line in various sites such as subcutaneous, intracutaneous, intraperitoneal and intravenous sites of immunodeficient mice such as nude mice. The isograft models for evaluation of the medicament of the present invention can be prepared by introducing a CCR4 gene into a mouse culture cell line such as EL4 cell to form a CCR4-positive transformant and grafting this transformant into various sites of wild-type mice having a normal immune system. The effect of the medicament of the present invention can be evaluated by comparing an effect of administration of the antibody alone or an effect of administration of the agent alone with an effect of the medicament of the present invention using the animal models. The medicament of the present invention can be administered alone, but it is generally preferred to provide it in the form of a pharmaceutical preparation produced by mixing it with one or more pharmaceutically acceptable carriers in accordance with any method well known in the technical field of pharmaceutics. It is preferable to select a route of administration which is most effective in treatment. Examples include oral administration and parenteral administration, such as intraoral, tracheobronchial, intrarectal, subcutaneous, intramuscular and intravenous. In an protein preparation, intravenous administration is preferred. Examples of the preparation suitable for the oral administration are spray, capsule, tablet, granule, syrup, emulsion, suppository, injection, ointment, tape and the like. Liquid preparation such as emulsion and syrup can be produced using water, saccharides such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, antiseptics such as p-hydroxybenzoate, flavors such as strawberry flavor and peppermint flavor and the like, as additives. Capsule, tablet, diluted powder, granule, and the like can be produced using excipients such as lactose, glucose, sucrose and mannitol, disintegrating agents such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactants such as fatty acid ester, plasticizers such as glycerol, as additives. Examples of the preparation suitable for parenteral administration are injection, suppository, air spray and the like. Suppository is prepared using a carrier such as cacao butter, hydrogenated fat or carboxylic acid. Air spray is prepared using the medicament as such or using, for example, a carrier which does not stimulate the mouth and the airway mucous membrane of a person to be administered, and which disperses the medicament into fine particles and makes the absorption easy. Specific examples of the carrier are lactose and glycerol. Depending upon the property of the medicament and the carrier used, it is possible to prepare aerosol, dry powder, and the like. In addition, even in the parenteral preparation, components exemplified as additives in the oral preparation may be added. A dose or an administration schedule vary depending on a desired therapeutic effect, an administration method, a therapeutic period, an age, a body weight and the like. The dose of the antibody in one administration is usually from 0.1 to 20 mg/kg for an adult. The agent used in combination with the antibody is administered at a dose equal to or lower than the dose when the agent is used alone in clinic. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows an enhancement effect of a cytokine against a cytotoxic activity of an anti-CCR4 antibody. The ordinate shows a cytotocity. ▪ indicates a cytotoxic activity without addition of cytokine, □ indicates a cytotoxic activity in addition of IL-2, and a hatch indicates a cytotoxic activity in addition of IL-15 respectively. A bar indicates a standard deviation. FIG. 2 indicates an effect provided by combined use of an anti-CCR4 antibody and vincristine against CCRF-CEM cells grafted in a nude mouse. The ordinate shows a V/V0 value. □ indicates a V/V0 value of a negative control group, a slashed bar indicates a V/V0 value of KM 2760 administration group, a gray indicates a V/V0 value of a vincristine administration group, and ▪ indicates a V/V0 value of a group of administrating KM 2760 and vincristine in combination, respectively. A bar indicates a standard deviation. FIG. 3 indicates an effect provided by combined use of an anti-CCR4 antibody and cyclophosphamide against CCRF-CEM cells grafted in a nude mouse. The ordinate shows a V/V0 value. □ indicates a V/V0 value of a negative control group, a slashed bar indicates a V/V0 value of a KM 2760 administration group, a gray indicates a V/V0 value of a cyclophosphamide administration group, and ▪ indicates a V/V0 value of a group of administration of KM 2760 and cyclophosphamide in combination, respectively. A bar indicates a standard deviation. FIG. 4 indicates an effect provided by combined use of an anti-CCR4 antibody and etopiside against CCRF-CEM cells grafted in a nude mouse. The ordinate shows a V/V0 value. □ indicates a V/V0 value of a negative control group, a slashed bar indicates a V/V0 value of a KM 2760 administration group, a gray indicates a V/V0 value of an etoposide administration group, and ▪ indicates a V/V0 value of a group administrating KM 2760 and etoposide in combination, respectively. A bar indicates a standard deviation. FIG. 5 shows an effect provided by combined use of an anti-CCR4 antibody and Methotrexate against CCRF-CEM cells grafted in a nude mouse. The ordinate shows a V/V0 value. □ indicates a V/V0 value of a negative control group, a slashed bar indicates a V/V0 value of a KM 2760 administration group, a gray indicates a V/V0 value of a Methotrexate administration group, and ▪ indicates a V/V0 value of a group administrating of KM 2760 and Methotrexate in combination, respectively. A bar indicates a standard deviation. FIG. 6 shows an effect provided by combined use of an anti-CCR4 antibody and G-CSF against CCR4/EL4 cells grafted in C57BL/6 mouse. The abscissa shows the number of days after grafting the tumor, the ordinate shows a tumor volume respectively. X indicates a negative control group, ▴ indicates a group of using KM 2760 alone, ● indicates a group of using G-CSF alone, and □ indicates a group of combined use respectively. A bar indicates a standard deviation. FIG. 7 shows an effect provided by combined use of an anti-CCR4 antibody and IFN-α against CCR4/EL4 cells grafted in C57BL/6 mouse. The ordinate shows a weight ratio of a liver. A bar indicates a standard deviation. The present invention is described in detail below. The present application claims the Convention priority from Japanese Patent Application Nos. 2003-406590 and 2004-155141 filed Dec. 4, 2003 and May 25, 2004, including the contents described in the specifications and/or drawings of these applications. BEST MODE FOR CARRYING OUT THE INVENTION Example 1 Effect of an Anti-CCR4 Antibody and a Cytokine in Combination in an In Vitro Cytotoxic Activity An effect of using anti-CCR4 human chimeric antibody KM 2760 (FERM BP-7054, WO 01/64754) and a cytokine in combination in an in vitro cytotoxic activity was measured by the following method. (a) Preparation of an Effector Cell Suspension A vein blood (50 mL) was collected from a healthy person, 0.5 mL of heparin sodium (manufactured by Shimizu Seiyaku K.K.) was added, and they were gently mixed. A mononuclear cell layer was separated from using a MONO-POLY separation solution (manufactured by Dainippon Pharmaceutical Co., Ltd.) according to the attached manual. After the layer was subjected to centrifugation and washed with RPMI 1640-FCS (5) medium [RPMI 1640 medium containing 5% FCS (Gibco. BRL)] for three times, the cells were resuspended in the same medium to a concentration of 3×106 cells/ml to give an effector cell suspension. (b) Stimulation of Effector Cells by a Cytokine The effector cell suspension obtained in the above (a) was dispensed at 50 μl/well in a 96-well U-bottom plate (manufactured by Falcon) in an amount of 50 μl/well. Further, either 50 μL of a 2 nm/mL IL-2 (manufactured by Peprotech) solution diluted with RPMI 1640-FCS(5) medium, 50 μL of a 2 ng/mL of IL-15 (manufactured by Peprotech) solution or 50 μL of RPMI 1640-FCS(5) as a negative control without addition of a cytokine were added to separate samples, and were allowed to stand still in a 5% CO2 incubator for 3 days. (c) Preparation of a Target Cell Suspension CCR4/EL4 cells (WO01/64754) which are transformant tumor cells obtained by introducing a human CCR4 gene into mouse thymoma cell line EL4 were cultured in RPMI 1640-FCS(10) medium [RPMI 1640 medium containing 10% FCS (manufactured by Gibco BRL)] containing 0.5 mg/mL of G418 (manufactured by Nacalai Tesque) washed with RPMI 1640-FCS(5) medium subjected to centrifugation and suspension, and then adjusted to a concentration of 2×105 cells/mL with RPMI 1640-FCS(5) medium to form a target cell suspension. (d) Measurement of a Cytotoxic Activity The target cell suspension (50 μL) prepared in the above (c) was added to each well of a 96-well U-shaped bottom plate containing the effector cells stimulated with the cytokine in the above (b) such that the concentration became 1×104 cells/well. At this time, the effector cell:target cell ratio is 15:1. Further, KM 2760 was added such that the final concentration became 1 or 100 ng/mL to each well was allowed to react, and at 37° C. for 4 hours. After the reaction, the plate was subjected to centrifugation, and a lactic acid dehydrogenase (hereinafter referred to as LDH) activity in the supernatant was measured by obtaining an absorbance data with CytoTox96 Non-Radioactive Cytotoxic activity Assay (manufactured by Promega) according to the attached manual. An absorbance data of target cell spontaneous release was obtained by the same procedure as above using RPMI 1640-FCS(5) medium in the same volume instead of the effector cell suspension and the antibody solution, and absorbance data of effector cell spontaneous release was obtained by the same procedure as above using RPMI 1640-FCS(5) medium in the same volume instead of the target cell suspension and the antibody solution. With respect to an absorbance data of target cell total release, a reaction was conducted using RPMI 1640-FCS(5) medium in the same volume instead of the antibody solution and the effector cell solution, 15 μL of a 9% Triton X-100 solution was added 45 minutes before completion of the reaction, and the same procedure as above was conducted to measure an LDH activity of the supernatant. ADCC was obtained using the following formula. Cytotoxic activity (%)=[(absorbance of a specimen)−(absorbance of effector cell spontaneous release)−(absorbance of target cell spontaneous release)]/[(absorbance of target cell total release)−(absorbance of target cell spontaneous release)]×100 (Formula 1) The results were shown in FIG. 1. The cytotoxic activity of KM 2760 was increased in a concentration-dependent manner. It was more increased by addition of the cytokine. The results show that the cytotoxic activity of the anti-CCR4 antibody is enhanced by the cytokine that activates the effector cells. Example 2 Antitumor Effect Provided by Administrating an Anti-CCR4 Antibody and Vincristine in Combination CCRF-CEM cells (human T cell leukemia cell line) were suspended in RPMI 1640 medium (Gibco BRL) at a concentration of 2×108 cells/mL, and 100 μL of the suspension was grafted into the ventral skin of Balb/c nude mouse (Nippon Crea, male). On Day 15 after the cell grafting, a diameter of a tumor was measured with calipers, and a tumor volume was calculated using the following formula. Tumor volume=short diameter×short diameter×long diameter×0.5 (Formula 2) Individuals having the tumor volume within the range of 140 to 342 mm3 (on average 260 mm3) were selected, and grouped such that the average of tumor volume to be almost the same. Each of following agents A to D was administered to the mice. Incidentally, the grouping day was defined as Day 0. A. Negative control group: No administration B. Group of administering KM 2760 alone: 800 μg of KM2760 was administered per mouse on Day 0 and Day 4. C. Group of administering vincristine (hereinafter referred to as VCR; Oncovin injection, Eli Lilly Japan K.K.) alone: 0.55 mg/kg of VCR was administered per mouse on Day 0. D. Group of administering KM 2760 and VCR in combination: 0.55 mg/kg of VCR was administered per mouse on Day 0, and 800 μg of KM 2760 was administered per mouse on Day 0 and Day 4. The experiment was conducted with groups each consisting of five mice. Each of the agents was diluted with a physiological saline (Otsuka Seiyaku), and the diluent was administered from the tail vein. On Day 10, the tumor volume was measured. The antitumor effect was evaluated by comparing average values of a tumor volume change (V/V0) on Day 10 when the tumor volume on Day 0 in each group was defined as V0. The average values of V/V0 in each group is shown in FIG. 2. As shown in FIG. 2, the administration of KM 2760 and VCR in combination exhibited the higher effect for suppressing growth than the administration of VCR or the antibody alone. A value (T/C) obtained by dividing V/V0 of each group by V/V0 of the negative control group is shown in Table 1. In comparison with a theoretical value of T/C when simply adding the pharmaceutical effects of both KM 2760 and VCR, namely, a value obtained by multiplying T/Cs of the groups of administering the respective agents alone, actual T/C of the combined administration group (C in the table) exhibited the lower value (0.11) than 0.21, the theoretical value on Day 10. TABLE 1 T/C of each group A. Negative B. KM Theoretical control 2760 C. VCR D. KM 2760 + VCR Value (B × C) 1 0.43 0.49 0.11 0.21 From the foregoing, it has been clarified that the administration of KM 2760 and VCR in combination has the higher antitumor effect than the administration of KM 2760 or VCR alone, and exhibits the synergistic effect. Example 3 Antitumor Effect Provided by Administrating an Anti-CCR4 Antibody and Cyclophosphamide in Combination CCRF-CEM cells (human T cell leukemia cell line) were suspended in RPMI 1640 medium (Gibco BRL) at a concentration of 2×108 cells/mL, and 100 μL of the suspension was grafted intradermally in the right flank of Balb/c nude mice (Nippon Crea, male). On Day 18 after the cell grafting, a diameter of a tumor was measured with calipers, and a tumor volume was calculated using formula 2 in Example 2. Individuals having the tumor volume within the range of 116 to 349 mm3 (on average 219 mm3) were selected, and grouped such that the average tumor volume to be almost the same. Each of the following agent A to D was administered to the mice. Incidentally, the grouping day was defined as Day 0. A. Negative control group: No administration B. Group of administering KM 2760 alone: 800 μg of KM2760 was administered per mouse on Day 0 and Day 4. C. Group of administering cyclophosphamide (hereinafter referred to as CPA; Endoxan for injection, Baxter) alone: 65 mg/kg of CPA was administered per mouse on Day 0. D. Group of administering KM 2760 and CPA in combination: 65 mg/kg of CPA was administered per mouse on Day 0, and 800 μg of KM 2760 was administered per mouse on Day 0 and Day 4. The experiment was conducted with groups each consisting of five mice. Each of the agents was diluted with a physiological saline (Otsuka Seiyaku), and the diluent was administered from the tail vein. On Day 4, the tumor volume was measured. The antitumor effect was evaluated by comparing an average values of a tumor volume change (V/V0) on each measurement day when the tumor volume on Day 0 in each group was defined as V0. The chronological change in average values of V/V0 in each group is shown in FIG. 3. As shown in FIG. 3, the administration of KM 2760 and CPA in combination exhibited the higher effect for suppressing growth than the administration of CPA or the antibody alone. A value (T/C) obtained by dividing V/V0 of each group by V/V0 of the negative control group is shown in Table 2. In comparison with a theoretical value of T/C when simply adding the pharmaceutical effects of both KM 2760 and CPA, namely, a value obtained by multiplying T/Cs of the groups of administering the respective agents alone, actual T/C of the combined administration group (D in the table) exhibited the lower value (0.35) than 0.39, the theoretical value. TABLE 2 T/C of each group A. Negative B. KM Theoretical control 2760 C. CPA D. KM 2760 + CPA Value (B × C) 1.00 0.80 0.48 0.35 0.39 From the foregoing, it has been clarified that the administration of KM2760 and CPA in combination has the higher antitumor effect than the administration of KM2760 or CPA alone, and exhibits the synergistic effect. Example 4 Antitumor Effect Provided by Administrating an Anti-CCR4 Antibody and Etoposide in Combination CCRF-CEM cells (human T cell leukemia cell line) were suspended in RPMI 1640 medium (Gibco BRL) at a concentration of 2×108 cells/mL, and 100 μL of the suspension was grafted into the ventral skin of Balb/c nude mice (Nippon Crea, male). On Day 17 after the cell grafting, a diameter of a tumor was measured with calipers, and a tumor volume was calculated using formula 2 in Example 2. Individuals having the tumor volume within the range of from 121 to 348 mm3 (on average 195 mm3) were selected, and grouped such that the average tumor volume to be almost the same. Each of the following agents A to D was then administered to the mice. Incidentally, the grouping day was defined as Day 0. A. Negative control group: No administration B. Group of administering KM 2760 alone: 800 μg of KM2760 was administered per mouse on Day 0 and Day 4. C. Group of administering etoposide (hereinafter referred to as VP-16; Lastet injection, Nippon Kayaku Co., Ltd.) alone: 10 mg/kg of VP-16 was administered per mouse for 5 days from Day 0 to Day 4. D. Group of administering KM2760 and VP-16 in combination: 10 mg/kg of VP-16 was administered per mouse for 5 days from Day 0 to Day 4, and 800 μg of KM 2760 was administered per mouse on Day 0 and Day 4. The experiment was conducted with groups each consisting of five mice. Each of the agents was diluted with a physiological saline solution (Otsuka Seiyaku), and the diluent was administered from the tail vein. On Day 7, the tumor volume was measured. The antitumor effect was evaluated by comparing average values of a tumor volume change (V/V0) on Day 7 when the tumor volume on Day 0 in each group was defined as V0. The average values of V/V0 in each group is shown in FIG. 4. As shown in FIG. 4, the administration of KM 2760 and VP-16 in combination exhibited the higher effect for suppressing growth than the administration of VP-16 or the antibody alone. A value (T/C) obtained by dividing V/V0 of each group by V/V0 of the negative control group is shown in Table 3. In comparison with a theoretical value of T/C when simply adding the pharmaceutical effects of both KM 2760 and VP-16, namely, a value obtained by multiplying T/Cs of the groups of administering the respective agents alone, actual T/C of the combined administration group (the value of D in the table) exhibited the lower value (0.38) than 0.46, the theoretical value. TABLE 3 T/C of each group A. Negative D. KM Theoretical control B. KM 2760 C. VP-16 2760 + VP-16 Value (B × C) 1.00 0.65 0.71 0.38 0.46 From the foregoing, it has been clarified that the administration of KM2760 and VP-16 in combination has the higher antitumor effect than the administration of KM2760 or VP-16 alone, and exhibits the synergistic effect. Example 5 Antitumor Effect Provided by Administrating an Anti-CCR4 Antibody and Methotrexate in Combination CCRF-CEM cells (human T cell leukemia cell line) were suspended in RPMI 1640 medium (Gibco BRL) at a concentration of 2×108 cells/mL, and 100 μL of the suspension was grafted into the ventral skin of Balb/c nude mice (CLEA Japan Inc. male). On Day 17 after the cell grafting, a diameter of a tumor was measured with calipers, and a tumor volume was calculated using formula 2 in Example 2. Individuals having the tumor volume within the range of 121 to 348 mm3 (on average 195 mm3) were selected, and grouped such that the average tumor volume to be almost the same. Each of the following agents A to D was administered to the mice. Incidentally, the grouping day was defined as Day 0. A. Negative control group: No administration B. Group of administering KM 2760 alone: 800 μg of KM2760 was administered per mouse on Day 0 and Day 4. C. Group of administering Methotrexate (hereinafter referred to as MTX; Methotrexate injection solution, Nippon Weisledary K.K.) alone: 15 mg/kg of MTX was administered per mouse for 5 days from Day 0 to Day 4. D. Group of administering KM 2760 and MTX in combination: 15 mg/kg of MTX was administered per mouse for 5 days from Day 0 to Day 4, and 800 μg of KM 2760 was administered per mouse on Day 0 and Day 4. The experiment was conducted with groups each consisting of five mice. Each of the agents was diluted with a physiological saline solution (Otsuka Seiyaku), and the diluent was administered from the tail vein. On Day 7, the tumor volume was measured. The antitumor effect was evaluated by comparing average values of a tumor volume change (V/V0) when the tumor volume on Day 0 in each group was defined as V0. The chronological change in average values of V/V0 in each group is shown in FIG. 5. As shown in FIG. 5, the administration of KM 2760 and MTX in combination exhibited the higher effect for suppressing growth than the administration of MTX or the antibody alone. A value (T/C) obtained by dividing V/V0 of each group by V/V0 of the negative control group is shown in Table 4. In comparison with a theoretical value of T/C when simply adding the pharmaceutical effects of both KM 2760 and MTX, namely, a value obtained by multiplying T/Cs of the groups of administering the respective agents alone, actual T/C of the combined administration group (the value of D in the table 4) exhibited the lower value (0.01) than 0.04, the theoretical value. TABLE 4 T/C of each group A. Negative D. KM Theoretical control B. KM 2760 C. MTX 2760 + MTX Value (B × C) 1.00 0.65 0.06 0.01 0.04 From the foregoing, it has been clarified that the administration of KM2760 and MTX in combination has the higher antitumor effect than the administration of KM2760 or MTX alone, and exhibits the synergistic effect. Example 6 Antitumor Effect Provided by Administrating an Anti-CCR4 Human Chimeric Antibody KM 2760 and G-CSF in Combination CCR4/EL4 Cells (WO 01/64754) were suspended in RPMI 1640 medium (Gibco BRL) at a concentration of 1×106 cells/mL, and 100 μL of the suspension was grafted into the right ventral skin of C57BL/6 mice (Nippon Crea, male, 8 weeks old). After, mice were grouped into A to D, each of the agents A to D were administered to each mouse. Incidentally, the day on which the tumor was grafted was defined as Day 0. A. Negative control group: No administration B. Group of administering KM 2760 alone: 100 μg of KM2760 was intravenously administered per mouse on Day 0 and Day 4. C. Group of administering G-CSF alone: 10 μg of G-CSF (Neuup Injection 100, manufactured by Kyowa Hakko Kogyo Co., Ltd.) was subcutaneously administered per mouse once a day for 10 days from 4 days before the tumor grafting (hereinafter referred to as Day-4) to Day 5. The administration site is near the hind limb on the right ventral portion which does not overlap with the tumor grafting site. D. Group of administering KM2760 and G-CSF in combination: 100 μg of KM 2760 was intravenously administered per mouse once a day on Day 0 and Day 4, and 10 μg of G-CSF was subcutaneously administered per mouse once a day for 10 days from Day-4 to Day 5. The administration site is near the hind limb on the right ventral portion which does not overlap with the tumor grafting site. The experiment was conducted with group A consisting of 10 mice and groups B, C and D each consisting of 7 mice. KM 2760 was diluted with a citrate buffer solution (10 mM citric acid, 150 mM sodium chloride, pH 6), and G-CSF was diluted with a physiological saline (Otsuka Seiyaku) respectively. Each of the diluent was administered at 100 μL. A diameter of a tumor was measured with calipers chronologically from Day 0 of each group. A tumor volume was calculated using formula 2 in Example 2. Since the tumor death of the mouse was started in group A from Day 17 on, the evaluation of the tumor volume was finished on Day 14. The chronological change in averages value of the tumor volume in each group is shown in FIG. 6. As shown in FIG. 6, antitumor effect was low in groups B and C compared to untreated group A, whereas an outstanding antitumor effect was observed in group D. T/C values on the final day of evaluation are shown in Table 5. The antitumor effect (T/C value) in each group was evaluated by calculation using the following formula 3 for comparison between the average value of the tumor volume in group A and the average values of the tumor volume in each group on the final evaluation day (Day 14). (T/C value)=(average value of tumor volume in each group on Day 14)/average value of tumor volume in group A on Day 14). (Formula 3) In comparison with a theoretical value of T/C when simply adding the pharmaceutical effects of both KM 2760 and G-CSF, namely, a value obtained by multiplying T/C values of the groups of administering the respective agents alone, actual T/C value of the combined administration group (C in the table) exhibited the lower value (0.10) than 0.30, the theoretical value. TABLE 5 Group A B C D Theoretical Value (B × C) T/C value 1.0 0.48 0.63 0.10 0.30 From the foregoing, it has been clarified that the administration of KM 2760 and G-CSF in combination has the higher antitumor effect than the administration of KM 2760 or G-CSF alone, and exhibits the synergistic effect. Example 7 Antitumor Effect Provided by Administrating an Anti-CCR4 Human Chimeric Antibody KM 2760 and IFN-α in Combination CCR4/EL4 cells were suspended in RPMI 1640 medium (manufactured by Gibco BRL) at a concentration of 5× cells/mL, and 100 μl of the suspension was grafted into the tail vein of C57BL/6 mice (CLEA Japan Inc., male, 8 weeks old). Further, mice were grouped into A to D, and each of the agents A to D were administered to the mice. Incidentally, the day on which the tumor was grafted was defined as Day 0. A. Negative control group: No administration B. Group of administering IFN-α alone: 5×104 units of IFN-α (Universal type I interferon, manufactured by PBL Biomedical Laboratories) was intravenously administered per mouse once a day for 5 days from Day 1 to Day 5. C. Group of administering KM 2760 alone: 0.5 μg of KM2760 was intravenously administered per mouse once a day on Day 1 and Day 5. D. Group of administering KM2760 and IFN-α in combination: 0.5 μg of KM 2760 was intravenously administered per mouse once a day on Day 1 and Day 5, and 5×104 units of IFN-α was intravenously administered per mouse once a day for 5 days from Day 1 to Day 5. The experiment was conducted with group A consisting of 7 mice and groups B, C and D each consisting of 6 mice. KM 2760 was diluted with a citrate buffer solution (10 mM citric acid, 150 mM sodium chloride, pH 6) and IFN-α was diluted PBS containing 0.1% bovine serum albumin respectively. 100 μL of each of the diluents was administered. The weight of all mice was measured on Day 14. After etherization and exsanguination, mice were brought to euthanasia by dislocation of the cervical spine. The liver was extracted, and the weight of the liver was then measured. A ratio of the liver weight to the weight of each individual (hereinafter referred to as a weight ration of a liver) was calculated by percentage. The antitumor effect was evaluated by comparing the liver weight ratio (average value of six mice) of untreated healthy mice measured simultaneously and the liver weight ratio of each group increased by metastasis of tumor cells. The liver weight ratio of each group is shown in FIG. 7. As shown in FIG. 7, antitumor effect was low in groups B and C compared to untreated group A, whereas an outstanding antitumor effect was observed in group D. Further, the residual amount of tumor cells in the liver in each group was calculated as a T/C value using the following formula. T/C=(average values of a weight ration of a liver of each group−average value of a weight ration of a liver of an untreated mouse) (average value of a weight ration of a liver of a negative control group−average value of a weight ration of a liver of an untreated mouse) (Formula 4) The resulting T/C values are shown in Table 6. In comparison with a theoretical value of T/C when simply adding the pharmaceutical effects of both KM 2760 and IFN-α, namely, a value obtained by multiplying T/C values of the groups of administering the respective agents alone, actual T/C value of the combined administration group (C in the table) exhibited the lower value (0.088) than 0.25, the theoretical value. TABLE 6 Group A B C D Theoretical Value (B × C) T/C value 1.0 0.48 0.52 0.088 0.25 From the foregoing, it has been clarified that the administration of KM 2760 and IFN-α in combination has the higher antitumor effect than the administration of KM 2760 or IFN-α alone, and exhibits the synergistic effect. Example 8 Antitumor Effect Provided by Administrating an Anti-CCR4 Human Chimeric Antibody KM 2760 and M-CSF in Combination CCR4/EL4 cells (WO 01/64754) were suspended in RPMI 1640 medium (manufactured by Gibco BRL) at a concentration of 1×105 cells/mL, and 200 μL of the suspension was grafted into the peritoneal cavity of C57BL/6 mice (CLEA Japan Inc., male, 8 weeks old). After, mice was grouped into A to D, and each of the agents A to D was administered to each mouse. The day on which the tumor was grafted was defined as Day 0. A. Negative control group: No administration B. Group of administering M-CSF alone: 100 μg of M-CSF (Leucoprol, manufactured by Kyowa Hakko Kogyo Co., Ltd.) was intraperitoneally administered per mouse twice a day from Day-3 to Day-1 and once a day on Day 0, seven times in total. C. Group of administering KM 2760 alone: 50 μg of KM2760 was intraperitoneally administered per mouse once a day on Day 0. D. Group of administering KM 2760 and M-CSF in combination: 50 μg of KM 2760 was intraperitoneally administered per mouse once a day on Day 0, and 100 μg was intraperitoneally administered per mouse twice a day from Day-3 to Day-1 and once a day on Day 1, seven times in total. The experiment was conducted with groups each consisting of 8 mice. Regarding the agents, KM 2760 was diluted with a citrate buffer (10 mM citric acid, 150 mM sodium chloride, pH 6), and M-CSF was diluted with a physiological saline solution (Otsuka Seiyaku) respectively. 100 μL of each of the diluents was administered. The antitumor effect was evaluated by a ratio of average values of the number of survival days of mice in each group to an average value of the number of survival days of mice in the negative control group (hereinafter referred to as a life prolongation ratio). The number of survival days of each mouse and the life prolongation ratio of each group are shown in Table 7. TABLE 7 Number of Average number Life prolongation Group survival days of survival days ratio A 17 18 18 19 19 20 20 22 19.3 1.00 B 17 17 18 18 18 19 19 22 18.8 0.974 C 19 21 21 21 22 24 26 27 22.9 1.19 D 25 25 25 26 26 26 27 >50 >28.8 >1.49 (theoretical value 1.16) As shown in Table 7, In comparison with untreated Group A, no antitumor effect was exhibited in group B, and antitumor effect was low in group C, whereas an outstanding antitumor effect was observed in group D. In comparison with a theoretical value of the life prolongation ratio when simply adding the pharmaceutical effects of both KM 2760 and M-CSF, namely, a value obtained by multiplying the life prolongation ratios of the groups of administering the respective agents alone, the actual life prolongation ratio of the combined administration group (D in the table) exhibited the higher value (>1.49) than 1.16, the theoretical value. Incidentally, one mouse in group D was still alive even after an observation period (Day 50). From the foregoing, it has been clarified that the administration of KM 2760 and M-CSF in combination has the higher antitumor effect than the administration of KM 2760 or M-CSF alone, and exhibits the synergistic effect. INDUSTRIAL APPLICABILITY A medicament comprising a combination of a recombinant antibody which specifically binds to human CC chemokine receptor 4 (CCR4) or an antibody fragment thereof and at least one agent is provided. SEQ ID No. 13—Description of an artificial sequence: Antibody heavy chain variable region amino acid sequence SEQ ID No. 14—Description of an artificial sequence: Antibody heavy chain variable region amino acid sequence SEQ ID No. 15—Description of an artificial sequence: Antibody light chain variable region amino acid sequence SEQ ID No. 16—Description of an artificial sequence: Antibody heavy chain variable region amino acid sequence SEQ ID No. 17—Description of an artificial sequence: Antibody heavy chain variable region amino acid sequence SEQ ID No. 18—Description of an artificial sequence: Antibody light chain variable region amino acid sequence

<SOH> BACKGROUND ART <EOH>When a ligand is bound to a chemokine receptor, migration of leukocytes is induced. Human CC chemokine receptor 4 (hereinafter referred to as CCR4) which is mainly expressed on a Th2-type CD4-positive helper T cell in a normal tissue is one type of a chemokine receptor family [Int. Immunol., 11, 81 (1999)]. CCR4 binds specifically to TARC (thymus and activation-regulated chemokine) or MDC (macrophage-derived chemokine). The Th2-type CD4-positive helper T cell which controls humoral immunity is considered to play an important role in allergic diseases or autoimmune diseases. In T cell-type leukemia/lymphoma cells described above, various chemokine receptors are expressed, and there is a relation between subtypes of T cell leukemia/lymphoma and types of receptors expressed in cells. It was reported that CCR4 is expressed at high frequency in leukemia/lymphoma cells [Blood, 96, 685 (2000)]. Since CCR4 is expressed at high frequency in ALK-positive anaplastic large-cell lymphoma and mycosis fungoides, a possibility of CCR4 being a tumor marker having quite a high selectivity in specific carcinomas was suggested [Blood, 96, 685 (2000), Mod. Pathol., 15, 838 (2002), J. Invest. Dermatol., 119, 1405 (2002)]. It was reported that CCR4 is expressed at quite a high frequency also in adult T-cell leukemia (hereinafter referred to as ATL) caused by infection with human T-cell leukemiavirus type I) [Blood, 99, 1505 (2002)]. Regarding the expression of CCR4 in ATL, the expression of CCR4 significantly correlates with bad prognosis [Clin. Cancer Res., 9, 3625 (2003)]. Further, CCR4 is selectively expressed in cells of chronic T cell lymphoma (hereinafter referred to CTL) [J. Invest. Dermatol., 119, 1405 (2002)]. Method for treating leukemia/lymphoma is mainly chemotherapy using a combination of plural low-molecular anticancer agents. However, chemotherapy that provides satisfactory therapeutic effects has been so far unknown [Gan to Kagaku Ryoho, 26, Supplement I, 165-172 (1999)]. Among the CCR4-positive leukemia/lymphoma described above, prognosis of ATL is poor in particular. Concerning patients who suffer from acute or lymphatic leukemia occupying more than 70% of total ATL and have experienced common CHOP therapy (therapy using cyclophosphamide, vincristine, doxorubicin and prednisone in combination), 4-year survival rate is approximately 5% [British J. Haematol., 79, 428-437 (1991)]. In usual chemotherapy, it is sometimes difficult to induce remission because of advent of drug-resistant tumor cells or the like. However, excellent therapeutic results are sometimes obtained by combination of chemotherapy and an antibody. Anti-HER2/neu humanized antibody rhuMAb HER2 (Herceptin/trastuzumab, Roche) exhibited an outstanding effect against breast cancer in combination therapy with a taxane anticancer agent [Clinical Therapeutics, 21, 309 (1999)]. Anti-CD20 human chimeric antibody IDEC-C2B8 (Rituxan/rituximab, IDEC) exhibited an outstanding effect against B cell lymphoma by combination therapy with multiple drug therapy [J. Clin. Oncol., 17, 268 (1999)]. Combination therapy using an antibody and a cytokine is also expected as new immunotherapy against tumors. A cytokine is a general term for various humoral factors that control intracellular interaction in an immune reaction. An antibody-dependent cell-mediated cytotoxic activity (hereinafter referred to as ADCC), one of cytotoxic activities, is induced by binding an antibody to an effector cell such as a mononuclear cell, a macrophage or an NK cell [J. Immunol., 138, 1992 (1987)]. For the purpose of activating an effector cell, combination therapy using a combination of an antibody and a cytokine has been attempted. With respect to B cell leukemia/lymphoma, a clinical test administrating IDEC-C2B8 and interleukin (IL)-2 [British J. Haematol., 117, 828-834 (2002)] or IDEC-C2B8 and granulocyte-colony stimulating factor [Leukemia, 17, 1658-1664 (2003)] in combination has been conducted. However, an outstanding therapeutic effect has not been observed in comparison with use of the antibody alone. Anti-CCR4 antibody KM2760 has been known as a therapeutic agent against the CCR4-positive leukemia/lymphoma that selectively reduces tumor cells via ADCC (WO 03/18635). Combined use of an anti-CCR4 antibody and a chemotherapeutic agent or a cytokine has been unknown so far. In treatment of cancers, especially, leukemia and lymphoma, a therapeutic method that brings forth satisfactory effects has been unknown so far.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows an enhancement effect of a cytokine against a cytotoxic activity of an anti-CCR4 antibody. The ordinate shows a cytotocity. ▪ indicates a cytotoxic activity without addition of cytokine, □ indicates a cytotoxic activity in addition of IL-2, and a hatch indicates a cytotoxic activity in addition of IL-15 respectively. A bar indicates a standard deviation. FIG. 2 indicates an effect provided by combined use of an anti-CCR4 antibody and vincristine against CCRF-CEM cells grafted in a nude mouse. The ordinate shows a V/V0 value. □ indicates a V/V0 value of a negative control group, a slashed bar indicates a V/V0 value of KM 2760 administration group, a gray indicates a V/V0 value of a vincristine administration group, and ▪ indicates a V/V0 value of a group of administrating KM 2760 and vincristine in combination, respectively. A bar indicates a standard deviation. FIG. 3 indicates an effect provided by combined use of an anti-CCR4 antibody and cyclophosphamide against CCRF-CEM cells grafted in a nude mouse. The ordinate shows a V/V0 value. □ indicates a V/V0 value of a negative control group, a slashed bar indicates a V/V0 value of a KM 2760 administration group, a gray indicates a V/V0 value of a cyclophosphamide administration group, and ▪ indicates a V/V0 value of a group of administration of KM 2760 and cyclophosphamide in combination, respectively. A bar indicates a standard deviation. FIG. 4 indicates an effect provided by combined use of an anti-CCR4 antibody and etopiside against CCRF-CEM cells grafted in a nude mouse. The ordinate shows a V/V0 value. □ indicates a V/V0 value of a negative control group, a slashed bar indicates a V/V0 value of a KM 2760 administration group, a gray indicates a V/V0 value of an etoposide administration group, and ▪ indicates a V/V0 value of a group administrating KM 2760 and etoposide in combination, respectively. A bar indicates a standard deviation. FIG. 5 shows an effect provided by combined use of an anti-CCR4 antibody and Methotrexate against CCRF-CEM cells grafted in a nude mouse. The ordinate shows a V/V0 value. □ indicates a V/V0 value of a negative control group, a slashed bar indicates a V/V0 value of a KM 2760 administration group, a gray indicates a V/V0 value of a Methotrexate administration group, and ▪ indicates a V/V0 value of a group administrating of KM 2760 and Methotrexate in combination, respectively. A bar indicates a standard deviation. FIG. 6 shows an effect provided by combined use of an anti-CCR4 antibody and G-CSF against CCR4/EL4 cells grafted in C57BL/6 mouse. The abscissa shows the number of days after grafting the tumor, the ordinate shows a tumor volume respectively. X indicates a negative control group, ▴ indicates a group of using KM 2760 alone, ● indicates a group of using G-CSF alone, and □ indicates a group of combined use respectively. A bar indicates a standard deviation. FIG. 7 shows an effect provided by combined use of an anti-CCR4 antibody and IFN-α against CCR4/EL4 cells grafted in C57BL/6 mouse. The ordinate shows a weight ratio of a liver. A bar indicates a standard deviation. The present invention is described in detail below. The present application claims the Convention priority from Japanese Patent Application Nos. 2003-406590 and 2004-155141 filed Dec. 4, 2003 and May 25, 2004, including the contents described in the specifications and/or drawings of these applications. detailed-description description="Detailed Description" end="lead"?

20060623

20130723

20070125

82334.0

A61K39395

WEN, SHARON X

MEDICAMENT COMPRISING RECOMBINANT ANTIBODY AGAINST CHEMOKINE RECEPTOR CCR4

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Modified Macromolescules and Associated Methods of Synthesis and Use

Described herein are compounds such as macromolecules that have been modified in order to facilitate crosslinking by introduction of at least one hydrazide-reactive group and/or aminooxy-reactive group, and methods of making and using thereof for scar-free wound healing, for delivering bioactive agents or living cells, for preventing adhesion after a surgical procedure or for bone and cartilage repair. The macromolecule can be an oligonucleotide, a necleic acid, a polypeptide, a lipid, a glycoprotein, a glycolipid, a polysaccharide, a protein or a synthetic polymer, preferably a glycosaminoglycan like hyaluronan.

1. A modified glycosaminoglycan comprising a glycosaminoglycan in which at least one hydroxyl group present in the molecular structure of the glycosaminoglycan has been chemically modified so that oxygen atom of the hydroxyl group is covalently bound to a hydrazide-reactive group or an aminooxy-reactive group instead of a hydrogen atom. 2. The modified glycosaminoglycan of claim 1, wherein the glycosaminoglycan comprises chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, or heparan sulfate. 3. The modified glycosaminoglycan of claim 1, wherein the glycosaminoglycan comprises hyaluronan. 4. The modified glycosaminoglycan of claim 3, wherein the at least one hydroxyl group is a primary C-6 hydroxyl group contained within an N-acetyl-glucosamine residue present in the molecular structure of the hyaluronan. 5. The modified glycosaminoglycan of claim 4, wherein at least one secondary hydroxyl group present in the molecular structure of the hyaluronan has also been modified so that the oxygen atom of the secondary hydroxyl group is covalently bound to the hydrazide-reactive group or the aminooxy-reactive group. 6. The modified glycosaminoglycan of claim 4, wherein up to 100% of the primary C-6 hydroxyl groups of the N-acetyl-glucosamine residues in the glycosaminoglycan structure are chemically modified so that the hydrogen atom of each hydroxyl group is replaced with the hydrazide-reactive group or the aminooxy-reactive group. 7. The modified glycosaminoglycan of claim 1, wherein the at least one hydroxyl group is a primary C-6 hydroxyl group contained within the non-uronic acid sugar component of the repeating disaccharide of the glycosaminoglycan. 8. The modified glycosaminoglycan of claim 1, wherein the hydrazide-reactive group or the aminooxy-reactive group is selected from carboxyl, a carboxylate salt, and a carboxylic acid ester. 9. The modified glycosaminoglycan of claim 1, wherein the hydrazide-reactive group or the aminooxy-reactive group has the formula —L—CO2H or is a salt or ester thereof, wherein L comprises an unsubstituted hydrocarbyl group, an unsubstituted heterohydrocarbyl group, a substituted hydrocarbyl group, and a substituted heterohydrocarbyl group. 10. The modified glycosaminoglycan of claim 9, wherein L comprises a polyalkylene group having the formula (CH2)n wherein n is from 1 to 10. 11-13. (canceled) 14. A method for making a modified glycosaminoglycan, comprising (a) reacting a glycosaminoglycan with a base to produce a deprotonated glycosaminoglycan, and (b) reacting the deprotonated glycosaminoglycan with a compound containing at least one hydrazide-reactive group or aminooxy-reactive group. 15-23. (canceled) 24. A modified glycosaminoglycan made by the process of claim 14. 25. The modified glycosaminoglycan of claim 24, comprising two or more hydrazide groups. 26-44. (canceled) 45. The method of claim 14, further comprising, after step (b), reacting the modified glycosaminoglycan with a hydrazide compound, to provide a further modified glycosaminoglycan. 46. The method of claim 14, further comprising, after step (b), reacting the modified glycosaminoglycan with an aminooxy ether compound, to provide a further modified glycosaminoglycan. 47. The further modified glycosaminoglycans produced by the methods of claims 45 or 46. 48. (canceled) 49. The compound of claim 232 wherein the macromolecule comprises an oligonucleotide, a nucleic acid or a metabolically stabilized analogue thereof, a polypeptide, a lipid, a glycoprotein, a glycolipid, or a pharmaceutically-acceptable compound. 50. The compound of claim 231, wherein the macromolecule comprises a polysaccharide, a protein, or a synthetic polymer. 51. The compound of claim 50, wherein the macromolecule comprises a sulfated glycosaminoglycan. 52. The compound of claim 231, wherein the macromolecule comprises chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, alginic acid, pectin, or carboxymethylcellulose. 53. The compound of claim 231, wherein the macromolecule comprises hyaluronan. 54. The compound of claim 231 wherein Z comprises a polyether. 55. The compound of claim 231 wherein R1, R2, R5, R6, R7, and R8 are hydrogen. 56-60. (canceled) 61. A method for producing a crosslinked glycosaminoglycan, comprising reacting the compound of any of claim 25 with a polycarbonyl crosslinker. 62-198. (canceled) 199. A pharmaceutical composition comprising a bioactive agent and a modified glycosaminoglycan in which at least one hydroxyl group has been modified so as to replace the hydrogen atom of the group with a hydrazide-reactive group or an aminooxy-reactive group, or a crosslinked such modified glycosaminoglycan. 200. A pharmaceutical composition comprising a living cell and a modified glycosaminoglycan in which at least one hydroxyl group has been modified so as to replace the hydrogen atom of the group with a hydrazide-reactive group or an aminooxy-reactive group, or a crosslinked such modified glycosaminoglycan. 201. A method for improving wound healing in a subject in need of such improvement, comprising contacting the wound of the subject with a modified glycosaminoglycan in which at least one hydroxyl group has been modified so as to replace the hydrogen atom of the group with a hydrazide-reactive group or an aminooxy-reactive group, or a crosslinked such modified glycosaminoglycan. 202. A method for delivering at least one bioactive agent to a patient in need of such delivery, comprising contacting at least one tissue capable of receiving the bioactive compound with the composition of claim 199. 203. A method for delivering living cells to a patient in need of such delivery, comprising contacting at least one tissue capable of receiving the living cells with the composition of claim 200. 204-223. (canceled) 224. The modified glycosaminoglycan of claim 1 or claim 24, containing at least one substituent having the structure of formula (I) wherein R1, R2, and R7 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl, and substituted heterohydrocarbyl, and R3 is selected from hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl, and substituted heterohydrocarbyl. 225. The modified glycosaminoglycan of claim 1 or claim 24, containing at least one substituent having the structure of formula (II) wherein L is selected from hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl, and substituted heterohydrocarbyl. 226. The modified glycosaminoglycan of claim 225, wherein L is selected from polyether, polyamide, polyimino, aryl, polyester, polythioether, polysaccharyl, and combinations thereof. 227. The modified glycosaminoglycan of claim 1 or claim 24, containing at least one substituent having the structure of formula (III) wherein: L is selected from hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl, and substituted heterohydrocarbyl; and Q is a bioactive agent, an SH group, or a thiol-reactive electrophilic functional group. 228. The modified glycosaminoglycan of claim 227, wherein L is selected from polyether, polyamide, polyimino, aryl, polyester, polythioether, polysaccharyl, and combinations thereof. 229. The modified glycosaminoglycan of claim 1 or claim 24, containing at least one substituent having the structure of formula (IV) wherein: L is selected from hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl, and substituted heterohydrocarbyl; and Q is a bioactive agent, an aminooxy group, an SH group, or a thiol-reactive electrophilic functional group. 230. The modified glycosaminoglycan of claim 229, wherein L is selected from polyether, polyamide, polyimino, aryl, polyester, polythioether, polysaccharyl, and combinations thereof. 231. A compound having the structure of formula (V) wherein: X is a macromolecule; Y is a modified glycosaminoglycan in which at least one hydroxyl group has been modified so as to replace the hydrogen atom of the group with a hydrazide-reactive group or an aminooxy-reactive group; R and R30 are independently selected from hydrogen and lower alkyl; R1, R2, R5, R6, R7, and R8 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl, and substituted heterohydrocarbyl; and Z, R3, and R4 are independently selected from hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl, and substituted heterohydrocarbyl. 232. A compound having the structure of formula (VI) wherein: X and Y are macromolecules; R27 and R28 are independently selected from hydrogen and lower alkyl; L and Z are independently selected from hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl, and substituted heterohydrocarbyl. 233. The compound of claim 232, wherein L and Z are independently selected from polyether, polyamide, polyimino, aryl, polyester, polythioether, polysaccharyl, and combinations thereof. 234. A compound comprising at least one fragment having the structure Y-S-S-G, wherein Y is a modified glycosaminoglycan in which at least one hydroxyl group has been modified so as to replace the hydrogen atom of the group with a hydrazide-reactive group or an aminooxy-reactive group, and G comprises a residue of a thiolated compound. 235. A compound comprising at least one fragment having the structure Y-(CO)-NH-NH-(CO)-L-S-S-G, wherein: L is selected from hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl, and substituted heterohydrocarbyl; Y is a modified glycosaminoglycan in which at least one hydroxyl group has been modified so as to replace the hydrogen atom of the group with a hydrazide-reactive group or an aminooxy-reactive group; and G comprises a residue of a thiolated compound. 236. The compound of claim 235, wherein L is selected from polyether, polyamide, polyimino, aryl, polyester, polythioether, polysaccharyl, and combinations thereof. 237. Use of the modified glycosaminoglycan of claim 1 to prevent adhesion after a surgical procedure. 238. The use of claim 237, wherein the surgical procedure comprises cardiosurgery and articular surgery, abdominal surgery, a surgical procedure performed in the urogenital region, a surgical procedure involving a tendon, laparascopic surgery, pelvic surgery, oncological surgery, sinus and craniofacial surgery, ENT surgery, or a procedure involving spinal dura repair. 239. Use of the modified glycosaminoglycan of claim 1 to support the growth of primary cells or immortalized cells. 240. Use of the modified glycosaminoglycan of claim 1 to support the growth of tumor cells, fibroblasts, chondrocytes, stem cells, epithelial cells, neural cells, cells derived from the liver, endothelial cells, cardiac cells, muscle cells, or osteoblasts. 241. Use of the modified glycosaminoglycan of claim 1 for bone or cartilage repair. 242. An article coated with the modified glycosaminoglycan of claim 1. 243. The article of claim 242, wherein the article is a suture, a clap, stent, a prosthesis, a catheter, a metal screw, a bone plate, a pin or a bandage. 244. Use of the modified glycosaminoglycan of claim 1 as a 3-D cell culture. 245. The use of claim 244, wherein the cell culture is used to determine the toxicity of a drug. 246. A cell culture produced by the modified glycosaminoglycan of claim 1.

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority upon U.S. provisional application Ser. No. 60/526,797, filed Dec. 4, 2003. This application is hereby incorporated by this reference in its entirety for all of its teachings. ACKNOWLEDGEMENTS The research leading to this invention was funded in part by the national Institutes of Health, Grant Nos. NIH 5R01 DC04663, R41 DC007015, and R41 EB004226. The U.S. Government may have certain rights in this invention. BACKGROUND The use of macromolecules in pharmaceutical applications has received considerable attention. At times, it is desirable to couple two or more macromolecules to produce new macromolecule scaffolds with multiple activities. Existing technologies used to couple two or macromolecules, however, present numerous difficulties. For example, the alkaline conditions or high temperatures necessary to create hydrogels with high mechanical strength are cumbersome and harsh. Although the use of crosslinkers to produce macromolecular scaffolds has met with some success, the crosslinking agents are often relatively small, cytotoxic molecules, and the resulting scaffold has to be extracted or washed extensively to remove traces of unreacted reagents and byproducts (Hennink, W. E.; van Nostrum, C. F. Adv. Drug Del. Rev. 2002, 54, 13-36), thus precluding use in many medical applications. A physiologically compatible macromolecular scaffold capable of being produced in a straightforward manner is needed before they will be useful as therapeutic aids. Described herein are compounds and methods that are capable of coupling two or more molecules, such as macromolecules, under mild conditions. SUMMARY Described herein are compounds such as macromolecules that have been modified in order to facilitate crosslinking. In one aspect, the macromolecule is modified via an alkoxyamination reaction, wherein the resultant alkoxyaminated macromolecule can undergo crosslinking with itself or another macromolecule. In another aspect, the macromolecule is modified with a group capable of reacting with a hydrazide compound, which will facilitate crosslinking. Also described herein are methods of making and using the modified macromolecules. The advantages described herein will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. FIG. 1 shows a reaction scheme for producing a bis(aminooxy) ether compound. FIG. 2 shows a reaction scheme for producing aminooxy ether compounds and thiolated aminooxy-modified hyaluronan. FIG. 3 shows a reaction scheme for producing aminooxy-modified hyaluronan. FIG. 4 shows a reaction scheme for producing thiolated hydrazide-modified carboxymethylhyaluronan. FIG. 5 shows a reaction scheme for producing carboxymethylhyaluronan (Carbylan™) and thiolated hydrazide-modified carboxymethylhyaluronan (Carbylan™-S). FIG. 6 shows the 1H NMR spectrum of Carbylan™-S. FIG. 7 shows the cytotoxicity of Carbylan™ (open circles) and Carbylan™-S (open triangles) using an MTS assay (n=6), where graph A is after 2 hours of culturing and panel B is after 24 hours of culturing. FIG. 8 shows a reaction scheme for producing Carbylan™-SX and Carbylan™-GSX. FIG. 9 shows the gelation time of Carbylan™-SX for different formulations. FIG. 10 shows the speed of gelation of Carbylan™-SX for different formulations. FIG. 11 shows the weight loss fraction vs. time for HAse degradation of Carbylan™-SX. Key: diamonds, no enzyme control; circles, 0.5 U/ml; squares, 2.0 U/ml; triangles, 20 U/ml. FIG. 12 shows the viscoelasticity of rabbit vocal folds injected with Carbylan™-SX and HA-DTPH-PEGDA hydrogels. FIG. 13 shows the airway lumen area and smallest airway diameter of rabbit trachea after removal of different stents. FIG. 14 shows ostial diameter as measured 14 days post sinus surgery in a rabbit model with and without the application of Carbylan™-S. FIG. 15 shows the visualization of F-actin with FITC-phalloidin staining of NIH 3T3 fibroblasts cultured on Carbylan™-GSX hydrogel surfaces for 24 h. Ratio of Carbylan™-S/Gelatin-DTPH: (a) 100/0, (b) 75/25, (c) 50/50), (d) 25/75, (e) tissue culture plate (control) and (e) enlarged picture of panel (b). FIG. 16 shows NIH 3T3 fibroblast proliferation on Carbylan™-GSX hydrogel surfaces after 24, 48 and 96 h in vitro culture. FIG. 17 shows tympanic membrane closure as a function of time in a guinea pig model. FIG. 18 shows two days post-operative healing following myringotomy and Carbylan™-GSX. FIG. 19 shows the macrographical observation of rat uterine horns after treatment with different films. FIG. 20 shows the histological observation of rat uterine horns after treatment with different films. FIG. 21 shows the macrographical view of tumors after subcutaneous injection of (a) MDA-MB-468 cells loaded in DPBS buffer, and (b) MDA-MB-468 cells loaded in Carbylan™-GSX hydrogels. Panel c shows the tumors after the skin was removed. FIG. 22 shows the histological examination of newly formed tumors after subcutaneous injection of MDA-MB-468 cells loaded in (a) DPBS buffer and in (b) Carbylan™-GSX hydrogels. H&E staining, scale bar: 0.5 mm. FIG. 23 shows the macrographical view of tumors after subcutaneous injection of Caco-2 cells loaded in DPBS buffer (left), Carbylan™-GSX (middle), and HA-DTPH-PEGDA/gelatin DTPH hydrogels. FIG. 24 shows the histological examination of newly formed tumors after subcutaneous injection of Caco-2 cells loaded in (a) DPBS buffer and (b) Carbylan™-GSX hydrogel. H&E staining, scale bar: 0.5 mm. FIG. 25 shows a mouse month after the intraperitoneal injection of Caco-2 cells suspended in DPBS buffer. FIG. 26 shows a mouse one month after the colon injection of Caco-2 cells encapsulated in Carbylan™-GSX hydrogels. FIG. 27 shows tumor cells one month after the intraperitoneal injection of Caco-2 cells suspended in DPBS buffer. FIG. 28 shows tumor cells one month after the colon injection of Caco-2 cells encapsulated in Carbylan™-GSX hydrogels. FIG. 29 shows the proliferation of different cell lines cultured on Carbylan™-GSX in the presence of LY294002 and paclitaxel. FIG. 30 shows the proliferation of different cell lines compared to untreated controls (difference=control−treatment). FIG. 31 shows the 3-D morphology of Caco-2 and SK-OV-3 cells grown in Carbylan™-GSX in normal drug-free medium (A and D) and in the presence of LY294002 (B and E) and Paclitaxel (C and F) after stained with FDA (living cells, green) and PI (dead cells, red). Scale bar: 200 μm. FIG. 32 shows a hepatocyte culture on a polystyrene plate in L15 medium. FIG. 33 shows the proliferation of hepatocytes on a 2D-polystyrene plate and 3-D Carbylan™-GSX as evaluated by MTS. FIG. 34 shows a 3-D culture of hepatocytes in Carbylan™-GSX at day 3. FIG. 35 shows reactions scheme for producing mono- and bisaminooxy pluronics. FIG. 36 is the 1H NMR spectrum of HA-aminooxy ether. FIG. 37 shows a reaction scheme for coupling aminooxy polymers with hyaluronan. FIG. 38 shows a reaction scheme for the self-assembly of an aminooxy polymer/hyaluronan into a hydrogel. FIG. 39 shows the fluorescence of immobilized fluorescein-HA with (A) a bis-aminooxy derivatized pluronic, (B) a bis-aminooxy derivatized pluronic and EDCI, and (C) no bis-aminooxy derivatized pluronic. FIG. 40 shows ELISA results for surface immobilization of heparin with bisAO-pluronic. DETAILED DESCRIPTION Before the present compounds, composites, compositions, and/or methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific compounds, synthetic methods, or uses as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings: It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like. “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the phrase “optionally substituted lower alkyl” means that the lower alkyl group can or can not be substituted and that the description includes both unsubstituted lower alkyl and lower alkyl where there is substitution. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. References in the specification and concluding claims to parts by weight, of a particular element or component in a composition or article, denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound. A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. A “residue” of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. For example, a polymer having the repeat unit A-B, where one of the B units is modified with C, the resultant polymer can be represented by the formula D-C, where D is the remainder (i.e., residue) of the polymer A-B. A fragment, as used in the specification and concluding claims, refers to a portion or section of a macromolecule or the entire macromolecule. For example, a polymer having the repeat unit A-B is depicted below, where one of the B repeat units is modified with C. The B-C unit is fragment E of the polymer composed of the repeat unit A-B as depicted below. Variables such as R1-R5, R7, R8, R20, R25-R30, n, n′, LG, A E, L, J, G, M, Q, U, V, W, X, X′, X″, Y, and Z used throughout the application are the same variables as previously defined unless stated to the contrary. The term “alkyl group” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A “lower alkyl” group is an alkyl group containing from one to six carbon atoms. The term “polyalkylene group” as used herein is a group having two or more CH2 groups linked to one another. The polyalkylene group can be represented by the formula —(CH2)n—, where n is an integer of from 2 to 25. The term “polyether group” as used herein is a group having the formula —[(CHR)nO]m—, where R is hydrogen or a lower alkyl group, n is an integer of from 1 to 20, and m is an integer of from 1 to 100. Examples of polyether groups include, polyethylene oxide, polypropylene oxide, and polybutylene oxide. The term “polythioether group” as used herein is a group having the formula —[(CHR)nS]m—, where R is hydrogen or a lower alkyl group, n is an integer of from 1 to 20, and m is an integer of from 1 to 100. The term “polyimino group” as used herein is a group having the formula —[(CHR)nNR]m—, where each R is, independently, hydrogen or a lower alkyl group, n is an integer of from 1 to 20, and m is an integer of from 1 to 100. The term “polyester group” as used herein is a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups. The term “polyamide group” as used herein is a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two unsubstituted or monosubstituted amino groups. The term “aryl group” as used herein is any carbon-based aromatic group including, but not limited to, benzene, naphthalene, etc. The term “aromatic” also includes “heteroaryl group,” which is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy. The term “hydrocarbyl group” as used herein means the monovalent moiety obtained upon removal of a hydrogen atom from a parent hydrocarbon. Representative of hydrocarbyl are alkyl of 1 to 20 carbon atoms, inclusive, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, decyl, dodecyl, octadecyl, nonodecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl and the isomeric forms thereof; aryl of 6 to 12 carbon atoms, inclusive, such as phenyl, tolyl, xylyl, naphthyl, biphenyl, tetraphenyl and the like; aralkyl of 7 to 12 carbon atoms, inclusive, such as benzyl, phenethyl, phenpropyl, phenbutyl, phenhexyl, napthoctyl and the like; cycloalkyl of 3 to 8 carbon atoms, inclusive, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like; alkenyl of 2 to 10 carbon atoms, inclusive, such as vinyl, allyl, butenyl, pentenyl, hexenyl, octenyl, nonenyl, decenyl, undececyl, dodecenyl, tridecenyl, pentadecenyl, octadecenyl, pentacosynyl and isomeric forms thereof. Preferably, the hydrocarbyl group has 1 to 20 carbon atoms, inclusive. The term “substituted hydrocarbyl and heterocarbyl” as used herein means the hydrocarbyl or heterocarbyl moiety as previously defined wherein one or more hydrogen atoms have been replaced with a chemical group, which does not adversely affect the desired preparation of the modified polysaccharide. Representative of such groups are amino, phosphino, quaternary nitrogen (ammonium), quaternary phosphorous (phosphonium), hydroxyl, amide, alkoxy, mercapto, nitro, alkyl, halo, sulfone, sulfoxide, phosphate, phosphite, carboxylate, carbamate groups and the like. The term “hydrazide compound” as used herein is any compound having at least one hydrazide group having the formula NH2NRC(O)—, wherein R can be hydrogen, a lower alkyl group, an amide group, a carbamate group, a hydroxyl group, or a halogen group. The term “hydrazide-reactive group” as used herein is any group that can react with the primary or secondary amino group of the hydrazide group to form a new covalent bond. Examples of hydrazide-reactive groups include, but are not limited to, a ketone, an aldehyde, or an activated carboxylate group. The term “aminooxy ether compound” as used herein is any compound having the formula RONHR′, wherein R can be substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof and R′ can be hydrogen or a lower alkyl group. The —ONHR′ group is referred to herein as an aminooxy group. The term “aminooxy-reactive group” as used herein is any group that can react with the amino group of the aminooxy group to form a new covalent bond. Examples of aminooxy-reactive groups include, but are not limited to, a ketone, an aldehyde, or an activated carboxylate group. A. Materials Disclosed are materials, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed method and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited, each is individually and collectively contemplated. Thus, in this example, each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. Likewise, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed. Any of the compounds, compositions, and composites described herein can be the pharmaceutically acceptable salt or ester thereof if they possess groups that are capable of being coverted to a salt or ester. Pharmaceutically acceptable salts are prepared by treating the free acid with an appropriate amount of a pharmaceutically acceptable base. Representative pharmaceutically acceptable bases are ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, and the like. In another aspect, if the compound possesses a basic group, it can be protonated with an acid such as, for example, HCl or H2SO4, to produce the cationic salt. In one aspect, the compound can be protonated with tartaric acid to produce the tartarate salt. In one aspect, the reaction of the compound with the acid or base is conducted in water, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from about 0° C. to about 100° C. such as at room temperature. In certain aspects where applicable, the molar ratio of the compounds described herein to base used are chosen to provide the ratio desired for any particular salts. For preparing, for example, the ammonium salts of the free acid starting material, the starting material can be treated with approximately one equivalent of pharmaceutically-acceptable base to yield a salt. Ester derivatives are typically prepared as precursors to the acid form of the compounds and accordingly can serve as prodrugs. Generally, these derivatives will be lower alkyl esters such as methyl, ethyl, and the like. 1. Macromolecules A macromolecule as disclosed herein is any compound having at least one hydrazide-reactive group and/or aminooxy-reactive group. Examples of hydrazide-reactive groups and aminooxy-reactive groups include, but are not limited to, a carboxyl group including the salt or ester thereof or an amide group. The hydrazide-reactive group or the aminooxy-reactive group can be naturally present on the macromolecule, or the macromolecule can be chemically modified to incorporate the hydrazide-reactive group or the aminoalkoxy-reactive group on the macromolecule. In one aspect, the macromolecule is an oligonucleotide, a nucleic acid or a metabolically stabilized analogue thereof, a polypeptide, a lipid, a glycoprotein, or a glycolipid. In another aspect, the macromolecule is a polysaccharide, a protein, or a synthetic polymer. a) Oligonucleotides The term “oligonucleotide” refers to an oligomer or polymer of ribonucleic acid or deoxyribonucleic acid. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent intersugar (backbone) linkages as well as modified oligonucleotides having non-naturally-occurring portions which function similarly. An oligonucleotide is a polymer of repeating units generically known as nucleotides or nucleosides. An unmodified (naturally occurring) nucleotide has three components: (1) a nitrogenous base linked by one of its nitrogen atoms to (2) a 5-carbon cyclic sugar and (3) a phosphate, esterified to carbon 5 of the sugar. When incorporated into an oligonucleotide chain, the phosphate of a first nucleotide is also esterified to carbon 3 of the sugar of a second, adjacent nucleotide. The “backbone” of an unmodified oligonucleotide consists of (2) and (3), that is, sugars linked together by phosphodiester linkages between the CS (5′) position of the sugar of a first nucleotide and the C3 (3′) position of a second, adjacent nucleotide. Oligonucleotides can be composed of nucleoside or nucleotide sequences sufficient in identity and number to effect specific hybridization with a particular nucleic acid. (1) Nucleic acids Nucleic acids such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and peptide nucleic acid (PNA) are polymeric, polyionic molecules soluble in aqueous solution under certain conditions. The assumed three-dimensional structures of nucleic acids in solution as a function of pH, ionic strength, counter ions, charge neutralization, hydration, organic precipitants, molecular composition, etc., are known by those skilled in the art. In one aspect, the nucleic acid can be single or double stranded DNA or RNA. There are a variety of molecules disclosed herein that are nucleic acid based, including for example the nucleic acids as well as any other proteins disclosed herein, as well as various functional nucleic acids. The disclosed nucleic acids are made up of for example, nucleotides, nucleotide analogs, or nucleotide substitutes. Non-limiting examples of these and other molecules are discussed herein. It is understood that for example, when a vector is expressed in a cell, the expressed mRNA will typically be made up of A, C, G, and U. (2) Nucleotides and related molecules A nucleotide is a molecule that contains a base moiety, a sugar moiety and a phosphate moiety. Nucleotides can be linked together through their phosphate moieties and sugar moieties creating an internucleoside linkage. The base moiety of a nucleotide can be adenin-9-yl (A), cytosin-1-yl (C), guanin-9-yl (G), uracil-1-yl (U), and thymin-1-yl (T). The sugar moiety of a nucleotide is a ribose or a deoxyribose. The phosphate moiety of a nucleotide is pentavalent phosphate. An non-limiting example of a nucleotide would be 3′-AMP (3′-adenosine monophosphate) or 5′-GMP (5′-guanosine monophosphate). A nucleotide analog is a nucleotide which contains some type of modification to either the base, sugar, or phosphate moieties. Modifications to nucleotides are well known in the art and would include for example, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, and 2-aminoadenine as well as modifications at the sugar or phosphate moieties. Nucleotide substitutes are molecules having similar functional properties to nucleotides, but which do not contain a phosphate moiety, such as peptide nucleic acid (PNA). Nucleotide substitutes are molecules that will recognize nucleic acids in a Watson-Crick or Hoogsteen manner, but which are linked together through a moiety other than a phosphate moiety. Nucleotide substitutes are able to conform to a double helix type structure when interacting with the appropriate target nucleic acid. It is also possible to link other types of molecules (conjugates) to nucleotides or nucleotide analogs to enhance for example, cellular uptake. Conjugates can be chemically linked to the nucleotide or nucleotide analogs. Such conjugates include but are not limited to lipid moieties such as a cholesterol moiety. (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), A Watson-Crick interaction is at least one interaction with the Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute. The Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute includes the C2, N1, and C6 positions of a purine based nucleotide, nucleotide analog, or nucleotide substitute and the C2, N3, C4 positions of a pyrimidine based nucleotide, nucleotide analog, or nucleotide substitute. A Hoogsteen interaction is the interaction that takes place on the Hoogsteen face of a nucleotide or nucleotide analog, which is exposed in the major groove of duplex DNA. The Hoogsteen face includes the N7 position and reactive groups (NH2 or O) at the C6 position of purine nucleotides. Thus, nucleic acids are polymers made up of nucleotides, called bases generically. The nucleic acid molecules can be characterized by the number of bases that make up the nucleic acid. For example, in certain embodiments the nucleic acid analytes are at least 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 295, 300, 320, 340, 360, 380, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3200, 3400, 3600, 3800, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000, 20000, 25000, 50000, 100000, 200000, 300000, 400000, 500000, and 1000000 bases or base pairs long. In another aspect, the DNA or RNA has at least about 1,500 bases or base pairs. b) Pharmaceutically-acceptable Compound In one aspect, the macromolecule can be a pharmaceutically-acceptable compound. Any of the biologically active compounds disclosed in U.S. Pat. No. 6,562,363 B1, which is incorporated by reference in its entirety, can be used as a pharmaceutically-acceptable compound. In one aspect, the pharmaceutically-acceptable compound includes substances capable of preventing an infection systemically in the biological system or locally at the defect site, as for example, anti-inflammatory agents such as, but not limited to, pilocarpine, hydrocortisone, prednisolone, cortisone, diclofenac sodium, indomethacin, 6∝-methyl-prednisolone, corticosterone, dexamethasone, prednisone, and the like; antibacterial agents including, but not limited to, penicillin, cephalosporins, bacitracin, tetracycline, doxycycline, gentamycin, chloroquine, vidarabine, and the like; analgesic agents including, but not limited to, salicylic acid, acetaminophen, ibuprofen, naproxen, piroxicam, flurbiprofen, morphine, and the like; local anesthetics including, but not limited to, cocaine, lidocaine, benzocaine, and the like; immunogens (vaccines) for stimulating antibodies against hepatitis, influenza, measles, rubella, tetanus, polio, rabies, and the like; peptides including, but not limited to, leuprolide acetate (an LH-RH agonist), nafarelin, and the like. All compounds are available from Sigma Chemical Co. (Milwaukee, Wis.). In another aspect, the pharmaceutically-acceptable compound can be a substance or metabolic precursor which is capable of promoting growth and survival of cells and tissues or augmenting the functioning of cells is useful, as for example, a nerve growth promoting substance such as a ganglioside, a nerve growth factor, and the like; a hard or soft tissue growth promoting agent such as fibronectin (FN), human growth hormone (HGH), a colony stimulating factor, bone morphogenic protein, platelet-derived growth factor (PDGF), insulin-derived growth factor (IGF-I, IGF-II), transforming growth factor-alpha (TGF-alpha), transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), fibroblast growth factor (FGF), interleukin-1 (IL-1), vascular endothelial growth factor (VEGF) and keratinocyte growth factor (KGF), dried bone material, and the like; and antineoplastic agents such as methotrexate, 5-fluorouracil, adriamycin, vinblastine, cisplatin, tumor-specific antibodies conjugated to toxins, tumor necrosis factor, and the like. In another aspect, the pharmaceutically-acceptable compound can include hormones such as progesterone, testosterone, and follicle stimulating hormone (FSH) (birth control, fertility-enhancement), insulin, and the like; antihistamines such as diphenhydramine, and the like; cardiovascular agents such as papaverine, streptokinase and the like; anti-ulcer agents such as isopropamide iodide, and the like; bronchodilators such as metaproternal sulfate, aminophylline, and the like; vasodilators such as theophylline, niacin, minoxidil, and the like; central nervous system agents such as tranquilizer, B-adrenergic blocking agent, dopamine, and the like; antipsychotic agents such as risperidone, narcotic antagonists such as naltrexone, naloxone, buprenorphine; and other like substances. All compounds are available from Sigma Chemical Co. (Milwaukee, Wis.). c) Lipids In one aspect, neutral lipids can include, but are not limited to, synthetic or natural phospholipids. Typically, though not required, a neutral lipid has two hydrocarbon chains, e.g., acyl chains, and either a polar, nonpolar, or zwitterionic head group. The two hydrocarbon chains can be any length. In one aspect, the hydrocarbon chain is between about 14 to about 22 carbon atoms in length, and can have varying degrees of unsaturation. In another aspect, the neutral lipid has a high molecular weight and high melting temperature. Neutral lipids that can be used in the methods and compositions described herein to create neutral liposomes include, but are not limited to, phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SPM), distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), diarachidonoylphosphatidylcholine (DAPC), egg phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), glycosphingolipids and glycoglycerolipids, and sterols such as cholesterol, either alone or in combination with other lipids. In one aspect, the neutral lipid is distearoyl-phosphatidylcholine. Such neutral lipids can be obtained commercially or can be prepared by methods known to one of ordinary skill in the art. Suitable anionic lipids include, but are not limited to, phospholipids that contain phosphatidylglycerol, phosphatidylserine or phosphatidic acid headgroups and two saturated fatty acid chains containing from about 14 to about 22 carbon atoms. Other suitable anionic lipids include, but are not limited to, phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidic acid (PA), phosphatidylinositol (PI), cardiolipin, dimyristoylphosphatidylglycerol (DMPG), and dipalmitoylphosphatidylglycerol (DPPG). In one aspect, the anionic lipid is dimyristoylphosphatidylglycerol. Such anionic lipids can be obtained commercially or can be prepared by methods known to one of ordinary skill in the art. In one aspect, the lipid can be any phosphoinositide in which the inositol head group has zero, one, or two phosphates. In another aspect, the lipid can be a lysolipid including, but not limited to, lysophosphatidic acid (LPA), lysophosphatidylcholines (LPCs), and lysophosphatidylinositol (LPI). In another aspect, the lipid can be a sphingolipid including, but not limited to, sphingosine-1-phosphate (S1P) or sphingophatidylcholines (LPC). In another aspect, the lipid can be ceramide. d) Polysaccharides Any polysaccharide known in the art can be used herein. Examples of polysaccharides include starch, cellulose, glycogen or carboxylated polysaccharides such as alginic acid, pectin, or carboxymethylcellulose. In one aspect, the polysaccharide is a glycosaminoglycan (GAG). A GAG is one molecule with many alternating subunits. For example, HA is (GlcNAc—GlcUA—)x. Other GAGs are sulfated at different sugars. Generically, GAGs are represented by the formula A-B-A-B-A-B, where A is a uronic acid and B is an aminosugar that is either O- or N-sulfated, where the A and B units can be heterogeneous with respect to epimeric content or sulfation. There are many different types of GAGs, having commonly understood structures, which, for example, are within the disclosed compositions, such as chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, or heparan sulfate. Any GAG known in the art can be used in any of the methods described herein. Glycosaminoglycans can be purchased from Sigma, and many other biochemical suppliers. Alginic acid, pectin, and carboxymethylcellulose are among other carboxylic acid containing polysaccharides useful in the methods described herein. In one aspect, the polysaccharide is hyaluronan (HA). HA is a non-sulfated GAG. Hyaluronan is a well known, naturally occurring, water soluble polysaccharide composed of two alternatively linked sugars, D-glucuronic acid and N-acetylglucosamine. The polymer is hydrophilic and highly viscous in aqueous solution at relatively low solute concentrations. It often occurs naturally as the sodium salt, sodium hyaluronate. Methods of preparing commercially available hyaluronan and salts thereof are well known. Hyaluronan can be purchased from Seikagaku Company, Clear Solutions Biotech, Inc., Pharmacia Inc., Sigma Inc., and many other suppliers. For high molecular weight hyaluronan it is often in the range of 100 to 10,000 disaccharide units. In another aspect, the lower limit of the molecular weight of the hyaluronan is from 1,000 Da, 2,000 Da, 3,000 Da, 4,000 Da, 5,000 Da, 6,000 Da, 7,000 Da, 8,000 Da, 9,000 Da, 10,000 Da, 20,000 Da, 30,000 Da, 40,000 Da, 50,000 Da, 60,000 Da, 70,000 Da, 80,000 Da, 90,000 Da, or 100,000 Da, and the upper limit is 200,000 Da, 300,000 Da, 400,000 Da, 500,000 Da, 600,000 Da, 700,000 Da, 800,000 Da, 900,000 Da, 1,000,000 Da, 2,000,000 Da, 4,000,000 Da, 6,000,000 Da, 8,000,000 Da, or 10,000,000 Da where any of the lower limits can be combined with any of the upper limits. In another aspect, Y in formula III is not hyaluronan. (1) Modified-glycosaminoglycans In one aspect, any glycosaminoglycan in the art can be chemically modified so that at least one of the hydroxyl groups present on the glycosaminoglycan is substituted with a hydrazide-reactive group to produce a modified-glycosaminoglycan. Glycosaminoglycans in general possess a plurality of hydroxyl groups. The phrase “at least one of the hydroxyl groups present on the glycosaminoglycan is chemically substituted with a hydrazide-reactive group or aminooxy-reactive group” as used herein refers to replacing or substituting hydrogen of the hydroxyl group with the hydrazide-reactive group or the aminooxy-reactive group via a chemical manipulation of the hydroxyl group present on the glycosaminoglycan. In one aspect, the modified-glycosaminoglycan is produced by (a) reacting a glycosaminoglycan with a base to produce deprotonated-glycosaminoglycan, and (b) reacting the deprotonated-glycosaminoglycan with a compound comprising at least one hydrazide-reactive group or aminooxy-reactive group. Not wishing to be bound by theory, it is believed that the base deprotonates at least one hydroxyl group to produce the corresponding alkoxide of the glycosaminoglycan. The alkoxide, which may be transient in nature, then reacts with the compound having at least one hydrazide-reactive group or aminooxy-reactive group to produce the modified-glycosaminoglycan. The deprotonated glycosaminoglycan may or may not react with the hydrazide-reactive group or the aminooxy-reactive group depending upon reaction conditions. Steps (a) and (b) can be performed stepwise, where the deprotonated glycosaminoglycan is isolated after step (a) followed by step (b) or, alternatively, steps (a) and (b) can be performed sequentially in situ. Depending upon reaction conditions such as pH, reaction temperature, solvent, and base, any of the hydroxyl groups present on the glycosaminoglycan can be substituted with the hydrazide-reactive group or the aminooxy-reactive group. Additionally, the number of hydroxyl groups that are substituted with the hydrazide-reactive group or the aminooxy-reactive group will vary depending upon the reaction conditions. The reaction conditions for carrying out the synthesis of the modified-glycosaminoglycan are discussed below. Any base known in the art can be used to produce the deprotonated glycosaminoglycan. Examples of bases useful herein include, but are not limited to, the base comprises a hydroxide, an alkoxide, a carbonate, an amine, phosphate, or an amide. In one aspect, sodium, potassium, or ammonium hydroxides, alkoxides, and carbonates can be used. Examples of amides useful in the present invention include, but are not limited to, potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium diisopropylamide, lithium hexamethyldisilazide, and lithium 2,2,6,6-tetramethylpiperidide. It is understood to one of ordinary skill in the art that non-aqueous solvents should be employed when the base is an amide. Examples of secondary amines include, but are not limited to, morpholine, diisopropylamine, pyrrolidine, 2,2,6,6-tetramethylpiperidine. Examples of tertiary amines include, but are not limited to, dimethyl ethyl amine, triethylamine, pyridine, diisopropylethylamine, collidine, or diazabicyclononane (DABCO). The amount of base used to deprotonate the glycosaminoglycan will also vary depending upon the desired degree of substitution. In one aspect, when deprotonation is performed in an aqueous solution, an excess of base relative to the glycosaminoglycan is used in order to ensure sufficient deprotonation. The synthesis of the modified-glycosaminoglycan is generally conducted in the presence of a solvent. Water, an organic solvent, or a combination thereof can be used as the reaction solvent. In one aspect, the organic solvent can be an alcohol, an ether, or a halogenated solvent. Examples of organic solvents useful in the present invention include, but are not limited to, dichloromethane, dimethylformamide, dimethylsulfoxide, dioxane, N-methylmorpholine, sulfolane, N-methylpyrrolidone, tetrahydrofuran, diethyl ether, toluene, dimethoxyethane, t-butyl methyl ether, or a mixture thereof. Reaction temperatures and times can vary when adding the base to the glycosaminoglycan. In one aspect, the base is added to the glycosaminoglycan from −50° C. to 80° C. In another aspect, the lower limit of the reaction temperature is −45° C., −40° C., −35° C., −30° C., −25° C., −20° C., or −15° C., and the upper limit is −5° C., −10° C., −15° C., −20° C., −25° C., 0° C., 20° C., 40° C., or 60° C., where any lower temperature limit can be combined with any upper temperature limit. The base is allowed to react with glycosaminoglycan at from 30 seconds to 100 hours. In another, the lower time limit can be 1, 5, 10, 15 minutes, and the upper limit can be 100 hours, 90 hours, 80 hours, 70 hours, 60 hours, 50 hours, 40 hours, 30 hours, 20 hours, 10 hours, 5 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, 10 minutes, or 5 minutes, where any lower time limit can be combined with any upper time limit. After the deprotonated glycosaminoglycan is produced, a compound having at least one hydrazide-reactive group or aminooxy-reactive group is allowed to react with the deprotonated glycosaminoglycan. Any compound that possesses a hydrazide-reactive group and/or an aminooxy-reactive group that is capable of reacting with the deprotonated glycosaminoglycan can be used to produce the modified-glycosaminoglycan. In one aspect, the compound having at least one hydrazide-reactive group and/or an aminooxy-reactive group possesses a leaving group, wherein upon reaction with the deprotonated glycosaminoglycan, the bond between the leaving group and the compound is broken and a new bond is formed between the oxygen of the deprotonated glycosaminoglycan and the atom that was bonded to the leaving group, which is usually carbon. A leaving group is any group that is readily liberated from a compound when that compound is allowed to react with a nucleophile. Examples of leaving groups include, but are not limited to, a halogen such as fluoro, chloro, bromo, or iodo, a carbonate, ammonium group, or activated leaving groups such as tosylate, mesylate, phosphate, or triflate. The use of leaving groups for forming new bonds by nucleophilic substitution is widely known in the art. In another aspect, when the hydrazide-reactive group or the aminooxy-reactive group is an ester, the ester is can be activated with a leaving group including, but not limited to, an ammonium group, or a tosylate, mesylate, phosphate, or triflate, where the leaving group is bonded to the carbonyl carbon. In one aspect, the compound having at least one hydrazide-reactive group or aminooxy group has the formula LG-L-G, wherein LG is a leaving group; L is a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof; and G is a hydrazide-reactive group or aminooxy-reactive group as defined above. In one aspect, LG can be a halogen. In another aspect, L can be a polyalkylene group having the formula (CH2)n, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In another aspect, G can be CO2H or the salt or ester thereof. When the compound having the formula LG-L-G reacts with the deprotonated glycosaminoglycan, a covalent bond is formed between the deprotonated oxygen of the hydroxyl group and L and LG− is produced. As described above, the selectivity and degree of substitution of the glycosaminoglycan will vary depending upon the reaction conditions selected. For example, depending upon the glycosaminoglycan selected, certain hydroxyl protons are more acidic than others. Thus by varying the pH (i.e., the amount and type of base) in the deprotonation step, it is possible to preferentially deprotonate one class of hydroxyl groups over another. In one aspect, a single hydroxyl group to 100% of the hydroxyl groups present on the glycosaminoglycan can be deprotonated and substituted. In one aspect, the primary hydroxyl group of the glycosaminoglycan is chemically substituted with a hydrazide-reactive group or an aminooxy-reactive group. When the glycosaminoglycan is any compound other than hyaluronan, the primary hydroxyl group of the glycosaminoglycan is the C-6 hydroxyl group of the non-uronic acid sugar component of the repeating disaccharide of the glycosaminoglycan. All other hydroxyl groups present in the glycosaminoglycan are referred to herein as secondary hydroxyl groups. In one aspect, when the glycosaminoglycan is hyaluronan, at least one primary hydroxyl group is chemically substituted with the hydrazide-reactive group or the aminooxy-reactive group. In the case of hyaluronan, the primary hydroxyl group is the C-6 hydroxyl group of the N-acetyl-glucosamine residue. All other hydroxyl groups present in hyaluronan that are not the primary hydroxyl group are referred to herein as the secondary hydroxyl group. In one aspect, one primary hydroxyl group of the glycosaminoglycan to 100% of the primary hydroxyl groups can be substituted with the hydrazide-reactive group or aminooxy-reactive group. In one aspect, 0.1% to 40%, 0.1% to 30%, 0.1% to 20%, 0.1% to 10%, or 0.1% to 5% of the primary hydroxyl groups of hyaluronan can be substituted. In another aspect, 0.1%, 0.5%, 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, or 30% of the primary hydroxyl groups to 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the primary hydroxyl groups of hyaluronan can be substituted, where any lower endpoint can be combined with any upper endpoint. In another aspect, when one or more primary hydroxyl groups of the glycosaminoglycan are substituted, one or more secondary hydroxyl groups can also be substituted with the hydrazide-reactive group or the aminooxy-reactive group depending upon reaction conditions. In one aspect, the modified-glycosaminoglycan can be hyaluronan with at least one primary hydroxyl group substituted with CH2CO2H or the salt or ester thereof, wherein the CH2 group is covalently bonded to oxide of the deprotonated glycosaminoglycan. (2) Glycolipids and Glycoproteins In one aspect, the macromolecule can be a glycolipid having at least one hydrazide-reactive group or aminooxy-reactive group. Examples of glycolipids include, but are not limited to, MGDG, diacylglucopyranosyl glycerols, and Lipid A. The glycolipids disclosed in U.S. Pat. No. 6,635,622, which is incorporated by reference in its entirety, can be used herein. In another aspect, the macromolecule can be a glycoprotein having at least one hydrazide-reactive group or aminooxy-reactive group. Examples of glycolipids include, but are not limited to, orosomucoid alpha-1-acid glycoprotein (AAG) and alpha-1-glycoprotein. The glycolipids disclosed in U.S. Pat. Nos. 6,617,450 and 6,656,714, which are incorporated by reference in their entirety, can be used herein. e) Synthetic polymers Any synthetic polymer known in the art can be used in the compositions and methods described herein. In one aspect, the synthetic polymer is glucuronic acid, polyacrylic acid, polyaspartic acid, polytartaric acid, polyglutamic acid, or polyfumaric acid. f) Proteins Any type of protein can be used in the compositions and methods described herein. For example, the protein can include peptides or fragments of proteins or peptides. The protein can be of any length, and can include one or more amino acids or variants thereof. The protein(s) can be fragmented, such as by protease digestion, prior to analysis. Proteins useful in the methods described herein include, but are not limited to, an extracellular matrix protein, a chemically-modified extracellular matrix protein, or a partially hydrolyzed derivative of an extracellular matrix protein. The proteins may be naturally occurring or recombinant polypeptides possessing a cell interactive domain. The protein can also be mixtures of proteins, where one or more of the proteins are modified. Specific examples of proteins include, but are not limited to, collagen, elastin, decorin, laminin, or fibronectin. (1) Protein variants As discussed herein there are numerous variants of proteins and that are known and herein contemplated. Protein variants and derivatives are well understood to those of skill in the art and in can involve amino acid sequence modifications. For example, amino acid sequence modifications typically fall into one or more of three classes: substitutional, insertional or deletional variants. Insertions include amino and/or carboxyl terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions ordinarily will be smaller insertions than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues. Immunogenic fusion protein derivatives, such as those described in the examples, are made by fusing a polypeptide sufficiently large to confer immunogenicity to the target sequence by cross-linking in vitro or by recombinant cell culture transformed with DNA encoding the fusion. Deletions are characterized by the removal of one or more amino acid residues from the protein sequence. Typically, no more than about from 2 to 6 residues are deleted at any one site within the protein molecule. These variants ordinarily are prepared by site specific mutagenesis of nucleotides in the DNA encoding the protein, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, for example M13 primer mutagenesis and PCR mutagenesis. Amino acid substitutions are typically of single residues, but can occur at a number of different locations at once; insertions usually will be on the order of about from 1 to 10 amino acid residues; and deletions will range about from 1 to 30 residues. Deletions or insertions preferably are made in adjacent pairs, i.e. a deletion of 2 residues or insertion of 2 residues. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final construct. The mutations must not place the sequence out of reading frame and preferably will not create complementary regions that could produce secondary mRNA structure. Substitutional variants are those in which at least one residue has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with the following Tables 1 and 2 and are referred to as conservative substitutions. TABLE 1 Amino Acid Abbreviations Amino Acid Abbreviations alanine Ala (A) alloisoleucine AIle arginine Arg (R) asparagine Asn (N) aspartic acid Asp (D) cysteine Cys (C) glutamic acid Glu (E) glutamine Gln (Q) glycine Gly (G) histidine His (H) isolelucine Ile (I) leucine Leu (L) lysine Lys (K) phenylalanine Phe (F) proline Pro (P) pyroglutamic acid Glu serine Ser (S) threonine Thr (T) tyrosine Tyr (Y) tryptophan Trp (W) valine Val (V) TABLE 2 Amino Acid Substitutions Original Residue Exemplary Conservative Substitutions, others are known in the art. Ala ser Arg lys or gln Asn gln or his Asp glu Cys ser Gln asn or lys Glu asp Gly pro His asn or gln Ile leu or val Leu ile or val Lys arg or gln; Met Leu or ile Phemet leu or tyr Ser thr Thr ser Trp tyr Tyr trp or phe Val ile or leu Substantial changes in function or immunological identity are made by selecting substitutions that are less conservative than those in Table 2, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site or (c) the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in the protein properties will be those in which (a) a hydrophilic residue, e.g. seryl or threonyl, is substituted for (or by) a hydrophobic residue, e.g. leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (b) a cysteine or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, e.g., lysyl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g., glutamyl or aspartyl; or (d) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine, in this case, (e) by increasing the number of sites for sulfation and/or glycosylation. For example, the replacement of one amino acid residue with another that is biologically and/or chemically similar is known to those skilled in the art as a conservative substitution. For example, a conservative substitution would be replacing one hydrophobic residue for another, or one polar residue for another. The substitutions include combinations such as, for example, Gly, Ala; Val, Ile, Leu; Asp, Glu; Asn, Gln; Ser, Thr; Lys, Arg; and Phe, Tyr. Such conservatively substituted variations of each explicitly disclosed sequence are included within the mosaic polypeptides provided herein. Substitutional or deletional mutagenesis can be employed to insert sites for N-glycosylation (Asn-X-Thr/Ser) or O-glycosylation (Ser or Thr). Deletions of cysteine or other labile residues also may be desirable. Deletions or substitutions of potential proteolysis sites, e.g. Arg, is accomplished for example by deleting one of the basic residues or substituting one by glutaminyl or histidyl residues. Certain post-translational derivatizations are the result of the action of recombinant host cells on the expressed polypeptide. Glutaminyl and asparaginyl residues are frequently post-translationally deamidated to the corresponding glutamyl and asparyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the o-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco pp 79-86 (1983)), acetylation of the N-terminal amine and, in some instances, amidation of the C-terminal carboxyl. It is understood that one way to define the variants and derivatives of the disclosed proteins herein is through defining the variants and derivatives in terms of homology/identity to specific known sequences. Those of skill in the art readily understand how to determine the homology of two proteins. For example, the homology can be calculated after aligning the two sequences so that the homology is at its highest level. Another way of calculating homology can be performed by published algorithms. Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman Adv. Appl. Math. 2: 482 (1981), by the homology alignment algorithm of Needleman and Wunsch, J. MoL Biol. 48: 443 (1970), by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85: 2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by inspection. The same types of homology can be obtained for nucleic acids by for example the algorithms disclosed in Zuker, M. Science 244:48-52, 1989, Jaeger et al. Proc. Natl. Acad. Sci. USA 86:7706-7710, 1989, Jaeger et al. Methods Enzymol. 183:281-306, 1989 which are herein incorporated by reference for at least material related to nucleic acid alignment. It is understood that the description of conservative mutations and homology can be combined together in any combination, such as embodiments that have at least 70% homology to a particular sequence wherein the variants are conservative mutations. As this specification discusses various proteins and protein sequences it is understood that the nucleic acids that can encode those protein sequences are also disclosed. This would include all degenerate sequences related to a specific protein sequence, i.e. all nucleic acids having a sequence that encodes one particular protein sequence as well as all nucleic acids, including degenerate nucleic acids, encoding the disclosed variants and derivatives of the protein sequences. Thus, while each particular nucleic acid sequence may not be written out herein, it is understood that each and every sequence is in fact disclosed and described herein through the disclosed protein sequence. It is also understood that while no amino acid sequence indicates what particular DNA sequence encodes that protein within an organism, where particular variants of a disclosed protein are disclosed herein, the known nucleic acid sequence that encodes that protein from which that protein arises is also known and herein disclosed and described. It is understood that there are numerous amino acid and peptide analogs which can be incorporated into the disclosed compositions. For example, there are numerous D amino acids or amino acids which have a different functional substituent then the amino acids shown in Table 1 and Table 2. The opposite stereo isomers of naturally occurring peptides are disclosed, as well as the stereo isomers of peptide analogs. These amino acids can readily be incorporated into polypeptide chains by charging tRNA molecules with the amino acid of choice and engineering genetic constructs that utilize, for example, amber codons, to insert the analog amino acid into a peptide chain in a site specific way (Thorson et al., Methods in Molec. Biol. 77:43-73 (1991), Zoller, Current Opinion in Biotechnology, 3:348-354 (1992); Ibba, Biotechnology & Genetic Engineering Reviews 13:197-216 (1995), Cahill et al., TIBS, 14(10):400-403 (1989); Benner, TIB Tech, 12:158-163 (1994); Ibba and Hennecke, Bio/technology, 12:678-682 (1994) all of which are herein incorporated by reference at least for material related to amino acid analogs). Molecules can be produced that resemble peptides, but which are not connected via a natural peptide linkage. For example, linkages for amino acids or amino acid analogs can include CH2NH—, —CH2S—, —CH2—CH2—, —CH═CH— (cis and trans), —COCH2—, —CH(OH)CH2—, and —CHH2SO—(These and others can be found in Spatola, A. F. in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Spatola, A. F., Vega Data (March 1983), Vol. 1, Issue 3, Peptide Backbone Modifications (general review); Morley, Trends Pharm Sci (1980) pp. 463-468; Hudson, D. et al., Int J Pept Prot Res 14:177-185 (1979) (—CH2NH—, CH2CH2—); Spatola et al. Life Sci 38:1243-1249 (1986) (—CH H2—S); Hann J. Chem. Soc Perkin Trans. I 307-314 (1982) (—CH—CH—, cis and trans); Almquist et al. J. Med. Chem. 23:1392-1398 (1980) (—COCH2—); Jennings-White et al. Tetrahedron Lett 23:2533 (1982) (—COCH2—); Szelke et al. European Appln, EP 45665 CA (1982): 97:39405 (1982) (—CH(OH)CH2—); Holladay et al. Tetrahedron. Left 24:4401-4404 (1983) (—C(OH)CH2—); and Hruby Life Sci 31:189-199 (1982) (—CH2—S—); each of which is incorporated herein by reference. A particularly preferred non-peptide linkage is —CH2NH—. It is understood that peptide analogs can have more than one atom between the bond atoms, such as b-alanine, g-aminobutyric acid, and the like. Amino acid analogs and analogs and peptide analogs often have enhanced or desirable properties, such as, more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum of biological activities), reduced antigenicity, and others. D-amino acids can be used to generate more stable peptides, because D amino acids are not recognized by peptidases and such. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) can be used to generate more stable peptides. Cysteine residues can be used to cyclize or attach two or more peptides together. This can be beneficial to constrain peptides into particular conformations. (Rizo and Gierasch Ann. Rev. Biochem. 61:387 (1992), incorporated herein by reference) 2. Modification of Macromolecules Described below are modifications of macromolecules using the methods and compositions described herein. The modifications generally involve the alkoxyamination of a macromolecule to produce an aminooxy-modified macromolecule, the hydrazide-modification of a macromolecule to produce a hydrazide-modified macromolecule, or a combination thereof. Any of the macromolecules described above, including the modified glycosaminoglycans, can be modified using the methods and compositions described below. a) Alkoxyamination Alkoxyamination involves reacting any of the macromolecules described above with a compound having at least one aminooxy group. A general reaction scheme that shows the reaction between a carboxylic acid group of macromolecule X, which is an aminooxy-reactive group, and an aminooxy ether compound is depicted in Scheme 1. The aminooxy group can react with any aminooxy-reactive group present on the macromolecule. Thus, in one aspect, the aminooxy group can react with a naturally-occurring aminooxy-reactive group present on the macromolecule. For example, hyaluronan has a plurality of COOH groups that can behave as aminooxy-reactive groups. In another aspect, when the macromolecule is any of the modified-glycosaminoglycans described above, the aminooxy group can react with the naturally-occurring aminooxy-reactive group present on the modified-glycosaminoglycan and/or the new aminooxy-reactive group that was chemically incorporated into the glycosaminoglycan. For example, in FIG. 3, compound F can be reacted with RONH2 to produce compound I, where the aminooxy ether compound reacted with naturally-occurring COOH group of the glucuronic acid unit, and compound J, where the aminooxy ether compound reacted with the C-6 carboxymethyl group of the N-acetyl-glucosamine unit. In one aspect, the aminooxy ether compound has the formula XXV where L can be a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof, and R25 and R26 can be, independently, hydrogen, alkyl, or aryl. In one aspect, L can be a polyalkylene having a disulfide linkage (—S—S—). In another aspect, the aminooxy ether compound has the formula XXVI where each L can be, independently, a polyalkylene group or an aryl group. Reaction schemes for making an aminooxy ether compound useful in the methods and compositions described herein are depicted in FIGS. 1 and 2. In one aspect, described herein are polymers comprising at least one —ONHR group covalently attached to the polymer, wherein R can be hydrogen, an alkyl group, or an aryl group as defined above. In one aspect, the polymer has one —ONHR group attached to the polymer. In another aspect, the polymer has two —ONHR groups attached to the polymer. In one aspect, the polymer has one —ONH2 group attached to the polymer. In another aspect, the polymer has two —ONH2 groups attached to the polymer. The polymer can be any compound having at least one hydroxyl group that can be converted to the corresponding —ONHR group. Examples of such polymers include, but are not limited to, polyethylene glycol (e.g., straight, branched, or a dendrimer), polypropylene oxide, or polyvinyl alcohol. Other molecules possessing at least one hydroxyl group can be derivatized with an aminooxy group. Examples of such molecules include, but are not limited to, a sugar, a saccharide (e.g., monosaccharide, oligosaccharide, or polysaccharide), a fatty alcohol, or a sterol. In one aspect, the polymer is a triblock polymer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide). These polymers are referred to as Pluronics®. Pluronics® are commercially available from BASF and have been used in numerous applications as emulsifiers and surfactants in foods, as well as gels and blockers of protein adsorption to hydrophobic surfaces in medical devices. These materials have low acute oral and dermal toxicity, and do not cause irritation to eyes or inflammation of internal tissues in man. The hydrophobic PPO block adsorbs to hydrophobic (e.g., polystyrene) surfaces, while the PEO blocks provide a hydrophilic coating that is protein-repellent. Pluronics® have low toxicity and are approved by the FDA for direct use in medical applications and as food additives. Surface treatments with Pluronics® can also reduce platelet adhesion, protein adsorption, and bacterial adhesion. In one aspect, the polymer is a triblock polymer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), wherein the polymer has a molecular weight of from 1,000 Da to 100,000 Da. In another aspect, the polymer is a triblock polymer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), wherein the polymer has a molecular weight of from having a lower endpoint of 1,000 Da, 2,000 Da, 3,000 Da, 5,000 Da, 10,000 Da, 15,000 Da, 20,000 Da, 30,000 and an upper endpoint of 5,000 Da, 10,000 Da, 15,000 Da, 20,000 Da, 25,000 Da, 30,000 Da, 40,000 Da, 50,000 Da, 60,000 Da, 70,000 Da, 80,000 Da, 90,000 Da, or 100,000 Da, wherein any lower endpoint can be matched with any upper endpoint, wherein the lower endpoint is less than the upper endpoint. In another aspect, the polymer is a triblock polymer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), wherein the polymer has a molecular weight of from 5,000 Da to 15,000 Da. In one aspect, the triblock polymer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) is PEO103-PPO39-PEO103, PEO132-PPO50-PEO132, or PEO100-PPO65-PEO100. In a further aspect, the polymer is PEO103-PPO39-PEO103, PEO132-PPO50-PEO132, or PEO100-PPO65-PEO100, wherein the polymer has one or two —ONH2 groups covalently bonded to it. In the case when the polymer is a triblock polymer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), one or both of the terminal hydroxy groups can be converted to an aminooxy group. For example, the synthetic scheme depicted in FIG. 32 shows the synthesis of mono- and bis(aminooxy) poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) polymers. The reaction generally involves protecting one or both of the hydroxy groups (e.g., with N-hydroxyphthalimide) followed by deprotection (e.g., with hydrazine). In the case of the mono(aminooxy) polymer, the other hydroxyl group can be converted to a variety of groups (e.g., alkoxy) using techniques known in the art. In one aspect, the reaction between the aminooxy ether compound and the macromolecule is carried out under mild conditions at a pH of about 0 to about 8, about 1 to about 7, or about 2 to about 6, or about 3 to about 5. In one aspect, the macromolecule is dissolved in water, which may also contain water-miscible solvents including, but not limited to, dimethylformamide, dimethylsulfoxide, and hydrocarbyl alcohols, diols, or glycerols. The number of aminooxy groups present on the aminooxy-modified macromolecule will vary depending upon the amounts of aminooxy ether compound and macromolecule used. In one aspect, 1% to 99%, 10% to 90%, 20% to 80%, 30% to 70%, or 40% to 50% of the aminooxy-reactive groups present on the macromolecule are converted to the aminooxy group. In one aspect, at least one molar equivalent of aminooxy ether compound per molar equivalent of macromolecule is added. In other aspects, for maximum percentage functionalization, a large molar excess of the aminooxy ether compound (e.g., 10-100 fold) dissolved in water or aqueous-organic mixture is added and the pH of the reaction mixture is adjusted by the addition of dilute acid, e.g., HCl. In one aspect, a condensing agent can be used to facilitate the reaction between the macromolecule and the aminooxy ether compound. Examples of condensing agents useful herein include, but are not limited to, a water soluble carbodiimide such as 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCI). In another aspect, the condensing agent can be a hydroxybenzotriazole. In another aspect, an active ester forming agent such as N-hydroxysulfosuccinimide (sulfo-NHS) or N-hydroysuccinimide (NHS) can be used in combination with the condensing agent. The active ester forming agents disclosed in U.S. Pat. No. 6,630,457, which is incorporated by reference in its entirety, can be used herein. A sufficient molar excess (e.g., 2 to 100 fold) of carbodiimide reagent dissolved in water, in any aqueous-organic mixture, or finely-divided in solid form is then added to the reaction mixture. In one aspect, after the macromolecule has reacted with the aminooxy ether compound, the resultant modified macromolecule has at least one fragment having the formula XVI wherein X can be a residue of macromolecule; Q can be a bioactive agent, an aminooxy group, a SH group, or a thiol-reactive electrophilic functional group; and L can be a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In formula XVI, X can be a residue of any of the macromolecules described herein. In one aspect, X is a residue of a modified-glycosaminoglycan described herein. In another aspect, L can be a polyalkylene group having the formula (CH2)n, wherein n is from 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 2. In one aspect, Q in formula XVI can be a bioactive agent. The term “bioactive agent” as used herein is any therapeutic, prophylactic, pharmacological or physiological active substance, or mixture thereof, which is delivered to a subject to produce a desired, usually beneficial, effect. In one aspect, any active agent that is capable of producing a pharmacological response, localized or systemic, irrespective of whether therapeutic, diagnostic or prophylactic in nature, can be used as bioactive agents in any of the methods and compositions described herein. It should be noted that the bioactive agent can be used singularly or as a mixture of two or more agents. Thus, it is possible to have two or more bioactive agents covalently attached to the macromolecule via the aminooxy ether compound. In one aspect, any of the macromolecules described above can be used as the bioactive agent. In another aspect, the bioactive agent can be a dye, a probe, a nucleic acid, an enzyme, an oligonucleotide, a label, a protein, a polypeptide, a lipid, a glycoprotein, a glycolipid, or a pharmaceutically-acceptable compound. In another aspect, any of the bioactive agents disclosed in U.S. Pat. No. 6,562,363 B1, which is incorporated by reference in its entirety, can be used herein. In one aspect, the bioactive agent can be linked to the aminooxy ether compound via a linkage. Examples of linkages include, but are not limited to, ethers, imidates, thioimidates, esters, amides, thioethers, thioesters, thioamides, carbamates, ethers, disulfides, hydrazides, hydrazones, oxime ethers, oxime esters, and amines. In another aspect, Q in formula XVI is a thiol-reactive electrophilic functional group. The term “thiol-reactive electrophilic group” as used herein is any group that is susceptible to nucleophilic attack by the lone-pair electrons on the sulfur atom of the thiol group or by the thiolate anion. Examples of thiol-reactive electrophilic groups include groups that have good leaving groups. For example, an alkyl group having a halide or alkoxy group attached to it or an α-halocarbonyl group are examples of thiol-reactive electrophilic groups. In another aspect, the thiol-reactive electrophilic group is an electron-deficient vinyl group. The term “an electron-deficient vinyl group” as used herein is a group having a carbon-carbon double bond and an electron-withdrawing group attached to one of the carbon atoms. An electron-deficient vinyl group is depicted in the formula Cβ=CαX, where X is the electron-withdrawing group. When the electron-withdrawing group is attached to Cα, the other carbon atom of the vinyl group (Cβ) is more susceptible to nucleophilic attack by the thiol group. This type of addition to an activated carbon-carbon double bond is referred to as a Michael addition. In another aspect, the thiol-reactive compound can be represented by the formula C═CW, where W is the thiol-reactive electrophilic functional group. In one aspect, W can be OC(O)R20, wherein R20 can be a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, or a combination thereof. Examples of electron-withdrawing groups include, but are not limited to, a nitro group, a cyano group, an ester group, an aldehyde group, a keto group, a sulfone group, or an amide group. Examples of compounds possessing thiol-reactive electrophilic groups include, but are not limited to, maleimides, vinyl sulfones, acrylonitriles, α-methylene esters, quinone methides, acryloyl esters or amides, or α-halo esters or amides. In another aspect, Q in formula XVI is an aminooxy group. In one aspect, a compound possessing two or more aminooxy groups, where one of the aminooxy groups does not react with an aminooxy-reactive group on the macromolecule, can result in a free aminooxy group Q. Depending upon the identity of L in formula XVI, it is possible to have two or more free or reacted aminooxy groups present in formula XVI. In one aspect, the modified macromolecule has at least one fragment having the formula II wherein Y is any modified glycosaminoglycan and linker, respectively, described herein. In another aspect, Q in formula XVI can be SH. FIG. 2 depicts one aspect of the method described above for producing a compound having the formula XVI, where Q is SH. The first step involves reacting the macromolecule hyaluronan (A) having the formula HA—COOH with the aminooxy ether compound B to produce compound C. In one aspect, the reaction can be performed in the presence of a condensing agent. In one aspect, a condensing agent is any compound that facilitates the reaction between the aminooxy group of compound B and the COOH group on the macromolecule A. Any of the condensing agents described above can be used in this aspect. In one aspect, the condensing agent is a carbodiimide, including, but not limited to, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCI). The disulfide bond in compound C can be cleaved with a reducing agent. In one aspect, the reducing agent is dithiothreitol. Cleavage of the disulfide bonds in compound C produces thiol compounds D, which fall under formula XVI. In one aspect, when Q is SH in formula XVI, L can be CH2, CH2CH2, CH2CH2CH2, or phenyl. In one aspect, it is contemplated the polymers comprising at least one aminooxy group can react with one or more macromolecules to produce a self-assembling extracellular matrix (ECM). Any of the macromolecules described herein can be used in this aspect. For example, the macromolecule can be chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, alginic acid, pectin, or hyaluronan. In another aspect, the polymer is a triblock polymer of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) comprising one or two —ONH2 groups and the macromolecule is hyaluronan. FIGS. 34 and 35 depict one aspect of the self assembling ECM. In FIG. 37, mono- and bis(aminooxy) pluronics are coupled with hyaluronan to produce an aminooxy-modified biopolymer. In FIG. 35, the aminooxy-modified biopolymer can react with itself (i.e., self-assemble) or a different aminooxy-modified biopolymer to form a hydrogel. Not wishing to be bound by theory, it is believed that the hydrophobic PPO blocks of the pluronic can permit the organization and assembly of the aminooxy-modified biopolymer into hydrogels without the need for chemically-reactive crosslinkers. b) Hydrazide-modification Hydrazide-modification of a macromolecule involves reacting any of the macromolecules described herein with a compound having at least one hydrazide group to produce a hydrazide-modified macromolecule. The mechanism is similar to that above in Scheme 1 for the reaction between the aminooxy ether compound and the macromolecule. Reaction scheme 2 that shows the reaction between a carboxylic acid of macromolecule X, which is a hydrazide-reactive group, and a hydrazide compound. Similar to the aminooxy group, the hydrazide-group can react with any hydrazide-reactive group present on the macromolecule. Thus, in one aspect, the hydrazide group can react with a naturally-occurring hydrazide-reactive group present on the macromolecule. In another aspect, when the macromolecule is any of the modified-glycosaminoglycans described above, the hydrazide group can react with the naturally-occurring hydrazide-reactive group present on the modified-glycosaminoglycan and/or the new hydrazide-reactive group that was chemically incorporated into the glycosaminoglycan. In one aspect, a hydrazide compound can be reacted with any of the modified-glycosaminoglycans described herein to produce a hydrazide-modified macromolecule. Any of the techniques and procedures disclosed in U.S. Pat. No. 5,874,417 for functionalizing hyaluronan with a hydrazide, which is incorporated by reference in its entirety, can be used to hydrazide-modify the any macromolecules described herein. For example, the modified-glycosaminoglycan can be reacted with a monohydrazide (i.e., a compound having only one hydrazide group) or a polyhydrazide (i.e., a compound having two or more hydrazide groups). Any of the hydrazide compounds disclosed in U.S. Pat. No. 5,874,417 can be used in this aspect. In one aspect, dihydrazides can be used to modify any of the macromolecules herein. In one aspect, the dihydrazide has the formula 1: H2N—NH—CO—A—CO—N—H—NH2 (1) wherein A is hydrocarbyl such as alkyl, aryl, alkylaryl or arylalkyl or A is heterohydrocarbyl, which also includes oxygen, sulfur, and/or nitrogen atoms in addition to carbon atoms. In this aspect, the alkyl group may be branched or unbranched and contain one to 20 carbons or other carbon-sized atoms, preferably 2 to 10, more preferably 4 to 8 carbons or carbon-sized heteroatoms, such as oxygen, sulfur or nitrogen. The alkyl group may be fully saturated or may contain one or more multiple bonds. The carbon atoms of the alkyl may be continuous or separated by one or more functional groups such as an oxygen atom, a keto group, an amino group, an oxycarbonyl group and the like. The alkyl group may be substituted with one or more aryl groups. The alkyl group may in whole or in part, be in form of rings such as cyclopentyl, cyclohexyl, and the like. Any of the alkyl groups described above may have double or triple bond(s). Any of the hydrocarbyl groups can be used as a heterocarbyl group, wherein the alkyl or aryl group contains a heteroatom such as oxygen, sulfur, or nitrogen incorporated within the chain or ring. Moreover, any of the carbon atoms of the alkyl group may be separated from each other or from the dihydrazide moiety with one or more groups such as carbonyl, oxycarbonyl, amino, and also oxygen and sulfur atoms singly or in a configuration such as —S—S—, —O—CH2—CH2—O—, S—S—CH2—CH2— and NH(CH2)nNH—, where n is from 1 to 20. Aryl substituents are typically substituted or unsubstituted phenyl, but may also be any other aryl group such as pyrrolyl, furanyl, thiophenyl, pyridyl, thiazoyl, etc. An inorganic, alkyl or other aryl group including halo, hydroxy, amino, thioether, oxyether, nitro, carbonyl, etc may further substitute the aryl group. The alkylaryl or arylalkyl groups may be a combination of alkyl and aryl groups as described above. These groups may be further substituted as described above. In another aspect, the dihydrazide has the formula (2) H2 N—NH—CO—NH—A—CO—NH—NH2 (2) In this aspect, A in formula 2 can be hydrocarbyl, heterocarbyl, substituted hydrocarbyl substituted heterocarbyl and the like. In another aspect, A can be any of the linkers denoted and referred to as L throughout the application. Generally, to obtain dihydrazides, two hydroxy groups of a dicarboxylic acid are substituted with NH2NH2 yielding the dihydrazide. Examples of dicarboxylic acids include, but are not limited to, maleic acid, fumaric acid, and aromatic dicarboxylic acids, such as terephthalic acid and isophthalic acid. In one embodiment, aliphatic dihydrazides, where A is an alkyl group, may have the formula 3: NH2 NHCO(CH2)n′CONHNH2 (3) wherein n′ can be any length but is preferably from 1 to 20. Aliphatic dihydrazides useful in the invention include, but are not limited to, succinic (butandioic) (n′=2), adipic (hexanedioic) (n′=4), suberic (octanedioic) (n′=6), oxalic (ethanedioic) (n′=0), malonic (propanedioic) (n′=1), glutaric (pentanedioic) (n′=3), pimelic (heptanedioic) (n′=5), azelaic (nonanedioic) (n′=7), sebacic (decanedioic) (n′=8), dodecanedioic, (n′=10), brassylic (tridecanedioic), (n′=11), (etc. up to n′=20). In one aspect, adipic dihydrazide, suberic dihydrazide, and butandioic dihydrazide are used to prepare the modified polysaccharide. Adipic dihydrazide can be purchased from Aldrich Chemical Co. (Milwaukee, Wis.). In another aspect, phthalic dihydrazide and dihydrazides with A containing oxa, thio, amino, disulfide (—CH2—S—S—CH2—), —S(CH2)2S—, —O(CH2)nO— or —NH(CH2)nNH— (n=2 to 4) groups. In one aspect, the dihydrazides are at least partially soluble in water. The dihydrazides are also weak bases or weak acids having a pKa for the protonated form, less than about 8, preferably in the range of 1 to 7 and most preferably 2 to 6. It will be understood that the term pKa is used to express the extent of dissociation or the strength of weak acids, so that, for example, the pKa of the protonated amino group of amino acids is in the range of about 12-13 in contrast to the pKa of the protonated amino groups of the dihydrazides useful herein which is less than about 7. As described above, the hydrazide compound reacts with a hydrazide-reactive group present on the macromolecule. In one aspect, the reaction is carried out under mild conditions at a pH of about 0 to about 8, about 1 to about 7, or about 2 to about 6, or about 3 to about 5. In one aspect, the macromolecule is dissolved in water, which may also contain water-miscible solvents including, but not limited to, dimethylformamide, dimethylsulfoxide, and hydrocarbyl alcohols, diols, or glycerols. Similar to above for the aminooxy ether compounds, the number of hydrazide groups present on the modified macromolecule will vary depending upon the amounts of hydrazide compound and macromolecule used. In one aspect, 1% to 99%, 10% to 90%, 20% to 80%, 30% to 70%, or 40% to 50% of the hydrazide-reactive groups present on the macromolecule are converted to the hydrazide group. In one aspect, at least one molar equivalent of hydrazide compound per molar equivalent of macromolecule is added. In other aspects, for maximum percentage functionalization, a large molar excess of the hydrazide compound (e.g., 10-100 fold) dissolved in water or aqueous-organic mixture is added and the pH of the reaction mixture is adjusted by the addition of dilute acid, e.g., HCl. A sufficient molar excess (e.g., 2 to 100 fold) of carbodiimide reagent dissolved in water, in any aqueous-organic mixture, or finely-divided in solid form is then added to the reaction mixture. In one aspect, the hydrazide-modified macromolecule has at least one fragment having the formula I wherein Y can be a residue of any modified-glycosaminoglycan described herein and R1, R2, R3, and R7 can be, independently, hydrogen, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, or a polyether group, wherein R3 is not hydrogen. In one aspect, R1, R2, and R7 are hydrogen. In another aspect, can be R3 can be alkyl group such as (CH2)n, wherein n is from 1 to 20, 1 to 15, 1 to 10, 1 to 8, 1 to 6, or 2 to 4. In one aspect, the hydrazide-modified macromolecule has at least one fragment having the formula III wherein Y can be a residue of any of the modified-glycosaminoglycan described herein; Q can be a residue of a bioactive agent, SH group or a thiol-reactive electrophilic functional group; and L can be a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. Any of the bioactive agents and thiol-reactive electrophilic functional groups described above can be used in this aspect. In one aspect, Q in formula III is SH. FIG. 4 depicts one aspect for making compounds having the formula III where Q is SH. The modified-hyaluronan compound F, where a primary hydroxyl group as defined above is converted to the carboxymethyl group, is reacted with 3,3′-dithiobis(propanoic dihydrazide) (DTP) in the presence of the condensing agent such as, for example, EDCI. The hydrazide compound can react with the carboxylic acid group on the glucuronic acid unit of hyaluronan and/or the C-6 carboxymethyl group of the N-acetyl-glucosamine unit of hyaluronan. This reaction produces dihydrazide/disulfide hyaluronan that can be isolated or further manipulated in situ. The disulfide bond of the dihydrazide/disulfide hyaluronan can be cleaved with a reducing agent such as, for example, dithiothreitol (DTT) to produce the hydrazide/thiol compound G and/or H. In one aspect, when Q in formula III is a SH group, L can be CH2, CH2CH2, or CH2CH2CH2. In another aspect, the hydrazide-modified macromolecule comprises at least one unit comprising the the formula L wherein X comprises a residue of a macromolecule; and R1 and R2 comprise, independently, hydrogen, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, or a polyether group; L1 and L2 comprise, independently, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a branched- or straight-chain alkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In one aspect of formula L, R1 and R2 are hydrogen. In another aspect of formula L, L1 and L2 are an alkylene group. Examples of alkylene groups can be denoted by the formula —(CH2)n—, where n is an integer from 1 to 20, 1 to 15, 1 to 10, 1 to 8, 1 to 6 or 1 to 4. In another aspect, L1 is CH2 and L2 is CH2CH2. In one aspect, X in formula L comprises chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, alginic acid, pectin, or hyaluronan. In another aspect of formula L, X is hyaluronan, R1 and R2 are hydrogen, L1 is CH2, and L2 is CH2CH2. This compound is referred to herein as Carbylan™-S. In another aspect, a compound having at least one unit of formula L can be produced by the process comprising (1) reacting a compound comprising the formula LX wherein X comprises a residue of a macromolecule; and L1 comprises a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a branched- or straight-chain alkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof, with a compound comprising the formula LXV wherein R1 and R2 comprise, independently, hydrogen, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, or a polyether group, and L2 comprises a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a branched- or straight-chain alkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. The methods described throughout the application can be used in the process above. In one aspect of formula LX, R1 and R2 are hydrogen. In another aspect of formula LX and LXV, L1 and L2 are an alkylene group. Examples of alkylene groups can be denoted by the formula —(CH2)n—, where n is an integer from 1 to 20, 1 to 15, 1 to 10, 1 to 8, 1 to 6 or 1 to 4. In another aspect, L1 is CH2 and L2 is CH2CH2. In one aspect, X in formula LX comprises chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, alginic acid, pectin, or hyaluronan. In another aspect of formula LX and LXV, X is hyaluronan, R1 and R2 are hydrogen, L1 is CH2, and L2 is CH2CH2. This compound is referred to herein as Carbylan™-S. 3. Crosslinked Macromolecules Described below are methods and compositions for crosslinking any of the modified macromolecules described herein to produce a physiologically compatible macromolecular scaffold useful as a therapeutic aid. “Crosslinking” is defined herein as the ability of two or more macromolecules to produce a pore-containing matrix, where the macromolecules can be the same or different. One or more of macromolecules can be modified using any of the methods and compositions described herein. The use of additional compounds that will facilitate crosslinking are also contemplated. a) Oxidative Coupling In general, oxidative coupling involves reacting two or more compounds that each have a SH group in the presence of an oxidant. It is also contemplated that the thiolated compound can couple with itself as well as the other thiolated compound. The reaction between the two SH groups produces a new disulfide bond (—S—S—). In one aspect, the oxidative coupling of a first thiolated compound Y—SH and a second thiolated compound G—SH produces a compound having the fragment VII wherein Y can be a residue of any macromolecule described herein such as a modified-glycosaminoglycan and G is a residue of the thiolated compound. Depending upon the selection of the macromolecule, the macromolecule can be chemically modified so that the macromolecule has at least on SH group. For example, any naturally-occurring COOH groups or COOH groups added to the macromolecule can be converted to a thiol group using the techniques described herein including, but not limited to, the hydrazide and aminooxy methods described herein. The second thiolated compound G—SH is any compound having at least one thiol group. The first and second thiolated compounds can be the same or different compounds. In one aspect, the second thiolated compound can be any macromolecule described above. In one aspect, the second thiolated compound is a polysaccharide having at least one SH group. Any of the polysaccharides described above can be used as the second thiolated compound. In another aspect, the second thiolated compound can be a sulfated-glycosaminoglycan. In a further aspect, the second thiolated compound includes chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, alginic acid, pectin, or carboxymethylcellulose, or hyaluronan, wherein each of these compounds has at least one SH group. The reaction between the first and second thiolated compounds is performed in the presence of an oxidant. In one aspect, the reaction between the first and second thiolated compounds can be conducted in the presence of any gas that contains oxygen. In one aspect, the oxidant is air. This aspect also contemplates the addition of a second oxidant to expedite the reaction. In another aspect, the reaction can be performed under an inert atmosphere (i.e., oxygen free), and an oxidant is added to the reaction. Examples of oxidants useful in this method include, but are not limited to, molecular iodine, hydrogen peroxide, alkyl hydroperoxides, peroxy acids, dialkyl sulfoxides, high valent metals such as Co+3 and Ce+4, metal oxides of manganese, lead, and chromium, and halogen transfer agents. The oxidants disclosed in Capozzi, G.; Modena, G. In The Chemistry of the Thiol Group Part II; Patai, S., Ed.; Wiley: New York, 1974; pp 785-839, which is incorporated by reference in its entirety, are useful in the methods described herein. The reaction between the first and second thiolated compounds can be conducted in a buffer solution that is slightly basic. The amount of the first thiolated compound relative the amount of the second thiolated compound can vary. In one aspect, the volume ratio of the first thiolated compound to the second thiolated compound is from 99:1, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, or 1:99. In one aspect, the first and second thiolated compound react in air and are allowed to dry at room temperature. In this aspect, the dried material can be exposed to a second oxidant, such as hydrogen peroxide. The resultant compound can then be rinsed with water to remove any unreacted first and/or second thiolated compound and any unused oxidant. One advantage of preparing coupled compound via the oxidative coupling methodology described herein is that crosslinking can occur in an aqueous media under physiologically benign conditions without the necessity of additional crosslinking reagents. In one aspect, described herein is a method for coupling two or more thiolated compounds by reacting a first thiolated compound having the formula X wherein Y can be a residue of any modified-glycosaminoglycan described herein, and L can be a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof, with a second thiolated compound having at least one SH group in the presence of an oxidant, wherein the first thiolated compound and second thiolated compound are the same or different compounds. In one aspect, the second thiolated compound has the formula X. In a further aspect, the first and second thiolated compounds are the same compound. The reaction between the thiolated compound having the formula X and the second thiolated compound produces a crosslinked compound having the fragment VIII where Y and L are as defined above. In one aspect, L in formula VIII can be CH2, CH2CH2, or CH2CH2CH2. In another aspect, G can be a polysaccharide residue such as, for example, a sulfated-glycosaminoglycan residue. In another aspect, G can be a residue of chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, alginic acid, pectin, or carboxymethylcellulose, or hyaluronan. In another aspect, described herein is a method for coupling two or more thiolated compounds by reacting a first thiolated compound having the formula XVII wherein X can be a residue of any macromolecule described herein and L can be a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof, with a second thiolated compound having at least one SH group in the presence of an oxidant, wherein the first thiolated compound and second thiolated compound are the same or different compounds. In one aspect, X is a residue of any modified-glycosaminoglycan described herein. In another aspect, X can be a residue of hyaluronan. In one aspect, the second thiolated compound has the formula XVII. In a further aspect, the first and second thiolated compounds are the same compound. The reaction between the thiolated compound having the formula XVII and the second thiolated compound produces a crosslinked compound having the fragment XVIII where X and L can be any macromolecule and linker, respectively, described herein. In one aspect, X is a modified-glycosaminoglycan described herein. In another aspect, X and G are a residue of hyaluronan. b) Coupling Compounds via the Reaction between a Thiol Compound and a Thiol-Reactive Compound In another aspect, described herein is a method for coupling two or more compounds by reacting a first thiolated compound having at least one SH group with at least one compound having at least one thiol-reactive electrophilic functional group. In one aspect, the compound has at least two-thiol reactive functional groups. Any of the thiolated macromolecules described above or macromolecules that can be thiolated can be used in this aspect as the first thiolated compound. Two or more different macromolecules can be used in this method. For example, a second thiolated compound can be used in combination with the first thiolated compound. In this aspect, the first and second thiolated compound can be the same or different compounds. In one aspect, the first and second thiolated compound can be a polysaccharide. In this aspect, the polysaccharide is a sulfated-glycosaminoglycan including, but not limited to, chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, alginic acid, pectin, or carboxymethylcellulose. In another aspect, the first thiolated compound is hyaluronan. In another aspect, the first thiolated compound has the formula XVII described above. In this aspect, X is a residue of hyaluronan and L is CH2, CH2CH2 or CH2CH2CH2. In another aspect, X is a residue of a modified-glycosaminoglycan. In another aspect, the first thiolated compound has the formula X described above. In one aspect, Y in formula X is a modified-glycosaminoglycan. In one aspect, the thiol-reactive compound contains one or more thiol-reactive electrophilic functional groups as defined above. In one aspect, the thiol-reactive compound has two electron-deficient vinyl groups, wherein the two electron-deficient vinyl groups are the same. In another aspect, the thiol-reactive compound is a diacrylate, a dimethacrylate, a diacrylamide, a dimethacrylamide, or a combination thereof. In another aspect, the thiol-reactive compound can be a dendrimer having a plurality of thiol-reactive groups. In one aspect, the thiol-reactive compound can have from 2 to 100, 2 to 90, 2 to 80, 2 to 70, 2 to 60, 2 to 50, 2 to 40, 2 to 30, 2 to 20 or 2 to 10 thiol-reactive groups. In another aspect, the thiol-reactive compound has the formula XX wherein R3 and R4 are, independently, hydrogen or lower alkyl; U and V are, independently, O or NR5, wherein R5 is, independently, hydrogen or lower alkyl; and M is a polyalkylene group, a polyether group, a polyamide group, a polyimino group, a polyester, an aryl group, or a polythioether group. In one aspect, R3 and R4 are hydrogen, U and V are oxygen, and M is a polyether group. This compound is referred to herein as polyetheylene glycol diacrylate or PEGDA. In another aspect, R3 and R4 are hydrogen, U and V are NH, and M is a polyether group. In a further aspect, R3 and R4 are methyl, U and V are oxygen, and M is a polyether group. In another aspect, R3 and R4 are methyl, U and V are NH, and M is a polyether group. In another aspect, the thiol-reactive compound is any bioactive agent described above containing at least one thiol-reactive electrophilic group. For example, Mitomycin C (MMC) can be converted to the corresponding acrylate (MMC-acrylate). MMC-acrylate can then be coupled with any of the thiolated macromolecules described herein. In another aspect, the first thiolated compound has the formula X or XVII described above, wherein L is CH2CH2 or CH2CH2CH2, and the thiol-reactive compound has the formula XX described above, wherein R3 and R4 are, independently, hydrogen or lower alkyl; U and V are, independently, O or NR5, wherein R5 is, independently, hydrogen or lower alkyl; and M is a polyether group. In another aspect, described herein is a method for coupling a compound by reacting a first thiolated compound having at least one thiol-reactive electrophilic functional group with at least one compound having at least two thiol groups. Any of the thiolated macromolecules and thiol-reactive electrophilic functional groups described above can be used in this aspect. In one aspect, a thiol-reactive compound having at least one fragment having the formula XVI wherein X can be a residue of any macromolecule described herein; Q is the thiol-reactive electrophilic functional group; and L can be a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof, is reacted with at least one compound having at least two thiol groups. In one aspect, when Q of formula XVI is thiol-reactive electrophilic functional group, X is a polysaccharide such as hyaluronan and L is CH2CH2 or CH2CH2CH2. In another aspect, Q is an acrylate, a methacrylate, an acrylamide, or a methacrylamide. In one aspect, examples of compounds having at least two thiol groups include, but are not limited to, propane-1,3-dithiol, polyethylene glycol-α,Ω-dithiol, para, ortho, or meta-bisbenzyl thiol, dithiothreitol, a peptide containing two or more cysteine residues, or dendrimeric thiols. The compounds produced by coupling a thiolated compound with a compound having at least one thiol-reactive electrophilic functional group possess at least one fragment of the formula XXVII wherein R7 and R8 are, independently, hydrogen or lower alkyl; W is an electron-withdrawing group described above; and X can be a residue of any macromolecule described herein. In one aspect, X can be a residue of a polysaccharide such as hyaluronan or a sulfated-glycosaminoglycan. In another aspect, X can be a residue of a modified-glycosaminoglycan. In another aspect, R7 is hydrogen and R8 is hydrogen or methyl. In another aspect, X is a residue of a modified-glycosaminoglycan; R7 is hydrogen; R8 is hydrogen or methyl; and W is an ester group or an amide group. In one aspect, the reaction product between the thiolated compound and thiol-reactive compound has at least one fragment having the formula XII wherein R7 and R8 can be, independently, hydrogen or lower alkyl; W can be any electron-withdrawing group described herein; Y can be a residue of any modified-glycosaminoglycan described herein; and L comprises a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In another aspect, the reaction product between the thiolated compound and thiol-reactive compound has at least one fragment having the formula XIII wherein R7 and R8 can be, independently, hydrogen or lower alkyl; W can be any electron-withdrawing group described herein; Y can be a residue of any modified-glycosaminoglycan described herein; and L comprises a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In another aspect, the reaction product between the thiolated compound and thiol-reactive compound has at least one fragment having the formula XIV wherein R3 and R4 can be, independently, hydrogen or lower alkyl; U and V can be, independently, O or NR5, wherein R5 is, independently, hydrogen or lower alkyl; Y can be a residue of any modified-glycosaminoglycan described herein; X can be a residue of any macromolecule described herein; and L and M can be, independently, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In one aspect, Y in formula XIV is X′OCH2—, wherein X′ comprises a residue of a macromolecule. Examples of the macromolecule X′ include, but are not limited to, chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, alginic acid, or pectin. In another aspect, X′ is hyaluronan. In another aspect of formula XIV, R3and R4 are hydrogen, U and V are oxygen, and M is a polyether group. In a further aspect, L in formula XIV is a CH2CH2 group. In another aspect of formula XIV, Y is X′OCH2—, wherein X′ is hyaluronan, R3 and R4 are hydrogen, U and V are oxygen, M is a polyether group, L is a CH2CH2 group, and X is CH2CH2C(O)NHNHC(O)X″, where X″ is a residue of hyaluronan. This compound is also referred to herein as Carbylan™-SX. In yet another aspect of formula XIV, Y is X′OCH2—, wherein X′ is hyaluronan, R3 and R4 are hydrogen, U and V are oxygen, M is a polyether group, L is a CH2CH2 group, and X is CH2CH2C(O)NHNHC(O)X″, where X″ is a residue of gelatin. This compound is also referred to herein as Carbylan™-GSX. In another aspect, the reaction product between the thiolated compound and thiol-reactive compound has at least one fragment having the formula XV wherein R3 and R4 can be, independently, hydrogen or lower alkyl; U and V can be, independently, O or NR5, wherein R5 is, independently, hydrogen or lower alkyl; Y can be a residue of any modified-glycosaminoglycan described herein; X can be a residue of any macromolecule described herein; and L and M can be, independently, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In another aspect, the reaction product between the thiolated compound and thiol-reactive compound has at least one fragment having the formula XXI wherein R7 and R8 can be, independently, hydrogen or lower alkyl; W can be any electron-withdrawing group described herein; X can be a residue of any macromolecule described herein; and L can be a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In another aspect, the reaction product between the thiolated compound and thiol-reactive compound has at least one fragment having the formula XXII wherein R3 and R4 can be, independently, hydrogen or lower alkyl; U and V can be, independently, O or NR5, wherein R5 is, independently, hydrogen or lower alkyl; Y can be a residue of any modified-glycosaminoglycan described herein; X can be a residue of any macromolecule described herein; and L and M can be, independently, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In another aspect, a compound produced by the process comprising reacting any of the thiolated compounds having the formula L with a compound comprising the formula XX wherein R3 and R4 comprise, independently, hydrogen or lower alkyl; U and V comprise, independently, O or NR5, wherein R5 is, independently, hydrogen or lower alkyl; and M comprises a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In one aspect, R3 and R4 in formula XX are hydrogen, U and V are oxygen, and M is a polyether group. In another aspect, R3 and R4 are hydrogen, U and V are NH, and M is a polyether group. In a further aspect, R3 and R4 are methyl, U and V are oxygen, and M is a polyether group. In another aspect, R3 and R4 are methyl, U and V are NH, and M is a polyether group. In one aspect, the thiolated compound has the formula L, wherein X is hyaluronan, R1 and R2 are hydrogen, L1 is CH2, and L2 is CH2CH2. In another aspect, the thiolated compound has the formula L, wherein X is hyaluronan, R1 and R2 are hydrogen, L1 is CH2, and L2 and the compound having the formula XX is poly(ethylene glycol) diacrylate. This reaction is depicted in FIG. 8. The reaction product is also referred to herein as Carbylan™-SX. It is also contemplated that the thiolated molecule can be two or more different thiolated molecules. In one aspect, the thiolated molecule comprises two thiolated molecules, wherein the first thiolated molecule is a compound having the formula L, wherein X is hyaluronan, R1 and R2 are hydrogen, L1 is CH2, and L2 is CH2CH2, the second thiolated molecule is a thiolated macromolecule, and the compound having the formula XX is poly(ethylene glycol) diacrylate. Examples of thiolated macromolecules include, but are not limited to, chondroitin sulfate, thiolated dermatan, thiolated heparan, thiolated heparin, thiolated dermatan sulfate, thiolated heparan sulfate, thiolated alginic acid, or thiolated pectin. In one aspect, the thiolated macromolecule can be modified with a hydrazide group having a thiol group using the techniques described herein. In one aspect, the second thiolated molecule is thiolated gelatin, wherein the gelatin is modified with a hydrazide group having a thiol group. In one aspect, the thiolated molecule comprises two thiolated molecules, wherein the first thiolated molecule is a compound having the formula L, wherein X is hyaluronan, R1 and R2 are hydrogen, L1 is CH2, and L2 is CH2CH2, the second thiolated molecule is thiolated gelatin, and the compound having the formula XX is poly(ethylene glycol) diacrylate. This reaction is depicted in FIG. 8, and the reaction product is referred to herein as Carbylan™-GSX. In one aspect, the reaction between the thiol reactive compound and thiol compound is generally conducted at a pH of from 7 to 12, 7.5 to 11, 7.5 to 10, or 7.5 to 9.5, or a pH of 8. In one aspect, the solvent used can be water (alone) or an aqueous containing organic solvent. In one aspect, when the mixed solvent system is used, a base such as a primary, secondary, or tertiary amine can used. In one aspect, an excess of thiol compound is used relative to the thiol-reactive compound in order to ensure that all of the thiol-reactive compound is consumed during the reaction. Depending upon the selection of the thiol reactive compound, the thiol compound, the pH of the reaction, and the solvent selected, coupling can occur from within minutes to several days. If the reaction is performed in the presence of an oxidant, such as air, the thiol compound can react with itself or another thiol compound via oxidative addition to form a disulfide linkage in addition to reacting with the thiol-reactive compound. c) Crosslinking via Polycarbonyl Crosslinkers In one aspect, a polycarbonyl crosslinker can react with any of the modified macromolecules described herein. The term “polycarbonyl crosslinker” is defined herein as a compound that possesses two or more groups represented by the formula C(O)R, where R is hydrogen, lower alkyl, or OR′, where R′ is a group that results in the formation of an activated ester. In one aspect, any of the hydrazide-modified macromolecules and aminooxy-modified macromolecules can be crosslinked with a polyaldehyde. A polyaldehyde is a compound that has two or more aldehyde groups [C(O)H]. In one aspect, the polyaldehyde is a dialdehyde compound. In one aspect, any compound possessing two or more aldehyde groups can be used as the polyaldehyde crosslinker. In one aspect, the polyaldehyde can be substituted or unsubstituted hydrocarbyl or substituted or unsubstituted heterohydrocarbyl. In another embodiment, the polyadlehyde can contain a polysaccharyl group or a polyether group. In a further aspect, the polyaldehyde can be a dendrimer or peptide. In one aspect, a polyether dialdehyde such as poly(ethylene glycol) propiondialdehyde (PEG) is useful in the compositions and methods described herein. PEG can be purchased from many commercial sources, such as Shearwater Polymers, Inc. (Huntsville, Ala.). In another aspect, the polyaldehyde is glutaraldehyde. In another aspect, when the polycarbonyl compound is a polyaldehyde, the polyaldehyde can be prepared by the oxidation of terminal polyols or polyepoxides possessing two or more hydroxy or epoxy groups, respectively, using techniques known in the art The method of crosslinking generally involves reacting the modified macromolecule with the polycarbonyl crosslinker in the presence of a solvent. In one aspect, the carbonyl group of the polycarbonyl reacts with the hydrazide group or the amino group of the aminooxy group of the modified macromolecule to produce a new carbon-nitrogen double bond. Scheme 3 depicts one aspect of using a dicarbonyl compound A, where R29 and R30 can be, independently, hydrogen, lower alkyl, or OR′ as defined above, as a crosslinker. The carbonyl group of compound B, which is the result of one condensation reaction between a first hydrazide-modified macromolecule and the dicarbonyl, can react with the hydrazide group of a second hydrazide-modified polysaccharide C to produce another carbon-nitrogen double bond, which results in the formation of a unit depicted in Formula V. In view of Scheme 3, it is possible to crosslink two or more modified macromolecules to produce a matrix. Although the polycarbonyl crosslinker is intended to react with hydrazide groups or aminooxy groups on different modified macromolecules, it is also possible that the polycarbonyl crosslinker can react with two or more hydrazide groups or aminooxy groups present on the same modified macromolecule It also evident in Scheme 3 that the modified macromolecules can be different or the same. Thus, in one aspect, X and Y in formula V can be the same macromolecule residue. In another aspect, X and Y can be different macromolecule residues. In one aspect, X and Y are, independently, a residue of chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, alginic acid, pectin, or carboxymethylcellulose. In another aspect, X and Y are a residue of hyaluronan. In another aspect, X and/or Y are a residue of a modified-glycosaminoglycan. In one aspect, when Y in formula V is a modified-glycosaminoglycan, Z can be a polyether. In another aspect, when Y in formula V is a modified-glycosaminoglycan, R1, R2, R5, R6, R7, and R8 are hydrogen. In another aspect, when Y in formula V is a modified-glycosaminoglycan, R3 and R4 can be an alkyl group such as, for example, (CH2)n, wherein n is from 1 to 20, 1 to 18, 1 to 16, 1 to 14, 1 to 12, 1 to 10, 1 to 8, 2 to 6, or 2 to 4. In another aspect, crosslinked macromolecules can be produced by reacting (1) a modified macromolecule comprising the reaction product between adipic dihydrazide and a modified-glycosaminoglycan and (2) a poly(ethylene glycol) propiondialdehyde. In another aspect, crosslinked macromolecules can be produced by reacting (1) a modified macromolecule comprising the reaction product between an aminooxy ether compound possessing two or more aminooxy groups and a macromolecule and (2) a poly(ethylene glycol) propiondialdehyde. In another aspect, the reaction product between a polycarbonyl crosslinker and an aminooxy-modified macromolecule has at least one fragment having the formula VI wherein X and Y can be a residue of any macromolecule described herein; R27 and R28 can be, independently, hydrogen or lower alkyl; and L and Z can be, independently, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof. In one aspect, X and Y are a residue of a polysaccharide such as a sulfated-glycosaminoglycan or hylauronan. In another aspect, Y can be a modified-glycosaminoglycan. In another aspect, one or more hydroxyl groups present on the macromolecule can be oxidized to the corresponding aldehyde, which then can undergo crosslinking with a hydrazide compound or an aminooxy ether compound. In one aspect, periodate can be used to oxidize the macromolecule. The overall number of crosslinks and the number of different modified macromolecules that are cross linked together are dependent on the number of reactive carbonyl groups in the polycarbonyl crosslinker and dihydrazide groups or aminooxy groups present on the modified macromolecule. In one aspect, there is at a minimum at least one crosslink (i.e., unit) having the formula V or VI. In one aspect, 1% to 100%, 10% to 90%, 30% to 80%, or 40% to 70% of the dihydrazide groups or aminooxy groups are crosslinked with the polycarbonyl crosslinker. In another aspect, the compound has from 10 to 10,000 units, 10 to 9,000 units, 10 to 8,000 units, 10 to 7,000 units, 10 to 6,000 units, 10 to 5,000 units, 10 to 4,000 units, 10 to 3,000 units, 10 to 2,000 units, or 10 to 1,000 units having the formula V or VI. In one aspect, adipic dihydrazide (ADH) will crosslink when it modifies the uronic acid in 1%-99% of the glycosaminoglycan or 1-50%. In one aspect, modification of the carboxylic acid containing polysaccharide such as glycosaminoglycan (for example HA) can contain 10-90% or 20-80% or 30-70% or 40-60% or about 50% derivatization and the derivatized polysaccharide can contain greater than 10% or 20% or 30% or 40% or 50% or 60% or 70% or 80% or 90% or 99% crosslinking. For example, a hyaluronan (HA) with 5,000 disaccharide units (normal high MW HA) has 5,000 carboxylic acid groups available. A 1% modification means that there are 50 ADHs per HA molecule, 10% would be 500 ADH/HA, etc. Thus, even at low modification levels, there are numerous sites per modified GAG molecule to form crosslinks. Any of the techniques and procedures for crosslinking polyaldehydes with polysaccharides disclosed in International publication no. WO 02/06373, which is incorporated by reference in its entirety, can be used in the methods described herein. In one aspect, after the reaction between the polycarbonyl crosslinker and the modified macromolecule is complete, the solvent present in the crosslinked macromolecule can be evaporated by any method known in the art such as air-drying, rotary evaporation at low pressure and/or lyophilization. In one aspect, at least 80%, at least 85%, at least 90%, at least 95%, and at least 98% of the solvent contained within the crosslinked macromolecule should evaporate. In one aspect, the reaction solvent is water. In addition, small amounts of water miscible organic solvents, such as an alcohol or DMF or DMSO, can be used as well. In one aspect, crosslinking can be performed at room temperature, for example, 25° C., but the cross-linking reaction can be performed within a range of temperatures from below 4° C. to above 90° C. but typically would be performed at between 4° C. and 60° C., more typically between 4° C. and 50° C., and more preferably at 4° C. or 30° C. or 37° C. The reaction will also work at a variety of pHs between, for example, pH from 3 to 10, or pH from 4 to 9, or pH from 5 to 8, or preferably at neutral pH. 4. Anti-adhesion Composites In one aspect, described herein are composites comprising (1) a first compound comprising a first anti-adhesion compound covalently bonded to a first anti-adhesion support and (2) a first prohealing compound. The term “anti-adhesion compound” as referred to herein is defined as any compound that prevents cell attachment, cell spreading, cell growth, cell division, cell migration, or cell proliferation. In one aspect, compounds that induce apoptosis, arrest the cell cycle, inhibit cell division, and stop cell motility can be used as the anti-adhesion compound. Examples of anti-adhesion compounds include, but are not limited to anti-cancer drugs, anti-proliferative drugs, PKC inhibitors, ERK or MAPK inhibitors, cdc inhibitors, antimitotics such as colchicine or taxol, DNA intercalators such as adriamycin or camptothecin, or inhibitors of PI3 kinase such as wortmannin or LY294002. In one aspect, the anti-adhesion compound is a DNA-reactive compound such as mitomycin C. In another aspect, any of the oligonucleotides disclosed in U.S. Pat. No. 6,551,610, which is incorporated by reference in its entirety, can be used as the anti-adhesion compound. In another aspect, any of the anti-inflammatory drugs described below can be the anti-adhesion compound. Examples of anti-inflammatory compounds include, but are not limited to, methyl prednisone, low dose aspirin, medroxy progesterone acetate, and leuprolide acetate. The term “anti-adhesion support” as referred to herein is defined as any compound that is capable of forming a covalent bond with the anti-adhesion compound that does not adhere to, spread, or proliferate cells. In one aspect, the anti-adhesion support is a hydrophilic, natural or synthetic polymer. Any of the polyanionic polysaccharides disclosed in U.S. Pat. No. 6,521,223, which is incorporated by reference in its entirety, can be used as the anti-adhesion support. Examples of polyanionic polysaccharides include, but are not limited to, hyaluronan, sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, carboxymethylcellulose, carboxymethyl amylose, or a mixture of hyaluronic acid and carboxymethylcellulose. The formation of the first compound involves reacting the anti-adhesion compound with the anti-adhesion support to form a new covalent bond. In one aspect, the anti-adhesion compound possesses a group that is capable of reacting with the anti-adhesion support. The group present on the anti-adhesion compound that can react with the anti-adhesion support can be naturally-occurring or the anti-adhesion compound can be chemically modified to add such a group. In another aspect, the anti-adhesion support can be chemically modified so that it is more reactive with the anti-adhesion compound. In one aspect, the first compound can be formed by crosslinking the anti-adhesion compound with the anti-adhesion support. In one aspect, the anti-adhesion compound and the anti-adhesion support each possess at least one hydrazide group or aminooxy group, which then can react with a crosslinker such as, for example, a polycarbonyl crosslinker having at least two hydrazide-reactive groups or at least two aminooxy-reactive groups. Any of the hydrazide-reactive groups, aminooxy-reactive groups, and polycarbonyl crosslinkers described above can be used in this aspect. In one aspect, the crosslinker is a polyethylene glycol dialdehyde. Additionally, any of the hydrazide-modified macromolecules and aminooxy-modified macromolecules described above can be used as the first anti-adhesion support. In another aspect, the first compound can be formed by the oxidative coupling of the anti-adhesion compound with the anti-adhesion support. In one aspect, when the anti-adhesion compound and the anti-adhesion support each possess a thiol group, the anti-adhesion compound and the anti-adhesion support can react with one another in the presence of an oxidant to form a new disulfide bond. Any of the oxidants described above can be used in this aspect. Additionally, any of the thiolated hydrazide-modified macromolecules and thiolated aminooxy-modified macromolecules described above can be used as first anti-adhesion support. For example, compounds having at least one fragment X or XVII can be used as the first anti-adhesion support. The reaction between the anti-adhesion compound and the anti-adhesion support can be conducted in a buffer solution that is slightly basic. The amount of the anti-adhesion compound relative the amount of the anti-adhesion support can vary. In one aspect, the volume ratio of the anti-adhesion compound to the anti-adhesion support is from 99:1, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, or 1:99. In one aspect, the anti-adhesion compound and the anti-adhesion support react in air and are allowed to dry at room temperature. In this aspect, the dried material can be exposed to a second oxidant, such as hydrogen peroxide. The resultant compound can then be rinsed with water to remove any unreacted anti-adhesion compound, anti-adhesion support, and any unused oxidant. One advantage of preparing the first compound via the oxidative coupling methodology described herein is that coupling can occur in an aqueous media under physiologically benign conditions without the necessity of additional crosslinking reagents. In another aspect, the first compound is produced by reacting the anti-adhesion support having at least one SH group with at least one anti-adhesion compound having at least one thiol-reactive electrophilic functional group. In one aspect, the anti-adhesion compound is mitomycin C having an acrylate group. In another aspect, the first compound is produced by reacting the anti-adhesion support having at least one thiol-reactive electrophilic functional group with at least one anti-adhesion compound having at least two thiol groups. Any of the compounds described above that possess a thiol-reactive electrophilic functional group can be used in this aspect. For example, compounds having at least one fragment having the formula III or XVI can be used as the first adhesion support. In one aspect, the reaction between the thiol reactive compound (anti-adhesion compound or the anti-adhesion support) and the thiol compound (anti-adhesion compound or the anti-adhesion support) is generally conducted at a pH of from 7 to 12, 7.5 to 11, 7.5 to 10, or 7.5 to 9.5, or a pH of 8. In one aspect, the solvent used can be water (alone) or an aqueous solution containing an organic solvent. In one aspect, when the mixed solvent system is used, a base such as a primary, secondary, or tertiary amine can be used. In one aspect, an excess of thiol compound is used relative to the thiol-reactive compound in order to ensure that all of the thiol-reactive compound is consumed during the reaction. Depending upon the selection of the thiol reactive compound, the thiol compound, the pH of the reaction, and the solvent selected, coupling can occur from within minutes to several days. If the reaction is performed in the presence of an oxidant, such as air, the thiol compound can react with itself or another thiol compound via oxidative addition to form a disulfide linkage in addition to reacting with the thiol-reactive compound. The composite can optionally contain unreacted (i.e., free) anti-adhesion compound. The unreacted anti-adhesion compound can be the same or different anti-adhesion compound that is covalently bonded to the anti-adhesion support. The composite is composed of a prohealing compound. The term “prohealing drug” as defined herein is any compound that promotes cell growth, cell proliferation, cell migration, cell motility, cell adhesion, or cell differentiation. In one aspect, the prohealing compound includes a protein or synthetic polymer. Proteins useful in the methods described herein include, but are not limited to, an extracellular matrix protein, a chemically-modified extracellular matrix protein, or a partially hydrolyzed derivative of an extracellular matrix protein. The proteins may be naturally occurring or recombinant polypeptides possessing a cell interactive domain. The protein can also be mixtures of proteins, where one or more of the proteins are modified. Specific examples of proteins include, but are not limited to, collagen, elastin, decorin, laminin, or fibronectin. In one aspect, the synthetic polymer has at least one carboxylic acid group or the salt or ester thereof, which is capable of reacting with a hydrazide or an aminooxy ether compound. In one aspect, the synthetic polymer comprises glucuronic acid, polyacrylic acid, polyaspartic acid, polytartaric acid, polyglutamic acid, or polyfumaric acid. In another aspect, the prohealing compound can be any of the supports disclosed in U.S. Pat. No. 6,548,081 B2, which is incorporated by reference in its entirety. In one aspect, the prohealing compound includes cross-linked alginates, gelatin, collagen, cross-linked collagen, collagen derivatives, such as, succinylated collagen or methylated collagen, cross-linked hyaluronan, chitosan, chitosan derivatives, such as, methylpyrrolidone-chitosan, cellulose and cellulose derivatives such as cellulose acetate or carboxymethyl cellulose, dextran derivatives such carboxymethyl dextran, starch and derivatives of starch such as hydroxyethyl starch, other glycosaminoglycans and their derivatives, other polyanionic polysaccharides or their derivatives, polylactic acid (PLA), polyglycolic acid (PGA), a copolymer of a polylactic acid and a polyglycolic acid (PLGA), lactides, glycolides, and other polyesters, polyoxanones and polyoxalates, copolymer of poly(bis(p-carboxyphenoxy)propane)anhydride (PCPP) and sebacic acid, poly(L-glutamic acid), poly(D-glutamic acid), polyacrylic acid, poly(DL-glutamic acid), poly(L-aspartic acid), poly(D-aspartic acid), poly(DL-aspartic acid), polyethylene glycol, copolymers of the above listed polyamino acids with polyethylene glycol, polypeptides, such as, collagen-like, silk-like, and silk-elastin-like proteins, polycaprolactone, poly(alkylene succinates), poly(hydroxy butyrate) (PHB), poly(butylene diglycolate), nylon-2/nylon-6-copolyamides, polydihydropyrans, polyphosphazenes, poly(ortho ester), poly(cyano acrylates), polyvinylpyrrolidone, polyvinylalcohol, poly casein, keratin, myosin, and fibrin. In another aspect, highly cross-linked HA can be the prohealing compound. In another aspect, the prohealing compound can be a polysaccharide. In one aspect, the polysaccharide has at least one group, such as a carboxylic acid group or the salt or ester thereof, that can react with a dihydrazide. In one aspect, the polysaccharide is a glycosaminoglycan (GAG). Any of the glycosaminoglycans described above can be used in this aspect. In another aspect, the prohealing compound is hyaluronan. The composite can optionally contain a second prohealing compound. In one aspect, the second prohealing compound can be a growth factor. Any substance or metabolic precursor which is capable of promoting growth and survival of cells and tissues or augmenting the functioning of cells is useful as a growth factor. Examples of growth factors include, but are not limited to, a nerve growth promoting substance such as a ganglioside, a nerve growth factor, and the like; a hard or soft tissue growth promoting agent such as fibronectin (FN), human growth hormone (HGH), a colony stimulating factor, bone morphogenic protein, platelet-derived growth factor (PDGF), insulin-derived growth factor (IGF-I, IGF-II), transforming growth factor-alpha (TGF-alpha), transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), fibroblast growth factor (FGF), interleukin-1 (IL-1), vascular endothelial growth factor (VEGF) and keratinocyte growth factor (KGF), dried bone material, and the like; and antineoplastic agents such as methotrexate, 5-fluorouracil, adriamycin, vinblastine, cisplatin, tumor-specific antibodies conjugated to toxins, tumor necrosis factor, and the like. The amount of growth factor incorporated into the composite will vary depending upon the growth factor and prohealing compound selected as well as the intended end-use of the composite. Any of the growth factors disclosed in U.S. Pat. No. 6,534,591 B2, which is incorporated by reference in its entirety, can be used in this aspect. In one aspect, the growth factor includes transforming growth factors (TGFs), fibroblast growth factors (FGFs), platelet derived growth factors (PDGFs), epidermal growth factors (EGFs), connective tissue activated peptides (CTAPs), osteogenic factors, and biologically active analogs, fragments, and derivatives of such growth factors. Members of the transforming growth factor (TGF) supergene family, which are multifunctional regulatory proteins. Members of the TGF supergene family include the beta transforming growth factors (for example, TGF-β1, TGF-β2, TGF-β3); bone morphogenetic proteins (for example, BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9); heparin-binding growth factors (for example, fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF)); inhibins (for example, Inhibin A, Inhibin B); growth differentiating factors (for example, GDF-1); and Activins (for example, Activin A, Activin B, Activin AB). Growth factors can be isolated from native or natural sources, such as from mammalian cells, or can be prepared synthetically, such as by recombinant DNA techniques or by various chemical processes. In addition, analogs, fragments, or derivatives of these factors can be used, provided that they exhibit at least some of the biological activity of the native molecule. For example, analogs can be prepared by expression of genes altered by site-specific mutagenesis or other genetic engineering techniques. In another aspect, the addition of a crosslinker can be used to couple the first compound with the prohealing compound. In one aspect, when the first compound and the prohealing compound possess free thiol groups, a crosslinker having at least two thiol-reactive electrophilic groups can be used to couple the two compounds. Additionally, the crosslinker can couple two first compounds or two prohealing compounds. In one aspect, the crosslinker is a thiol-reactive compound having two electron-deficient vinyl groups, wherein the two electron-deficient vinyl groups are the same. In another aspect, the thiol-reactive compound is a diacrylate, a dimethacrylate, a diacrylamide, a dimethacrylamide, or a combination thereof. In another aspect, the thiol-reactive compound has the formula XX discussed above. The composites described herein can assume numerous shapes and forms depending upon the intended end-use. In one aspect, the composite is a laminate, a gel, a bead, a sponge, a film, a mesh, or a matrix. The procedures disclosed in U.S. Pat. Nos. 6,534,591 B2 and 6,548,081 B2, which are incorporated by reference in their entireties, can be used for preparing composites having different forms. In one aspect, the composite is a laminate. In one aspect, the laminate includes a first layer and a second layer, wherein (1) the first layer comprises a first compound comprising a first anti-adhesion compound covalently bonded to a first anti-adhesion support, wherein the first layer has a first surface and a second surface, and (2) the second layer comprises a first prohealing compound, wherein the second layer has a first surface and a second surface, wherein the first surface of the first layer is adjacent to the first surface of the second layer. In this aspect, the first layer is adjacent to the second layer. Depending upon the selection of the first compound and the prohealing compound, the first compound and the prohealing compound can either be covalently bonded to one another or merely in physical contact with one another without any chemical reaction occurring between the two compounds. In one aspect, the first compound and the prohealing compound possess free thiol groups, which can form new disulfide bonds in the presence of an oxidant. In one aspect, a second layer of prohealing compound can be applied to a film of first layer. In one aspect, the width of the interface between the first and second layers can vary depending upon the casting time of the first layer. For example, if the casting time of the first layer is long, the width of the interface formed upon the application of the second layer will be decreased. Similarly, if the casting time of the first layer is short, a wider interface will be produced. By varying the width of the interface between the first and second layer, it is possible to create a gradient that will prevent cell growth either immediately (narrow interface) or gradually (wide interface). In another aspect, another layer of prohealing compound can be applied to the other surface of the first layer to produce a sandwich of first layer encased by prohealing compound. FIG. 4 depicts one aspect of this sandwich laminate. In one aspect, the composite can be molded into any desired shape prior to delivery to a subject. In another aspect, the second layer (prohealing compound) can be applied to a subject followed by the application of the first compound to the exposed second layer. In a further aspect, another layer containing the prohealing compound can be applied to the exposed surface of the first layer. In this aspect, a sandwich laminate is formed in situ in the subject. In one aspect, the first compound and prohealing compound can be used as a kit. For example, the first compound and prohealing compound are in separate syringes, with the contents being mixed using syringe-to-syringe techniques just prior to delivery to the subject. In this aspect, the first compound and prohealing compound can be extruded from the opening of the syringe by an extrusion device followed by spreading the mixture via spatula. In another aspect, the first compound and the prohealing compound are in separate chambers of a spray can or bottle with a nozzle or other spraying device. In this aspect, the first compound and prohealing compound do not actually mix until they are expelled together from the nozzle of the spraying device. 5. Crosslinked Proteins Described herein are methods for coupling a protein with another molecule using aminooxy ether compounds. In one aspect, a protein having at least one aminooxy-reactive group is reacted with a compound having at least one aminooxy group. In another aspect, a protein having at least one aminooxy group is reacted with a compound having at least one aminooxy-reactive group. In one aspect, the hydrazide-reactive group can be a —COOH group (or the salt or ester thereof), an aldehyde group, or a ketone group. The techniques disclosed in international publication nos. WO 02/06373 A1 and WO 02/090390 A1, which are incorporated by reference in their entireties, can be used in this aspect. In one aspect, the coupled protein has at least one fragment having the formula XXIII wherein J can be any protein residue; L can be a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyalkylene group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group, or a combination thereof; and E can be a fluorescent tag, a radiolabel, a targeting moiety, a lipid, a peptide, a radionuclide chelator with a radionuclide, a spin-label, a PEG camouflage, a metal surface, a glass surface, a plastic surface, or a combination thereof. The protein residue can be any protein that has at least one aminooxy-reactive group or at least one aminooxy group. Any of the protein known in the art capable of being modified with an aminooxy group can be used herein. In one aspect, the protein can be an extracellular matrix protein, a partially hydrolyzed extracellular matrix protein, or a chemically-modified extracellular matrix protein. In another aspect, the protein is collagen, elastin, decorin, laminin, or fibronectin. In one aspect, E in formula XXIII is a reporter group. Examples of reporter groups include, but are not limited to, a chelated paramagnetic ion for MRI imaging, a 18F-labelled compound having a thiol-reactive group for positron emission tomography, a fluorescent tag, a radiolabel, a targeting moiety, a lipid, a peptide, a radionuclide chelator with a radionuclide, a spin-label, a PEG camouflage, a glass surface, a plastic surface, or a combination thereof. Examples of spin labels include, but are not limited to, proxyl or doxyl groups. Examples of glass surfaces include, but are not limited to, glass silanized with an epoxy or activated ester or a thiol-reactive electrophilic functional group, beads, or coverslips. Examples of plastics include, but are not limited to, plasma-etched polypropylene or any other plastic material. In another aspect, described herein is a kit including (1) a compound having at least one aminooxy group; (2) a condensing agent; (3) a buffer reagent; and (4) a purification column. In one aspect, the compound can be any compound having at least one aminooxy group and at least one of the reporter groups described above. Use of the kit generally involves admixing components (1)-(3) together with a protein having at least one aminooxy-reactive group. Components (1)-(3) and the protein can be added in any order. After the protein and the compound having at least one aminooxy group have reacted with one another to produce the coupled protein, the coupled protein is then purified by passing the admixture containing the coupled protein through a purification column. Purification columns and techniques for using the same are known in the art. B. Pharmaceutical Compositions In one aspect, any of the compounds, composites, and compositions produced by the methods described above can include at least one bioactive agent defined above that is not covalently attached to the macromolecule. The resulting pharmaceutical composition can provide a system for sustained, continuous delivery of drugs and other biologically-active agents to tissues adjacent to or distant from the application site. The bioactive agent is capable of providing a local or systemic biological, physiological or therapeutic effect in the biological system to which it is applied. For example, the agent can act to control infection or inflammation, enhance cell growth and tissue regeneration, control tumor growth, act as an analgesic, promote anti-cell attachment, and enhance bone growth, among other functions. Additionally, any of the compounds, composites, and compositions described herein can contain combinations of two or more bioactive agents. In one aspect, the bioactive agents can include substances capable of preventing an infection systemically in the biological system or locally at the defect site, as for example, anti-inflammatory agents such as, but not limited to, pilocarpine, hydrocortisone, prednisolone, cortisone, diclofenac sodium, indomethacin, 6∝-methyl-prednisolone, corticosterone, dexamethasone, prednisone, and the like; antibacterial agents including, but not limited to, penicillin, cephalosporins, bacitracin, tetracycline, doxycycline, gentamycin, chloroquine, vidarabine, and the like; analgesic agents including, but not limited to, salicylic acid, acetaminophen, ibuprofen, naproxen, piroxicam, flurbiprofen, morphine, and the like; local anesthetics including, but not limited to, cocaine, lidocaine, benzocaine, and the like; immunogens (vaccines) for stimulating antibodies against hepatitis, influenza, measles, rubella, tetanus, polio, rabies, and the like; peptides including, but not limited to, leuprolide acetate (an LH-RH agonist), nafarelin, and the like. All compounds are available from Sigma Chemical Co. (Milwaukee, Wis.). Additionally, a substance or metabolic precursor which is capable of promoting growth and survival of cells and tissues or augmenting the functioning of cells is useful, as for example, a nerve growth promoting substance such as a ganglioside, a nerve growth factor, and the like; a hard or soft tissue growth promoting agent such as fibronectin (FN), human growth hormone (HGH), a colony stimulating factor, bone morphogenic protein, platelet-derived growth factor (PDGF), insulin-derived growth factor (IGF-I, IGF-II), transforming growth factor-alpha (TGF-alpha), transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), fibroblast growth factor (FGF), interleukin-l (IL-1), vascular endothelial growth factor (VEGF) and keratinocyte growth factor (KGF), dried bone material, and the like; and antineoplastic agents such as methotrexate, 5-fluorouracil, adriamycin, vinblastine, cisplatin, tumor-specific antibodies conjugated to toxins, tumor necrosis factor, and the like. Other useful substances include hormones such as progesterone, testosterone, and follicle stimulating hormone (FSH) (birth control, fertility-enhancement), insulin, and the like; antihistamines such as diphenhydramine, and the like; cardiovascular agents such as papaverine, streptokinase and the like; anti-ulcer agents such as isopropamide iodide, and the like; bronchodilators such as metaproternal sulfate, aminophylline, and the like; vasodilators such as theophylline, niacin, minoxidil, and the like; central nervous system agents such as tranquilizer, B-adrenergic blocking agent, dopamine, and the like; antipsychotic agents such as risperidone, narcotic antagonists such as naltrexone, naloxone, buprenorphine; and other like substances. All compounds are available from Sigma Chemical Co. (Milwaukee, Wis.). The pharmaceutical compositions can be prepared using techniques known in the art. In one aspect, the composition is prepared by admixing a modified or crosslinked macromolecule described herein with a bioactive agent. The term “admixing” is defined as mixing the two components together so that there is no chemical reaction or physical interaction. The term “admixing” also includes the chemical reaction or physical interaction between the compound and the pharmaceutically-acceptable compound. Covalent bonding to reactive therapeutic drugs, e.g., those having reactive carboxyl groups, can be undertaken on the compound. For example, first, carboxylate-containing chemicals such as anti-inflammatory drugs ibuprofen or hydrocortisone-hemisuccinate can be converted to the corresponding N-hydroxysuccinimide (NHS) active esters and can further react with the NH2 group of the dihydrazide-modified polysaccharide. Second, non-covalent entrapment of a bioactive agent in any of the compounds, composites, and compositions described herein is also possible. Third, electrostatic or hydrophobic interactions can facilitate retention of a bioactive agent in the compound, composite, and composition described herein. For example, the hydrazido group can non-covalently interact, e.g., with carboxylic acid-containing steroids and their analogs, and anti-inflammatory drugs such as Ibuprofen (2-(4-iso-butylphenyl) propionic acid). The protonated hydrazido group can form salts with a wide variety of anionic materials such as proteins, heparin or dermatan sulfates, oligonucleotides, phosphate esters, and the like. It will be appreciated that the actual preferred amounts of bioactive compound in a specified case will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, and the particular situs and subject being treated. Dosages for a given host can be determined using conventional considerations, e.g. by customary comparison of the differential activities of the subject compounds and of a known agent, e.g., by means of an appropriate conventional pharmacological protocol. Physicians and formulators, skilled in the art of determining doses of pharmaceutical compounds, will have no problems determining dose according to standard recommendations (Physicians Desk Reference, Barnhart Publishing (1999). Pharmaceutical compositions described herein can be formulated in any excipient the biological system or entity can tolerate. Examples of such excipients include, but are not limited to, water, saline, Ringer's solution, dextrose solution, Hank's solution, and other aqueous physiologically balanced salt solutions. Nonaqueous vehicles, such as fixed oils, vegetable oils such as olive oil and sesame oil, triglycerides, propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate can also be used. Other useful formulations include suspensions containing viscosity enhancing agents, such as sodium carboxymethylcellulose, sorbitol, or dextran. Excipients can also contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability. Examples of buffers include phosphate buffer, bicarbonate buffer and Tris buffer, while examples of preservatives include thimerosol, cresols, formalin and benzyl alcohol. Pharmaceutical carriers are known to those skilled in the art. These most typically would be standard carriers for administration to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Molecules intended for pharmaceutical delivery can be formulated in a pharmaceutical composition. Pharmaceutical compositions can include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions can also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like. The pharmaceutical composition can be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration can be topically (including ophthalmically, vaginally, rectally, intranasally). Preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles, if needed for collateral use of the disclosed compositions and methods, include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles, if needed for collateral use of the disclosed compositions and methods, include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like. Formulations for topical administration can include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be necessary or desirable. Dosing is dependent on severity and responsiveness of the condition to be treated, but will normally be one or more doses per day, with course of treatment lasting from several days to several months or until one of ordinary skill in the art determines the delivery should cease. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. In one aspect, any of the compounds, composites, and compositions described herein can include living cells. Examples of living cells include, but are not limited to, fibroblasts, hepatocytes, chondrocytes, stem cells, bone marrow, muscle cells, cardiac myocytes, neuronal cells, or pancreatic islet cells. C. Methods of Use Any of the compounds, composites, compositions, and methods described herein can be used for a variety of uses related to drug delivery, small molecule delivery, wound healing, bum injury healing, and tissue regeneration. The disclosed compounds, composites, compositions, and methods are useful for situations which benefit from a hydrated, pericellular environment in which assembly of other matrix components, presentation of growth and differentiation factors, cell migration, or tissue regeneration are desirable. The compounds, composites, and compositions described herein can be placed directly in or on any biological system without purification as it is composed of biocompatible materials. Examples of sites the compounds, composites, and compositions can be placed include, but not limited to, soft tissue such as muscle or fat; hard tissue such as bone or cartilage; areas of tissue regeneration; a void space such as periodontal pocket; surgical incision or other formed pocket or cavity; a natural cavity such as the oral, vaginal, rectal or nasal cavities, the cul-de-sac of the eye, and the like; the peritoneal cavity and organs contained within, and other sites into or onto which the compounds can be placed including a skin surface defect such as a cut, scrape or bum area. Alternatively, the compounds, composites, and compositions described herein can be used to extend the viability of of damaged skin. The compounds, composites, and compositions described herein can be biodegradable and naturally occurring enzymes will act to degrade them over time. Components of the compounds, composites, and compositions can be “bioabsorbable” in that the components of the compounds, composites, and compositions will be broken down and absorbed within the biological system, for example, by a cell, tissue and the like. Additionally, the compounds, composites, and compositions, especially the compounds, composites, and compositions that have not been rehydrated, can be applied to a biological system to absorb fluid from an area of interest. The compounds, composites, and compositions described herein can be used in a number of different surgical procedures. In one aspect, the compounds, composites, and compositions can be used in any of the surgical procedures disclosed in U.S. Pat. Nos. 6,534,591 B2 and 6,548,081 B2, which are incorporated by reference in their entireties. In one aspect, the compounds, composites, and compositions described herein can be used in cardiosurgery and articular surgery; abdominal surgery where it is important to prevent adhesions of the intestine or the mesentery; operations performed in the urogenital regions where it is important to ward off adverse effects on the ureter and bladder, and on the functioning of the oviduct and uterus; and nerve surgery operations where it is important to minimize the development of granulation tissue. In surgery involving tendons, there is generally a tendency towards adhesion between the tendon and the surrounding sheath or other surrounding tissue during the immobilization period following the operation. In another aspect, the compounds, composites, and compositions described herein can be used to prevent adhesions after laparascopic surgery, pelvic surgery, oncological surgery, sinus and craniofacial surgery, ENT surgery, or in procedures involving spinal dura repair. In another aspect, the compounds, composites, and compositions can be used in ophthalmological surgery. In ophthalmological surgery, a biodegradable implant could be applied in the angle of the anterior chamber of the eye for the purpose of preventing the development of synechiae between the cornea and the iris; this applies especially in cases of reconstructions after severe damaging events. Moreover, degradable or permanent implants are often desirable for preventing adhesion after glaucoma surgery and strabismus surgery. In another aspect, the compounds, composites, and compositions can be used in the repair of tympanic membrane perforations (TMP). The tympanic membrane (TM) is a three-layer structure that separates the middle and inner ear from the external environment. These layers include an outer ectodermal portion composed of keratinizing squamous epithelium, an intermediate mesodermal fibrous component and an inner endodermal mucosal layer. This membrane is only 130 μm thick but provides important protection to the middle and inner ear structures and auditory amplification. TMP is a common occurrence usually attributed to trauma, chronic otitis media or from PE tube insertion. Blunt trauma resulting in a longitudinal temporal bone fracture is classically associated with TMP. More common causes include a slap to the ear and the ill-advised attempt to clean an ear with a cotton swab (Q-tip™) or sharp instrument. Any of the compounds, composites, and compositions described herein can be administered through the tympanic membrane without a general anesthetic and still provide enhanced wound healing properties. In one aspect, the compounds, composites, and compositions can be injected through the tympanic membrane using a cannula connected to syringe. In another aspect, the compounds, composites, and compositions described herein can be used as a postoperative wound barrier following endoscopic sinus surgery. Success in functional endoscopic sinus surgery (FESS) is frequently limited by scarring, which narrows or even closes the surgically widened openings. Spacers and tubular stents have been used to temporarily maintain the opening, but impaired wound healing leads to poor long-term outcomes. The use of any compounds, composites, and compositions described herein can significantly decrease scar contracture following maxillary sinus surgery. In another aspect, the compounds, composites, and compositions described herein can be used for the augmentation of soft or hard tissue. In another aspect, the compounds, composites, and compositions described herein can be used to coat articles such as, for example, a surgical device, a prosthetic, or an implant (e.g., a stent). In another aspect, the compounds, composites, and compositions described herein can be used to treat aneurisms. The compounds, composites, and compositions described herein can be used as a carrier and delivery device for a wide variety of releasable bioactive agents having curative or therapeutic value for human or non-human animals. Any of the bioactive agents described above can be used in this aspect. Many of these substances which can be carried by the compounds, composites, and compositions are discussed above. Depending upon the selection of the bioactive agent, the bioactive agent can be present in the first compound or the prohealing compound. Included among pharmaceutically-acceptable compounds that are suitable for incorporation into the compounds, composites, and compositions described herein are therapeutic drugs, e.g., anti-inflammatory agents, anti-pyretic agents, steroidal and non-steroidal drugs for anti-inflammatory use, hormones, growth factors, contraceptive agents, antivirals, antibacterials, antifungals, analgesics, hypnotics, sedatives, tranquilizers, anti-convulsants, muscle relaxants, local anesthetics, antispasmodics, antiulcer drugs, peptidic agonists, sympathiomimetic agents, cardiovascular agents, antitumor agents, oligonucleotides and their analogues and so forth. The pharmaceutically-acceptable compound is added in pharmaceutically active amounts. The rate of drug delivery depends on the hydrophobicity of the molecule being released. For example, hydrophobic molecules, such as dexamethazone and prednisone are released slowly from the compound as it swells in an aqueous environment, while hydrophilic molecules, such as pilocarpine, hydrocortisone, prednisolone, cortisone, diclofenac sodium, indomethacin, 6∝-methyl-prednisolone and corticosterone, are released quickly. The ability of the compound to maintain a slow, sustained release of steroidal anti-inflammatories makes the compounds described herein extremely useful for wound healing after trauma or surgical intervention. In certain methods the delivery of molecules or reagents related to angiogenesis and vascularization are achieved. Disclosed are methods for delivering agents, such as VEGF, that stimulate microvascularization. Also disclosed are methods for the delivery of agents that can inhibit angiogenesis and vascularization, such as those compounds and reagents useful for this purpose disclosed in but not limited to U.S. Pat. Nos. 6,174,861 for “Methods of inhibiting angiogenesis via increasing in vivo concentrations of endostatin protein;” 6,086,865 for “Methods of treating angiogenesis-induced diseases and pharmaceutical compositions thereof;” 6,024,688 for “Angiostatin fragments and method of use;” 6,017,954 for “Method of treating tumors using O-substituted fumagillol derivatives;” 5,945,403 for “Angiostatin fragments and method of use;” 5,892,069 “Estrogenic compounds as anti-mitotic agents;” for 5,885,795 for “Methods of expressing angiostatic protein;” 5,861,372 for “Aggregate angiostatin and method of use;” 5,854,221 for “Endothelial cell proliferation inhibitor and method of use;” 5,854,205 for “Therapeutic antiangiogenic compositions and methods;” 5,837,682 for “Angiostatin fragments and method of use;” 5,792,845 for “Nucleotides encoding angiostatin protein and method of use;” 5,733,876 for “Method of inhibiting angiogenesis;” 5,698,586 for “Angiogenesis inhibitory agent;” 5,661,143 for “Estrogenic compounds as anti-mitotic agents;” 5,639,725 for “Angiostatin protein;” 5,504,074 for “Estrogenic compounds as anti-angiogenic agents;” 5,290,807 for “Method for regressing angiogenesis using o-substituted fumagillol derivatives;” and 5,135,919 for “Method and a pharmaceutical composition for the inhibition of angiogenesis” which are herein incorporated by reference for the material related to molecules for angiogenesis inhibition. In one aspect, the pharmaceutically-acceptable compound is pilocarpine, hydrocortisone, prednisolone, cortisone, diclofenac sodium, indomethacin, 6∝-methyl-prednisolone, corticosterone, dexamethasone and prednisone. However, methods are also provided wherein delivery of a pharmaceutically-acceptable compound is for a medical purpose selected from the group of delivery of contraceptive agents, treating postsurgical adhesions, promoting skin growth, preventing scarring, dressing wounds, conducting viscosurgery, conducting viscosupplementation, engineering tissue. In one aspect, the compounds, composites, and compositions described herein can be used for the delivery of living cells to a subject. Any of the living cells described above can be used in the aspect. In one aspect, the living cells are part of the prohealing compound. For example, when the composite is a laminate, the living cells are present in the prohealing layer. In another aspect, the compounds, composites, and compositions described herein can be used to support the growth of a variety of cells including, but not limited to, tumor cells, fibroblasts, chondrocytes, stem cells (e.g., embryonic, preadipocytes, mesenchymal, cord blood derived, bone marrow), epithelial cells (e.g., breast epithelial cells, intestinal epithelial cells), cells from neural lineages (e.g., neurons, astrocytes, oligodendrocytes, and glia), cells derived from the liver (e.g., hepatocytes), endothelial cells (e.g., vascular endothelial), cardiac cells (e.g., cardiac myocytes), muscle cells (e.g., skeletal or vascular smooth muscle cells), or osteoblasts. Alternatively, cells may be derived from cell lines or a primary source (e.g., human or animal), a biopsy sample, or a cadaver. In one aspect, the compounds, composites, and compositions can be used for the delivery of growth factors and molecules related to growth factors. Any of the growth factors described above are useful in this aspect. In one aspect, the growth factor is part of the prohealing compound. In one aspect, described herein are methods for reducing or inhibiting adhesion of two tissues in a surgical wound in a subject by contacting the wound of the subject with any of the compounds, composites, and compositions described herein. Not wishing to be bound by theory, it is believed that the first compound will prevent tissue adhesion between two different tissues (e.g., organ and skin tissue). It is desirable in certain post-surgical wounds to prevent the adhesion of tissues in order to avoid future complications. The second layer and optional third layer will promote healing of the tissues. In another aspect, when the composite is laminate, the laminate includes a first layer of anti-adhesion compound/support and a second layer composed of a prohealing compound, wherein the laminate is wrapped around a tissue. For example, the laminate can be wrapped around a tendon, where the first layer is in contact with the tendon, and the second layer is in contact with surrounding muscle tissue. In this aspect, the laminate contributes a cylindrical anti-adhesion layer around the tendon, while healing of the tendon is promoted by the inner layer of the cylindrical material. The compounds, composites, and compositions described herein provide numerous advantages. For example, the composites provide a post-operative adhesion barrier that is at least substantially resorbable and, therefore, does not have to be removed surgically at a later date. Another advantage is that the compounds, composites, and compositions are also relatively easy to use, are capable of being sutured, and tend to stay in place after it is applied. In another aspect, described herein are methods for improving wound healing in a subject in need of such improvement by contacting any of the compounds, composites, and compositions described herein with a wound of a subject in need of wound healing improvement. Also provided are methods to deliver at least one bioactive agent to a patient in need of such delivery by contacting any of the compounds, composites, and compositions described herein with at least one tissue capable of receiving said bioactive agent. The disclosed compounds, composites, and compositions can be used for treating a wide variety of tissue defects in an animal, for example, a tissue with a void such as a periodontal pocket, a shallow or deep cutaneous wound, a surgical incision, a bone or cartilage defect, bone or cartilage repair, vocal fold repair, and the like. For example, the compounds, composites, and compositions described herein can be in the form of a hydrogel film. The hydrogel film can be applied to a defect in bone tissue such as a fracture in an arm or leg bone, a defect in a tooth, a cartilage defect in the joint, ear, nose, or throat, and the like. The hydrogel film composed of the compounds, composites, and compositions described herein can also function as a barrier system for guided tissue regeneration by providing a surface on or through which the cells can grow. To enhance regeneration of a hard tissue such as bone tissue, it is preferred that the hydrogel film provides support for new cell growth that will replace the matrix as it becomes gradually absorbed or eroded by body fluids. The compounds, composites, and compositions described herein can be delivered onto cells, tissues, and/or organs, for example, by injection, spraying, squirting, brushing, painting, coating, and the like. Delivery can also be via a cannula, catheter, syringe with or without a needle, pressure applicator, pump, and the like. The compounds, composites, and compositions described herein can be applied onto a tissue in the form of a film, for example, to provide a film dressing on the surface of the tissue, and/or to adhere to a tissue to another tissue or hydrogel film, among other applications. In one aspect, the compounds, composites, and compositions described herein are administered via injection. For many clinical uses, when the compounds and composites are in the form of a hydrogel film, injectable hydrogels are preferred for three main reasons. First, an injectable hydrogel could be formed into any desired shape at the site of injury. Because the initial hydrogels can be sols or moldable putties, the systems can be positioned in complex shapes and then subsequently crosslinked to conform to the required dimensions. Second, the hydrogel would adhere to the tissue during gel formation, and the resulting mechanical interlocking arising from surface microroughness would strengthen the tissue-hydrogel interface. Third, introduction of an in situ-crosslinkable hydrogel could be accomplished using needle or by laparoscopic methods, thereby minimizing the invasiveness of the surgical technique. The compounds, composites, and compositions described herein can be used to treat periodontal disease, gingival tissue overlying the root of the tooth can be excised to form an envelope or pocket, and the composition delivered into the pocket and against the exposed root. The compounds, composites, and compositions can also be delivered to a tooth defect by making an incision through the gingival tissue to expose the root, and then applying the material through the incision onto the root surface by placing, brushing, squirting, or other means. When used to treat a defect on skin or other tissue, the compounds, composites, and compositions described herein can be in the form of a hydrogel film that can be placed on top of the desired area. In this aspect, the hydrogel film is malleable and can be manipulated to conform to the contours of the tissue defect. The compounds, composites, and compositions described herein can be applied to an implantable device such as a suture, claps, stents, prosthesis, catheter, metal screw, bone plate, pin, a bandage such as gauze, and the like, to enhance the compatibility and/or performance or function of an implantable device with a body tissue in an implant site. The compounds, composites, and compositions can be used to coat the implantable device. For example, the compounds, composites, and compositions could be used to coat the rough surface of an implantable device to enhance the compatibility of the device by providing a biocompatible smooth surface which reduces the occurrence of abrasions from the contact of rough edges with the adjacent tissue. The compounds, composites, and compositions can also be used to enhance the performance or function of an implantable device. For example, when the compounds, composites, and compositions are a hydrogel film, the hydrogel film can be applied to a gauze bandage to enhance its compatibility or adhesion with the tissue to which it is applied. The hydrogel film can also be applied around a device such as a catheter or colostomy that is inserted through an incision into the body to help secure the catheter/colosotomy in place and/or to fill the void between the device and tissue and form a tight seal to reduce bacterial infection and loss of body fluid. In one aspect, the aminooxy-derivatized polymers such as, for example, pluronics, can couple to GAGs such as, for example, hyaluronan or heparin, and self-assemble into hydrogels. Alternatively, solutions of aminooxy derivatized polymer-GAGs can be coated on a hydrophobic surface such as, for example, a medical device. For example, heparin can be coupled with an aminooxy-derivatized pluronic, wherein the resultant gel possesses desirable growth-binding factor capabilities but does not possess anti-coagulant properties associated with heparin. Not wishing to be bound by theory, the pluoronic portion of the hydrogel can prevent coagulation, which is undesirable side-effect of heparin. In one aspect, aminooxy derivatized polymer-hyaluronan can prevent biofilm formation on a surface because hyaluronan can block bacterial adhesion to the surface of a device. It is understood that the disclosed compounds, composites, and compositions can be applied to a subject in need of tissue regeneration. For example, cells can be incorporated into the composites described herein for implantation. Examples of subjects that can be treated with the compounds, composites, and compositions described herein include mammals such as mice, rats, cows or cattle, horses, sheep, goats, cats, dogs, and primates, including apes, chimpanzees, orangatangs, and humans. In another aspect, the compounds, composites, and compositions described herein can be applied to birds. When being used in areas related to tissue regeneration such as wound or burn healing, it is not necessary that the disclosed compounds, composites, and compositions, and methods eliminate the need for one or more related accepted therapies. It is understood that any decrease in the length of time for recovery or increase in the quality of the recovery obtained by the recipient of the disclosed compounds, composites, and compositions, and methods has obtained some benefit. It is also understood that some of the disclosed compounds, composites, and compositions, and methods can be used to prevent or reduce fibrotic adhesions occurring as a result of wound closure as a result of trauma, such surgery. It is also understood that collateral affects provided by the disclosed compounds, composites, and compositions, and methods are desirable but not required, such as improved bacterial resistance or reduced pain etc. In one aspect, the compounds or compositions described herein can be used to prevent airway stenosis. Subglottic stenosis (SGS) is a condition affecting millions of adults and children world-wide. Causes of acquired SGS range from mucosal injury of respiratory epithelia to prolonged intubation. Known risk factors of SGS in intubated patients include prolonged intubation, high-pressure balloon cuff, oversized endotracheal (ET) tube, multiple extubations or re-intubations, and gastro-esophageal reflux. There are also individuals in whom stenosis develops as a result of surgery, radiation, autoimmune disease, tumors, or other unexplained reasons. While very diverse, the etiologies of SGS all have one aspect in common, narrowing of the airway resulting in obstruction. This narrowing most commonly occurs at the level of the cricoid cartilage due to its circumferential nature and rigidity. Such etiologies have been found in various SGS models: activation of chondrocytes and formation of fibrous scar, infiltration of polymorphonuclear leukocytes and chronic inflammatory cells with squamous metaplasia, and morphometric changes in airway lumen. Each presents a problem requiring immediate attention. In another aspect, any of the compounds or compositions described herein can be used as a 3-D cell culture. In one aspect, the hydrogel can be lyophilized to create a porous sponge onto which cells may be seeded for attachment, proliferation, and growth. It is contemplated that miniarrays and microarrays of 3-D hydrogels or sponges can be created on surfaces such as, for example, glass, and the resulting gel or sponge can be derived from any of the compounds or compositions described herein. The culture can be used in numerous embodiments including, but not limited to, determining the efficacy or toxicity of experimental therapeutics. It is understood that any given particular aspect of the disclosed compositions and methods can be easily compared to the specific examples and embodiments disclosed herein, including the non-polysaccharide based reagents discussed in the Examples. By performing such a comparison, the relative efficacy of each particular embodiment can be easily determined. Particularly preferred assays for the various uses are those assays which are disclosed in the Examples herein, and it is understood that these assays, while not necessarily limiting, can be performed with any of the compositions and methods disclosed herein. EXAMPLES The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, and methods described and claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions. I. Synthesis of Carboxymethyl Derivatives of Hyaluronan 1. Materials Fermentation-derived hyaluronan (HA, sodium salt, Mw 1.5 MDa) was purchased from Clear Solutions Biotechnology, Inc. (Stony Brook, N.Y.). 1-Ethyl-3-[3-(dimethylamino)propyl] carbodiimide (EDCI), and chloroacetic acid were purchased from Aldrich Chemical Co. (Milwaukee, Wis.). Poly(ethylene glycol) diacrylate (Mw 3400 Da) was purchased from Nektar Therapeutics (formerly Shearwater)(Huntsville, Ala.). Dulbecco's phosphate buffered saline (DPBS), cysteine and bovine testicular hyaluronidase (HAse, 330 U/mg) was obtained from Sigma Chemical Co. (St. Louis, Mo.). Dithiothreitol (DTT) was purchased from Diagnostic Chemical Limited (Oxford, Conn.). 3,3′-Dithiobis(propanoic dihydrazide) (DTP) was synthesized as described before. (Vercruysse, K. P.; Marecak, D. M.; Marecek, J. F.; Prestwich, G. D. Synthesis and in vitro degradation of new polyvalent hydrazide cross-linked hydrogels of hyaluronic acid. Bioconjugate Chem. 1997, 8, 686-694; Shu, X. Z.; Liu, Y.; Luo, Y.; Roberts, M. C.; Prestwich, G. D. Disulfide crosslinked hyaluronan hydrogels. Biomacromolecules 2002, 3, 1304-1311). 2. Analytical Instrumentation Proton NMR spectral data were obtained using a Varian INOVA 400 at 400 MHz. UV-vis spectral data were recorded using a Hewlett Packard 8453 UV-visible spectrophotometer (Palo Alto, Calif.). Gel permeation chromatography (GPC) analysis was performed using the following system: Waters 515 HPLC pump, Waters 410 differential refractometer, Waters™ 486 tunable absorbance detector, Ultrahydrogel 250 or 1000 columns (7.8 mm i.d.×130 cm) (Milford, Mass.). The eluent was 200 mM phosphate buffer (pH 6.5): MeOH=80:20 (v/v) and the flow rate was either 0.3 or 0.5 ml/min. The system was calibrated with standard HA samples provided by Dr. U. Wik (Pharmacia, Uppsala, Sweden). Fluorescence images of viable cells were recorded using confocal microscopy (LSM 510 Carl Zeiss Microimaging, Inc., Thornwood, N.Y.). Cell proliferation was determined by MTS assay at 550 mn, which was recorded on an OPTImax microplate reader (Molecular Devices, Sunnyvale, Calif.). 3. Synthesis of Carboxymethyl-HA (CM-HA or Carbylan™) (FIG. 5) HA powder (20 g) was added to a 500-ml beaker. Aqueous NaOH solution (200 ml, 45% w/v) was added to the beaker and stirred mechanically (with a spatula) at ambient temperature until a paste formed, which takes about 5 minutes or less for the paste to form. After standing for 2 hours, the HA paste was transferred into a 5,000-ml beaker with 1,500 ml isopropanol and a Teflon-coated magnetic stir bar, and then a solution of 20 g of chloroacetic acid in 500 ml isopropanol was added with magnetic stirring. After 1 hour stirring at ambient temperature, the product was collected by filtration using a paper filter in a porcelain filter. The beaker was washed with a small amount of isopropanol to recover the modified pasty product. The crude filtrate was then dissolved in 2,000 ml of distilled water. The solution pH was adjusted to ca. pH 7.0 by adding 6.0 N HCl. Next, the solution was purified by dialysis (dialysis tubing, Mw cutoff 3,500) extensively (currently 2 days, with 8 changes of outside water solution) and then lyophilized to give solid white Carbylan™ (ca. 15 g) as a white foam. 4. Synthesis of Carboxymethyl-HA (CM-HA-DTPH or Carbylan™-S) (FIG. 5) HA powder (20 g) was added to a 500-ml beaker. Aqueous NaOH solution (200 ml, 45% w/v) was added to the beaker and stirred mechanically (with a spatula) at ambient temperature until a paste formed, which takes about 5 minutes or less for the paste to form. After standing for 2 hours, the HA paste was transferred into a 5,000-ml beaker with 1,500 ml isopropanol and a Teflon-coated magnetic stir bar, and then a solution of 20 g of chloroacetic acid in 500 ml isopropanol was added with magnetic stirring. After 1 hour stirring at ambient temperature, the product was collected by filtration using a paper filter in a porcelain filter. The beaker was washed with isopropanol to recover the product. The crude filtrate was then dissolved in 2,000 ml of distilled water. The solution pH was adjusted to ca. pH 7.0 by adding 6.0 N HCl. Next, the solution was purified by dialysis (dialysis tubing, Mw cutoff 3,500) for 24 h with 4 changes of water. The dialyzed solution of Carbylan™ can be used directly in following step, or can be degraded to lower molecular weight as described below. (Optional-acid degradation to reduce molecular weight) The purified solution was transferred into a 5000-ml beaker, and then 80 ml of 6.0 N HCl was added and the solution was stirred magnetically at room temperature. Then, the mixture was transferred to an rotary incubator (37° C., 150 rpm) for defined time. Typically, 24 h of stirring under these conditions would afford Carbylan™ with approximately 100-150 kDa molecular weight. DTP (16.7 g, 0.07 mol) was added to the Carbylan™ solution, and the solution pH was adjusted to 4.75 by adding either HCl or NaOH solution. Then, 6.72 g (0.035 mol) EDCI was added, and the solution pH was maintained at a pH of 4.75 by adding 1.0 N HCl with continuous magnetic stirring at room temperature. After 4 h, 50 g of DTT was added, and the solution pH was adjusted to 8.5 by adding conc. NaOH solution. Then after 12-24 h under magnetic stirring at room temperature, the pH of the reaction mixture was adjusted to pH 3.5 by the addition of 1.0 N HCl. The acidified solution was transferred to dialysis tubing (Mw cut-off 3,500) and dialyzed exhaustively against dilute HCl (pH 3.5) containing 100 mM NaCl, followed by dialysis against dilute HCl, pH 3.5. The solution was then centrifuged, and the supernatant was lyophilized to give solid white Carbylan™-S (ca. 13 g). 5. Characterization of Carbylan™ and Carbylan™-S a. 1H NMR spectra in D2O of Carbylan™ and Carbylan™-S Carbylan™ and Carbylan™-S were dissolved in D2O, and 1H-NMR spectral data were obtained using a Varian INOVA 400 at 400 MHz. Compared to the spectrum of HA (the N-acetyl methyl protons of HA were at δ 1.95), new resonance for Carbylan™ appeared at δ4.05-4.20, corresponding to the side chain methylene (CH2OCH2COO−Na+). Another two new resonances for Carbylan™-S appeared at δ 2.72 and δ 2.58, which correspond to the two side chain methylenes in the DTPH modification (CH2CH2SH) (FIG. 6). b. Determination of in vitro Cytotoxicity of Carbylan™ and Carbylan™-S Carbylan™ and Carbylan™-S were dissolved in complete DMEM/F-12 medium supplemented with 10% new-born calf serum, 2 mM L-glutamine and 100 units/ml antibotic-antimycotic (GIBCO BRL, Life Technologies, Grand Island, N.Y.), to give 1, 2.5, 5 and 10 mg/ml solutions. NIH 3T3 fibroblast was cultured in 96-well plate for 24 h (5,000 cells/well), then 0.2 ml above solutions were added into each well. After culture in vitro for 2 and 24 h, the live cell count was determined using the CyQUANT™ cell proliferation assay and MTS assay (FIG. 7). The CyQUANT™ cell proliferation assay is a cellular nucleic acid determination method, which is linear with the density of cells in culture. This assay revealed that that Carbylan™ and Carbylan™-S are fully cytocompatible. That is, the cell density after culturing fibroblasts in medium containing 1 mg/mil, 2.5 mg/ml, 5 mg/ml and 10 mg/ml of either Carbylan™ or Carbylan™-S is comparable to that for cells cultured in the control medium (results not shown). The MTS assay is a colorimetric method for determining the number of viable cells in culture. In this assay, a tetrazolium salt (MTS) becomes reduced by the mitochondria of living cells into a colored formazan product, the presence of which can be detected with a spectrophotometer. The results in FIG. 7 indicated that Carbylan™ and Carbylan™-S are fully cytocompatible; indeed, they may even enhance mitochondrial function. c. Carbylan™-S Gelation in Air 2 mL each of high, medium and low molecular weight Carbylan-S at a concentration of 1.25% were used as starting materials. Through a series of dilutions, 300 μL of 4 different concentrations (1.25%, 0.625%, 0.3125% and 0.15625%) were tested for time to gelation in air (without a crosslinker). The fields marked with a time in Tables 3-5 are the time at which the material formed a gel. The fields with no time recorded are the materials that have not yet formed a gel. Carbylan-S at the 0.3125% and 0.15625% concentrations for all three molecular weights was tested for gelation at pH 5.5. None of these materials have formed a gel yet. TABLE 3 (25° C.; pH 7.4) 1.25% hmw 0.625% hmw 0.3125% hmw 0.15625% hmw Carbylan-S Carbylan-S Carbylan-S Carbylan-S II. 8 Hours III. 22 Hours IV. 42 Hours V. No Gel Formation 1.25% mmw 0.625% mmw 0.3125% mmw 0.15625% mmw Carbylan-S Carbylan-S Carbylan-S Carbylan-S VI. 36 Hours VII. 57 Hours VIII. 153 Hours No Gel Formation 1.25% lmw 0.625% lmw 0.3125% lmw 0.15625% lmw Carbylan-S Carbylan-S Carbylan-S Carbylan-S IX. 63 Hours X. 131 Hours XI. 244 Hours No Gel Formation TABLE 4 (37° C.; pH 6.5) 1.25% hmw 0.31% hmw 0.125% hmw 0.031% hmw Carbylan-S Carbylan-S Carbylan-S Carbylan-S XII. 77 Hours XIII. 103 Hours No Gel Formation No Gel Formation 1.25% mmw 0.31% mmw 0.125% mmw 0.031% mmw Carbylan-S Carbylan-S Carbylan-S Carbylan-S XIV. 128 Hours 114 Hours No Gel Formation No Gel Formation 1.25% lmw 0.31% lmw 0.125% lmw 0.031% lmw Carbylan-S Carbylan-S Carbylan-S Carbylan-S 222 Hours 279 Hours No Gel Formation No Gel Formation TABLE 5 (37° C.; pH 5.5) 1.25% hmw 0.31% hmw 0.125% hmw 0.031% hmw Carbylan-S Carbylan-S Carbylan-S Carbylan-S XV. 279 Hours XVI. 307 Hours No Gel Formation No Gel Formation 1.25% mmw 0.31% mmw 0.125% mmw 0.031% mmw Carbylan-S Carbylan-S Carbylan-S Carbylan-S XVII. 291 Hours 322 Hours No Gel Formation No Gel Formation 1.25% lmw 0.31% lmw 0.125% lmw 0.031% lmw Carbylan-S Carbylan-S Carbylan-S Carbylan-S XVIII. > 400 >400 Hours No Gel Formation No Gel Hours Formation 6. Crosslinking of Carbylan™-S and Gelatin-DTPH with PEGDA to give Carbylan™-SX and Carbylan™-GSX (FIG. 8) Hydrogels (Carbylan™-SX) were formed by Michael-type conjugate addition of Carbylan™-S to poly(ethylene glycol)diacrylate PEGDA using techniques described in International Patent Application Publication No. WO 2004/037,164, which is incorporated by reference in its entirety. The gelation time depends primarily on the concentration of Carbylan™-S and PEGDA, the thiol:acrylate ratio, and the pH. By optimizing these parameters, Carbylan™-SX can be formulated as an in situ-crosslinking injectable product for a variety of medical applications. Carbylan™-GSX was produced by reacting Carbylan™-S, gelatin-DTPH, and PEGDA (FIG. 8). The linker as labeled in FIG. 8 is derived from PEGDA. a. Dynamic Mechanical Properties of Carbylan™-SX Gelation of hydrogels with varying linker lengths, crosslinking ratios and concentrations was quantitatively examined using dynamic rheology (Model AR550; TA Instruments; New Castle, Del.) according to ASTM D4473-01. The response of the hydrogel to the applied stress was measured and the storage modulus (G′), loss modulus (G″) and dynamic viscosity (η*) were examined over time. Gel point was defined as the time at which the storage modulus (G′) and loss modulus (G″) curves cross and where there is a dramatic increase in complex viscosity, representing a change in hydrogel behavior from more viscous to more elastic (Peter, Kim et al. 1999; Nowak, Breedveld et al. 2002; Au, Ha et al. 2003). For this study, a parallel plate set up was used with 20 mm diameter plates and a 0.8 mm gap. The Carbylan™-S and PEDGA were vortex mixed and the suspension was immediately placed on the Teflon plate of the rheometer. The stainless steel parallel plate geometry was lowered approximately 0.2 mm into the sample, and time-dependent changes in G′, G″ and η* were recorded during an oscillatory controlled stress experiment with a time sweep. All tests were performed at room temperature under a controlled frequency of 1 Hz and 0.25% strain to avoid destroying sample structure. The crossover of the G′ and G″ curves as well as the slope of the complex viscosity curve were analyzed using Rheology Advantage Data Analysis software (v4.1.2; TA Instruments). In FIG. 9, the data show that the gel point ranges from approximately 10 minutes to almost 170 minutes. Higher molecular weights for both the starting material, Carbylan™-S, and crosslinker, PEGDA, generally result in materials with a faster gel time. In FIG. 10, the graph shows the slope of the complex viscosity, η*, curve from the gel point to approximately 10 minutes following the onset of gelation. The slope of this curve describes the speed with which the material's viscosity increases. While two materials may have similar gel points, their viscosity may increase a different rates giving the materials different properties at different times following gelation. b. Enzymatic degradation in vitro of Carbylan™-SX Hydrogel preparation. A 1.25% (w/v) solution of Carbylan™-S was prepared in DPBS, and then the solution ph was adjusted to 7.4 by adding 0.1 N NaOH. Then Carbylan™-SX hydrogel was prepared in a petri dish (3.5 cm in diameter) by adding 1.2 ml 4.5% (w/v) PEGDA in DPBS into 4.8 ml of an aqueous Carbylan™-S solution. The hydrogel was allowed to react to completion for 4-12 hours. A 3.0-mm diameter biopsy punch was then used to cut a cylindrical piece of hydrogel from the gel in a petri dish. This disc was placed into a small glass vial containing 2.0 ml of hyaluronidase (HAse) solutions (0, 0.5 U/ml, 2 U/ml and 20 U/ml) that were prepared in 30 mM citric acid, 150 mM Na2HPO4, 150 mM NaCl (pH 6.3). The vials were incubated at 37° C. with orbital agitation at 150 rpm. The weight of each sample was monitored using a digital scale and was measured every 24 hrs for 5 days. The samples were removed from the incubator and the enzyme solution was discarded. The hydrogel cylinders were then placed on filter paper and allowed to blot dry for several seconds. The samples were then weighed using a digital scale and returned to the glass vial with fresh HAse solution. The weight loss fraction was defined as 1−Wt/Wo, where Wt is the weight of the sample at time t and Wo is the original weight of the sample. The values for the weight loss percent were plotted as a function of time shown in FIG. 11. The result indicated that the digestion was dependent on enzyme concentration. After 5 days at 37° C. with gentle agitation, ca. 63% of the hydrogel was digested at the highest HAse concentration (20 U/ml) employed. No significant degradation occurred in the absence of added HAse. This result revealed that Carbylan™-SX is slowly hydrolyzed in vivo and that this degradation rate is similar to that found previously for PEGDA-crosslinked HA-DTPH. II. Applications of Carbylan™-SX and Carbylan™-GSX 1. Prophylaxis of Extracellular Matrix (ECM)-Based Dysphonias With Carbylan™-SX Hydrogels Utilization of injectable proprietary chemically-modified HA derivatives at the time of intentional resection may facilitate wound repair for prevention of ECM based dysphonias. Thirty-three rabbit vocal folds were biopsied bilaterally. Two groups of rabbits were unilaterally treated with two different HA-based hydrogels (Carbylan™-SX and HA-DTPH-PEGDA) at the time of resection. At first, a 1.5% (w/v) Carbylan™-S (medium molecular weight, 50% degree of substitution) solution and 1.5% (w/v) HA-DTPH (medium molecular weight, 50% degree of substitution) solution were prepared in DPBS. The solution pH was then adjusted 7.4 by adding 0.1 N NaOH. The solutions were then sterilized by filtering through 0.45 μm filter. Finally, hydrogels of Carbylan™-SX and HA-DTPH-PEGDA were prepared by adding 4.5% PEGDA (MW 3400) into the corresponding Carbylan™-S or HA-DTPH solution with volume ratio of 1 to 4. Just prior to gelation, i.e., within 5-10 min, the partially gelled hydrogels were injected into the one vocal fold of the rabbit while saline was injected into the contralateral fold. Animals were sacrificed three weeks after biopsy and injection. Levels of HA in the treated vocal folds were not significantly different than controls as measured by ELISA (result not shown). Vocal folds receiving the Carbylan™-SX injections had significantly improved biomechanical properties relative to controls. Both elasticity and viscoelasticty were improved and were very close to the properties of normal vocal folds, as measured with a Bohlin CVO Rheometer (FIG. 12). HA-DTPH-PEGDA injections yielded significantly improved viscosity but not improved elasticity. Prophylactic in vivo manipulation of the ECM with our injectable Carbylan™-SX hydrogel appears to induce tissue regeneration to yield optimal tissue composition and biomechanical properties. 2. Use of Carbylan™-SX in Preventing Airway Stenosis Materials and Methods Twenty-four white, female New Zealand rabbits were chosen as subjects. They ranged in weight from 3.0 to 4.5 kgs. Rabbits were randomly assigned to one of four different groups. Group 1, six rabbits underwent airway injury with no further interventions. Group 2, six rabbits underwent airway injury and were immediately stented with dry (uncoated) stents. Group 3, six rabbits underwent airway injury and were immediately stented with a HA-gel coated stents. Group 4, six rabbits underwent airway injury and were immediately stented with HA-film coated stents. Stent Preparation A 1.5% (w/v) carbylan™-S (medium molecular weight, 50% degree of substitution) solution was prepared in DPBS. Then the solution pH was adjusted 7.4 by adding 0.1 N NaOH solution, and then the solutions were sterilized by filtering through 0.45 μm filter. After that a 4.5% PEGDA (MW 3400) solution in DPBS was added carbylan™-S solution according to volume ratio of 1 to 4. Right before its gelation, the gelling hydrogels were coated on the outside of tracheal stents that were fashioned out of 1 cm segments of polyvinylchloride (PVC) endotracheal (ET) tubes. Stents were cut from 3.0 mm ID ET tubing for group 3 and 3.5 mm ID ET tubing for groups 2 & 4. The stents were 1 cm in length based on previous success in a rabbit model. Then the coated tube was dried in sterile culture hood. The Carbylan™-S gel-coated stents were prepared in the operating suite just prior to implantation. Procedures All animals were anesthetized intramuscularly prior to procedures. Tracheal injury and stent placement were performed by anterior. A mid-line incision was made from the inferior border of the cricothyroid space to the superior border of the third tracheal ring, completely bisecting the cricoid cartilage. After opening the airway, the tracheal mucosa was denuded ¾ of the complete circumference, at the level of the cricoid, using a j-curette. Epithelial scrapings were limited to 6 mm in longitudinal length. Stents were then implanted in study groups 2-4 and anchored in place with one nylon suture tied external to the skin of the neck. The trachea and neck were then closed with Vicryl® sutures and the rabbits were allowed to recover three weeks. After three weeks recovery the tracheal stents were removed using a trans-oral endoscopic technique. The animals were then given an additional three weeks recovery prior to euthanasia. They were then sacrificed and the airways were harvested for histological and morphometric measurements. Results Preliminary results have shown that airway cross-sectional areas are significantly smaller in study groups 1 & 2. The average lumen area in group 2 was measured to be 37,904 while those of groups 3 & 4 were 296,024 and 186,444 (FIG. 13A). These numbers are unit-less as they were assigned by imaging software (imageProPlus). In addition to having larger cross-sectional areas, groups 3 & 4 also appear to have largest diameter measurements when comparing smallest diameters (˜463 and ˜315) (FIG. 13B). Likewise, these measurements were made by imaging software and are therefore unit-less. 3. Prevention of Ostia Scarring After Sinus Surgery Materials Carbyla™-S was prepared using the techniques described above at three different molecular weights (low (LMW), medium (MMW) and high (HMW)). Two different starting concentrations (1.25 and 1.75 mg/ml) were crosslinked to form Carbylan™-SX with three different sizes of PEGDA (1000, 3400 and 10,000 Da) at three different crosslinking ratios (PEGDA:thiol=1:2, 1:3 and 1:4). Gels with favorable rheological properties were used to establish efficacy of nanostenting Carbylan™-SX gels in preventing sinus scarring in vivo in a rabbit sinus ostium model. Briefly, the animals were anesthetized and the soft tissue and periosteum overlying the maxillary sinuses was elevated. The anterior wall of the maxillary sinus was removed with a microsurgical drill and 4 mm. through-and-through wounds created within the medial walls of the sinuses. The gels were injected into one side (chosen randomly); the contralateral sinus wound was untreated. In this way, each animal had an experimental and control side. After 14 days, the animals were euthanized and the wounds examined. The diameter of each rabbit ostia was measured and the untreated and experimental groups were compared using a paired, two-tailed Student's t test with significance at p<0.05. Results For ease of application, the ideal material would exhibit a fast gelation time 25 coupled with a rapid increase in viscosity with the intention that a physician could mix the Carbylan™-S with PEGDA and inject into a patient without much delay and have the material remain in the sinus cavity. From examination of the rheological data, six combinations of the starting material, linker length and crosslinking ratio best suited for nanostenting gels were chosen from the original fifty-four and are shown in Table 6. TABLE 6 Six combinations of Carbylan ™-SX chosen for use in animal studies Starting Material Crosslinker/Ratio 1.75% HMW Carbylan ™-S 3400 Da PEGDA, 1:4 1.75% HMW Carbylan ™-S 10 kDa PEGDA, 1:4 1.25% MMW Carbylan ™-S 3400 Da PEGDA, 1:2 1.25% MMW Carbylan ™-S 3400 Da PEGDA, 1:4 1.75% MMW Carbylan ™-S 10 kDa PEGDA, 1:4 1.75% MMW Carbylan ™-S 3400 Da PEGDA, 1:4 These six materials will then be used for further animal studies. Preliminary results from animal studies performed with the MMW Carbylan™-S crosslinked with the 3400 Da PEGDA at a ratio of 1:4 are shown in FIG. 14. For the untreated side, the ostial diameter for 8 animals was 0.6 mm, this opening significantly increased to 2.2 mm following treatment with Carbylan™-SX. The data show that Carbylan™-SX application following sinus surgery significantly decreases scar contracture. 4. Co-Crosslinked Gelatin-DTPH With Carbylan™-SX as a Matrix for Cell Growth a. The Cytoskeletal Organization of NIH 3T3 on Hydrogel Surface Solution preparation. Carbylan™-S and gelatin-DTPH were dissolved in cell culture medium to give 1.5% (w/v) and 3.0% (w/v) solution respectively. The solution pH was adjusted to 7.4 with 0.1 N NaOH. PEGDA (MW 3400) was dissolved in DPBS to give a 4.5% (w/v) stock solution to produce Carbylan™-GSX (FIG. 8). Each of the three solutions was sterilized by filtering through 0.45 μm filters. Blends. The Carbylan™-S solution and gelatin-DTPH solution were mixed according to volume ratio 100/0, 85.7/14.3, 66.3/33.3, 31.5/68.5 and 0/100, which is corresponds to a weight ratio of 100/0, 75/25, 50/50, 25/75 and 0/100. Hydrogel preparation. Four volumes of the blended solutions were crosslinked by adding one volume of the PEGDA stock solution, mixing, and placing a 0.3-ml aliquot was injected into each well of 24 well plates for gelation to occur. Cell culture. After 1 h, 30,000 NIH 3T3 fibroblasts were seeded onto the surface of each hydrogel. After 24 h culture in vitro, cells were fixed by formalin and stained with Oregon green. The result in FIG. 15 indicated that Carbylan™-SX is a good candidate for anti-adhesion, since fibroblasts fail to attach (FIG. 15a). In contrast, the blended Carbylan™-SX/gelatin-DTPH (Carbylan™-GSX) was an excellent matrix for cell attachment and spreading, and promotes cell growth (FIG. 15b, c, d) similar to the results obtain in disulfide crosslinked HA-gelatin gels and sponges. More actin filaments formed in the blended hydrogel (FIG. 15g) than gelatin-DTPH hydrogel alone and also control (tissue culture plate). b. Cell Proliferation on Hydrogel Surfaces Blended hydrogels were prepared on the bottom of the 96 well plates as described in section i, and then 2,500 NIH 3T3 fibroblast was seeded on hydrogel surface of each well. After in vitro culture for 24, 48 and 96 h, the cell number was determined by MTS assay (FIG. 16). The results also indicated that Carbylan™-SX/gelatin-DTPH blended hydrogels (Carbylan™-GSX) are better matrices for supporting cell proliferation than gelatin-DTPH alone and control (tissue culture plate). 5. Tympanic Membrane Perforation Repair Methods The following materials were prepared for analysis of TMP repair: Carbylan™-S, Gelatin-DTPH, Carbylan™-S/Gelatin-DTPH (Carbylan™-GSX), Gelfoam™, and Epifilm™. Briefly, Carbylan™-S was dissolved in DBPS buffer to form a 1.5% (w/v) solution. The pH was adjusted to 7.4 using aliquots of NaOH. Gelatin-DTPH was dissolved in DPBS buffer to form a 3.0% (w/v) solution and the pH was adjusted to 7.4 using aliquots of NaOH. PEGDA (Nektar) was dissolved in DBPS buffer to fonn a 4.5% (w/v) solution. The solutions were then sterilized in a sterilization hood using a bottle top filter (Corning) with a 0.45 μm cellulose acetate membrane. After sterilization, the solutions were placed in 1.0 ml sterile centrifuge tubes containing 0.4 ml of Carbylan™-S, 0.4 ml of Carbylan™-S/Gelatin-DTPH (1:1 w/w), 0.4 ml of Gelatin-DTPH, and 0.1 ml of PEGDA for the proper mixture of 4:1 GAG to crosslinker ratio. The materials were then frozen at −80° C. for later use. Epifilm™ (Medtronic) and Gelfoam™ (Pfizer) were purchased already sterilized for the study. Hartley pigmented guinea pigs (Elm Hill) were obtained and anesthetized using isoflurane gas. Auditory brainstem response (ABR) tests were then performed using Intelligent Hearing System (SmartEP™) software. A myringotomy (perforation) was then performed on both ears just anterior to the umbo. One ear was left as a control while the contralateral ear was injected through the myringotomy site. Approximately 0.4 ml of Carbylan™-S, Carbylan™-S/Gelatin-DTPH, and Gelatin-DTPH were aspirated into a 1 ml syringe along with 0.1 ml of the crosslinker PEGDA. The materials were then mixed thoroughly and injected into the middle ear via the myringotomy site and allowed to gel for several minutes. The hydrogels formed in 7-14 min. The animals were examined daily until the TMP was fully closed. Results The results of the study are displayed in FIG. 17. Carbylan™-SX/Gelatin-DTPH-PEGDA (Carbylan™-GSX) had the quickest time of 1.8±0.45 days followed by Gelfoam™ at 3.5±0.71 days, Carbylan™-SX at 3.7±2.5 days and the control at 4.2±1.1 days. Epifilm™ and Gelatin-DTPH had values higher than the control at 4.7±1.5 and 4.7±1.2 respectively. There were no significant differences observed between the pre- and post-operative ABR data. This study demonstrates the validity of Carbylan™-S Gelatin-DTPH-PEGDA as a material to promote re-epithelialization and complete closure of TMP's within 2 days (FIG. 18). This will allow the procedure to be performed in-office and eliminate the morbidity associated with the anesthesia involved in the current treatment. 6. Prevention of Intraperitoneal Adhesions Using Carbylan-SX Films in Rat Uterine Horn Model (Pilot Study) Grouping: four rats/per group. (1) No treatment; (2) Carbylan-S-PEGDA (Carbylan-SX) film; and (3) Carbylan-SX film with 0.5% MMC. The rats were sacrificed two weeks after the surgery. The adhesions between the two injured uterine horns were assessed macrographically. Then the uterine horns with surrounding tissues were excised and processed for Masson's trichrome staining. Results are shown in FIGS. 19 and 20. FIG. 19 shows the macrographical observation of uterine horns after different treatment. Panel a, without treatment, very firm adhesion formed between two uterine horns. Adhesions were also found between the uterine horn and surrounding intraperitoneal fat. Panel b, treated with Carbylan-S-PEGDA film, no adhesions formed between two uterine horns but there were some degree of adhesions formed between the uterine horn and surrounding intraperitoneal fat. Panel c, treated with carbylan-S-MMC(0.5%)-PEGDA film, no adhesions formed between two uterine horns. No adhesions formed between the uterine horn and surrounding intraperitoneal fat. FIG. 20 shows the histological observation of uterine horns after different treatments. Panel a, no treatment; very firm adhesions formed between the two uterine horns. Adhesions were also found between the uterine horn and surrounding intraperitoneal fat. Panel b, treated with Carbylan™-SX film; no adhesions formed between two uterine horns but there was some degree of adhesions formed between the uterine horn and surrounding intraperitoneal fat. Panel c, treated with Carbylan-S-MMC(0.5%)-PEGDA film; no adhesions formed between two uterine horns. Moreover, no adhesions formed between the uterine horn and surrounding intraperitoneal fat. Masson's trichrome staining, scale bar: 400 μm. The insertion of crosslinked Carbylan™-SX films without MMC prevented the adhesions formed between the two uterine horns but not between the uterine horn and surrounding intraperitoneal fat. The insertion of crosslinked Carbylan-SX films containing covalently-linked 0.5% MMC could prevent the adhesions formed between the two uterine horns and the uterine horns to surrounding intraperitoneal fat. 7. The Establishment of Breast, Colon, and Ovarian Cancer Animal Model in Nude Mouse Human breast cancer cell lines (MDA-MB-231, MDA-MB-468, SK-Br-3, and MCF-10A), colon cancer lines (Caco-2, HCT-116, and HCA-7), and one ovarian cancer cell line (SK-OV-3) were loaded in Carbylan™-GSX and HA-DTPH-gelatin-DTPH-PEGDA hydrogel at concentration of 50×106 cells/ml and injected subcutaneously into the backs of nude mice. In addition, the Caco-2 cells loaded into Carbylan™-GSX hydrogels were injected into the subserosal layer of the cecum in a nude mouse. The SK-OV-3 cells loaded in a Carbylan™-GSX hydrogels were injected into the capsule of the ovary in a nude mouse. As controls, cells suspended in DPBS at the same concentration were injected subcutaneously or intraperitoneally into nude mice. One month after the injection, the injected sites were examined macrographically and histologically. The results are shown in FIGS. 21-28. FIG. 21 shows the macrographical view of tumors after subcutaneous injection of (a) MDA-MB-468 cells loaded in DPBS buffer, and (b) MDA-MB-468 cells loaded in Carbylan™-GSX hydrogels. Panel c shows the tumors after the skin was removed. FIG. 22 shows the histological examination of newly formed tumors after subcutaneous injection of MDA-MB-468 cells loaded in (a) DPBS buffer and in (b) Carbylan™-GSX hydrogels. H&E staining, scale bar: 0.5 mm. FIG. 23 (panels a and b) show the macrographical view of tumors after subcutaneous injection of Caco-2 cells loaded in DPBS buffer (left), Carbylan™-S (middle), and HA-DTPH-PEGDA hydrogels. Panel c shows the cross section of tumors after the skin was removed. Note the abnormal necrotic core of the cell-only tumor, and the healthier more “normal” tumors grown in sECM hydrogels. FIG. 24 shows the histological examination of newly formed tumors after subcutaneous injection of Caco-2 cells loaded in (a) DPBS buffer and (b) Carbylan™-GSX hydrogel. The H&E staining scale bar is 0.5 mm. FIG. 25 shows a mouse one month after the intraperitoneal injection of Caco-2 cells suspended in DPBS buffer. The waistline was increased significantly. There were multiple tumors formed in the peritoneal cavity. FIG. 26 shows a mouse one month after the colon injection of Caco-2 cells encapsulated in Carbylan™-GSX hydrogels. The general status of the mouse was good and there was no significant increase on the waistline after the injection. The tumors were individually distributed on the surface of the colon. FIG. 27 shows a mouse one month after the intraperitoneal injection of Caco-2 cells suspended in DPBS buffer. The waistline was increased significantly. There were multiple tumors formed in the peritoneal cavity. FIG. 28 shows a mouse one month after the colon injection of Caco-2 cells encapsulated in Carbylan™-GSX hydrogels. The general status of the mouse was good and there was no significant increase on the waistline after the injection. The tumors individually distributed on the surface of the colon. Based on the results presented above, the following conclusions were made. (1) Breast tumors formed following the subcutaneous injection of MDA-MB-468 cells in both DPBS and Carbylan™-GSX hydrogel, but the quality of tumors formed was different. Necrosis was found in the tumors formed from the injection of MDA-MB-468 cells suspended in DPBS buffer but not in the sECM-grown tumors (2) The intraperitoneal injection of Caco-2 cells in both DPBS and Carbylan™-GSX hydrogel had multiple tumors formed in the peritoneal cavity and the tumors were separate from the colon and intestine. The body weight and waistline of the mouse increased significantly and more bloody peritoneal fluid was found in the peritoneal cavity. Tumor metastases were found on the liver. The same phenomenon was found in the colon injection of Caco-2 cells suspended in DPBS buffer. Individual tumors formed on the colon after the injection of Caco-2 cells loaded in Carbylan™-GSX hydrogel into subserosal layer of colon. There were no liver metastases observed and no significant increase in body weight or waistline. No bloody peritoneal fluid was found. (3) The same above results for Caco-2 colon cancer cells were found using HCT-116 colon cancer cells. (4) The intraperitoneal injection of SK-OV-3 cells in both DPBS and Carbylan™-GSX hydrogel had multiple tumors formed in the peritoneal cavity and the tumors were separate from the colon and intestine. The body weight and waistline of the mouse increased significantly and more bloody peritoneal fluid were found in the peritoneal cavity. Tumor metastasis to the liver was observed. There was no tumor formed in the injection of SK-OV-3 cells loaded in Carbylan™-GSX hydrogel into ovarian capsules. (5) Taken together, the tumors cultered in the sECM (Carbylan™-GSX) hydrogels more resemble tumors in human patients than do i.p. or s.c. injected tumor cell lines in mouse xenograft models. 8. Effects of a PI3K Inhibitor and Taxol Using Cancer Cells Cultured in 3-D Culture (Carbylan™-GSX Hydrogels) a. Cell Lines and Culture Human breast cancer cell lines (MDA-MB-231 and MDA-MB-468), colon adenocarcinoma cell lines (Caco2, HCT116, and HCA7), and ovarian cancer cell (SK-OV-3) were obtained from American Type Culture Collections (ATCC) and maintained in RPMI 1640 medium (GIBCO) supplemented with 10 mM HEPES, 10% fetal bovine serum (Hyclone), 0.4 mM sodium pyruvate, and 0.5 mg/ml hydrocortisone, 100 U/ml penicillin, and 100 ug/ml streptomycin. b. The Sensitivity of Cell Lines to a Known PI3K Inhibitor and to Taxol When reaching 80-90% confluence, the above cell lines were trypsinized with 0.25% trypsin containing 1 mM EDTA and suspended in 1.25% (w/v) Carbylan™-S and 3% (w/v) gelatin-DTPH in a 50:50 (v/v) ratio in serum-free RPMI medium (pH 7.4), and then 4% (w/v) solution of PEGDA in DPBS buffer was added to the Carbylan™-S/gelatin-DTPH solution at a ratio of 4:1 (Carbylan™-S :PEGDA, v:v) and mixed by vortexing for 30 second. The final concentration of cells in Carbylan™-GSX solution was 2.0×106/ml. Aliquots (100 ml) of each reaction mixture loaded with cells were transferred by pipette into 24-well cell culture inserts (Coming incorporated, Coming, N.Y.) with 6.5 mm in diameter and 8.0 mm pore size. The cell loaded inserts were incubated in incubator (37° C. and 5% CO2) for two hours and then 2 ml of RPMI 1640 medium containing 10% FBS was added into each into each insert. The media were changed every two days. Two weeks after the initial culture, the media were removed from the inserts and changed with 10 mM of LY-294002 (Sigma) and 1 mg/ml of paclitaxel (Sigma) in RPMI 1640 medium containing 0.5% FBS. There were total eight inserts for each reagent each cell line. The media were also changed every two days. Two weeks after the media were changed to LY-294002 and paclitaxel containing media, the media were removed from the inserts and changed with 1.5 ml RPMI 1640 media containing 5% FBS and 15% (v/v) CellTiter 96 aqueous one solution cell proliferation assay (Promega, Madison, Wis.) and incubated in incubator (37° C. and 5% CO2) for three hours and then the reaction solution was transferred into 96-well plate (150 ml/per well) and the absorbance was read at 550 nm with an OPTI Max microplate reader (Molecular Devices). The inserts were rinsed twice with DPBS buffer and stained with FDA and PI at RT for 5 min and observed using a confocal laser scanning microscope (LSM 510, Carl Zeiss Microimaging, Inc., Thornwood, N.Y.). c. Results FIG. 29 shows the proliferation of different cell lines in the presence of LY294002 and paclitaxel. FIG. 30 replots the data to compare the differential responses of each cell line in normal medium to the same two drugs. In FIG. 30, for each pair of bars, a positive absorbance difference indicates that the drugs are cytotoxic, while a negative value indicates that the drugs have little or no effect on the cells treated at the doses employed. The proliferation of MDA-MB-468, CaCo-2, HCT116, and HCA7 cell lines was inhibited by LY294002 and paclitaxel, in which MDA-MB-468 revealed the greatest response to LY294002 and paclitaxel. It also demonstrated that the anti-tubulin drug paclitaxel exhibited somewhat stronger inhibition effects than the PI 3-K inhibitor LY294002. Neither LY294002 and paclitaxel showed any inhibition effects on MDA-MB-231 and SK-OV-3 cell lines at the doses employed. FIG. 31 shows the 3-D morphology of Caco-2 and SK-OV-3 in normal medium (A and D) and in the presence of LY294002 (B and E) and Paclitaxel (C and F) after stained with FDA (living cells, green) and PI (dead cells, red) (scale bar is 200 μm). FDA/PI staining (FIG. 31) revealed that Caco-2 cell density in sECM hydrogels decreased in the presence of LY294002 and paclitaxel compared to the cells cultured in normal medium. Dead cells (in red color) and living cell debris were also observed in LY294002 and paclitaxel treated samples (FIGS. 31A, 31B, and 31C). In contrast, no obvious difference was observed in SK-OV-3 cells when cultured in normal medium or in the presence of LY294002 and paclitaxel (FIGS. 31D, 31E, and 31F). 9. The Isolation and Culture of Hepatocyte in 3-D Carbylan™-GSX Hydrogels and in 2-D Polystyrene Plate a. The Isolation of Hepatocytes The rat was anesthetized with chloral hydrate (360 mg/kg) by i.p. injection. The abdomen of the rat was shaved and washed with 70% ethanol. The abdominal cavity was then opened, the intestines were gently moved to the right, the portal vein was dissected, and a suture (4/0) was placed around the portal vein and tied. Next, another 4/0 suture was placed around the portal vein above the tie, a small incision on the portal vein was made, a PE tube was inserted into the portal vein, and the suture was tied. Next, the lower abdominal vena cava was dissected, and a hemostat was placed around the vein. The diaphragm was cut to expose inferior vena cava, and the vein was cut. The liver was then perfused with Hanks' solution for 4 min (40 ml/min, total about 160 ml), and then perfused with enzyme solution for about 10 min (20 ml/min, total about 200 ml). The liver was excised from the body and transfered to a petri dish (100 mm) containing 15 ml of collagenase perfusate. Excess tissue and debris was then trimmed from the liver. The gall bladder can be removed carefully to prevent the leakage of bile. Hepatocytes were stripped from the connective tissue stroma with a stainless steel dog comb in fresh, room temperature collagenase, and the residual white fibrous tissue was discarded. The cells were separated by repeated pipetting (10 times) with wide-mouth pipette. An equal volume of L15 medium supplemented with 1% calf serum can be added to the cell suspension. The cells were passed through a cell strainer (70 μm) into a 50 ml centrifuge tube, and the tube was centrifuged at 50×g for 5 min at 10° C. The cells were resuspended in modified L15 medium containing 10% heat inactivated fetal bovine serum, and gentamicin (50 ug/ml). The viable cells were counted after incubating the cells in 0.4% trypan blue for 5 min and the the total number of cells was calculated. b. The Culturing of Hepatocytes The cells were cultured in 2-D or 3-D. Two media were tested for hepatocyte culture: Leibovitz modified medium (L15) and Williams' medium E (MWE). L15 was good for the hepatocyte culture. Moreover, collagen coating to polystyrene plate was useful for hepatocyte attachment. FIG. 32 shows a hepatocyte culture on a polystyrene plate in L15 medium. The pictures on the left were taken in transmission light. The pictures on the right were taken after double fluorescence staining (FDA/PI staining). FIG. 33 shows that the proliferation of hepatocytes on 3D Carbylan™-GSX was similar to that of the 2-D polystyrene plate when evaluated by MTS. The cell morphology of hepatocytes on the 3D-Carbylan™-GSX was also similar to that of the 2-D polystyrene plate after cultured for three days (FIG. 34, double staining with FDA/PI). III. Synthesis of Aminooxy Derivatives of Hyaluronan 1. Synthesis of Unsubstituted Aminooxy Derivatives For this study three different Pluronic were chosen: F88 (PEO103-PPO39-PEO103) (1a), F108 PEO132PO50EO132) (1b), and F127 (PEO100-PPO65-PEO100) (1c), characterized by different PPO/PEO ratio and molecular weight, respectively: 11,400, 14,600 and 12,600 kDa. A reaction scheme for producing the aminooxy derivatives is shown in FIG. 35. The bis-aminooxy derivative of Pluronic F88 (1a) was synthesized under Mitsunobu reaction's conditions, (Ishikawa, T., Kawakami, M., Fukui, M., Yamashita, A., Urano, J., Saito, S. J. MA. Chem. Soc. 2001, 123, 7734-7735) in the presence of large excess triphenylphosphine (Ph3P), N-hydroxyphtalimide and diethyl azodicarboxylate (DEAD). The crude product (2a) was precipitated from the reaction mixture with petroleum ether and re-crystallized four times using two solvent systems: THF/diethyl ether and THF/petroleum ether. The pure product was analyzed by 1H NMR 400 MHz in CDCl3. The choice of the solvent was made to obtain completely resolved terminal methylene peaks of bis-phtalimide derivative. The terminal methylene peak-triplet (δ4.33 ppm, 4H, J=4.4), was identified and integrated against the multiple signal of phtalimide aromatic rings (δ7.81-7.73 ppm, 8H), which confirmed, that received Pluronic derivative 2a was double protected by phtalimide. Next, deprotection reaction of phtalimide with hydrazine monohydrate in methylene chloride gave, after crystallization, bis-aminooxy Pluronic 3a, with good overall yield. All three Pluronics F88, F108 and F127 were converted into bis-AO derivatives using the same general method. Presented synthetic path way allows producing that kind of derivatives in good yields, basing on simple chemical transformations and purification methods. Experimental Section General Methods. Chemicals were obtained from Aldrich, Acros and BASF and were used without further purification. Solvents were reagent-grade and distilled before use: THF was distilled from sodium wire, and CH2Cl2 was distilled from CaH2. Reactions requiring anhydrous conditions were carried out in oven-dried glassware (2 h, 120° C.) under inert atmosphere (Ar) unless otherwise indicated. Concentration in vacuo refers to the use of rotary evaporator for solvent removal; NMR spectra were recorded at 400 MHz (1H) and 101 MHz (13C) at ambient temperature. Chemical shifts are reported relative to those of internal chloroform (δH 7.24), for 1H; chloroform (δC 77.0) for 13C. Pluronic F88 bis-O-phtalimide derivative (2a). To a stirred solution of Pluronic F88 (13.98 g, 1.16 mmol) and Ph3P (6.1 g, 23.3 mmol), N-hydroxyphtalimide (3.78 g, 23.2 mmol) in THF (75 ml) was added DEAD (3.5 ml, 23.2 mmol) at 10° C. The reaction was stirred overnight at room temperature and finished by precipitation of the product with petroleum ether. The crude 2a was re-crystallized four times using two solvent systems: THF/petroleum ether and THF/diethyl ether (two times for each system). The pure product 2a was obtained in form of white loose solid (12.28 g, 86%). 1H NMR (400 MHz, CDCl3) δ 7.80-7.78 (4H, m), 7.72-7.69 (4H, m), 4.32 (t, 4H, J=4.4 Hz), 3.83-3.68 (m, 9H), 3.60-3.27 (m, 1052H), 2.21 (s, 9H), 1.10-1.08 (m, 123H). 13C NMR (101 MHz, CDCl3) δ 134.2, 123.2, 75.2, 75.0, 74.8, 73.1, 72.6, 70.26, 33.2, 17.2, 17.1 Pluronic F88 bis-aminooxy derivative (3a). Hydrazine monohydrate (0.71 ml) was added to a stirred solution of 2a (12.38 g) in CH2Cl2 (50 ml) at 0° C. It was stirred for 1.5 h at room temperature and precipitate was filtered off. After concentration the residue was dissolved in THF and precipitated using diethyl ether. Re-crystallization using THF/petroleum ether led to obtain pure compound 3a as a white loose solid (11 g, 90%). 1H NMR (400 MHz, CDCl3) δ 3.81-3.78 (m, 8H), 3.71-3.30 (m, 874H), 2.02 (s, 10H), 1.24-0.98 (m, 100H); 13C NMR (101 MHz, CDCl3) δ 75.5, 75.3, 75.2, 73.3, 72.9, 70.5, 33.3, 17.4, 17.3. 2. Synthesis of Substituted Aminooxy Derivatives Low molecular weight HA (190 KDa) (0.458 g, 1.145 mmol) was dissolved in 46 ml distilled water. Then, 0.5 g O-phenylhydroxylamine hydrochloride (OPH) (3.434 mmol) was added, and the solution pH was adjusted to 4.75 by adding 1.0 N HCl. Next, 0.11 g EDCI (0.057 mmol) was added under magnetic stirring, and the solution pH was maintained at 4.75 for 4 h by adding 0.1 N HCl. The solution was dialyzed extensively against 100 mM NaCl, followed by dialysis against distilled water. After that the solution was filtered to remove extraneous solids and lyophilized to give the HA-OPH product as a white powder. The peaks at δ 7.30 (2 protons) and 7.05 (3 protons) (FIG. 36) were from the phenyl group, and the degree of substitution was found to be ca. 21% based on integration of the proton NMR resonances. Expected resonances for N-acetylurea-modified hyaluronan were detected at δ 1.10 and δ 2.78. 3. Coupling of an Aminooxy-Derivatized Polymer with Hyaluronan An experiment was designed to test whether an aminooxy (AO) derivative of Pluronic F108 could be employed for covalent coupling with resulting surface immobilization of HA. Pluronic F108 is commonly used to coat plastic surfaces via hydrophobic adsorption of the PPO block of the PEO-PPO-PEO triblock, rendering the surface resistant to protein adsorption. In addition, amine-reactive Pluronic derivatives are commercially available from allvivo, inc., and can be used to immobilize specific growth factors and proteins on surfaces. In this experiment, it was demonstrated that a fluorescent derivative of HA, fluorescein-HA, can be covalently attached to a surface-adsorbed bis-aminooxy derivatized pluronic. Materials and Methods F108-BisAO was dissolved in distilled water to give 0.5% (w/v) solution. Then 0.1 ml solution was added into each well of 96-well plate. After 12 h, the plate was washed 5 times with distilled water. Then 0.1 ml EDCI (10 mg/ml in 0.1 N MOPS) (pH 4.7) was added into each well, and then 0.1 ml fluorescein-HA (MW 150 kDa) (2 mg/ml in 0.1 N MOPS) (pH 4.7) was added. (Note: fluorescein-HA was separately prepared using fluorescein hydrazide (Molecular Probes, Inc.), EDCI, 150 kDa HA, at pH 4.75 following standard hydrazide coupling protocols.) This surface reaction was allowed to proceed for 3 days in the dark. Next, the plate was washed 5× with DPBS, and the fluorescence was measured in a fluorescence plate reader using λex=496 mn and λem=520 nm. Results FIG. 39 shows the fluorescence of immobilized fluroescein-HA with (A) a bis-aminooxy derivatized pluronic, (B) a bis-aminooxy derivatized pluronic and EDCI, and (C) no bis-aminooxy derivatized pluronic. The fluorescent absorption of experimental group (A) was significantly higher than the control groups (B, no EDCI, and C, no Pluronic). This result indicated that F-108 BisAO was adsorbed to the 96-well plate through hydrophobic interactions, and that EDCI-mediated coupling of fluorescein-HA via the F-108 BisAO aminooxy to HA carboxylate condensation was achieved on the plate surface. The high absorption in control group B may result from the hydrophobic and charge interactions of fluorescein-HA to F-108 BisAO on the surface. 4. Self-Assembling Hyaluronan Hydrogels Formation with Monofunctional Pluronic-AO The hypothesis that the attachment of a Pluronic to HA would result in a self-assembling hydrogel based on the intermolecular and intramolecular hydrophobic interactions of multiple PEO-PPO-PEO triblock polymers attached to HA was tested. The experiment also tested the feasibility of using the aminooxy condensation as a new chemistry for chemical modification of HA carboxylate groups with aminooxy-containing polymers in solution as claimed and validated for small molecule aminooxy compounds. Materials and Methods A 50-mg sample of HA (830 kDa) was dissolved in 20 ml of distilled water to give 0.5% (w/v) solution, and then 1.5 g of the monomethoxy, monoaminooxy-Pluronic F88 derivative, MeO-F88-AO, was added. Next, the solution pH was adjusted to ca. 4.7, and 50 mg of EDCI was added. After 15 min, a gel formed. After 2 h, the gel was put in dialysis tubing (MW cut-off 50,000), and dialysis against 0.1 N NaCl solution was allowed to proceed for 3 days, followed by dialysis against water for one day. The gel is only 0.3% HA w/v at present and is a gel at both room temperature and 4° C. Results Neither Pluronic F88 nor the chemically-synthesized MeO-F88-AO formed gels at 20° C. or 4° C. at concentrations up to 5 mg/ml. In contrast, the covalent coupling of MeO-F88-AO to make HA through carbodiimide-mediated coupling of the HA carboxylates to the aminooxy groups of one or more MeO-F88-AO molecules led to the formation of a physical gel. Not wishing to be bound by theory, the driving force for formation of this physically crosslinked gel is consistent with the proposed hydrophobic interaction of the multiple PPO blocks present in the covalently-modified macromolecules. Both intermolecular and intramolecular hydrophobic interactions may contribute to this gelation effect. The loose physical gel has significant potential as a novel hyperviscous, slowly degraded HA material for use in adhesion prevention, injection as a dermal filler, incorporation in topical cosmetics or drug delivery formulations, injection for reduction of pain and inflammation in osteoarthritis, for ophthalmic surgery, for soft tissue bulking in plastic surgery, for injection into the vocal folds for prophylaxis or treatment of dysphonias, and other clinical applications. 5. Conjugation of Heparin with Bis-Aminooxy Derivatized Pluronic Materials and Methods BisAO-F108 in water (5 mg/ml) was loaded at 0.1 ml per well and incubated for overnight on 96-well plate. The wells were washed with distilled water (5×) and then 0.1 ml per well of a solution of EDCI (10 mg/ml) in MOPS (0.1 N, pH 4.7) was added, followed by 0.1 ml per well of heparin sodium salt (average Mw 15 kD, in 1:2 serial dilutions from 4 mg/ml to 0.25 mg/ml) in MOPS (0.1N, pH 4.7). The heterogeneous reaction allowed to proceed for for 3 days at room temperature. The plate was washed 5× with Tris-HCl buffer (TBS, 20 mM, pH 7.5), and blocked with StabilGuard solution (Surmodics) at 200 μl/well for 1 hr. The immobilized heparin on plate was examined with using an ELISA based on a published method (S. Cai, J. L. Dufner-Beattie, and G. D. Prestwich, “A Selective Protein Sensor for Heparin Detection,” Analyt. Biochem., 326, 33-41 (2004)). Briefly, after the plate was blocked and washed 3× with, a heparin binding protein GST-HB3 (100 μg/ml) was added at 100 μl/well. The plate was incubated for 1 hr and washed again with TBS, followed by addition with 1:1000 anti-GST (Sigma) in TBS at 100 μl/well and incubation for 1 hr. Next, 1:3000 anti-mouse IgG-HRP conjugate (Sigma) in TBS of 100 μl/well was added and incubated for another 1 hr. Finally, the substrate 3,3′,5,5′-tetramethylbenzidine (TMB, Sigma) as added at 100 μl/well was added and the reaction was quenched with 1 M H2SO4 as the color appearance became stable. The plate was read at 450 nm and the absorbance was corrected by subtracting the blank wells loaded with GST-HB3 followed by the same ELISA procedure (background reading). Results FIG. 40 shows clearly that neither heparin alone nor heparin plus EDCI result in surface immobilization of heparin. (Note: for these two groups—HP and EDCI+HP —the heparin concentration tested was 2 mg/ml). The use of the EDCI and F108 alone, however, creates a surface that appears to show some nonspecific binding to the ELISA reagents in this preliminary test. A similar effect was observed from the combined hydrophobic and charge interactions of fluorescein-HA to F108-bisAO on the surface. Nonetheless, the conjugation and absorption of heparin in this proof of concept experiment shows a trend toward heparin dose-dependency, despite the fact that the GST-HB3 protein detection is at maximal binding capacity and the top of its dynamic range. In our experience, changing wash conditions and adjusting immobilization amounts and detection reagent amounts can produce a lower background, improve sensitivity, and yield a quantitative assay based on this method. Various modifications and variations can be made to the compounds, compositions and methods described herein. Other aspects of the compounds, compositions and methods described herein will be apparent from consideration of the specification and practice of the compounds, compositions and methods disclosed herein. It is intended that the specification and examples be considered as exemplary.

<SOH> BACKGROUND <EOH>The use of macromolecules in pharmaceutical applications has received considerable attention. At times, it is desirable to couple two or more macromolecules to produce new macromolecule scaffolds with multiple activities. Existing technologies used to couple two or macromolecules, however, present numerous difficulties. For example, the alkaline conditions or high temperatures necessary to create hydrogels with high mechanical strength are cumbersome and harsh. Although the use of crosslinkers to produce macromolecular scaffolds has met with some success, the crosslinking agents are often relatively small, cytotoxic molecules, and the resulting scaffold has to be extracted or washed extensively to remove traces of unreacted reagents and byproducts (Hennink, W. E.; van Nostrum, C. F. Adv. Drug Del. Rev. 2002, 54, 13-36), thus precluding use in many medical applications. A physiologically compatible macromolecular scaffold capable of being produced in a straightforward manner is needed before they will be useful as therapeutic aids. Described herein are compounds and methods that are capable of coupling two or more molecules, such as macromolecules, under mild conditions.

<SOH> SUMMARY <EOH>Described herein are compounds such as macromolecules that have been modified in order to facilitate crosslinking. In one aspect, the macromolecule is modified via an alkoxyamination reaction, wherein the resultant alkoxyaminated macromolecule can undergo crosslinking with itself or another macromolecule. In another aspect, the macromolecule is modified with a group capable of reacting with a hydrazide compound, which will facilitate crosslinking. Also described herein are methods of making and using the modified macromolecules. The advantages described herein will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

20070713

20110719

20080131

98273.0

A61K31726

GOON, SCARLETT Y

MODIFIED MACROMOLESCULES AND ASSOCIATED METHODS OF SYNTHESIS AND USE

SMALL

ACCEPTED

A61K

ACCEPTED

Method Of Dynamic Transporting Of Object With Flow Of Carrying Medium

In a method of the energy-saving dynamic transporting of object with a flow of a carrying medium, action are applied to the carrying medium which are created in an action element during a process of conversion of an energy supplied to it, so that the flow of a carrying medium created thereby acts on the object for performing a process of its transporting in a given direction, and a modulation of a value of the action is performed in the action element sq. that the, flow of the carrying medium which is dynamically created moves with a given dynamic periodically changing sign-alternating acceleration during the process of transporting of the object.

1. In a conveyor, comprising a cyclic drive means transporting a fluid medium having at least one object entrained therein through an enclosed passage, said drive means interposed between upstream and downstream segments of said passage and comprising a first working zone in a negative drive cycle and a second working zone in a positive drive cycle; a method of optimizing at least one value of said object entrained fluid medium characteristic of said transporting of said object entrained fluid medium with respect to drive means energy consumption comprising: providing at least one shunt passage from said second working zone to said first working zone; flowing said object entrained fluid medium through said shunt passage from said second working zone to said first working zone thereby changing said at least one value of said object entrained fluid medium and the difference in magnitude between said cycles; modulating the flow through said shunt passage to optimize said at least one value with respect to drive means energy consumption. 2. The method of optimizing of claim 1, wherein said modulating comprises frequency modulation. 3. The method of optimizing of claim 1, wherein said modulating comprises amplitude modulation. 4. The method of optimizing of claim 1, wherein said modulating comprises a standing wave input. 5. The method of optimizing of claim 4, wherein said standing wave modulation is achieved by modulating the geometry of a minimum cross section of said shunt passage. 6. The method of optimizing of claim 1, wherein said modulating comprises a parametric input. 7. The method of optimizing of claim 1, wherein said modulating comprises discrete input. 8. The method of optimizing of claim 1, wherein said drive means comprises a displacement means. 9. The method of optimizing of claim 8, wherein said displacement means comprises a pressure drop. 10. The method of optimizing of claim 1, wherein said object entrained fluid medium is in turbulent flow. 11. The method of optimizing of claim 1, wherein said shunt passage comprises a filter. 12. The method of optimizing of claim 1, wherein said object is said fluid medium and performs a function of said carrying medium. 13. A method of dynamic transporting of object with a flow of a carrying medium, comprising the steps of: applying to a carrying medium an action which is created in an action means during a process of a conversion of an energy supplied to the action means so that a flow of a carrying medium created in this way acts on an object for providing a process of its transporting in a given direction; and performing a given modulation of a value of said action in said action means, includes providing a given dynamic periodic change of a value of at least one parameter which is dynamically connected with a process of conversion in the action means of said energy supplied to it into said action, with a simultaneous given change of said value of said parameter in each period of its change during said process of transporting of said object, to provide a given dynamic periodic change of said value of said action on said carrying medium, so that said flow of said carrying medium which is created dynamically moves with a given dynamic periodically changing sign-alternating acceleration during a process of transporting of said object. 14. The method of claims 13, wherein said object is said fluid medium and performs a function of said carrying medium. 15. The method of claim 13, wherein said object is structurally not connected with said action means during said process of transporting. 16. The method of claim 13, wherein said object is structurally connected with said action means during said process of transporting. 17. The method of claim 13, wherein said action means is formed as a means for a direct energy action. 18. The method of claim 13, wherein said action means is formed as a pressure drop means. 19. The method of claim 13, wherein said object has a structural part which performs a function of a converting element of said action means to provide a process of conversion of said energy supplied to said action means and generated during a forced interaction of said structural part of said object with said medium which is a flowing medium. 20. The method of claim 13, wherein said modulation of said value of said action in said action means includes introduction of values of its parameters selected from a group consisting of a frequency, a range and a law of a dynamic periodic change of said value of said action during said process of transporting of said object. 21. The method of claim 20; and further comprising changing a value of at least one of said parameters of said modulation in dependence on a change of at least one characteristic to be controlled, which is connected with said process of transporting of said object, to energy optimize at least one parameter which is connected with said process of transporting. 22. The method of claim 21; and further comprising using as said control characteristic, of values of at least one of parameters of conversion of energy of movement of said flow of carrying medium into another type of energy during said process of transporting.

TECHNICAL FIELD The present invention relates to methods and devices which provide transporting of an object with a flow of a carrying medium. It encompasses a broad class of various systems which are used, for example: in industry; in energy-related systems; in pipelines, ground, air, abovewater, underwater, and other types of transportation; in medical and household technique; in converting and special technique; in special destructive and explosive technique; in research devices and systems; in physiological systems and in other areas. In the present time the broad class of such systems under consideration represents one of important developing areas in the world, characterized with significant energy consumption. BACKGROUND ART Various methods and devices are known, which provide transporting of objects with a flow of a carrying medium. A common traditional methodological approach which is used in various systems in the above mentioned class is application of an action to the above mentioned carrying medium from an action means which creates during the process of conversion of the energy supplied to it, and integrally constant in time action so that the above mentioned flow of the carrying medium created in this way acts on the above mentioned object for providing the process of its transporting in a given direction. This approach is realized in various systems which use mainly two types of means for action: means of pressure drop (pumps; screw, turbine, turbo reactive and reactive systems; explosive devices of pumping or vacuum action; means of action which use a forced aerodynamic or hydrodynamic interaction of the object or its structural part, correspondingly with gaseous or liquid medium, for example a region of an outer surface of a casing of a flying, speedy ground or underwater moving apparatus, etc.), and means for direct energy action (magnetohydrodynamic pumps; magnetic and electromagnetic acceleration systems, etc.). The object can be structurally not connected or structurally connected (for example in a flying apparatus) with the action means. In some cases the object, being a flowable medium, performs a function of the carrying medium (for example gas or liquid product such as oil transported in a pipeline). In various known action means, energy which is supplied to them and is converted in them can be of various types, such as for example: electrical, electromagnetic, magnetic, mechanical, thermal energy; energy generated for example as a result of performing correspondingly: a chemical reaction, a nuclear reaction, a laser action, etc., or for example energy generated during operation of a physiological system; or generated during a forced aerodynamic interaction of an object with a gaseous medium or during a forced hydrodynamic interaction of an object with a liquid medium. In some known action means, as the supplied energy a combination of several different types of supplied energy is utilized (for example, a combination of magnetic and electrical energy as in a magnetohydrodynamic pump). As the carrying medium, mainly a flowing (gaseous or liquid) medium is utilized. The object of transportation can be for example: powder or granular material; gaseous or liquid medium; excavated product (coal, ore, oil, gas, gravel, etc.); a mixture of materials and media; a component or refuse of manufacturing process; fast movable or immovable objects; physiological or physical substance; and many others. Common disadvantages of the known traditional methodological approach which is realized in such systems for providing a process of transporting an object with a flow of a carrying medium are as follows: limited possibilities for reduction of specific consumption of energy for providing the process of transporting of the objects; impossibility of performing efficient dynamic control of the process of transporting, with the purpose of optimization of its energy characteristics; presence of negative side effects which accompany work of some of such systems and significantly worsen their operational and energy characteristics (for example “sticking” during suction; adhesion of particles on inner walls or clogging of a portion of a channel which limits the transported flow; a fast clogging of filtering devices which operate in a multi-phase flow; and so on). The above listed disadvantages significantly reduce energy, and therefore also economical efficiency of application of such traditional systems for providing the process of transporting an object unit by a flow of a carrying medium. Other methods and devices for such transporting of an object with a flow of a carrying medium are known, as disclosed for example in U.S. Pat. Nos. 5,201,877 (1993); 5,593,252 (1997); and 5,865,568 (1999)—A. Relin, et al. The above-mentioned methods and devices realize a methodological approach which was first proposed by Dr. A. Relin in 1990 and utilizes a modulation of the suction force, performed outside of the action means by connection of an inner cavity of the suction area of the transporting line with atmosphere through a throughgoing passage and simultaneous periodic change of an area and shape of the throughgoing passage during transporting of the object. The use of this approach (which is named by Dr. A. Relin “AM-method”), which realizes the “principle of controlled exterior dynamic shunting” of the suction portion proposed by the author opens qualitatively new possibilities for significant increase of efficiency of operation and exploitation of a certain class of devices and systems for suction transporting of various objects. In particular, the use of modulation of the suction force over a limited suction portion of movement of the flow in a closed passage, for example in vacuum cleaning systems, in various medical suction instruments, and also in pneumotransporting systems of various materials and objects allows to minimize and even completely eliminate the above mentioned common disadvantages which are inherent to known traditional approach realized in the known systems of this type. However, the necessity and possibility of performing the connection of the interior cavity of only the suction portion of the transporting line (outside of the above mentioned action means) with the atmosphere through the throughgoing passage does not allow to use this principle of modulation in a sufficiently broad class of other types of known devices and systems which can provide a process of transporting an object with the flow of carrying medium: which do not allow a contact with atmospheric medium of the object transported in the closed passage, for example various gasses, chemical and physiological materials and media; which do not allow an entraining of atmospheric medium (for example air) into the hydrotransporting system which can lead to cavitation effects are damaging for the pipeline and the hydraulic pump, and also to energy losses in the process of transporting an object with a flow of a carrying medium; which do not allow a possibility of performing the connection of the inner cavity of the pumping line of transportation with atmosphere through the throughgoing passage, causing expelling of the transporting medium into atmosphere; which provide identical speed characteristics over the whole extension of the movable flow: both at its suction portion and its pumping portion; which do not allow a possibility of realization of such approach due to absence of a closed long suction portion of the passage during the use of various types of above mentioned action means on the carrying medium with a pressure drop, for example: connected with the object of transporting—screw, turbine, turbo reactive and reactive systems; various explosive devices; action means which use forced aerodynamic and hydrodynamic action of the object, correspondingly, with gaseous and liquid medium; and other similar types of action means; which do not provide a pressure drop with the action means used in them, realizing other principles of performing of the above mentioned action, for example during the use of the above mentioned means of direct energy action. In addition, during the development of the construction of the modulator which realizes the above mentioned “principle of controlled exterior dynamic shunting” of the suction portion it is necessary to solve additional problems, for example: connected with a reduction of the level of additional noise effect caused during a periodic connection of the atmospheric medium with the internal cavity of the suction portion of the transporting line; and also effects connected with protection of the throughgoing passage of connection of the modulator from possible sucking into it of various components of an exterior medium or foreign objects. The attempts to take into consideration these factors in such cases additionally complicates and makes more expensive the construction and the operation of the modulator. The above explained disadvantages significantly limit the possibilities during solution of real problems connected with energy optimization of processes of transporting of an object with a flow of a carrying medium, and also areas of application of the above analyzed efficient methodological approach which use the modulation of the suction force over the suction portion, performed with the use of the above mentioned “Principle of controlled exterior dynamic shunting”. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a method of dynamic transporting of an object with a flow of a carrying medium which is in principle new. The proposed method (which is named by the inventor “R-method”) is based on works of Dr. A. Relin and confirmed by scientific research of concepts of a new theory “Modulating aero- and hydrodynamics of processes of transporting objects with a flow of a carrying medium”. This scientific concepts consider new laws which are developed by the author and connected with a significant reduction of a complex of various known components of energy losses (and therefore of specific consumption of energy) during creation of a dynamically controlled process of movement of the flow of a carrying medium with a given dynamic periodically changing sign-alternating acceleration during the process of transporting of the above mentioned object. The proposed method minimizes or completely eliminates the above mentioned disadvantages in providing an efficient process of transporting of an object with a flow of a carrying medium which are inherent to the known traditional methodological approach and the above mentioned second approach which uses the modulation of suction force based on the “Principle of controlled exterior dynamic shunting” of the suction portion. High energy efficiency of the new method is obtained due to the fact that it solves a few main problems: it provides minimization of negative dominating influence of turbulence on losses of kinetic component-of the applied energy in a zone of a border layer and in a nucleus of the flow of carrying medium during providing the process of transporting of an object; it provides minimization of various components of energy losses connected with the process of transporting of the object itself by the flow of carrying medium during whole period of this process; it provides possibility of a given multi-parameter dynamic control of the process of transporting of an object with a flow of carrying medium during its whole realization; it provides possibility of significant reduction of integral value of energy action applied to the above mentioned flow and as a result, provides practically analogous significant reduction of consumption of the supplied energy which is converted (consumed) by the action means to the flow; it provides possibility of dynamic consideration of characteristics (criteria) of the process of transporting of an object with the flow of carrying medium for optimization of the given multi-parameter dynamic control by executing this process with the purpose of increasing of its energy efficiency. In keeping with these objects and with others which will become apparent hereinafter, one of the new features of the present invention resides, briefly stated, in a method of transporting of an object with a flow carrying medium, which includes the following steps: application to the above mentioned carrying medium of an action which is created in an action means during a process of conversion of an energy applied to it so that the above mentioned flow of carrying medium created this way acts on the above mentioned object for providing the process of its transporting in a given direction; and performing a given modulation of a value of said action in said action means, which provides a given dynamic periodic change of said value of said action on said carrying medium so that said flow of carrying medium which is dynamically created moves with a given dynamic periodically changing sign-alternating acceleration in a process of said providing the process of transporting of said object. As the above mentioned action means, either a means of pressure drop or a means of direct energy action can be utilized. The proposed method embraces all possible spacial conditions of the transporting object. In some cases the object can be a flowable medium and in this case can perform a function of the above mentioned carrying medium. In other cases the object can be structurally not connected or structurally connected with the action means in the process of its transporting. In certain situations the structural part of the object can perform the function of a converting element of the action means so as to provide the process of conversion of energy supplied to it and generated during forced interaction of this structural part of the object with the flowable medium. Another important feature of the present invention is that the above mentioned given modulation of the value of the action in the action means is performed by providing a given dynamic periodic change of the value of a parameter which is dynamically connected with the process of conversion of the action means of the energy supplied to it into the action with simultaneous given change of the value of this parameter in each period of its change during the process of transporting of the object. This approach can be used both in the case of utilization of the pressure drop action means and in the case of utilization of the direct energy action means. As the parameter of the process of conversion of the supplied energy the following can be utilized, for example: electrical, electromagnetic, magnetic, structural, technical, physical, chemical or physico-chemical parameter; or a combination of various types of these parameters can be utilized. As the energy supplied to the action means, the following energy for example can be used: electrical, electromagnetic, magnetic, mechanical, thermal energy; energy generated as a result of performing of chemical or nuclear reaction; energy generated during the operation of a physical system; energy of forced aerodynamic interaction of a structural part of the object with a gaseous medium (performing the function of the action means); energy of forced hydrodynamic interaction of the structural part of the object with liquid medium (performing the function of the action means); or it can use a combination of several types of the supplied energy. In accordance with another feature of the present invention, the given modulation of the value of the action in the pressure drop means is performed by providing a simultaneous given dynamic periodic change in working zones of the pressure drop means, correspondingly, of a value of a negative over pressure and a value of a positive over pressure with a simultaneous their change in each period of the change of the above mentioned values of the above mentioned actions, generated in the process of conversion of the energy supplied to the pressure drop means in the work zones which are in contact with the carrying medium, so as to provide application of the generated given dynamic periodic action determined by the above mentioned values of the negative and positive over pressures during the process of transporting of the object. The simultaneous given dynamic periodic change in the working zones of the pressure drop means, and correspondingly of the value of negative over pressure and the value of positive over pressure with simultaneous their change in each period of the change of the values of the pressures is performed by a given dynamic periodic change of the value of connection between the working zones with a simultaneous given change of the value of the connection in each its period during the process of transporting of the object. At the same time the given dynamic periodic change of the value of connection of the working zone with the simultaneous given change of the value of the connection in each its period is performed by a given dynamic periodic generation on a portion of a border of separation between the working zone of a throughgoing passage (or several passages) with a simultaneous given change of the value of a given area of a minimal cross-section of the passage (or several passages) in each period of the generation, accompanied by performing correspondingly of a given dynamic periodic local destruction and subsequent reconstruction of the portion of the border with a simultaneous given change of the value of area of its local destruction in each period during the process of transporting of the object. The above mentioned local destruction is performed by destruction means, for example: technical, physical, chemical, physico-chemical; or is performed by a combination of several types of the destruction means. The portion of the border of separation between the working zones can be identified either structurally or spatially. In some cases of utilization of the new method, in a process of the given dynamic periodic generation on a portion of the border of separation between the working zones of the throughgoing passage (or several passages) with simultaneous given change of the value of the given area of a minimal throughgoing cross-section of the passage (or several passages) in each period of its action, a filtration of local volume of the carrying medium which in a zone of the given throughgoing passage during the process of the transporting of the object is performed. The above mentioned new features of the present invention reflect a new “Principle of controlled interior dynamic shunting” of working zones of the pressure drop means. In accordance with the important features of the present invention, in the method for performing the given modulation of the value of the action in the action means, values of its parameters are given: frequency, range and law of dynamic periodic change of the value of the action during the process of transporting of the object. A new method makes possible a realization of one of several main variants of giving of the values of the parameters: the given values of parameters of modulation do not change during the process of transporting; the values of one (or several) of the given parameters of the modulation is or are changed in a given dependency from changes of a controlled characteristic connected with the process of transporting of the object; values of the changing parameters of the given modulation are changed in a given dependency from changes of a combination of several types of the control characteristics connected with the process of transporting of the object. The process provides a possibility to use as the control characteristic, without any limitation, for example as follows: value of one of the parameters of the process of transporting of the object (energy, consumption, optimized specific consumption energy or speed parameter); values of one of parameters of the transporting object (speed, consumption, aerodynamic, hydrodynamic, structural, physical, amplitude-frequency, chemical or geometric parameter); values of one of parameters of spacial position of the object during the process of transporting; values of one of parameters of a surface of a position of the object during the process of transporting (for example physico-mechanical); values of one of parameters of the flow of the carrying medium during the process of transporting of the object (for example speed, structural, physical or chemical parameter); values of one of parameters of a turbulent process in the flow of carrying medium during the process of transporting of the object (for example amplitude, frequency or energy parameter); value of one of parameters of a process of conversion of energy of movement of the flow of carrying medium into another type of energy (during interaction or without interaction with an additional source of energy, which acts on the flow) during the process of transporting of the object. The novel features which are considered as characteristic for the present invention are set forth in particular in the appended claims. The invention itself, however, both as to its construction and its method of operation, together with additional objects and advantages thereof, will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view showing a diagram of a functional structure of a system of a pipeline transportation, with an example of a dynamic pumping hydrotransportation, which realizes a method of dynamic transporting of an object with a flow of carrying medium in accordance with the invention; FIG. 2 is a view showing a block diagram of a possible functional structure of a controlled dynamic action means, with an example of a control dynamic hydropump, in accordance with the present invention; FIG. 3 is a view illustrating an example of a given dynamic periodic change of a value of connection of working zones provided by a modulator which realizes the “Principle of controlled internal dynamic shunting”; FIG. 4 is a view showing an example of simultaneous given dynamic periodical change of a value of a negative over pressure (−P) and a value of a positive over pressure (+P) in each period of a change in corresponding working zones of a controlled dynamic hydropump; FIG. 5 is a view showing an example of a dynamic change of a value of a speed of movement of dynamically created flow of a carrying medium during a process of transporting of an object; FIG. 6 is a view showing an example of a given dynamic periodic change of a value of sign-alternating acceleration of movement of a dynamically created flow of a carrying medium during the process of transporting of the object. DESCRIPTION OF THE PREFERRED EMBODIMENTS A new method of dynamic transporting of object with a flow of carrying medium can be realized in the following way. A typical structure of a system of a pipeline transportation (with an example of a dynamic pumping hydrotransportation) is presented in FIG. 1 and in general includes a controlled dynamic action means (in this example it is a controlled dynamic hydropump) 1, a suction portion 2, and a pumping portion 3 of a hydrotransporting line with an inner cavity 4 and a suction inlet 5, a transporting object, for example gravel 6, a carrying medium (for example water) 7, a sensor 8 which controls a characteristic connected with providing a process of transporting of the object 6 by the carrying medium 7. The dynamic hydropump 1 includes in general a electromechanical pumping device (a pressure drop means) 9 and also a modulator 10 which realizes a “Principle of controlled inner dynamic shunting” of working zones of the pressure drop means (the pumping device 9). In accordance with a block diagram of a possible functional structure of the controlled dynamic hydropump 1 (FIG. 2), the electromechanical pumping device 9 has an electrical drive 11 which is structurally connected with a multi-blade wheel 12, a working casing 13 which is structurally separated into two working zones 14 and 15. The working zone 14 in which during operation of the pumping device 9 a negative over pressure (−P) is generated, is connected with the inner cavity 4 of the suction portion 2 of the hydrotransporting line. The working zone 15 in which during the operation of the pumping device 9 a positive over pressure (+P) is generated, is connected with the inner cavity 4 of the pumping portion 3 of the hydrotransporting line. The over pressures (−P) and (+P) are generated in the working zones correspondingly with respect to a normal pressure of an ambient medium (Patm). The modulator 10 functionally has a throughgoing passage 16 which is connected with its end to inner cavities of the working zones 14 and 15 of the pumping device 9, a filter (or several filters) 17 for the carrying medium (water) 7, a correcting unit 18 used for setting (giving) initial area and shape of a minimal cross-section of the throughgoing passage 16, a valve unit 19 which is used for periodically changing the given area of the minimal cross-section (of a given shape) of the throughgoing passage 16 during modulation of the value of the action in the pressure drop action means (electromechanical pumping device 9), a drive 20 of the correcting unit 18 for displacing of its moving elements for setting (giving) of given initial area and shape of the minimal cross-section of the throughgoing passage 16, a drive 21 of the valve unit 19 for displacing of its movable valve element for providing a periodical change of the given area of the minimal cross-section (of a given shape) of the throughgoing passage 16 and a control block 22 having a setting input “a” and control input “b” connected with the sensor 8. A setting signal Ui is supplied to the setting input “a” of the controls block 22. In the given example of the hydrotransportation of gravel, the sensor 8 controls a current volume rate (Qo) of the transporting material (gravel) 6. A signal U (Qo) is supplied to the control input “b” of the control block 22, the signal characterizing a current value Oo. The control block 22 has three controlling outputs. One output (Uf) is connected with the drive 21 of the valve unit 19. Two other outputs (Ud) and (Ul) connected with the drive 20 of the correcting unit 18. The above described system of pipeline transportation (with an example of dynamic pumping hydrotransportation) which realizes the method of dynamic transporting of an object with a flow of carrying medium in accordance with the present invention operates in the following manner. After supplying electrical energy to the electrical drive 11, structurally the multi-blade wheel 12 of the electromechanical pumping device 9 connected to it is driven in rotation. Conversion of mechanical energy of the rotatable wheel 12 into the action or in other words a pressure drop (ΔP) is performed in the working casing 13 and applied to the carrying medium (water) 7. The pressure drop (ΔP) is formed by a simultaneous creation in the working zone 14 of the negative over pressure (−P) and in the working zone 15 of the positive over pressure (+P). The working zones 14 and 15 contact with the carrying medium so that the flow of the carrying medium created thereby acts on the object 6 (in the given case it is gravel) for providing the process of its transporting in a given direction (see FIG. 1). Under the action of the negative over pressure and correspondingly a suction force created thereby at the suction inlet 5 and in the interior cavity 4 of the suction portion 2 of the hydrotransporting line, gravel (object 6) is displaced under the action of the flow of the carrying medium 7 from the zone of its creation to the pumping device 9. This is predetermined by the value of the negative over pressure (−P) which is created in the working zone 14 of the pumping device 9. Then the flow of water with gravel passes the working passage of the pumping device 9 and continues its movement in the inner hollow 4 of the pumping portion 3 of the hydrotransporting line to its end. The latter takes place under the action of the pumping force which is determined by the value of the positive over pressure (+P) created in the working zone 15 of the pumping device 9 of the hydropump 1. The above described process corresponds to the realization of a traditional methodological approach (traditional mode of operation), which takes place in known systems of pipeline hydrotransportation, using integral action which is constant in time the pressure drop (ΔP) applied to the carrying medium by the pressure drop means (in this example—an electromechanical pumping device 9). At the same time in the described example of the dynamic pumping hydrotransportation, controlled dynamic action means is utilized, in particular the controlled dynamic hydropump 1 which, in addition to the pumping device 9, also has the modulator 10 which realizes the “Principle of controlled interior dynamic shunting” of the working zones 14 and 15 of the pressure drop means (pumping device 9). During the operation of the modulator 10, a new dynamic (modulating) mode of operation of the controlled dynamic hydropump 1 will be realized. In an initial position before the operation of the modulator 10 the throughgoing passage 16 is closed by the valve unit 19 which creates a local zone of structural border of separation between the working zones 14 and 15. When the modulator 10 is turned on, the movable valve element of the valve unit 19 moves under the action of the drive 21. The given periodic change of the given area of the minimal cross-section of the given shape of the throughgoing passage 16 takes place, in which was preliminarily set in the process of displacement of the movable elements of the correcting unit 18 under the action of its drive 20. The displacement of the movable value element of the valve unit 19 in turn leads to a given dynamic periodic “destruction” and subsequent restoration of the given created local zone of the portion of structural border of separation between the working zones 14 and 15 with a simultaneous given change of the valve of the area of local “destruction” in each period. A given dynamic periodic generation of a throughgoing passage is provided at the given portion of the border of separation between the working zones (through the throughgoing passage 16) with a simultaneous given change of the value of the given area of a minimal cross-section of the passage in each period of its creation. Thereby a given dynamic periodic change of the value of connection between two working zones 14 and 15 is performed, with a simultaneous given change of the value of the connection in each of its periods. During this process under the action of the difference of the over pressures in the working zones (+P) and (−P), the throughgoing passage 16 in each period of the connection is filled with the carrying medium (water) 7 which passes through the filter (or several filters) 17. The filter performs filtration of a local volume of the carrying medium in the zone of connection of the throughgoing passage during the transporting of the object 6 by the flow of the carrying medium 7. The filter 17 provides a protection of the internal cavity of the throughgoing passage 16 from entering of the material transported by the flow or other foreign inclusions. In turn, the given change of the value of the connection (C) in each period Tc which is performed by the above described technical means with the passage 16 of the modulator 10 (FIG. 3) leads to a simultaneous given dynamic periodic change of the value of the negative over pressure (−P) and the value of the positive over pressure (+P) in each period of their change in corresponding working zones 14 and 15 of the pressure drop means (in this example it is the electromechanical pumping device 9). The value of the negative over pressure (−P) as shown in FIG. 4 is dynamically periodically changing in a given range (−Pmax)÷(−Pmin), while the value of the positive over pressure (+P) simultaneously periodically changes within a given range (+Pmax)÷(+Pmin). The above mentioned values of the over pressures (−Pmax) and (+Pmax) correspond to a moment when the displacing movable valve element of the valve unit 19 completely closes the given minimal cross-section of the given form of the throughgoing passage 16. This situation occurs in each period (Tc) periodically (with the frequency f=1/Tc) of the repeating displacements of the movable valve element of the valve unit 19. In this moment the above mentioned local zone of the given portion of the structural border of separation between the working zones 14 and 15 in the throughgoing passage 16 is completely restored to provide a minimal (in this case it is zero) value of their connection (C0). The values of the over pressures (−Pmin) and (+Pmin) correspond to a moment when the above mentioned displacing movable valve unit 19 completely opens the given minimal cross-section of the given form of the throughgoing passage 16. In this moment the local zone of the portion of the structural border of separation between the working zones 14 and 15 in the throughgoing passage 16 is completely “destroyed” so as to provide (FIG. 3) a maximal value of their connection (Cmax). Therefore as a result of the above mentioned dynamic periodic shunting interaction of the elements of the modulator 10 with the working zones 14 and 15 of the pumping device 9 in the controlled dynamic hydropump 1, a given modulation of the value of action in the pressure drop means (ΔP) in the given range of (d) of its dynamic periodic change (ΔPmax) (ΔPmin) is performed during the process of transporting of the object (FIG. 4). The given modulation is performed with given values of its parameters: frequency, range and law of dynamic periodic change of the value of the action. (ΔP). In the given example the given range (d) of the given modulation is determined the value of the given area of a minimal cross-section of the throughgoing passage 16 which is established by a given displacement of the movable element of the correcting unit 18 by means of its drive 20, which is set by a command (Ud) supplied to it from the control block 22. For technical realization it is possible to use for example various types of closing flaps or locks with a controlled drive (electrical, electromagnetic, pneumatic, hydraulic, etc.). The above mentioned law (I) of the given modulation is determined by the given shape of the given minimal cross-section of the throughgoing passage 16, which is set by the displacement of another shape-providing movable element of the correcting unit 18. The given displacement is set by another command (Ul) which is supplied from the control block 22 to the same drive 20, which switches in accordance with this command for the displacement of the shape-providing movable element. It is possible to use here, for example, ring-shaped or disc-shaped controlled movable elements which have various shapes of edges of their cross-section, superposed on the minimal cross-section of the throughgoing passage 16. When it is structurally necessary, the form-shaping movable element of the correcting unit 18 can have its own controlled drive which is connected directly with the output (Ul) of the control block 22. At the same time the given frequency (f) of the modulation is determined by a speed of displacement of the movable valve element of the valve unit 19 under the action of the drive 21, which is provided by command (Uf) supplied from the control block 22. The valve unit can be provided for example with rotatable disc-shaped or cylindrical valve elements (with one or two throughgoing “windows”), the nearly linearly moving spherical or conical valve elements, etc. The movable valve element of the valve unit also is structurally connected with the controlled drive (electrical, electro-magnetic, pneumatic, hydraulic, etc.). At the same time, in addition to the above mentioned technical principles, the device of the modulator can have analogous functional elements which use other controlling principles (physical, chemical, physical-chemical, etc., and also their possible combination). This makes possible to use in the modulator a “destruction means” which is analogous in its principle of operation and provides the given dynamic periodic local destruction of the portion of the border of separation between the working zones of the pressure drop means. The control block 22 in the given example is formed so that it provides performance of two control modes for providing the modulation of the value of action in the pressure drop means (ΔP). A first (“open”) mode of operation of the control block 22 provides fixing of given values of parameters of the modulation: frequency, range and law of dynamic periodic change of the value of the action (ΔP). In this mode a setting signal Ul is supplied to the setting input “a” of the control block 22. The block 22 (with consideration of introduction of new setting elements into its operational algorithm) develops required fixed commands (Ud), (UL) and (Uf) which are supplied to the corresponding inputs of the drives 20 and 21. The latter act on the corresponding movable elements of the correcting unit 18 and the valve unit 19 to provide fixed setting of values of the parameters of the modulation: frequency, range and law of dynamic periodic change of the value of action (ΔP). If the setting signal Ui remains unchanged during the transporting of the object 6, then the given values of parameters of the modulation do not change. In the case of fixed change of the setting signal (Ui) the given values of parameters of the given modulation are changed also in fixed fashion. Depending on the algorithm of operation of the block 22, values of one or several parameters can be fixedly changed. A second (“closed”) mode of operation of the control block 22 provides a current control of values of the parameters of modulation (“floating” mode). In this mode a signal U(Qo) which characterizes a current value of the volume rate (Qo) of the transporting material (gravel) 6 is supplied to the control input “b” connected with the sensor 8. The block 22, with consideration of the comparison of the current value of signal U(Qo) with given values of parameters of the algorithm of its operation, generates a required current command (Ud), (Ul) and (Uf) which are supplied to the corresponding inputs of the drives 20 and 21. The latter continuously act on the corresponding movable elements of the correcting unit 18 and valve unit 19 to provide a current control of given of the value of the parameters of modulation of the value action (ΔP). With the consideration of the algorithm of the operation of the control block 22, it is possible to provide a current change of a value only one or values of several of the giving parameters of the modulation in given dependence on current changes of controlled characteristic (Qo) connected with the process of transporting of the object. Thereby, an algorithm “adaptation” of the combination of the parameters of the modulation to a current change of the controlled (in this example) characteristic (Qo) is performed. The dynamic optimization of the current control of the process of transporting of the object in accordance with a selected controlled criterion (QO) is provided. In various systems when it is necessary to solve various optimization problems of the current control, the algorithm of the control block 22 can provide one of seven main dynamic modes of the given modulation. Possible variants of the algorithms, with which the current control for giving values of only one of the above mentioned parameters of the given modulation is provided a the of range dynamic periodic change of the value of action (ΔP), during the current constancy of setting of two others parameters (frequency and law), provide realization of the dynamic mode of the given “amplitude” modulation. In this case the current values of the range (d) given by the algorithm can change within any limits and can be selected from zero to tens percentages of the ΔPmax (with consideration of the concrete task of the current control). The realization of the other dynamic mode, a given “frequency” modulation, can be performed during the current control of giving of the values also of only one from the parameters of the modulation: frequency, with current constancy of giving of two other parameters (range and law). mere the current values of the frequency (f) given by the algorithm can also change within any limits and can be selected from zero to tens Hertz (with consideration of the concrete task of the current control). During the realization of one more possible dynamic mode: given “modification” modulation, the current control of giving the values of also only one from the parameters of the given modulation: law, with current constancy of giving of two other parameters (range and frequency) is performed. In this case the current types of the law (I) which is given (modified) by the algorithm can also be changed within any possible limits for realization and can be selected with consideration of the concrete task of the current control. By means of the correcting unit 18 of the modulator 10, various laws of the modulation can be given, for example trapezoidal, sinusoidal, rectangular, triangular and other more complicated laws. Variants of the algorithms are possible, with which the current control of giving the values of only two of the parameters of the given modulation can be performed: a range and a frequency of dynamic periodic change of the value of the action (ΔP), with a current constancy of giving of only one of the parameters, law, can be performed, which provide realization of the dynamic mode of given “amplitude-frequency” modulation. The realization of another dynamic mode given “amplitude-modification” modulation can be performed during the current control of giving of the values also of only two of the parameters of the given modulation: a range and a law, with current constancy of giving of only one of the parameters (frequency). During realization of one more possible dynamic mode of given “frequency-modification” modulation, the current control of giving of the values also of only two of the parameters of the given modulation: a frequency and a law is performed, with the current constancy of giving of only one its parameter (range). More complicated variants of the algorithms are possible, with which the current control of giving of the values of all parameters of the given modulation is performed: frequency, range and law of dynamic periodic change of the value of the action (ΔP), for providing realization of the dynamic mode of a given “complex” modulation. It is necessary to mention that in some cases in the systems which are similar to the above described system, the values of the changing parameters of the modulation can be given (optimized) during the process of current control with them in a given dependency from the current changes of a combination of several controlled characteristics, connected with the process of transporting of the object. In this case the control block 22 can have some control inputs, for example “b1”, “b2” . . . “bn”. In addition, the control block 22 can have also several giving control inputs, for example “a1”, “a2” . . . “an”, which are used for fixed input giving of a value of one or values of simultaneously several parameters of the modulation, and also are used for giving variants of algorithm of operation of this block. The above mentioned process of realization of given modulation of the action value (ΔP), with given frequency and law in a given range (ΔPmax)÷(ΔPmin), its dynamic periodic change in the pumping device 9, determine an adequate (dynamic) process of change of the speed of movement of the flow of carrying medium (water) 7 during the process of transporting of the object (gravel) 6. In this case the dynamic reduction of the value of speed (Vf) of the movement of the flow of carrying medium corresponds to the dynamic reduction of the value of the action (ΔP) as shown in FIG. 5, which in turn characterizes the time interval (t−a) of the movement of the flow with a negative acceleration: −a=−dVf/dt (FIG. 6). At the same time the dynamic increase of the value of speed (Vf) of the movement of the flow of the carrying medium corresponds to the dynamic increase of the value of the action (ΔP) which in turn characterizes the time interval (t+a) of the movement of the flow with positive acceleration: +a=+dVf/dt. Therefore the forcedly modulated dynamic speed process characterizes the mode of movement, with which the whole dynamically created flow of the carrying medium moves with a given dynamic periodically changing alternating-current acceleration (±a), which is forcedly rigidly given during the process of transporting of the object (FIG. 6). Dynamic parameters of the above mentioned mode of movement with alternating-current acceleration (±a) reflect the dynamics of the energy action applied to the flow. It is necessary to mention that high frequency of a periodic dynamic change of the value and sign of the acceleration determines a principally new mode of dynamic creation of the flow. This mode of movement of the whole flow of the carrying medium is a main (determinative) characteristic of the proposed method, and its realization in this example is provided due to a relatively high-frequency use of the “Principle of controlled internal dynamic shunting” of working zones of the pressure drop means. It has been determined by the research of the author that with the realization of the new method in systems of pipeline transporting of various materials and media, high energy efficiency is achieved first of all due to minimization of a negative dominating influence of turbulence on losses of kinetic component of the applied energy in the zone of a boundary layer and in a nucleus of the flow of carrying medium in the process of transporting of object. The latter effect is achieved due to longitudinal “vectorization” of the turbulent flow, which reflects the influence of dynamic force energy action on coherent whirling structures of the flow (up to their “suppression”-“throw off”) and as a result—“pseudo-laminarization” of flow. At the same time practical non-compressibility of the carrying medium is taken into consideration, which determines the speed of propagation of the wave of the applied energy action along the flow, practically equal to the speed of sound. Application to the dynamically created flow of the dynamic forcibly-modulated in value over pressure (energy action), which predetermines its movement with the given dynamic periodic sign-alternating acceleration, provides this dynamic energy action on the transporting object during a whole period of process of its transportation by the flow of carrying medium. During this process, interphase friction is reduced and positive role “phasing” (or temporary shifts) is increased with occurrence of hydrodynamic processes in a turbulent flow located in a non-linear region of their influence (with consideration of times of “generation” and “destruction” of coherent structures, and also of inertia properties of movement of the object and a nucleus of the dynamic flow). During selection of the modes of modulation, differences are taken into consideration between dependencies of processes of “formation” and “destruction” of its coherent whirling structures, correspondingly from positive or negative sign and also from dynamic change of the value of sign-alternating acceleration (±a), which reflect resulting dynamic characteristics of corresponding “fronts” of relatively high-frequency energy action on the dynamically created flow of carrying medium. In addition, the above described possibility of the inventive-method to provide the given dynamic multi-parameter modulating control of the process of dynamic transporting of an object with a flow of carrying medium is in principle a new characteristic for solving of such tasks. This possibility of the inventive method allows to give and control in dynamics, one or simultaneously several parameters of modulation of the energy action applied to the flow (in the given example-ΔP). The time (frequency) parameter of modulation of the applied energy action can be provided to be similar (up to “resonance” occurrences) with time (frequency) characteristics of turbulent pulsations in the flow. These parameters of modulation of the value of action (ΔP) can be set so as to provide “determination” of more high frequency local turbulent waves (whirling formations) so as to determine reduction of their “lifetime” and as a result, the optimization (minimization) of energy losses connected with occurrence of negative factors in the turbulent flow. Possibilities of technical realization of the proposed method to provide optimizing “search” of these “resonance” modes of control with the above mentioned parameters of the process of modulation energy of action on the flow open the perspectives of establishing in the flow of a principally new state-energy mode “standing wave”. These factors are qualitatively new and decisive in the process of providing a significant minimization of various components of energy losses during transporting of the object with the use of the proposed method. It is necessary to note that the process of minimization of energy losses reflects the possibilities of the method, as a method for controlling of energy parameters of a turbulent flow (method of “controlling” turbulence). Taking into consideration the main role of the turbulent processes in energy losses in a flow, it is possible to make a conclusion about significant possibilities of the proposed method to provide dynamic energy optimization of the process of transporting of object with a flow of carrying medium (including a principally new condition of the energy mode of the flow—“Superconductive flow”, as it is named by Dr. A. Relin). In addition, the above mentioned possibilities for controlling with the proposed method allow to change dynamically integral speed (rate) parameters of the flow of carrying medium, and therefore of the object transported thereby. It is necessary to mention that the above mentioned minimization of various hydrodynamic components of energy losses is provided on the background of a significant (reaching tens percentages) reduction of integral value of the energy action applied to the flow. The latter is connected with the above mentioned process of modulation of a difference of over pressures in the working zones 15 and 14: (+P) and (−P) of the pumping device 9 with the use of the “Principle of controlled interior dynamic shunting” of working zone of the pressure drop means. At the same time the process of modulation determines the reduction of consumption (a conditional “recuperation”) of the supplied electrical energy which is converted (through its conversion into a mechanical energy) into the above mentioned operational over pressures. In this process the “Principle of controlled internal dynamic shunting” of working zones is characterized by exceptionally low losses of energy. This can be explained by realization of the process of dynamic periodic connection of the working zones through a minimal cross-section of a given form of the throughgoing passage 16 of relatively low length, which is characterized by an insignificantly low hydrodynamic resistance. This in turn determines a significant reduction of consumption of the supplied energy which is converted (consumed) by the action means (in this example—electrical energy consumed by the electromechanical pumping device 9 of the controlled dynamic hydropump 1). These conditions, and also maintenance by the flow of carrying medium of high integral speed parameters (due to the significant reduction of energy losses in the flow and its inertia properties) determines the possibility of providing a significant specific energy efficiency of the proposed method. In addition, the use of the proposed method in such systems of pipeline transportation of various materials and media determines a significant reduction of adhesion of their particles on the surface of the inner wall of the pipeline. This is connected with dynamic changes of the value of sign-alternating acceleration (±a), which reflect resulting dynamic energy characteristics of corresponding “fronts” of the energy action on the flow of carrying medium and as a result on the particles. The effect of longitudinal “swinging” of the particles which is generated in this case, significantly reduces a probability of their possible “adhesion” with one another, and also with the surface of the inner wall of the pipeline. The same dynamic characteristics of the method determine also other possibilities: significant reduction of a possibility of “clogging” of the pipeline with the transporting material; significant increase (by tens percentages) of energy efficiency of suction of the material with a surface to be cleaned (due to the “agitation” effect generated during this process); and also a significant reduction (several times) of a force necessary for displacement of the suction element (for example the suction inlet 5) near the surface to be cleaned which practically excludes the possibility of its “sticking”. At the same time the dynamic nature of the action on the flow leads to a significant improvement of its structurization, and also to the increase of efficiency of its possible technological filtration All listed possibilities of the method in turn also determine a significant contribution to a general reduction of technological components of energy losses. As a result, with the use of optimal modes of controlling of the process of dynamic transporting of the object with a flow of carrying medium, the reduction of specific consumption of energy consumed by the process can reach tens percentages. The above mentioned additional possibilities of the proposed method are connected with a dynamic consideration of characteristics (criteria) of the process of transporting of object with the flow of carrying medium for optimization of the multi-parameter dynamic control, by providing of the above mentioned process (for the purpose of increase of its energy efficiency). In the presented example of realization of the inventive method, as a controlling characteristic connected with the provision of the process of transporting of the object 6 by the carrying medium 7, a current value of a volume rate (Qo) of the transporting material (gravel) controlled by the sensor 8 with a signal U(Qo) is utilized. However, for solution of various specific tasks of controlling of similar hydrotransporting or pneumotransporting processes of various materials and media, also other controlled characteristics can be utilized, for example: values of various parameters of the process of transporting of the object with a flow of carrying medium (energy, rate, optimized specific rate of energy or speed); value of various parameters of the object to be transported (speed, structure, physical, chemical, geometrical or amplitude-frequency); and also in some cases a physical-chemical characteristic of the surface on which the object is located; values of various parameters of the flow of carrying medium (speed, structure, physical or chemical; pressure in internal cavity of a suction or pressure parts of a pipeline; amplitude parameter or frequency parameter characterizing a turbulent process of movement of the flow of carrying medium during the process of dynamic transporting of the object; and also an energy parameter characterizing influence of turbulence during the movement of flow of carrying medium on energy characteristics on the Process of transporting of the object); etc. Various types of known and special means for controlling of the above listed (or other) characteristics to be controlled can be utilized. For example, for the current dynamic control of speed of movement, volume concentration and volume rate of the material transported by the flow, special means for control developed by the author can be utilized, such as those disclosed in U.S. Pat. No. 5,502,658 (1996) “SCP Method of Velocity Measurement of the Object.” (A. Relin), or in the book “The Systems of Automatic Monitoring of Technological Parameters of Suction Dredger” Moscow, 1985 (A. Relin). The “SCP method” of measurement can be also used for dynamic control of speed of movement of the flow of carrying medium or parameters of its sign-alternating acceleration. Such means for control can be successively used in the inventive method, for example in the systems of hydrotransportation of pneumo transportation of double-phase or multi-phase flows which are characterized by the presence, correspondingly, of liquid or gaseous carrying medium and also transporting material, medium or mixture (object). As the object, it is possible to use for example: gravel, coal, ore, cement, natural resources to be excavated or powder materials, components or refuses of industrial manufacture, physiological substance, etc. In some systems of pipeline transportation, the transporting object (for example oil, natural gas, water, liquid chemical medium, liquid or gaseous fuel) is practically a single-phase flowable medium and performs the functions of the carrying medium. Analogous use in such systems of the inventive method (with consideration of its optimization possibilities) also allows to significantly increase their energy efficiency. The use of these principles of formation of dynamic means of action on a flow of carrying medium (of the type of the above mentioned controlled dynamic hydropump 1) allows to create a principally new class of controlled dynamic optimization pressure drop means (pumps, etc.) which is defined as “Dynamic optimization systems”. Such a system is characterized by structurally united and functionally connected main functional components: an action means for acting on a flow of carrying medium; built-in modulation means for modulation of the action; control means for controlling the operation of the modulation means; means (one or several means) of current control of a characteristic connected with providing the process of transporting of the object by the carrying medium. Such “Dynamic optimization system” can be produced as an independent dynamic controlled means of automation for use in various systems of a pipeline transportation. At the same time, for providing of the inventive method in acting systems of a pipeline transportation, the pressure drop means which preliminarily is installed in them (pump, etc) must be additionally equipped with the device “Modulator” (like modulator 10). Such a device “Modulator” can be also produced as an independent means for automation, for example in various systems of pipeline transportation. Such a device “Modulator” can have various structural solutions for units of their external connection to the working zones of the conditional pressure drop means. These units can be disconnectable and also non disconnectable and must provide a reliable structural connection of the ends of the throughgoing passage of the device “Modulator” (as the throughgoing passage 16 of the modulator 10) to internal cavities of the working zones from their accessible external side connected with the pipeline. These units can be additionally provided with a means for fixed closing of a connection of the working zones with the throughgoing passage (valve, flap, etc.). Such a technical solution will allow to remove the device “Modulator”, for example for performing repair works without disturbing a mode of exploitation of the pipeline transportation. In addition, such units can be additionally provided with special “reflectors” which provide additional protection of an inlet of the throughgoing passage from entering of large solid inclusions from the flow during the period realization of the process of connection of the working zones. In some cases, for finding the solution of special technological tasks in manufacturing processes (for example with long pipelines provided by traditional means of pressure drop and not allowing a connection of a transporting fluid with an ambient medium), the inventive method can be also used efficiently also analogous for dynamic energy “control” of a long portion of the pipeline transportation. In this case, on conditional “working ends” of the portion in the flow, conditional working zones are separated which determine a working pressure drop. In this case the throughgoing passage of the device “Modulator” is structurally connected with its ends to the internal cavities of the working zones. Such functional configuration of the system to be created provides a possibility of realization of the “Principle of controlled internal dynamic shunting” of internal cavities of the working zones of the conditional pressure drop means (the portion). In this case, the possibility is provided for creating the above mentioned controlled dynamic energy action on the flow. Such a solution, in some cases, can be also efficiently used for long ascending portions of suction pipes which are used widely for example in a metallurgical, chemical, energy-related and other facilities. This use of the inventive method significantly improves aspiration and possible filtration of technologically withdrawable flow. The inventive method can be also used for optimization of turbulent structure and geometry of a burning zone (for example in a turbo-reactive system or during flowing of fuel into a furnace) for the purpose of increasing of energy efficiency. All above mentioned “pipeline” examples of possible use of the proposed method are characterized by the presence of long portions of a pipeline, along which a transporting “closed” flow of carrying medium is movable. However, in practice there are “open” systems in which the action means (for example a pressure drop means) act on the flow of carrying medium which is not limited by a long pipeline. In this case the flow which is created acts on the object which is located on a fixed (or changeable) distance from the action means. Depending on the direction of application of the flow on the object, pumping or suction action on it can be created for its possible displacement in a given direction or for its destruction (with a subsequent transportation). The use in these systems of the inventive method also significantly increases their energy efficiency due to the creation of optimal characteristics of a dynamic energy action of flow of the carrying medium on the object. For this purpose it is possible also to use efficiently one of the above mentioned technical solutions which realize the method: “Dynamic optimization system” or the device “Modulator” connected to the working zones of the exploitational pressure drop means. In such “open” systems for creating the optimal characteristics of dynamic action, a special importance resides in the possibility of consideration and current control of several special characteristics. They can include (but not limited) value of parameters of the transporting object (aerodynamic, hydrodynamic, structural or geometric; and also a size parameter which characterizes a mutual location of the means of action and the object; a rate parameter of the object; a parameter which characterizes amplitude-frequency characteristic of the object, or a parameter characterizing a physico-mechanical characteristic of a surface on which the object is located). The current control of some of the specific characteristics during the realization of the inventive method allows to optimize the process of creation of dynamic energy action on the object, for example with consideration of “resonance” characteristics of the process of its destruction or tearing off from a surface, and in some technological tasks also for providing a given selection (sorting) of objects which have various parameters. The inventive method can be also used for optimization of turbulent structure and geometry of a burning zone (for example in a turbo-reactive system or during blowing of fuel into a furnace) for the purpose of increasing energy efficiency. All above described examples of possible realization of the inventive method in “structurally non-connected” systems of transporting of object with a flow of carrying medium are characterized by the absence of structural (rigid) connection between the transporting object and the action means. In this case the object is moved relative to the action means by a flow of the carrying medium. At the same time the proposed inventive method can be also efficiency used in known “structurally connected” systems of transporting of an object with the flow of carrying medium. Such systems are characterized by a structural (rigid) connection between the transporting object and the action means. In this case the object is displaced together with the action means under the action of a flow of carrying medium created by the action means, which flow interacts with the object. Examples of such objects of “structurally-connected” systems can be: air apparatus (for example an airplane or a rocket); speedy abovewater and underwater apparatuses, or for example speedy overground apparatuses, used as the action means for example pump, screw, turbine, turbo-reactive or reactive means for energy action on the carrying their medium. For realization of the inventive method in such “structurally connected” systems, the action means can be provided either by a built-in modulator such as the above mentioned “Dynamic optimization system”, or by additional modulator such as the above mentioned “Modulator”, connected to the working zones of the used action means (for example pressure drop means). The throughgoing passage 16 of the modulator (like the modulator 10) is structurally connected with its ends correspondingly to the inner cavities of the two working zones separated in the action means of such a system: to a working zone of conditional “negative over” pressure and to the working zone of conditional “positive over” pressure. Such functional configuration of the system provides the above mentioned possibility of realization of the “Principle of controlled internal dynamic shunting” of inner cavities of the above mentioned working zones of the pressure drop means, so as to create the controlled dynamic energy action on the flow. The realization of the inventive method in such “structurally connected” systems leads to the situation that the whole dynamically created flow of carrying medium will move with a given dynamic periodically changing sign-alternating acceleration during the process of transporting of the object. In this case the object is also moving dynamically with the sign-alternating acceleration. The dynamic forced aerodynamic or hydrodynamic interaction of the moving object with a gaseous or liquid medium flowing around its surface (for example a portion of an exterior surface of a casing of flying or submarine apparatus) will provide minimization of various components, correspondingly aerodynamic and hydrodynamic energy losses. In this 36. process, one of the main factors is the factor of minimization of negative dominating influence of turbulence on the losses of kinetic component of the applied energy in the zone of a border layer and in the nucleus of the flow of carrying medium during transporting of such an object. Another important factor of minimization of energy losses is a significant reduction of aerodynamic (hydrodynamic) “front” resistance during the above mentioned dynamic mode of movement of the apparatus. Taking into consideration the significant reduction of consumption of the supplied energy in the inventive method, which is converted (consumed) by the action means, inertia of the moving object, as well as the positive factors providing minimization of various components of losses of the energy, it is possible to expect a high energy efficiency of the use of the inventive method in such “structurally-connected” systems. Optimization of multi-parameter dynamic control by the inventive process of dynamic transportation of such apparatuses is connected also with efficient use of various specific controlled characteristics, such as for example: value of speed, aerodynamic, hydrodynamic and geometric parameters of the object; value of a size parameter which characterizes a position in space of the object during the process of its transporting; values of various parameters of the flow of carrying medium, etc. The above mentioned, with consideration of the dynamic control of the systems which realize the inventive method, determines a significant (reaching tens percentages) reduction of a specific consumption of energy for transportation of such apparatuses, which allows to obtain an additional energy resource for possible increase of maximal speed or distance of their movement. At the same time, it is known that the supplied energy of forced aerodynamic or hydrodynamic interaction of the exterior surface of the moving speed apparatus (with any engine) with a gaseous or liquid exterior medium flowing around it in turn is converted into action energy in this “convertor”. Such “surface-energy” systems are characterized in that the structural part of the object (apparatus) during the process of forced interaction with the carrying medium performs the function of a “converting” element of a conditional means of energy action. With this, the main type of energy action (in the shown example) is the energy of pressure drop. This pressure drop is created on the “converting” element in the process of conversion of the energy supplied to the “converter” due to provision of a working zone of the conditional “negative over” pressure and the working zone of conditional “positive over” pressure on various portions of a different-profile external surface of the moving speed apparatus (object). In the present case the working zones perform the functions of working zones of a conditional action means (pressure drop means), which acts on the exterior flowing medium. The local flow of the medium created in this process interacts in turn with the external surface of the structural part of the speed apparatus (object) so as to form known additional energy losses during its movement. One of the many examples of such “surface-energy” systems can be an exterior surface of a wing or other different-profile parts of a body of an airplane, and also different-profile exterior surfaces of various known air, submarine, overwater and overground speed apparatuses. With consideration of a relative inertia of the moving object, the use of the inventive method for dynamic control of a process of interaction (“transportation”) of the local created flow of “carrying” medium with the structural part of the speed apparatus (object), opens qualitatively new possibilities of minimization of the energy losses. For realization of the proposed inventive method in such “surface-energy” systems, the conditional action means can be provided with a modulator, such as the above mentioned “Modulator”. The throughgoing passage of the modulator is connected with its ends structurally to a working zone of the conditional “negative over” pressure and the working zone of conditional “positive over” pressure, separated on various portions of a different-profile exterior surface of the moving speed apparatus. Such a functional configuration of the “surface-energy” dynamic system will provide the possibility of realization of the “Principle of controlled internal dynamic shunting” of internal cavities of the working zones of the conditional pressure drop means. In this case the creation of the above mentioned controlled dynamic energy action on the local flow of a “carrying” medium is provided. The realization of the inventive method in such “surface energy” system leads to the situation that the whole local flow of a “carrying” medium will move with the given dynamic periodic sign-alternating acceleration during the process of interaction (“transporting”) of the created local flow of the “carrying” medium with the structural part of the speed apparatus (object). In this case also the action on the structural part of the object will have an analogous dynamic nature. This determines the aerodynamic (hydrodynamic) effects which minimize various known components of energy losses connected mainly with a negative domineering influence of turbulence of the created local flow of a “carrying medium ” on the losses of kinetic component of energy (applied to the structural part of the object) in the zone of a border layer above its exterior surface. One more important factor for minimization of losses of energy in such “surface energy” dynamic systems is a significant reduction of aerodynamic (hydrodynamic) “surface” resistance during the above mentioned dynamic mode of interaction of the created local flow of a “carrying” medium with the structural part of the speed apparatus (object). Optimization of a multi-parameter dynamic control of the process of interaction of the local flow of a “carrying” medium with the structural part of the speed apparatus (object) is also connected with efficient use of specific controlled characteristics for example: value of various parameters of the created flow of a “carrying” medium (speed, structure, physical and chemical); values of amplitude parameter or frequency parameter which characterize a turbulent process of movement of the local flow; and also values of an energy parameter which characterizes the influence of turbulence on the movement of the created flow on the energy characteristics of the process of transporting of the object; or values of various parameters of the exterior surface of the structural part of the transported object (speed, aerodynamic, hydrodynamic, physical, chemical or geometric). It is possible to expect here a high energy efficiency of the use of the inventive method in the system of this type taking into consideration several factors: significant reduction of consumed energy supply to such “surface-energy” converting system, which is converted (consumed) in it by the conditional action means; inertia of the moving object; minimization of various components of losses of a kinetic component of its energy, etc. As a result, the energy efficiency can be expressed in a significant economy of energy, which is consumed by the speed apparatus, and also in obtaining of an additional energy resource for a possible increase of maximum speed or distance of its movement. It should be noted that the above mentioned local principle of possible creation of functional creation of such “surface-energy” dynamic systems (with the use of the possibilities of the inventive method) allows to structurally overcome a great number of structural portions of such speed apparatuses (objects). In each such system (subsystem) it is possible to use for example one or several single-channel modulators (such as Modulator 10); single-channel modulators with several valve units operating in accordance with different laws; or a multi-channel Modulator. The distinguishing structural principles for creating of such a multi-channel modulator is so that it provides a periodic connection of the above mentioned separated “paired” working zones with simultaneous given change of the value of the connection of them with one another in each period. The latter is achieved by creating of a dynamic periodic formation on the border of separation between several “paired” working zones, simultaneously of several throughgoing passages. These throughgoing passages have a uniting common portion with a given area of its minimal throughgoing cross-section. The given change of the value of the given area of the minimal cross-section of the common portion in such a multi-channel modulator is performed in each period of the process of creation of the throughgoing passages (and simultaneously with it) in the process of dynamic transporting of the object. With this, the above mentioned separated “paired” (having a pressure with a different sign) working zones have portions with a structural and also with a spacial border of separation between them. The above mentioned connection of the “paired” working zones which is performed by any of the above mentioned modulators, determines the dynamic periodic “destruction” of the integrity (with a subsequent “restoration”) of one or several local zones on the portions (or portions) of a structural border of separation between them. These possible variants of the structural realization of the proposed inventive method in such “surface-energy” dynamic systems determine a principally new structural realization of the so-called “breathing” surfaces (structurally connected with the channels of the modulators) on the structural parts of the speed apparatuses (objects). This allows to create principally new types of various speed apparatuses with practically non-inertia aerodynamic (hydrodynamic) surface-distributed controlled “dynamic rudders”. In turn, these possibilities of the use of a method open qualitatively new ways to provide a dynamic energy efficient control of aerodynamic (hydrodynamic) characteristics of such apparatuses (objects) in the process of their movement. It is necessary to mention that the above considered technical principles for creation of the dynamic systems can be used as a single-channel (one or several) and also multi-channel principles for formation of the modulator. The use of several controlled channels of modulation allow to build the control block with the possibility of realization of both “synchronous” and “asynchronous” control of their operation. Such an approach opens additional possibilities for creating of more complicated laws of the modulation in the case of solution of special tasks for providing dynamically complicated types of energy actions. At the same time it is necessary to mention that the above described technical solutions for creation of the dynamic systems (in the process of performing of the modulation) do not allow a contact of the inner cavity of the transporting closed channel with a surrounding ambience, for example atmosphere. In this case practically it is not necessary to solve structurally the tasks connected with a reduction of the level of an additional noise effect, which occurs in modulators realizing the “Principle of controlled exterior dynamic shunting” of a suction portion of the pipeline. Another wide area of possible use of the proposed method includes various known processes of transporting (destruction) of an object by a flow of carrying medium, which use the action means of “explosive” principle of energy conversion. Such devices are for example known explosion devices of pumping and vacuum “spacious” action on the object. In addition, they also include various object transporting systems which used explosion energy for forming a “structurally-limited” action on the carrying medium, with a flow which displaces the object (for example piston systems of internal combustion engines, barrel weapon systems, etc.). In these systems “explosive” action means are utilized (chemical, physical-chemical, physico, etc.) which are characterized by an explosive principle of conversion of energy and using the “supplied” energy generated for example as a result of a chemical reaction, nuclear reaction thermal laser action, electrical discharge action, etc. In the process of conversion in such “explosive” action means of the “supplied” energy, spacially (or partially structurally) limited working zones of a negative over pressure (−P) and a positive over pressure (+P) are created, which contact with the carrying medium so that the flow of carrying medium which is created in this situation acts on the object for providing the process of its transporting in a given direction (or for destruction). In such explosion devices of pumping or vacuum “spacial” action which destroys the object, the working zones can have a conditional (spacial) border of separation between them. It is possible to realize in this case the inventive method with creation of the given dynamic periodical connection of the working zones with one another with a simultaneous given change of the value of the connection in each period during a dynamic action on the object of the “explosive” action means. The latter is provided by given dynamic periodic creation on the portion (or portions) of the spacial border of separation between the working zones of one (or several) throughgoing passages with simultaneous given change of value of the area of minimal throughgoing cross-section of each of the passages in each period of their creation during the “explosive” action on the object. This is achieved as a result of a given dynamic periodic local “destruction” with the subsequent “restoration” of the given portion of the spacial border of separation between the working zones with a simultaneous given change of the value of area of the local “destruction” in each period of its implementation. The process of the given dynamic periodic local “destruction” of the spacial portion of the border of separation between the working zones can be performed by an additional “destructive” means (for example physical, chemical or physico-chemical) or by a combination of several types of destructive” means. In this process the “destructive means” (“spacial modulator”) periodically “triggers” in accordance with a given law in the process of explosion, and provides a realization of the “Principle of controlled internal dynamic shunting” of the internal cavities of the working zones of the “explosive” action means (as pressure drop means). This periodical “triggering” of the “spacial modulator” can be set, for example: by a number of parts “destructive” component; their different volumes; different chemical and physical critical parameters which determine a moment of beginning and end of their “destructive” action on the spacial portion (or portions) of the border of separation between the working zones; and also by a critical parameters which determine a time shift (periodicity) between the “destructive” actions, etc. In the process of implementation of the modulation of the value of “explosive” action the above mentioned dynamic energy action on the flow of the carrying medium which is created is performed, and the carrying medium in turn acts dynamically on the object. In the explosive devices of pumping “spacial” action which destroys the object, the working zone of the negative over pressure (-P) is created in a center of the explosion, while the working zone of the positive over pressure (+P) is created in an external zone from the center of explosion. Therefore during the interaction of the working zones with the carrying medium its flow is created, which acts on the object for providing the process of its transporting (or its destruction) in a given direction from the center of explosion. In such explosive devices of vacuum (spacial) action which destroys the object, in the center of explosion the working zone of the positive over pressure (+P) is created, and in the external zone from the center of explosion the working zone of negative over pressure (-P) is created. Thereby, in this case during the interaction of the working zones with the carrying medium its flow is created which acts on the object for providing the process of its transporting (or its destruction) in a given direction toward the center of explosion. The possible realization of the inventive method in this case provides a given modulation of the value of the action in the “explosive” action means (pressure drop means). The modulation is performed by a simultaneous given dynamic periodic change of the value of the negative over pressure and the value of the positive over pressure with a simultaneous given change of the values of the pressures in each period of their change in corresponding working zones. This is performed so that the whole flow of carrying medium which is dynamically created, moves with a given dynamic periodic sign-alternating acceleration during the process of dynamic “spacial” action on the object. At the same time, the possible losses of energy of action connected with known turbulent effects during interaction of the flow with the object are minimized. The given parameters of the modulation can be provided by fixedly given characteristics of the “spacial modulator”. This is done with consideration of the amplitude-frequency characteristics of possible (selective) object of destruction (transportation). The frequency of modulation must be selected from the given time interval of occurrence of an explosive process. This approach opens qualitatively new ways for creation and significant increase of destructive (transporting) energy possibilities of such dynamic explosive devices. The above mentioned “spacial modulator” (“destruction means”) in such a dynamic explosive device can be structurally formed for example as: physical, chemical or physico-chemical component (or components), constantly technologically introduced into the structure of the explosive device. In addition, the above mentioned “spacial modulator” can be formed as a separate exchangeable block which can be structurally installed (or replaced) in the construction of the explosive device. The block solution of the “spacial modulator” can have different fixedly given characteristics, which determine the parameters of modulation; or it can provide a possibility of selective setting (selection) of one of several variants of the characteristics. Such block solutions allow to significantly expand selective explosion (transporting) energy possibilities of such dynamic explosive devices, and therefore also to increase the efficiency of their use for solution of various tasks, for example in construction, in mineral and excavation industry and also in defense technologies. The known explosive system which transporting of the object and use the energy of explosion for creating the “structurally-limited” action on the carrying medium for transporting of an object (for example piston systems of internal combustion engines, barrel gun systems, etc.) are characterized by the presence of structurally identified (for example on an inner wall of their guiding structure) portions of a border of separation between working zones created in them (−P) and (+P). Therefore, for realization of the proposed inventive method it is possible to use in them: the above mentioned types of the “spacial modulator” introduced into the zone of explosion (during a period of its implementation) by various technological and structural ways; and also the above mentioned types of structural modulator (the device “Modulator”), which provide the periodic dynamic connection of the separated working zones through its throughgoing passage (or passages). The last mentioned technical solutions allows to create dynamically similar systems of “structurally-limited” action with the possibility of flexible control (or optimization) of an energy process of dynamic action on a displacing object (for example, a piston or a missel) realized in them. This opens principally new possibilities for improvement of energy characteristics of the technical systems, which is achieved due to reduction of losses, for example for friction of object against an inner wall of the guiding structure; from turbulence of the flow of carrying medium, etc. In addition, in such dynamic systems a minimization of adhesion of products of combustion on the internal working walls will be achieved, as well as improvement of the operational of a filtering device which dynamically interacts with the created flow of carrying medium discharged from the system. This “Principle of controlled interior dynamic shunting” of inner cavities of the working zones of the pressure drop means can be efficiently used for realization of the inventive method in other types of new dynamic systems, to provide the creation of the above mentioned controlled dynamic energy action on the flow (and on the object). They can include for example: dynamic single-contour (or double-contour) vacuum cleaning systems; dynamic medical suction devices for removal of non-conditioned physiological media; for taking gaseous and liquid physical probes; for providing gynecological processes, for therapeutic massaging procedures, for artificially created dynamic physiological systems based on physiological organs of life organism (heart, lungs, etc) with the use of converted energy which is discharged in them; for dynamic technological systems (for example for vacuum forming of mixtures, for selection of objects during their sorting, for underwater cleaning of surfaces of various objects, etc.). The realization of the inventive method in these and other similar systems significantly improves their energy and exploitation efficiency. At the same time the proposed method can be efficiently realized not only in these systems which use as the action means acting on the carrying medium, the above mentioned types of pressure drop means. The inventive method can be efficiently realized in “energy” systems which use as the means of action on the carrying medium, a means of direct energy action (magneto-hydrodynamic pumps, magnetic and electromagnetic acceleration systems, etc.). In such action means the energy supplied to them (or several types of energy) is converted directly into a direct energy action on the carrying medium for creating its flow. As the supplied energy it is possible to use for example: electrical, electromagnetic, magnetic, etc. energy, or a combination of several types of energy (for example a combination of magnetic and electrical energy as in a magneto-hydrodynamic pump). However, in such “energy” systems the modulation, as believed to be clear, can not be performed by-realization of the “Principle of controlled internal dynamic shunting” which is used in the pressure drop means. In these “energy” systems the modulation of the value of the action in the means of direct energy action can be performed by providing of the given dynamic periodic change of the value of a parameter, which is dynamically connected with the process of conversion in the action means of the energy supplied to it into the action, with simultaneous given change of the value of the parameter in each period of its change, so that the flow of carrying medium which is dynamically created here moves with a given dynamic periodically changing sign-alternating acceleration in the process of transporting of the object. For example in a magneto-hydrodynamic pump, as the changing parameter it is possible to use an induction of a magnetic field or an electrical voltage, applied to a portion of the carrying medium; an additional resistance introduced into an electrical circuit in series with the above mentioned portion of the carrying medium, etc. In this case for realization of the inventive method, the magneto-hydrodynamic pump must be additionally provided with a special device or “parametric modulator” for the given dynamic periodic change of the value of the selected one (from the above mentioned) parameter. In some cases for performing the modulation it is possible to use the combination of several types of such parameters for providing a more complicated law of the modulation. In such “energy” systems, the optimization of control of the modulation is also connected with the use of some of the controlled characteristics, which reflect the process of transporting of the object with the flow of carrying medium. In some of these systems, as specified herein above (with consideration of their specifics), as the controlled characteristic it is possible to use values of a parameter which characterizes the process of conversion of the energy of movement of the flow of the carrying medium with a transporting object, into another type of energy during their interaction (or without interaction) with an additional source of energy which acts on the flow during the process of transporting. These systems can include various “beam” systems of conversion of energy; gas flow systems with the use of a magneto-hydrodynamic generator, etc. The efficiency of use in such “energy” systems of the proposed inventive method can be connected with the increase of the converted (into other type) energy, and also with the increase of parameters characterizing its quality. The latter is determined by a possibility of minimization of influence on the process of conversion of turbulent factors and also by the dynamic nature of movement of the flow. At the same time this approach to provide the modulation of the use of various types of the special devices of “parametric modulator” can be efficiently used in some of the above mentioned systems which have the pressure drop means as the action means. In this case as the changing parameter it is possible to use for example: electrical, electromagnetic, magnetic, technical, physical, chemical, physical-chemical parameters or a combination of several of these or other parameters. The parameter (parameters) can be selected with the consideration of the type of the supplied energy and the principle of action of the pressure drop means. This can be a functionally-structural or energy parameter which is connected dynamically with the process of conversion of the supplied energy into the action and significantly directly acting on the process of conversion (with its given change). The function of the “parametric modulator” can be realized in various dynamic control devices which provide the possibility of the given dynamic periodic change of the value of the selected “modulated” parameter, for example with the use of dynamic electromagnetic coupling, on the basis of special modulators of “position” of functional structural elements of the action means, or special modulators of its main energy parameters, etc. Therefore, the above mentioned approach with the use of various types of the special devices of “parametric modulator” as a methodological solution in performing of the modulation of the value of the action, can be used also in various action means of dynamic systems of transporting of the object by the created flow of carrying medium. The above mentioned analysis of examples of possible efficient use of the proposed method convincingly illustrates the common most characteristic decisive and distinctive features of the present invention. They include the performance of a controlled given modulation of the value of the action in the action means so that the whole dynamically created flow of carrying medium moves with a given dynamic periodically changing sign-alternating acceleration, to provide optimization of energy parameters of the process of transporting of the object with a given dependency from changes of a controlled characteristic, connected with the process of transporting. The optimal dynamic modulation control by “flow-forming” dynamic energy action determines the energy and exploitation efficiency of the process of transporting of the object by the flow of carrying medium. In turn the above mentioned advantages of the proposed inventive method (new method of dynamic energy-saving optimization control of conveying fluid) open wide possibilities to create a principally new class of energy-saving dynamically controlled systems which provide efficient energy and exploitation characteristics of various processes of transporting of objects by a dynamic flow of carrying medium which is created and controlled by them. This reflects the possibility of a transition of the traditional processes of transporting to a qualitatively new step of their development. This step of development will be characterized by a wide use of the energy-saving dynamic technologies connected with the above mentioned “flow-forming” dynamic energy actions on the carrying medium, and also with dynamic, multi-parameter control which uses a current control of dynamic characteristics of such processes of dynamic transporting of various objects by a created flow of carrying medium. It will be understood that each of the elements described above, or two or more together, may also find a useful application in other types of methods and devices differing from the types described above. While the invention has been illustrated and described as embodied in a method of dynamic transporting of object with flow of carrying, it is not intended to be limited to the details shown, since various modifications and structural changes may be made without departing in any way from the spirit of the present invention. Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention.

<SOH> BACKGROUND ART <EOH>Various methods and devices are known, which provide transporting of objects with a flow of a carrying medium. A common traditional methodological approach which is used in various systems in the above mentioned class is application of an action to the above mentioned carrying medium from an action means which creates during the process of conversion of the energy supplied to it, and integrally constant in time action so that the above mentioned flow of the carrying medium created in this way acts on the above mentioned object for providing the process of its transporting in a given direction. This approach is realized in various systems which use mainly two types of means for action: means of pressure drop (pumps; screw, turbine, turbo reactive and reactive systems; explosive devices of pumping or vacuum action; means of action which use a forced aerodynamic or hydrodynamic interaction of the object or its structural part, correspondingly with gaseous or liquid medium, for example a region of an outer surface of a casing of a flying, speedy ground or underwater moving apparatus, etc.), and means for direct energy action (magnetohydrodynamic pumps; magnetic and electromagnetic acceleration systems, etc.). The object can be structurally not connected or structurally connected (for example in a flying apparatus) with the action means. In some cases the object, being a flowable medium, performs a function of the carrying medium (for example gas or liquid product such as oil transported in a pipeline). In various known action means, energy which is supplied to them and is converted in them can be of various types, such as for example: electrical, electromagnetic, magnetic, mechanical, thermal energy; energy generated for example as a result of performing correspondingly: a chemical reaction, a nuclear reaction, a laser action, etc., or for example energy generated during operation of a physiological system; or generated during a forced aerodynamic interaction of an object with a gaseous medium or during a forced hydrodynamic interaction of an object with a liquid medium. In some known action means, as the supplied energy a combination of several different types of supplied energy is utilized (for example, a combination of magnetic and electrical energy as in a magnetohydrodynamic pump). As the carrying medium, mainly a flowing (gaseous or liquid) medium is utilized. The object of transportation can be for example: powder or granular material; gaseous or liquid medium; excavated product (coal, ore, oil, gas, gravel, etc.); a mixture of materials and media; a component or refuse of manufacturing process; fast movable or immovable objects; physiological or physical substance; and many others. Common disadvantages of the known traditional methodological approach which is realized in such systems for providing a process of transporting an object with a flow of a carrying medium are as follows: limited possibilities for reduction of specific consumption of energy for providing the process of transporting of the objects; impossibility of performing efficient dynamic control of the process of transporting, with the purpose of optimization of its energy characteristics; presence of negative side effects which accompany work of some of such systems and significantly worsen their operational and energy characteristics (for example “sticking” during suction; adhesion of particles on inner walls or clogging of a portion of a channel which limits the transported flow; a fast clogging of filtering devices which operate in a multi-phase flow; and so on). The above listed disadvantages significantly reduce energy, and therefore also economical efficiency of application of such traditional systems for providing the process of transporting an object unit by a flow of a carrying medium. Other methods and devices for such transporting of an object with a flow of a carrying medium are known, as disclosed for example in U.S. Pat. Nos. 5,201,877 (1993); 5,593,252 (1997); and 5,865,568 (1999)—A. Relin, et al. The above-mentioned methods and devices realize a methodological approach which was first proposed by Dr. A. Relin in 1990 and utilizes a modulation of the suction force, performed outside of the action means by connection of an inner cavity of the suction area of the transporting line with atmosphere through a throughgoing passage and simultaneous periodic change of an area and shape of the throughgoing passage during transporting of the object. The use of this approach (which is named by Dr. A. Relin “AM-method”), which realizes the “principle of controlled exterior dynamic shunting” of the suction portion proposed by the author opens qualitatively new possibilities for significant increase of efficiency of operation and exploitation of a certain class of devices and systems for suction transporting of various objects. In particular, the use of modulation of the suction force over a limited suction portion of movement of the flow in a closed passage, for example in vacuum cleaning systems, in various medical suction instruments, and also in pneumotransporting systems of various materials and objects allows to minimize and even completely eliminate the above mentioned common disadvantages which are inherent to known traditional approach realized in the known systems of this type. However, the necessity and possibility of performing the connection of the interior cavity of only the suction portion of the transporting line (outside of the above mentioned action means) with the atmosphere through the throughgoing passage does not allow to use this principle of modulation in a sufficiently broad class of other types of known devices and systems which can provide a process of transporting an object with the flow of carrying medium: which do not allow a contact with atmospheric medium of the object transported in the closed passage, for example various gasses, chemical and physiological materials and media; which do not allow an entraining of atmospheric medium (for example air) into the hydrotransporting system which can lead to cavitation effects are damaging for the pipeline and the hydraulic pump, and also to energy losses in the process of transporting an object with a flow of a carrying medium; which do not allow a possibility of performing the connection of the inner cavity of the pumping line of transportation with atmosphere through the throughgoing passage, causing expelling of the transporting medium into atmosphere; which provide identical speed characteristics over the whole extension of the movable flow: both at its suction portion and its pumping portion; which do not allow a possibility of realization of such approach due to absence of a closed long suction portion of the passage during the use of various types of above mentioned action means on the carrying medium with a pressure drop, for example: connected with the object of transporting—screw, turbine, turbo reactive and reactive systems; various explosive devices; action means which use forced aerodynamic and hydrodynamic action of the object, correspondingly, with gaseous and liquid medium; and other similar types of action means; which do not provide a pressure drop with the action means used in them, realizing other principles of performing of the above mentioned action, for example during the use of the above mentioned means of direct energy action. In addition, during the development of the construction of the modulator which realizes the above mentioned “principle of controlled exterior dynamic shunting” of the suction portion it is necessary to solve additional problems, for example: connected with a reduction of the level of additional noise effect caused during a periodic connection of the atmospheric medium with the internal cavity of the suction portion of the transporting line; and also effects connected with protection of the throughgoing passage of connection of the modulator from possible sucking into it of various components of an exterior medium or foreign objects. The attempts to take into consideration these factors in such cases additionally complicates and makes more expensive the construction and the operation of the modulator. The above explained disadvantages significantly limit the possibilities during solution of real problems connected with energy optimization of processes of transporting of an object with a flow of a carrying medium, and also areas of application of the above analyzed efficient methodological approach which use the modulation of the suction force over the suction portion, performed with the use of the above mentioned “Principle of controlled exterior dynamic shunting”.

<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, it is an object of the present invention to provide a method of dynamic transporting of an object with a flow of a carrying medium which is in principle new. The proposed method (which is named by the inventor “R-method”) is based on works of Dr. A. Relin and confirmed by scientific research of concepts of a new theory “Modulating aero- and hydrodynamics of processes of transporting objects with a flow of a carrying medium”. This scientific concepts consider new laws which are developed by the author and connected with a significant reduction of a complex of various known components of energy losses (and therefore of specific consumption of energy) during creation of a dynamically controlled process of movement of the flow of a carrying medium with a given dynamic periodically changing sign-alternating acceleration during the process of transporting of the above mentioned object. The proposed method minimizes or completely eliminates the above mentioned disadvantages in providing an efficient process of transporting of an object with a flow of a carrying medium which are inherent to the known traditional methodological approach and the above mentioned second approach which uses the modulation of suction force based on the “Principle of controlled exterior dynamic shunting” of the suction portion. High energy efficiency of the new method is obtained due to the fact that it solves a few main problems: it provides minimization of negative dominating influence of turbulence on losses of kinetic component-of the applied energy in a zone of a border layer and in a nucleus of the flow of carrying medium during providing the process of transporting of an object; it provides minimization of various components of energy losses connected with the process of transporting of the object itself by the flow of carrying medium during whole period of this process; it provides possibility of a given multi-parameter dynamic control of the process of transporting of an object with a flow of carrying medium during its whole realization; it provides possibility of significant reduction of integral value of energy action applied to the above mentioned flow and as a result, provides practically analogous significant reduction of consumption of the supplied energy which is converted (consumed) by the action means to the flow; it provides possibility of dynamic consideration of characteristics (criteria) of the process of transporting of an object with the flow of carrying medium for optimization of the given multi-parameter dynamic control by executing this process with the purpose of increasing of its energy efficiency. In keeping with these objects and with others which will become apparent hereinafter, one of the new features of the present invention resides, briefly stated, in a method of transporting of an object with a flow carrying medium, which includes the following steps: application to the above mentioned carrying medium of an action which is created in an action means during a process of conversion of an energy applied to it so that the above mentioned flow of carrying medium created this way acts on the above mentioned object for providing the process of its transporting in a given direction; and performing a given modulation of a value of said action in said action means, which provides a given dynamic periodic change of said value of said action on said carrying medium so that said flow of carrying medium which is dynamically created moves with a given dynamic periodically changing sign-alternating acceleration in a process of said providing the process of transporting of said object. As the above mentioned action means, either a means of pressure drop or a means of direct energy action can be utilized. The proposed method embraces all possible spacial conditions of the transporting object. In some cases the object can be a flowable medium and in this case can perform a function of the above mentioned carrying medium. In other cases the object can be structurally not connected or structurally connected with the action means in the process of its transporting. In certain situations the structural part of the object can perform the function of a converting element of the action means so as to provide the process of conversion of energy supplied to it and generated during forced interaction of this structural part of the object with the flowable medium. Another important feature of the present invention is that the above mentioned given modulation of the value of the action in the action means is performed by providing a given dynamic periodic change of the value of a parameter which is dynamically connected with the process of conversion of the action means of the energy supplied to it into the action with simultaneous given change of the value of this parameter in each period of its change during the process of transporting of the object. This approach can be used both in the case of utilization of the pressure drop action means and in the case of utilization of the direct energy action means. As the parameter of the process of conversion of the supplied energy the following can be utilized, for example: electrical, electromagnetic, magnetic, structural, technical, physical, chemical or physico-chemical parameter; or a combination of various types of these parameters can be utilized. As the energy supplied to the action means, the following energy for example can be used: electrical, electromagnetic, magnetic, mechanical, thermal energy; energy generated as a result of performing of chemical or nuclear reaction; energy generated during the operation of a physical system; energy of forced aerodynamic interaction of a structural part of the object with a gaseous medium (performing the function of the action means); energy of forced hydrodynamic interaction of the structural part of the object with liquid medium (performing the function of the action means); or it can use a combination of several types of the supplied energy. In accordance with another feature of the present invention, the given modulation of the value of the action in the pressure drop means is performed by providing a simultaneous given dynamic periodic change in working zones of the pressure drop means, correspondingly, of a value of a negative over pressure and a value of a positive over pressure with a simultaneous their change in each period of the change of the above mentioned values of the above mentioned actions, generated in the process of conversion of the energy supplied to the pressure drop means in the work zones which are in contact with the carrying medium, so as to provide application of the generated given dynamic periodic action determined by the above mentioned values of the negative and positive over pressures during the process of transporting of the object. The simultaneous given dynamic periodic change in the working zones of the pressure drop means, and correspondingly of the value of negative over pressure and the value of positive over pressure with simultaneous their change in each period of the change of the values of the pressures is performed by a given dynamic periodic change of the value of connection between the working zones with a simultaneous given change of the value of the connection in each its period during the process of transporting of the object. At the same time the given dynamic periodic change of the value of connection of the working zone with the simultaneous given change of the value of the connection in each its period is performed by a given dynamic periodic generation on a portion of a border of separation between the working zone of a throughgoing passage (or several passages) with a simultaneous given change of the value of a given area of a minimal cross-section of the passage (or several passages) in each period of the generation, accompanied by performing correspondingly of a given dynamic periodic local destruction and subsequent reconstruction of the portion of the border with a simultaneous given change of the value of area of its local destruction in each period during the process of transporting of the object. The above mentioned local destruction is performed by destruction means, for example: technical, physical, chemical, physico-chemical; or is performed by a combination of several types of the destruction means. The portion of the border of separation between the working zones can be identified either structurally or spatially. In some cases of utilization of the new method, in a process of the given dynamic periodic generation on a portion of the border of separation between the working zones of the throughgoing passage (or several passages) with simultaneous given change of the value of the given area of a minimal throughgoing cross-section of the passage (or several passages) in each period of its action, a filtration of local volume of the carrying medium which in a zone of the given throughgoing passage during the process of the transporting of the object is performed. The above mentioned new features of the present invention reflect a new “Principle of controlled interior dynamic shunting” of working zones of the pressure drop means. In accordance with the important features of the present invention, in the method for performing the given modulation of the value of the action in the action means, values of its parameters are given: frequency, range and law of dynamic periodic change of the value of the action during the process of transporting of the object. A new method makes possible a realization of one of several main variants of giving of the values of the parameters: the given values of parameters of modulation do not change during the process of transporting; the values of one (or several) of the given parameters of the modulation is or are changed in a given dependency from changes of a controlled characteristic connected with the process of transporting of the object; values of the changing parameters of the given modulation are changed in a given dependency from changes of a combination of several types of the control characteristics connected with the process of transporting of the object. The process provides a possibility to use as the control characteristic, without any limitation, for example as follows: value of one of the parameters of the process of transporting of the object (energy, consumption, optimized specific consumption energy or speed parameter); values of one of parameters of the transporting object (speed, consumption, aerodynamic, hydrodynamic, structural, physical, amplitude-frequency, chemical or geometric parameter); values of one of parameters of spacial position of the object during the process of transporting; values of one of parameters of a surface of a position of the object during the process of transporting (for example physico-mechanical); values of one of parameters of the flow of the carrying medium during the process of transporting of the object (for example speed, structural, physical or chemical parameter); values of one of parameters of a turbulent process in the flow of carrying medium during the process of transporting of the object (for example amplitude, frequency or energy parameter); value of one of parameters of a process of conversion of energy of movement of the flow of carrying medium into another type of energy (during interaction or without interaction with an additional source of energy, which acts on the flow) during the process of transporting of the object. The novel features which are considered as characteristic for the present invention are set forth in particular in the appended claims. The invention itself, however, both as to its construction and its method of operation, together with additional objects and advantages thereof, will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.

20060601

20090707

20080417

89579.0

B65G5300

HARP, WILLIAM RAY

METHOD OF DYNAMIC TRANSPORTING OF OBJECT WITH FLOW OF CARRYING MEDIUM

SMALL

CONT-ACCEPTED

B65G

ACCEPTED

Process for Preparing Phenolic Polymer by Using Phenothiazines Mediator

The present invention relates to a process for preparing a phenolic polymer using a phenothiazine-based mediator, in particular, to a process for preparing a phenolic polymer via polymerization of phenolic monomers by using a phenothiazine-based mediator in the presence of peroxidase biocatalyst and an oxidant, thereby drastically improving the enzyme reactivity of peroxidase. The phenolic polymers prepared according to the polymerization of this invention maintain unsaturated hydrocarbon groups linked to their side chains, so that they are very useful as a curing resin because they can easily form coatings through radical curing. In addition, the coating formed using the curing resin has an antioxidation effect and a low surface energy, so that they can prevent physical attachment of marine livings. Because the antifouling-causing functional groups are not consumed, the coatings continuously exhibit durability.

1. A process for preparing a phenolic polymer via polymerization of phenolic monomers having unsaturated aliphatic chains in the presence of peroxidase biocatalyst and an oxidant, wherein said polymerization uses as a mediator a phenothiazine derivative substituted with an alkyl group or alkyl carbonic acid. 2. The process according to claim 1, wherein said phenothiazine derivative is used in a concentration of 20-100 μM with respect to the total reactant. 3. The process according to claim 1, wherein said phenothiazine derivative is ethyl phenothiazine or phenothiazine-10-propionic acid. 4. The process according to claim 1, wherein said phenolic monomer is a plant phenolic oil. 5. The process according to claim 1, wherein said peroxidase biocatalyst is a plant- or fungus-derived peroxidase including horseradish peroxidase, soybean peroxidase, Coprinus peroxidase and Aspergillus peroxidase. 6. The process according to claim 1, wherein said oxidant is hydrogen peroxide or hydroalkyl peroxide. 7. A radical cured resin of the phenolic polymer prepared according to claim 1. 8. A coating material comprising the radical cured resin of claim 7. 9. A radical cured resin of the phenolic polymer prepared according to claim 2. 10. A radical cured resin of the phenolic polymer prepared according to claim 3. 11. A radical cured resin of the phenolic polymer prepared according to claim 4. 12. A radical cured resin of the phenolic polymer prepared according to claim 5. 13. A radical cured resin of the phenolic polymer prepared according to claim 6.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing a phenolic polymer using a phenothiazine-based mediator, in particular, to a process for preparing a phenolic polymer by polymerizing phenolic monomers by use of a phenothiazine-based mediator in the presence of peroxidase biocatalyst and oxidant, thereby dramatically improving the enzyme reactivity of peroxidase. The phenolic polymers prepared according to the polymerization of this invention maintain unsaturated hydrocarbon groups linked to their side chains, so that they are very useful as a curing resin because they can easily form coatings through radical curing. In addition, the coatings formed using the curing resin have antioxidation effect and lower surface energy, so that they can prevent physical attachment of marine livings. Because the antifouling-causing functional groups are not consumed, the coatings continuously exhibit durability. 2. Description of the Related Art Phenolic polymers are known to be useful as paints and various coating materials, due to their excellent anti-corrosiveness and capability of forming a firm coating. For synthesizing phenolic polymers chemically, formalin or hexamethylene tetraamine generated by the condensation of formaldehyde and ammonia is employed in high-temperature polymerization. However, such method has some shortcomings in which formalin and formaldehyde are toxic and unreacted reactants toxic to environment and human body are remained after reaction. In addition, when phenolic polymers are synthesized using chemicals such as formalin, the double bonds of a lipid group side chain linked to phenolic compounds are consumed, so that the resulting phenolic polymers is unlikely to form coating due to the difficulty in setting by radical reaction. Therefore, a biochemical preparation using a biocatalyst is recognized as a preferred environment-friendly approach instead of chemical synthesis using toxic materials. Where phenolic polymers are synthesized using a biocatalyst such as enzyme, it is essential to establish optimal polymerization conditions in consideration of substrate specificity of enzyme. For example, a polymer derived from 4-methoxybenzyl alcohol and 2-hydroxy-4-methoxyphenyl acetic acid may not be synthesized using unassisted lignin peroxidase. In contrast, the presence of mediator such as veratryl alcohol allows the polymerization to be promoted (Harvey et al., FEBS Lett. 195:242-246 (1986)). Furthermore, it has been known that phenolic compounds having significantly long alkyl chains at their meta-position cannot be polymerized by use of horseradish peroxidase. As discussed above, the polymerization of phenol compounds using a biocatalyst demands the establishment of optimal polymerization conditions because of substrate specificity of enzyme. The present inventors have conducted extensive researches to develop a novel polymerization system which is applicable to all peroxidase biocatalysts generally known to be involved in polymerization of phenolic monomers, and as a result, found that phenothiazine derivatives could serve as mediators to activate enzymatic reaction of general peroxidases. Accordingly, it is an object of this invention to provide a process for preparing a phenolic polymer by using a phenothiazine derivative as a mediator in polymerization system of phenolic monomers using a general peroxidase biocatalyst. Further, it is another object of this invention to provide a use of thus obtained phenolic polymers for preparing radical-curing resin. Still further, it is another object of this invention to provide a coating material comprising the curing resin. DETAILED DESCRIPTION OF THIS INVENTION In one aspect of this invention, there is provided a process for preparing a phenolic polymer, which comprises polymerizing phenolic monomers with unsaturated aliphatic chains in the presence of peroxidase biocatalyst and an oxidant; wherein said polymerizing employs as a mediator a phenothiazine derivative substituted with an alkyl group or alkyl carbonic acid. The present invention is described in more detail as follows. The present invention improves a polymerization of phenolic monomers using peroxidase biocatalyst by adding phenothiazine-based mediators. This invention allows the increase of the overall yield and the polymerization of phenolic monomers at its meta-position substituted with long alkyl chains, which have been known not to polymerize in peroxidase-catalyzed enzymatic reaction. In addition, the phenolic polymers generated by this invention maintain the double bonds of a lipid group linked to their side chain, so that they can easily form coatings through radical curing. The striking feature of this invention lies in the addition of a specific mediator to polymerization of phenolic monomers using biocatalyst. The addition of the mediator greatly affects the reactivity of polymerization of phenolic monomers and the phenothiazine derivatives as mediators make the polymerization of phenolic monomers highly active. The phenothiazine derivatives serving as mediators in this invention are phenothiazine-based compounds substituted with an alkyl group or alkyl carbonic acid. More particularly, the exemplified phenothiazine derivatives are phenothiazine-based compounds substituted with an alkyl group having 1-6 of carbon atoms or alkyl carbonic acid having 1-6 of carbon atoms. Further, the exemplified phenothiazine derivatives include ethylphenothiazine and phenothiazine-10-propionic acid. The phenothiazine derivative is used in a concentration of 20-100 μM with respect to the total polymerization reactants. If the concentration of phenothiazine derivatives is lower than 20 μM, the effect derived from the addition of phenothiazine derivatives becomes far poor; however, if the concentration is higher than 100 μM, the increase of concentration barely affect the polymerization. In addition, the excess of phenothiazine derivatives is very likely to induce the decrease of enzyme activity. Therefore, the excessive amount of phenothiazine derivatives is not suitable. The phenolic monomers to be polymerized are aromatic hydrocarbons having unsaturated aliphatic substituents and hydroxyl groups, including natural-occurring and synthetic compounds. Plant-derived phenolic oils are preferable. Exemplified phenolic monomers include cardanol, cardol, 2-methylcardol, urushiol, thitsiol, ranghol, laccol, 1-hydroxy-2-carboxy-3-pentanylbenzene, 1-hydroxy-2-carboxy-3-(8′,11′,11′-pentadicadiyl)benzene, anacardic acid and zincoic acid. The plant-derived phenolic oils as raw materials in this invention are annually produced as by-product in the amount of about one million tons in the course of food production and its majority is consumed as a fuel. Therefore, the supply of the phenolic oils is never problematic. The present invention uses peroxidase as a biocatalyst and the scope of peroxidase type is broadened in this invention due to the use of phenothiazine mediator. The present invention may use any conventional peroxidase known to one skilled in the art. It is preferable that peroxidases derived from plants or fungi are used. More preferably, horseradish peroxidase, soybean peroxidase, Coprinus peroxidase or Aspergillus peroxidase are used. Preferably, peroxidase as a biocatalyst is used in the amount of 0.1-1.0 wt % with respect to the amount of the phenolic monomer. If the amount is less than 0.1 wt %, the reaction rate is greatly reduced thus requiring more time for polymerization; in contrast, if the amount is more than 1.0 wt %, the cost is increased and also the final polymers produced are obtained in a crosslinked form, thus not applicable to paints or coatings. It is generally known that oxidants are used in the polymerization of phenolic monomers using peroxidase. The present invention uses an oxidant known to one skilled in the art. As oxidants, hydrogen peroxide or organic hydrogen peroxide may be employed. The organic hydrogen peroxide includes hydroalkyl peroxide, in particular, t-butylhydroperoxide and ethylhydroperoxide. It is preferred that the amount of oxidant 0.1-1.0 mol with respect to 1 mol of the phenolic monomer. If the amount of oxidant is less than 0.1 mol, the yield of polymerization is decreased; in contrast, if the amount is more than 1.0 mol, the activity of peroxidase is remarkably reduced. If necessary, an organic solvent is employed in the polymerization of phenolic monomers. It is recommended that the type of the organic solvent be selected depending on the type of phenolic monomers to be polymerized through experiments in view of stable maintenance of enzyme activity. It has been revealed that an alcoholic solvent such as isopropanol, methanol, ethanol and t-butanol is suitable in the polymerization of this invention. Other solvents have been revealed to much reduce the activity and stability of peroxidase as biocatalysts, resulting in significant decrease in the yield of a polymer produced thereof. It is preferred that the organic solvent is used in the amount of 30-70 vol % with respect to the total polymerization volume. If the amount of organic solvent is less than 30 vol %, the solubility of phenolic monomers is declined thus causing separation of layers in the reaction system, so that the high concentrated monomers may not be involved in the reaction. If the amount is more than 70 vol %, the activity of peroxidase as biocatalyst is drastically reduced and therefore the reaction is very unlikely to be maintained. Further, it is important to adjust the pH range of a polymerization solution to promote the enzyme activity of peroxidase as biocatalysts. The pH range of the polymerization solution should be adjusted to fall within pH 5-8 by using a buffer. The phenolic polymers produced under conditions described above maintain the double bonds of a lipid group linked to their side chains, so that they can easily form coatings through radical curing. In addition, thus formed coatings have an antioxidation effect and their significantly low surface energy exhibit an antifouling effect thus preventing physical attachment of marine livings similar to silicone-based antifouling coatings. Accordingly, in another aspect of this invention, there is provided a use of phenolic polymer obtained by the polymerization described above for preparing a radical cured resin. In still another aspect of this invention, there is provided a coating comprising the radical cured resin. The radical polymerization for preparing coatings of this invention may be controlled using transition metals and complex of organic ligand serving radical initiators. The transition metal and radical initiator applied to curing are conventional ingredients used in the art to which the invention pertains. The following examples are intended to be illustrative of this invention and should not be construed as limiting the scope of this invention as defined by appended claims. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph representing the change in the polymerization yield of cardanol depending on the type of a mediator. (A: ethylphenothiazine, B: phenothizine-10-propionic acid, C: phenothiazine, and D: veratryl alcohol) FIG. 2 represents the function of a mediator in the polymerization of cardanol. FIG. 3 represents the results of infrared spectrophotometry of cardanol polymer. (A: cardanol monomer, B: polycardanol (ethylphenothiazine), and C: polycardanol (phenothizine-10-propionic acid)). EXAMPLE Cardanol (Palmer International, USA) isolated from Cashewnut extract was used as a phenolic monomer. Its purity was 90-95 wt % and contained about 3-6 wt % of cardol. 0.6 g of cardanol was dissolved in a mixed solution of 12.5 ml of isopropanol and 12.5 ml of a phosphate buffer (0.1 M, pH 7.0), and then 20 mg of horseradish peroxidase (Sigma, USA) were added to the resulting solution. Phenothiazine-10-propionic acid was added to the above mixture as a mediator to a concentration of 20-150 μM. Then, 300 μl of 30% hydrogen peroxide was homogenously added to the resultant over the period of 6 hr. The reaction temperature was set at room temperature and the reaction solution was homogeneously mixed. Upon completion of the reaction, the reaction solution was concentrated under vacuum to remove isopropanol and then added with 20 ml of ethyl acetate. Thereafter, a solution layer dissolved in ethyl acetate solvent was collected after separation and concentrated under vacuum by removing the solvent. The activity of peroxidase involved in the reaction was measured according to the calorimetric method using ABTS (azinobisethylbenzothiazoline sulfonate). The molecular weight of thus obtained product was measured using GPC (Gas permeation chromatography) equipped with a detector for refractive index. The mean molecular weight (Mw) of thus obtained product was 8,000-12,000 g/mol and the average yield to be above 60%. The following Table 1 shows the change in yield of the phenolic polymer according to the concentration of phenothiazine-10-propionic acid as a mediator. TABLE 1 Change in yield according to the concentration of phenothiazine-10-propionic acid Conc. Mean molecular weight (Mw) (μM) Yield (%) (Measurement with GPC) 0 0 — 30 55 6,560 74 65 7,090 110 54 6,640 150 45 6,800 As indicated in Table 1, the reaction catalyzed by a peroxidase biocatalyst in the absence of a mediator was not led to the polymerization of cardanol. In addition, Table 2 represents the change in yield of the phenolic polymer according to the type of peroxidase. TABLE 2 Yield change depending on the type of peroxidase Biocatalyst Conc. Mean molecular weight (Mw) Type (μM) Yield (%) (Measurement with GPC) HRP 20 55 6,560 SBP 20 65 10,000 CiP 20 85 12,050 AGP 20 75 11,500 Note: HRP (horseradish peroxidase), SBP (Soybean peroxidase) CiP (Coprinus peroxidase), AGP (Aspergillus peroxidase) As indicated in Table 2, the presence of a phenothiazine-based mediator results in much increased yield irrespective of the type of peroxidases. To examine the polymerization efficiency depending on the type of a mediator, the change of yield was analyzed under conditions described above with varying types of the mediators. The yield of phenolic polymer was examined using 74 μM of each of ethylphenothiazine(A), phenothiazine-10-propionic acid(B), phenothiazine(C) and veratryl alcohol(D) or no addition of a mediator. The results are summarized in Table 3 and FIG. 1, respectively. TABLE 3 Yield change depending on the type of mediator Mediator Yield (%) No addition 0 Ethylphenothiazine 42 Phenothiazine-10-propionic 65 acid Phenothiazine 0 Veratryl alcohol 0 The polymerization reactions using phenothiazine derivatives exhibited a considerable amount of yield. In particular, phenothiazine-10-propionic acid contributed to a remarkably high yield. This result suggests that propionic acid linked to pheothiazine increases the water-solubility of a mediator thus better facilitating its contact to horseradish peroxidase. As shown in FIG. 2, the mediator transfers electrons between horseradish peroxidase and cardanol substrate. Furthermore, phenothiazines not substituted with an alkyl group or alkyl carbonic acid did not help to promote the polymerization reaction. Ethylphenothiazine with an ethyl group in excess (2,000 μM) was revealed to mediate the polymerization of cardanol. In addition, as shown in FIG. 3, it was confirmed that the double bonds of a lipid group linked to the meta-position of cardanol are intactly maintained with the addition of phenothiazine-10-propionic acid mediator, which was observed at 3050 cm−1 on infrared spectrophotometer. This result urges us to reason that the mediator may oxidize phenolic monomers in position-selective manner through intimate interaction with enzyme. In other words, the double bond at 3050 cm−1 was commonly observed in polycardanol generated by polymerization using cardanol monomers and a mediator. Experimental Example 1: Evaluation On Antioxidation of Cured Coatings The cured coatings were obtained by curing a phenolic polymer wherein cobalt naphthenate and methylethyl ketoperoxide were added to phenolic polymer prepared in Example such as polycardanol, polycardol, polycardanol/phenol and polycardanol/ethylphenol. 1 ml of 500 pM 1,1-diphenyl-2-picryl hydrazine (DPPH) was added to 100 ml of distilled water and 1 g of coating was immersed in the resulting solution. The optical density of DPPH at 517 nm was measured with the lapse of time, which reflects the capacity of antioxidation. The results are summarized in Table 4. TABLE 4 Phenolic polymer Antioxidation Polycardanol 60 Polycardol 70 Polycardanol/phenol copolymer 50 Polycardanol/ethylphenol 40 copolymer Commercial-available phenolic resin 5 (Novolak resin, Kukdochemical, Inc.) As indicated in Table 4, the phenolic polymer of this invention shows a better antioxidation result than conventional ones. The improved antioxidizing ability may prevent curing of an adhesive protein secreted by marine periphytons and therefore renders it an antifouling capacity. Experimental Example 2: Evaluation On Antifouling Capacity of Cured Coatings For evaluation on the antifouling capacity of each coating prepared in Experimental Example 1, the coating was immersed in sea water and the contamination by marine periphytons such as barnacles was examined. The results are summarized in Table 5. TABLE 5 Antifouling capacity Phenolic polymer (No. of barnacles attached) Polycardanol 6 Polycardol 1 Polycardanol/phenol copolymer 12 Polycardanol/ethylphenol 14 copolymer Commercially available phenolic resin 35 (Novolak resin, Kukdochemical, Inc.) As represented in Table 5, the attachment capacity of barnacles is significantly decreased to the cured coatings of phenolic polymer according to this invention. These results correspond to the antioxidation capacity indicated in Table 4. INDUSTRIAL APPLICABILITY As described previously, the most prominent feature of the present polymerization lies in the additional employment of phenothiazine-based mediators in polymerization of phenolic monomers using a peroxidase biocatalyst and an oxidant. The phenothiazine-based mediators exhibited activities for all peroxidases generally known to one skilled in the art, thus making it possible that phenolic monomers, which have not been able to be polymerized due to their long alkyl chains at their meta-position, to be polymerized. In addition, the phenolic polymers prepared according to the polymerization of this invention can maintain unsaturated hydrocarbon groups linked to their side chains, so that they are very useful as a curing resin because they can easily form coatings via radical curing. Further, the coatings formed using the curing resin exhibit a relatively low surface energy, so that they can prevent physical attachment of marine livings and the coatings can continuously exhibit durability because the antifouling-causing functional groups are not consumed.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to a process for preparing a phenolic polymer using a phenothiazine-based mediator, in particular, to a process for preparing a phenolic polymer by polymerizing phenolic monomers by use of a phenothiazine-based mediator in the presence of peroxidase biocatalyst and oxidant, thereby dramatically improving the enzyme reactivity of peroxidase. The phenolic polymers prepared according to the polymerization of this invention maintain unsaturated hydrocarbon groups linked to their side chains, so that they are very useful as a curing resin because they can easily form coatings through radical curing. In addition, the coatings formed using the curing resin have antioxidation effect and lower surface energy, so that they can prevent physical attachment of marine livings. Because the antifouling-causing functional groups are not consumed, the coatings continuously exhibit durability. 2. Description of the Related Art Phenolic polymers are known to be useful as paints and various coating materials, due to their excellent anti-corrosiveness and capability of forming a firm coating. For synthesizing phenolic polymers chemically, formalin or hexamethylene tetraamine generated by the condensation of formaldehyde and ammonia is employed in high-temperature polymerization. However, such method has some shortcomings in which formalin and formaldehyde are toxic and unreacted reactants toxic to environment and human body are remained after reaction. In addition, when phenolic polymers are synthesized using chemicals such as formalin, the double bonds of a lipid group side chain linked to phenolic compounds are consumed, so that the resulting phenolic polymers is unlikely to form coating due to the difficulty in setting by radical reaction. Therefore, a biochemical preparation using a biocatalyst is recognized as a preferred environment-friendly approach instead of chemical synthesis using toxic materials. Where phenolic polymers are synthesized using a biocatalyst such as enzyme, it is essential to establish optimal polymerization conditions in consideration of substrate specificity of enzyme. For example, a polymer derived from 4-methoxybenzyl alcohol and 2-hydroxy-4-methoxyphenyl acetic acid may not be synthesized using unassisted lignin peroxidase. In contrast, the presence of mediator such as veratryl alcohol allows the polymerization to be promoted (Harvey et al., FEBS Lett. 195:242-246 (1986)). Furthermore, it has been known that phenolic compounds having significantly long alkyl chains at their meta-position cannot be polymerized by use of horseradish peroxidase. As discussed above, the polymerization of phenol compounds using a biocatalyst demands the establishment of optimal polymerization conditions because of substrate specificity of enzyme. The present inventors have conducted extensive researches to develop a novel polymerization system which is applicable to all peroxidase biocatalysts generally known to be involved in polymerization of phenolic monomers, and as a result, found that phenothiazine derivatives could serve as mediators to activate enzymatic reaction of general peroxidases. Accordingly, it is an object of this invention to provide a process for preparing a phenolic polymer by using a phenothiazine derivative as a mediator in polymerization system of phenolic monomers using a general peroxidase biocatalyst. Further, it is another object of this invention to provide a use of thus obtained phenolic polymers for preparing radical-curing resin. Still further, it is another object of this invention to provide a coating material comprising the curing resin. detailed-description description="Detailed Description" end="lead"?

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a graph representing the change in the polymerization yield of cardanol depending on the type of a mediator. (A: ethylphenothiazine, B: phenothizine-10-propionic acid, C: phenothiazine, and D: veratryl alcohol) FIG. 2 represents the function of a mediator in the polymerization of cardanol. FIG. 3 represents the results of infrared spectrophotometry of cardanol polymer. (A: cardanol monomer, B: polycardanol (ethylphenothiazine), and C: polycardanol (phenothizine-10-propionic acid)).

20060606

20100615

20071108

71156.0

C12P1500

HEINCER, LIAM J

PROCESS FOR PREPARING PHENOLIC POLYMER BY USING PHENOTHIAZINES MEDIATOR

SMALL

ACCEPTED

C12P

ACCEPTED

Method of manufacturing actuator device and liquid-jet apparatus

A method of manufacturing an actuator device configured to prevent separation of a vibration plate and to enhance durability and reliability, and a liquid-jet apparatus are provided. The method includes the steps of forming a vibration plate on one surface of a substrate, and forming a piezoelectric element having a lower electrode, a piezoelectric layer, and an upper electrode on the vibration plate. The step of forming a vibration plate at least includes an insulation film forming step of forming an insulation film made of zirconium oxide by forming a zirconium layer on the one surface side of the substrate in accordance with a sputtering method and subjecting the zirconium layer to thermal oxidation by inserting the substrate formed with the zirconium layer to a thermal oxidation furnace heated to a temperature greater than or equal to 700° C. at a speed greater than or equal to 200 mm/min.

1. A method of manufacturing an actuator device comprising the steps of: forming a vibration plate on one surface of a substrate; and forming a piezoelectric element having a lower electrode, a piezoelectric layer, and an upper electrode on the vibration plate, wherein the step of forming a vibration plate at least includes an insulation film forming step of forming an insulation film made of zirconium oxide by forming a zirconium layer above the one surface side of the substrate in accordance with a sputtering method and subjecting the zirconium layer to thermal oxidation by inserting the substrate formed with the zirconium layer to a thermal oxidation furnace heated to a temperature greater than or equal to 700° C. at a speed greater than or equal to 200 mm/min. 2. The method of manufacturing an actuator device according to claim I, wherein the temperature for heating the thermal oxidation furnace is set in a range from 850° C. to 1000 ° C. 3. The method of manufacturing an actuator device according to claims 1, wherein a rate of temperature increase of the zirconium layer upon insertion of the substrate into the thermal oxidation furnace is set greater than or equal to 300° C./min. 4. The method of manufacturing an actuator device according to claim 3, wherein a density of the insulation film is set greater than or equal to 5.0 g/cm3 in the insulation film forming step. 5. The method of manufacturing an actuator device according to claim 4, wherein a film thickness of the insulation film is set greater than or equal to 40 nm in the step of forming the insulation film. 6. A method of manufacturing an actuator device comprising the steps of: forming a vibration plate above one surface of a substrate; and forming a piezoelectric element having a lower electrode, a piezoelectric layer, and an upper electrode above the vibration plate, wherein the step of forming the vibration plate at least includes the steps of: forming an insulation film made of zirconium oxide by forming a zirconium layer above the one surface side of the substrate and subjecting the zirconium layer to thermal oxidation while heating the zirconium layer up to a predetermined temperature at a predetermined rate of temperature increase, and adjusting stress of the insulation film by annealing the insulation film at a temperature less than or equal to a maximum temperature in thermal oxidation of the zirconium layer. 7. The method of manufacturing an actuator device according to claim 6, wherein the rate of temperature increase upon thermal oxidation of the zirconium layer is set greater than or equal to 5° C./sec. 8. The method of manufacturing an actuator device according to claim 7 wherein the rate of temperature increase upon thermal oxidation of the zirconium layer is set greater than or equal to 50° C./sec. 9. The method of manufacturing an actuator device according to claim 8, wherein the zirconium layer is heated by an RTA method upon thermal oxidation of the zirconium layer. 10. The method of manufacturing an actuator device according to claims 7, wherein a density of the insulation film is set greater than or equal to 5.0 g/cm3 in the step of forming the insulation film. 11. The method of manufacturing an actuator device according to claim 10, wherein a film thickness of the insulation film is set greater than or equal to 40 nm in the step of forming the insulation film. 12. The method of manufacturing an actuator device according to claims 6, wherein a temperature upon thermal oxidation of the zirconium layer is set in a range from 800° C. to 1000° C. 13. The method of manufacturing an actuator device according to claim 12, wherein a temperature upon annealing the insulation film is set in a range from 800° C. to 900° C. 14. The method of manufacturing an actuator device according to claim 13, wherein a time period for annealing the insulation film is adjusted in a range from 0.5 hours to 2 hours. 15. The method of manufacturing an actuator device according to claims 1, wherein the step of forming the vibration plate comprises the step of forming an elastic film made of silicon oxide (SiO2) above the one surface of the substrate made of a single crystal silicon substrate, and the insulation film is formed above the elastic film. 16. The method of manufacturing an actuator device according to claims 1, wherein the step of forming the piezoelectric element at least comprises the step of forming the piezoelectric layer made of lead zirconate titanate (PZT) above the vibration plate. 17. A liquid-jet apparatus, comprising: a liquid-jet head applying the actuator device manufactured by the method according to any one of claims 1 to 16 as liquid ejecting means.

TECHNICAL FIELD The present invention relates to a method of manufacturing an actuator device configured to construct part of a pressure generating chamber-by use of a vibration plate, to form a piezoelectric element having a piezoelectric layer above this vibration plate, and to deform the vibration plate by displacement of the piezoelectric element, and relates to a liquid-jet apparatus for ejecting droplets by use of the actuator device. BACKGROUND ART An actuator device including a piezoelectric element configured to be displaced by application of a voltage is used as liquid ejecting means of a liquid-jet head mounted on a liquid-jet apparatus for injecting droplets, for example. As for the liquid-jet apparatus described above, there is known an ink-jet recording device including an ink-jet recording head, which is configured to construct part of a pressure generating chamber communicating with a nozzle orifice by use of a. vibration plate, to pressurize ink in the pressure generating chamber by deforming this vibration plate with a piezoelectric element, and thereby to eject ink droplets out of a nozzle orifice. Two types of inkjet recording heads are put into practical use, namely, one mounting an actuator device of a longitudinal vibration mode configured to expand and contract in an axial direction of a piezoelectric element, and one mounting an actuator device of a flexural vibration mode. Moreover, as the one applying the actuator device of the flexural vibration mode, there is one configured to form a uniform piezoelectric film across the entire surface of the vibration plate in accordance with a film forming technique, and to form piezoelectric elements independently of respective pressure generating chambers by cutting this piezoelectric layer into shapes corresponding to the pressure generating chambers in accordance with a lithography method, for example. As a material of a piezoelectric material layer constituting such piezoelectric elements, lead zirconate titanate (PZT) is used, for example. In this case, when sintering the piezoelectric material layer, a lead component of the piezoelectric material layer is diffused into a silicon oxide (SiO2) film, which is provided on a surface of a passage-forming substrate made of silicon (Si) for constituting the vibration plate. Accordingly, there is a problem that the melting point of silicon oxide drops by diffusion of this lead component and silicon oxide melts away owing to the heat at the time of backing the piezoelectric material layer. To solve this problem, for example, there is a technique configured to construct a vibration plate on a silicon oxide film, to provide a zirconium oxide film having a predetermined thickness, to provide a piezoelectric material layer on this zirconium oxide layer, and thereby to prevent diffusion of a lead component from the piezoelectric material layer into the silicon oxide film (see Patent Document 1, for example). This zirconium oxide film is formed for instance by forming a zirconium film in accordance with a sputtering method and then subjecting this zirconium layer to thermal oxidation. For this reason, there is a problem of occurrence of defects, such as occurrence of cracks on the zirconium oxide film due to stress generated at the time of subjecting the zirconium film to thermal oxidation. Meanwhile, if a large difference in stress exists between the passage-forming substrate and the zirconium oxide film, there also occurs a problem that the zirconium film comes off after forming the pressure generating chambers on the passage-forming substrate, for example, due to deformation of the passage-forming substrate and the like. Patent Document 1: Japanese Unexamined Patent Publication No. 11(1999) - 204849 (FIG. 1, FIG. 2, p. 5) DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention A first aspect of the present invention for solving the above-described problems is a method of manufacturing an actuator device including the steps of forming a vibration plate on one surface of a substrate, and forming a piezoelectric element having a lower electrode, a piezoelectric layer, and an upper electrode on the vibration plate. Here, the step of forming the vibration plate at least includes an insulation film forming step of forming an insulation film made of zirconium oxide by forming a zirconium layer above the one surface side of the substrate in accordance with a sputtering method and subjecting the zirconium layer to thermal oxidation by inserting the substrate formed with the zirconium layer to a thermal oxidation furnace heated to a temperature greater than or equal to 700° C. at a speed greater than or equal to 200 mm/min. According to the first aspect, it is possible to enhance adhesion of the insulation film and to prevent occurrence of separation of the insulation film, and the like. A second aspect of the present invention is the method of manufacturing an actuator device according to the first aspect, in which the temperature for heating the thermal oxidation furnace is set in a range from 850° C. to 1000° C. According to the second aspect, it is possible to suppress an increase in stress of the insulation film by setting a relatively high temperature for heating the thermal oxidation furnace, and thereby to prevent occurrence of cracks on the insulation film which is attributable to the stress. A third aspect of the present invention is the method of manufacturing an actuator device according to the first or second aspect, in which a rate of temperature increase of the zirconium layer upon insertion of the substrate into the thermal oxidation furnace is set greater than or equal to 300° C./min. According to the third aspect, it is possible to suppress an increase in stress of the insulation film more reliably by setting a relatively fast rate of temperature increase of the zirconium layer, and to increase a density of the insulation film. A fourth aspect of the present invention is the method of manufacturing an actuator device according to the third aspect, in which a density of the insulation film is set greater than or equal to 5.0 g/cm3 in the insulation film forming step. According to the fourth aspect, the insulation film is formed into a dense film. Therefore, it is possible to suppress diffusion of a lead (Pb) component of the piezoelectric layer into an elastic film effectively. A fifth aspect of the present invention is the method of manufacturing an actuator device according to any of the first to fourth aspects, in which a film thickness of the insulation film is set greater than or equal to 40 nm in the step of forming the insulation film. According to the fifth aspect, it is possible to suppress diffusion of the lead (Pb) component of the piezoelectric layer into the elastic film reliably. A sixth aspect of the present invention is a method of manufacturing an actuator device including the steps of forming a vibration plate above one surface of a substrate, and forming a piezoelectric element having a lower electrode, a piezoelectric layer, and an upper electrode above the vibration plate. Here, the step of forming the vibration plate at least includes the steps of forming an insulation film made of zirconium oxide layer by forming a zirconium layer above the one surface side of the substrate and subjecting the zirconium layer to thermal oxidation while heating the zirconium layer up to a predetermined temperature at a predetermined rate of temperature increase, and adjusting stress of the insulation film by annealing the insulation film at a temperature less than or equal to a maximum temperature in thermal oxidation of the zirconium layer. According to the sixth aspect, adhesion of the insulation film constituting the vibration plate is enhanced. Moreover, it is also possible to suppress unevenness in adhesion of the insulation film in the same wafer, and to manufacture an actuator device having a uniform displacement characteristic of the piezoelectric element. A seventh aspect of the present invention is the method of manufacturing an actuator device according to the sixth aspect, in which the rate of temperature increase upon thermal oxidation of the zirconium layer is set greater than or equal to 5° C./sec. According to the seventh aspect, it is possible to further enhance the adhesion of the insulation film. Moreover, since the density of the insulation film is increased, it is possible to suppress diffusion of the lead (Pb) component of the piezoelectric layer into the elastic film. An eighth aspect of the present invention is the method of manufacturing an actuator device according to the seventh aspect, in which the rate of temperature increase upon thermal oxidation of the zirconium layer is set greater than or equal to 50° C./sec. According to the eighth aspect, the insulation film is formed into a denser film by setting the rate of temperature increase greater than or equal to the predetermined value, and the adhesion of the insulation film is enhanced reliably. A ninth aspect of the present invention is the method of manufacturing an actuator device according to the eighth aspect, in which the zirconium layer is heated by an RTA method upon thermal oxidation of the zirconium layer. According to the ninth aspect, it is possible to heat the zirconium layer at a desired rate of temperature increase by use of the RTA method. A tenth aspect of the present invention is the method of manufacturing an actuator device according to any of the seventh to tenth aspects, in which a density of the insulation film is set greater than or equal to 5.0 g/cm3 in the step of forming the insulation film. According to the tenth aspect, the insulation film is formed into a dense film. Therefore, it is possible to suppress diffusion of a lead (Pb) component of the piezoelectric layer into an elastic film effectively. An eleventh aspect of the present invention is the method of manufacturing an actuator device according to the tenth aspect, in which a film thickness of the insulation film is set greater than or equal to 40 nm in the step of forming the insulation film. According to the eleventh aspect, it is possible to suppress diffusion of the lead (Pb) component of the piezoelectric layer into the elastic film reliably. A twelfth aspect of the present invention is the method of manufacturing an actuator device according to any of the sixth to eleventh aspects, in which a temperature upon thermal oxidation of the zirconium layer is set in a range from 800° C. to 1000° C. According to the twelfth aspect, it is possible to subject the zirconium layer to thermal oxidation favorably, and to enhance the adhesion of the insulation film more reliably. A thirteenth aspect of the present invention is the method of manufacturing an actuator device according to the twelfth aspect, in which a temperature upon annealing the insulation film is set in a range from 800° C. to 900° C. According to the thirteenth aspect, it is possible to adjust the stress of the insulation film without reducing the adhesion. A fourteenth aspect of the present invention is the method of manufacturing an actuator device according to the thirteenth aspect, in which a time period for annealing the insulation film is adjusted in a range from 0.5 hours to 2 hours. According to the fourteenth aspect, it is possible to adjust the stress of the insulation film reliably without reducing the adhesion. A fifteenth aspect of the present invention is the method of manufacturing an actuator device according to any of the first to fourteenth aspects, in which the step of forming the vibration plate includes the step of forming an elastic film made of silicon oxide (SiO2) above the one surface of the substrate made of a single crystal silicon substrate. Here, the insulation film is formed above the elastic film. According to the fifteenth aspect, the adhesion is enhanced even when the film below the insulation film is the elastic film made of silicon oxide. A sixteenth aspect of the present invention is the method of manufacturing an actuator device according to any of the first to fifteenth aspects, in which the step of forming a piezoelectric element at least includes the step of forming a piezoelectric layer made of lead zirconate titanate (PZT) above the vibration plate. According to the sixteenth aspect, it is possible to prevent diffusion of the lead component of the piezoelectric layer into the vibration plate, and thereby to form the vibration plate and the piezoelectric element favorably. A seventeenth aspect of the present invention is a liquid-jet apparatus, which includes a liquid-jet head applying the actuator device manufactured by the method according to any of the first to sixteenth aspects as liquid ejecting means. According to seventeenth aspect, it is possible to enhance durability of the vibration plate and to enhance an amount of displacement of the vibration plate by a drive of the piezoelectric element. Hence it is possible to realize the liquid-jet apparatus having an enhanced droplet ejecting characteristic. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an exploded perspective view of a recording head according to Embodiment 1. FIG. 2(a) is a plan view and FIG. 2(b) is a cross-sectional view of the recording head according to Embodiment 1. FIGS. 3(a) to 3(d) are cross-sectional views showing a manufacturing process of the recording head according to Embodiment 1. FIGS. 4(a) to 4(d) are cross-sectional views showing the manufacturing process of the recording head according to Embodiment 1. FIGS. 5(a) and 5(b) are cross-sectional views showing the manufacturing process of the recording head according to Embodiment 1. FIG. 6 is a schematic drawing of a diffusion furnace used in the manufacturing process. FIG. 7 is a graph showing a relation between a boat load speed and adhesion. FIG. 8 is a graph showing a relation between a thermal oxidation temperature and stress. FIG. 9 is a graph showing a relation between the boat load speed and the stress. FIG. 10 is a schematic drawing of a recording device according to an embodiment of the present invention. FIG. 11 is a view for explaining positions of measurement of the adhesion. FIG. 12 is a graph showing a relation between a rate of temperature increase and the adhesion. FIGS. 13(a) to 13(c) are SEM images showing cross sections of insulation films. FIG. 14 is a graph showing a relation between elapsed time for annealing and stress of an insulation film. FIG. 15 is a graph showing unevenness in adhesion of insulation films according to comparative examples. FIG. 16 is a graph showing unevenness in adhesion of insulation films according to examples. EXPLANATION OF REFERENCE NUMERALS 10 PASSAGE-FORMING SUBSTRATE 12 PRESSURE GENERATING CHAMBER 20 NOZZLE PLATE 21 NOZZLE ORIFICE 30 PROTECTIVE PLATE 31 PIEZOELECTRIC ELEMENT HOLDING PORTION 32 RESERVOIR PORTION 40 COMPLIANCE PLATE 50 ELASTIC FILM 55 INSULATION FILM 60 LOWER ELECTRODE FILM 70 PIEZOELECTRIC LAYER 80 UPPER ELECTRODE FILM 100 RESERVOIR 110 PASSAGE-FORMING SUBSTRATE WAFER 300 PIEZOELECTRIC ELEMENT BEST MODES FOR CARRYING OUT THE INVENTION The present invention will be described below in detail based on embodiments. (Embodiment 1) FIG. 1 is an exploded perspective view showing an inkjet recording head according to Embodiment 1 of the present invention. FIG. 2(a) is a plan view and FIG. 2(b) is a cross-sectional view of FIG. 1. As shown in the drawings, a passage-forming substrate 10 is made of a single crystal silicon substrate having a (110) plane orientation in this embodiment, and an elastic film 50, which is made of silicon dioxide and formed in advance by thermal oxidation, is formed in a thickness from 0.5 to 2 μm on one surface thereof. On the passage-forming substrate 10, a plurality of pressure generating chambers 12 are arranged in a width direction thereof. Moreover, a communicating portion 13 is formed in a region outside in a longitudinal direction of the pressure generating chambers 12 of the passage-forming substrate 10, and the communicating portion 13 communicates with the respective pressure generating chambers 12 through ink supply paths 14 provided for the respective pressure generating chambers 12. Here, the communicating portion 13 constitutes part of a reservoir, which communicates with a reservoir portion of a protective plate to be described later and forms a common ink chamber to the respective pressure generating chambers 12. The ink supply paths 14 are formed in a narrower width than the pressure generating chambers 12, and maintain constant passage resistance of ink flowing from the communicating portion 13 into the pressure generating chambers 12. Meanwhile, a nozzle plate 20, on which nozzle orifices 21 for communicating with the vicinity of an end portion on an opposite side to the ink supply paths 14 of the respective pressure generating chambers 12 are drilled, is fixed to an opening surface side of the passage-forming substrate 10 through an adhesive, a thermowelding film or the like. Here, the nozzle plate 20 is made of a glass ceramic having a thickness in a range from 0.01 to 1 mm, for example, and a coefficient of linear expansion in a range from 2.5 to 4.5 [×10−6/° C.] at a temperature less than or equal to 300° C., for example, a single crystal silicon substrate, stainless steel or the like. In the meantime, as described previously, the elastic film 50 made of silicon dioxide (SiO2) in the thickness of about 1.0 μm, for example, is formed on the opposite side to the opening surface of this passage-forming substrate 10, and an insulation film 55 made of zirconium oxide (ZrO2) in a thickness of about 0.4 μm, for example, is formed on this elastic film 50. Moreover, a lower electrode film 60 in a thickness of about 0.2 μm, for example, a piezoelectric layer 70 in a thickness of about 1.0 μm, for example, and an upper electrode film 80 in a thickness of about 0.05 μm, for example, are formed by lamination in a process to be described later on this insulation film 55, thereby constituting a piezoelectric element 300. Here, the piezoelectric element 300 means the portion including the lower electrode film 60, the piezoelectric layer 70, and the upper electrode film 80. In general, one of the electrodes of the piezoelectric element 300 is used as a common electrode; meanwhile, the other electrode and the piezoelectric layer 70 are patterned for each of the pressure generating chambers 12. Moreover, the portion including one of the electrodes and the piezoelectric layer 70 thus patterned and configured to cause a piezoelectric strain by application of a voltage to the both electrodes is herein referred to as a piezoelectric active portion. In this embodiment, the lower electrode film 60 is used as the common electrode to the piezoelectric elements 300 and the upper electrode film 80 is used as an individual electrode of the piezoelectric element 300. However, there is no problem if this configuration is inverted on grounds of a driving circuit or wiring. In any case, the piezoelectric active portion will be formed for each of the pressure generating chambers. Moreover, the piezoelectric element 300 and the vibration plate causing displacement by a drive of the piezoelectric element 300 are herein collectively referred to as a piezoelectric actuator. Note that lead electrodes 90 made of gold (Au), for example, are connected to the upper electrode films 80 of the respective piezoelectric elements 300 described above, and a voltage is selectively applied to the respective piezoelectric elements 300 through these lead electrodes 90. Meanwhile, a protective plate 30 having a piezoelectric element holding portion 31, which is capable of securing an adequate space in a region facing the piezoelectric elements 300 so as not to inhibit movement thereof, is bonded to a surface of the passage-forming substrate 10 on the side of the piezoelectric elements 300. The piezoelectric elements 300 are formed inside this piezoelectric element holding portion 31, and are therefore protected in a state virtually insusceptible to influences of an external environment. In addition, the protective plate 30 is provided with a reservoir portion 32 in a region corresponding to the communicating portion 13 of the passage-forming substrate 10. In this embodiment, this reservoir portion 32 is provided along the direction of arrangement of the pressure generating chambers 12 while penetrating the protective plate 30 in the thickness direction, communicates with the communicating portion 13 of the passage-forming substrate 10, and thereby constitutes a reservoir 100 which forms the common ink chamber to the respective pressure generating chambers 12 as described previously. Meanwhile, a through hole 33 penetrating the protective plate 30 in the thickness direction is provided in a region of the protective plate 30 between the piezoelectric element holding portion 31 and the reservoir portion 32. Part of the lower electrode film 60 and tip portions of the lead electrodes 90 are exposed in this through hole 33. Although it is not illustrated in the drawing, one end of a connection line extending from a driver IC is connected to the lower electrode film 60 and to the lead electrodes 90. Here, the material of the protective plate 30 may include glass, a ceramic material, metal, resin, and the like, for example. However, it is preferable to form the protective plate 30 by use of a material having a substantially identical thermal expansion coefficient as that of the passage-forming substrate 10. In this embodiment, the protective plate 30 was formed by use of a single crystal silicon substrate which was the same material as the passage-forming substrate 10. Moreover, a compliance plate 40 including a sealing film 41 and a fixation plate 42 is bonded onto the protective plate 30. The sealing film 41 is made of a low-rigidity material having flexibility (such as a polyphenylene sulfide (PPS) film having a thickness of 6 μm, for example), and one surface of the reservoir portion 32 is sealed with this sealing film 41. Meanwhile, the fixation plate 42 is formed of a hard material such as metal (stainless steel (SUS) in a thickness of 30 μm, for example). A region of this fixation plate 42 facing the reservoir 100 is entirely removed in the thickness direction and is formed into an open portion 43. Accordingly, the one surface of the reservoir 100 is sealed only with the sealing film 41 having flexibility. In the above-described inkjet recording head of this embodiment, ink is loaded from unillustrated external ink supplying means. After the inside ranging from the reservoir 100 to the nozzle orifices 21 is filled with the ink, a voltage is applied between the lower electrode film 60 and the upper electrode film 80 corresponding to each of the pressure generating chambers 12 in accordance with a recording signal from the unillustrated driver IC so as to subject the elastic film 50, the insulation film 55, the lower electrode film 60, and the piezoelectric layer 70 to flexural deformation, whereby pressure inside the respective pressure generating chambers 12 is increased and ink droplets are ejected from the nozzle orifices 21. Here, a method of manufacturing the above-described inkjet recording head will be explained with reference to FIG. 3(a) to FIG. 5(b). Note that FIG. 3(a) to FIG. 5(b) are cross-sectional views of the pressure generating chamber 12 taken in the longitudinal direction. Firstly, as shown in FIG. 3(a), a passage-forming substrate wafer 110 which is a silicon wafer is subjected to thermal oxidation in a diffusion furnace at about 1100° C., and a silicon dioxide film 51 constituting the elastic film 50 is formed on a surface thereof. Here, in this embodiment, a high-rigidity silicon wafer having a relatively large film thickness of about 625 μm is used as the passage-forming substrate wafer 110. Subsequently, as shown in FIG. 3(b), the insulation film 55 made of zirconium oxide is formed on the elastic film 50 (the silicon dioxide film 51). To be more precise, a zirconium layer in a predetermined thickness, which is equal to about 300 nm in this embodiment, is formed on the elastic film 50 in accordance with a DC sputtering method, for example. Then, the passage-forming substrate wafer 110 formed with the zirconium layer is inserted into a thermal diffusion furnace heated greater than or equal to 700° C. at a speed greater than or equal to 200 mm/min to subject the zirconium layer to thermal oxidation, thereby forming the insulation film 55 made of zirconium oxide. As shown in FIG. 6, a diffusion furnace 200 used for thermal oxidation of the zirconium layer includes a core tube 203 having a throat 201 on one end side and an introducing port 202 for reactive gas on the other end, and a heater 204 disposed outside the core tube 203, for example. The throat 201 can be opened and closed by a shutter 205. Moreover, in this embodiment, multiple pieces of the passage-forming substrate wafers 110 formed with the zirconium layers are fixed to a boat 206 which is a fixing-member, then this boat 206 is inserted into the diffusion furnace 200 heated to about 900° C. at a speed greater than or equal to 200 mm/min, and then the zirconium layers are subjected to thermal oxidation for about one hour while closing the shutter 205 to form the insulation films 55. The speed of insertion of this boat 206. (hereinafter, a boat load speed) at least needs to be faster than 200 mm/min, but is preferably set greater than or equal to 500 mm/min. Meanwhile, a rate of temperature increase of the zirconium layer when inserting the passage-forming substrate wafer 110 into the diffusion furnace 200 is preferably set greater than or equal to 300° C./min. For this reason, it is preferable to adjust the boat load speed appropriately in response to a heating temperature of the diffusion furnace 200 so as to establish this rate of temperature increase. The passage-forming substrate wafer 110 formed with the zirconium layer as described above is inserted into the diffusion furnace 200 heated greater than or equal to 700° C. at the boat load speed faster than 200 mm/min in order to subject the zirconium layer to thermal oxidation. Hence, it is possible to form the insulation film 55 into a dense film, and to prevent occurrence of cracks on the insulation film 55. Moreover, since adhesion of the insulation film 55 is enhanced, it is possible to prevent separation of the insulation film 55 even in the case of repetitive deformation by the drive of the piezoelectric element 300. Here, zirconium oxide layers (the insulation films) were formed by changing the boat load speed in a range from 20 mm/min to 1500 mm/min while maintaining the diffusion furnace 200 at a constant temperature of about 900° C., and adhesion was investigated by performing scratch tests on these zirconium oxide layers. The result is shown in FIG. 7. As shown in FIG. 7, the adhesion of the zirconium oxide layers (the insulation films) was increased along with an increase in the boat load speed. When the boat load speed was greater than 200 mm/min, the adhesion at least greater than or equal to 150 mN was obtained. As it is apparent from this result, it is preferable to set the boat load speed as fast as possible in order to obtain the adhesion of the insulation film 55. However, it is possible to form the insulation film 55 having sufficient adhesion if the boat load speed is greater than 200 mm/min. Meanwhile, the heating temperature of the diffusion surface 200 is not particularly limited as long as the temperature is set greater than or equal to 700° C. However, it is preferable to set the temperature in a range from 850° C. to 1000° C. By setting the heating temperature of the diffusion furnace 200 in this temperature range, stress of the insulation film 55 becomes weak in tensile stress, or more precisely, stress in a range from about −100 MPa to −250 MPa, which is balanced with stress of other films such as the elastic film 50. Accordingly, it is possible to prevent occurrence of cracks attributable to the stress of the insulation film 55, separation of the insulation film 55, and the like. Here, variation in the stress of the zirconium oxide layers (the insulation layers) when forming the zirconium layers, which were formed at different sputtering temperatures, at different thermal oxidation temperatures was investigated. The result is shown in FIG. 8. Note that the boat load speed in this case was stabilized at 500 mm/min. As shown in FIG. 8, when the thermal oxidation temperature was set to 900° C., the stress of the zirconium oxide layers was around −200 MPa irrespective of the sputtering temperature upon formation of the zirconium layers. On the contrary, when the thermal oxidation temperature was set to about 800° C., the stress of the zirconium oxide layers was around one-fourth (about −50 MPa) as compared to the case of setting the thermal oxidation temperature to 900° C. As described above, the stress of the zirconium oxide layer (the insulation film) is also influenced slightly by the sputtering temperature, but varies largely depending on the thermal oxidation temperature. That is, the tensile stress tends to become larger as the thermal oxidation temperature is set higher. Moreover, when the thermal oxidation temperature (the temperature of the diffusion furnace) is set in the range from about 850° C. to 1000° C., the stress of the insulation film 55 is set to the range from about −100 MPa to −250 MPa. Here, the thermal oxidation temperature (the temperature of the diffusion furnace) was stabilized at 900° C., and the stress of the zirconium oxidation layers (the insulation films) was further investigated while changing the boat load speed. The result is shown in FIG. 9. As shown in FIG. 9, it is obvious that the tensile stress of the zirconium oxide layer, tends to become smaller along with an increase in the boat load speed. Moreover, by setting the boat load speed faster than 200 mm/min, the stress of the zirconium oxide film (the insulation film) becomes greater than −250 MPa, or in other words, the tensile stress of the zirconium oxide layer becomes smaller than 250 MPa. As described above, by setting the temperature of the diffusion furnace 200 in the range from about 850° C. to 1000° C. and setting the boat load speed faster than about 200 mm/min, it is possible to form the insulation film 55 into a dense and highly adhesive film. In addition, the stress of the insulation film 55 is set in the range from about −100 MPa to −250 MPa and is balanced with the stress of other films. Accordingly, it is possible to prevent occurrence of cracks on the insulation film 55 due to the stress, or separation of the insulation film 55 when forming the insulation film 55 or when forming the pressure generating chambers 12 in a process to be described later, and so forth. Here, after forming the above-described insulation film 55, the lower electrode film 60 is formed by laminating platinum and iridium, for example, above the insulation film 55 as shown in FIG. 3(c), and then this lower electrode film 60 is patterned into a predetermined shape. Subsequently, as shown in FIG. 3(d), the piezoelectric layer 70 made of lead zirconate titanate (PZT), for example, and the upper electrode film 80 made of iridium, for example, are formed above the entire surface of the passage-forming substrate wafer 110. Here, in this embodiment, the piezoelectric layer 70 made of lead zirconate titanate (PZT) is formed by use of a so-called sol-gel method, which is configured to obtain the piezoelectric layer 70 made of a metal oxide by coating and drying a so-called sol including a metal-organic matter dissolved and dispersed in a catalyst into a gel, and then by sintering the gel at a high temperature. Here, when the piezoelectric layer 70 is formed as described above, there is a risk that a lead component of the piezoelectric layer 70 be dispersed into the elastic film 50 at the time of sintering. However, since the insulation film 55 made of zirconium oxide is provided below the piezoelectric layer 70, it is possible to prevent dispersion of the lead component of the piezoelectric layer 70 into the elastic film 50. Here, as the material of the piezoelectric layer 70, it is also possible to use a relaxor ferroelectric material formed by adding metal such as niobium, nickel, magnesium, bismuth, yttrium or the like to a ferroelectric piezoelectric material such as lead zirconate titanate (PZT), for example. Although the composition may be selected appropriately in consideration of a characteristic, an application, and the like of the piezoelectric element, the composition may be PbTiO3 (PT), PbZrO3 (PZ), Pb(Zrx Ti1−x)O3(PZT), Pb(Mg1/3Nb2/3)O3—PbTiO3 (PMN-PT), Pb(Zn1/3Nb2/3)O3—PbTiO3 (PZN-PT), Pb(Ni1/3Nb2/3)O3—PbTiO3(PNN-PT), Pb(In1/2Nb1/2)O3—PbTiO3 (PIN-PT), Pb(Sc1/3Ta2/3)O3 —PbTiO3(PST-PT), Pb(Sc1/3 Nb2/3)O3—PbTiO3(PSN-PT), BiScO3—PbTiO3 (BS-PT), BiYbO3—PbTiO3 (BY-PT), and the like, for example. Meanwhile, the method of manufacturing the piezoelectric layer 70 is not limited to the sol-gel method, and it is also possible to use a MOD (metal-organic decomposition) method, for example. Subsequently, as shown in FIG. 4(a), the piezoelectric layer 70 and the upper electrode film 80 are patterned into regions so as to face the respective pressure generating chambers 12, thereby forming the piezoelectric elements 300. Next, the lead electrodes 90 are formed. To be more precise, as shown in FIG. 4(b), a metal layer 91 made of gold (Au) or the like, for example, is formed above the entire surface of the passage-forming substrate wafer 110. Thereafter, the lead electrodes 90 are formed by patterning the metal layer 91 for the respective piezoelectric element 300 through a mask pattern (not shown) made of resist or the like, for example. Next, as shown in FIG. 4(c), a protective plate wafer 130, which is a silicon wafer for constituting a plurality of protective plates 30, is bonded to the passage-forming substrate wafer 110 on the side of the piezoelectric elements 300. Here, this protective plate wafer 130 has a thickness of about 400 μm, for example. Accordingly, rigidity of the passage-forming substrate wafer 110 is significantly enhanced by bonding the protective plate wafer 130. Subsequently, as shown in FIG. 4(d), the passage-forming substrate wafer 110 is polished to a certain thickness, and then the passage-forming substrate wafer 110 is further formed into a predetermined thickness by wet etching with fluoro-nitric acid. For example, in this embodiment, the passage-forming substrate wafer 110 was subjected to an etching process so as to achieve a thickness of about 70 μm. Subsequently, as shown in FIG. 5(a), a mask film 52 made of silicon nitride (SiN), for example, is newly formed on the passage-forming substrate wafer 110 and is patterned into a predetermined shape. Then, by subjecting the passage-forming substrate wafer 110 to anisotropic etching through this mask film 52, the pressure generating chambers 12, the communicating portion 13, the ink supply paths 14, and the like are formed in the passage-forming substrate wafer 110 as shown in FIG. 5(b). Thereafter, unnecessary portions on the outer peripheries of the passage-forming substrate wafer 110 and of the protective plate wafer 130 are cut out and removed by dicing, for example. Then, the nozzle plate 20 including the nozzle orifices 21 drilled thereon is bonded to the passage-forming substrate wafer 110 on the'side opposite to the protective plate wafer 130, and the compliance plate 40 is bonded to the protective plate wafer 130. Then, the passage-forming substrate wafer 110 and the like are divided into the passage forming substrate 10 and the like in one chip size as shown in FIG. 1, thereby forming the inkjet recording head of this embodiment. Here, the inkjet recording head manufactured in accordance with the above-described manufacturing method constitutes part of a recording head unit including an ink passage which communicates with an ink cartridge and the like, and is mounted on an inkjet recording device. FIG. 10 is a schematic drawing showing an example of the inkjet recording device. As shown in FIG. 10, cartridges 2A and 2B constituting ink supplying means are detachably provided to recording head units 1A and 1B including inkjet recording heads. A carriage 3 mounting these recording head units 1A and 1B is provided to a carriage shaft 5 fitted to a device body 4 as movable in the direction of the shaft. For example, these recording head units 1A and 1B are configured to eject a black ink composition and color ink compositions, respectively. Moreover, as a drive force of a drive motor 6 is transmitted to the carriage 3 through an unillustrated plurality of gears and a timing belt 7, the carriage 3 mounting the recording head units 1A and 1B is moved along the carriage shaft 5. Meanwhile, the device body 4 is provided with a platen 8 along the carriage shaft 5, and a recording sheet S as a recording medium, which is made of paper or the like and is fed by an unillustrated paper feed roller, is conveyed on the platen 8. (Embodiment 2) This embodiment is another example of the method of manufacturing an inkjet recording head, or an actuator device in particular. Specifically, although the inkjet recording head is manufactured in the same procedures as Embodiment 1 (see FIG. 3(a) to FIG. 5(b)) in this embodiment as well, but the method of manufacturing the insulation film 55 is different. Now, the method of manufacturing the insulation film 55 according to this embodiment will be described below. To be more precise, first as similar to the above-described embodiment, the zirconium layer is formed in the thickness of about 300 nm on the elastic film 50 in accordance with the DC sputtering method, for example. Thereafter, in this embodiment, the insulation film 55 is formed by heating the passage-forming substrate wafer 110 formed with this zirconium layer up to a predetermined temperature at a predetermined rate of temperature increase by use of an RTA apparatus, for example. The rate of temperature increase for subjecting the zirconium layer to thermal oxidation as described above is set preferably greater than or equal to 5° C./sec. Particularly, it is desirable to set a relatively fast rate greater than or equal to 50° C./sec. Moreover, it is preferable to set a density of the insulation film 55 made of zirconium oxide equal to 5 g/cm3 by setting the relatively fast rate of temperature increase as described above. Here, although the method of heating the zirconium layer is not particularly limited, it is preferable to use an RTA (rapid thermal annealing) method as in this embodiment. In this way, it is possible to set the relatively fast rate of temperature increase. Meanwhile, the temperature upon thermal oxidation of the zirconium layer is set preferably in a range from 800° C. to 1000° C. In this embodiment, the temperature was set to about 900° C. As described above, by heating and oxidizing the zirconium layer at the relatively fast rate of temperature increase, it is possible to form the insulation film 55 into a dense film, and thereby to prevent occurrence of cracks on the insulation film 55. To be more precise, it is possible to surely prevent occurrence of cracks on the insulation film 55 by setting the density of the insulation film 55 greater than or equal to 5 g/cm3. Moreover, the fact that the insulation film 55 is formed into the dense film as described above also derives an effect to prevent diffusion of the lead component of the piezoelectric layer 70 made of PZT into the elastic film formed on the surface of the passage-forming substrate wafer 110 through this insulation film 55. Here, the insulation films were formed while changing the rate of temperature increase as shown in Table 1 below upon oxidation of the zirconium layers, and a plurality of Samples 1 to 5 were fabricated by forming the piezoelectric layers made of PZT directly on these insulation layers without forming the lower electrode films. Then, with reference to these Samples 1 to 5, densities of the insulation films and depths of diffusion of the Pb components of the piezoelectric layers into the elastic films (the passage-forming substrate wafers) were investigated. The result is also shown in Table 1 below. TABLE 1 Oxidation rate of temperature Density Pb diffusion increase (° C./sec) (g/cm3) depth (nm) Sample 1 0.1 4.13 60 Sample 2 4.5 4.80 45 Sample 3 6.0 5.01 40 Sample 4 15.0 5.32 40 Sample 5 19.0 5.37 40 As shown in Table 1 above, the density of the insulation film becomes higher in proportion to the oxidation rate of temperature increase for the zirconium layer. Moreover, it was confirmed that the increase in the density of the insulation film stopped when the density of the insulation film exceeded 5 g/cm3, in other words, when the oxidation rate of temperature increase exceeded approximately 5° C./sec, and that the density of the insulation film remained almost constant even when the rate of temperature increase was set faster. For example, even when the rate of temperature increase is set to about 150° C./sec, the density of the insulation film will be almost equal to the value of Sample 5. Meanwhile, as shown in Table 1, it was confirmed that the Pb diffusion depth was reduced along with the increase in the density of the insulation film. Moreover, as it is obvious from this result, it is possible to regulate the diffusion of the Pb component into the elastic film (the passage-forming substrate wafer) to a constant amount by setting the rate of temperature increase greater than or equal to 5° C./sec or preferably equal to 50° C./sec upon oxidation of the zirconium layer so as to control the density of the insulation film equal to or greater than 5 g/cm3 as in this embodiment. Furthermore, it is possible to prevent diffusion of the Pb component into the elastic film (the passage-forming substrate wafer) reliably by setting the thickness of the insulation film equal to or greater than 40 nm. In addition, adhesion between the insulation film 55 and the elastic film 50 is enhanced by heating the zirconium layer at the relatively fast rate of temperature increase for achieving thermal oxidation as in this embodiment. Accordingly, there is also an effect that separation of the insulation film 55 can be prevented even in the case of repetitive deformation by the drive of the piezoelectric element 300. Here, the adhesion of the insulation film was investigated with reference to different rates of temperature increase. To be more precise, the insulation films (the zirconium oxide layers) of Samples 6 to 9 were formed by forming the zirconium layers on the elastic films, setting constant conditions except the rate of temperature increase, and subjecting the zirconium layers to thermal oxidation while setting the rate of temperature increase to 15, 50, 100, and 150° C./sec. Then, a scratch test was performed with reference to the insulation film of each of these samples. Here, as shown in FIG. 11, the scratch test was performed with reference to three points on a y axis in a perpendicular direction to an orientation flat plane 110a while defining the center of the passage-forming substrate wafer 110 as a reference point P0, or to be more precise, with reference to the center point P0 of the passage-forming substrate wafer 110, a position P1 which was 60 mm away from the center point on the y axis in a plus direction, and a position P2 which was 60 mm away from the center point on the y axis in a negative direction, respectively. The results are shown in FIG. 12. As shown in FIG. 12, the insulation film of Sample 6 applying the rate of temperature increase of 15° C./sec had adhesion around 100 mN. Meanwhile, adhesion around 200 mN was obtained from the insulation film of Sample 7 applying the rate of temperature increase of 50° C./sec, and extremely favorable adhesion around 300 mN was obtained from the insulation films of Sample 8 and Sample 9 applying the rate of temperature increase greater than or equal to 100° C./sec. As described above, the adhesion of the insulation film to the elastic film is increased more as the rate of temperature increase is set faster upon thermal oxidation of the zirconium layer. To be more precise, it is possible to obtain sufficient adhesion by setting the rate of temperature increase greater than or equal to 50° C./sec or more particularly greater than or equal to 100° C./sec. Moreover, here, cross-sectional SEM images of the insulation films 55 of Samples 10 to 12, which were obtained by subjecting the zirconium layers to thermal oxidation while setting constant conditions except the rate of temperature increase and setting the rate of temperature increase to 4, 19, and 150° C./sec, are shown in FIGS. 13(a) to 13(c). As shown in FIGS. 13(a) and 13(b), when the rate of temperature increase was set relatively slow as in the insulation films 55 of Samples 10 and 11, a low-density layer made of a glassy substance is formed on an interface between the insulation film 55 and the elastic film 50. Note that black portions observed on the interfaces between the insulation films 55 and the elastic films 50 are the low-density layers. In Sample 10, as indicated with arrows in the drawing, it is confirmed that the-low-density layer apparently exists. Moreover, when this low-density layer exists, the adhesion of the insulation film 55 to the elastic film 50 is reduced. On the contrary, in the SEM image of Sample 12 applying the relatively high rate of temperature increase of 150° C./sec, the low-density layer was not confirmed at all as shown in FIG. 13(c). As it is apparent from these results, in order to obtain the adhesion of the insulation film 55, it is preferable to avoid existence of the low-density layer on the interface between the elastic film 50 and the insulation film 55 by setting the relatively fast rate of temperature increase upon thermal oxidation of the zirconium layer, or to be more precise, by setting the rate greater than or equal to 50° C./sec. Moreover, in the manufacturing method of the present invention, the insulation film 55 thus formed is further subjected to annealing at a predetermined temperature so as to adjust the stress of the insulation film 55. To be more precise, the stress of the insulation film 55 is adjusted by annealing the insulation film 55 at a temperature less than or equal to the above-described maximum temperature upon thermal oxidation of the zirconium layer, for example, at a temperature less than or equal to 900° C., and changing the conditions such as the temperature or the time period on this occasion. For example, in this embodiment, the stress of the insulation film 55 was adjusted by annealing the insulation film 55 under the conditions of the heating temperature at 850° C. and the heating time period for 1 h. The stress of insulation film 55 after thermal oxidation was compressive stress around 2.4×108. On the contrary, the stress of the insulation film 55 as a consequence of annealing became a tensile stress of around 2.94×108. As described above, stress balance among all the films including the respective layers constituting the piezoelectric element is achieved by annealing the insulation film 55 and performing adjustment of the stress. Accordingly, it is possible to prevent separation of the film attributable to the stress, and occurrence of cracks. Moreover, it is also possible to maintain the adhesion of the insulation film 55 by setting the heating temperature for annealing less than or equal to the maximum temperature upon thermal oxidation of the zirconium layer. Here, the heating temperature for annealing is not particularly limited as long as the temperature is set less than or equal to the above-described maximum temperature. However, it is preferable to set the heating temperature as high as possible. As described above, the stress of the insulation film is determined by the conditions for annealing such as the heat temperature or the heating time period. For this reason, by setting a high heating temperature, it is possible to complete adjustment of the stress (annealing) in a relatively short time and thereby to increase manufacturing efficiency. Here, variation in the stress of the insulation film before and after annealing was investigated. To be more precise, the insulation film is formed by subjecting the zirconium layer formed on the elastic film to thermal oxidation under the conditions of the heating temperature at 900° C. and the heating time period of 5 sec. Thereafter, this insulation film is annealed under the conditions of the heating temperature at 900° C. and the heating time period of 60 min. Then, at the time of annealing, an amount of warpage of the insulation film was investigated at every predetermined elapsed time. The result is shown in FIG. 14. Note that the amount of warpage cited herein is equivalent to an amount of warpage of the insulation film at the central portion of the passage-forming substrate wafer in a span of about 140 mm. As shown in FIG. 14, the largest amount of warpage of the insulation film before annealing was approximately equal to +30 μm. That is, warpage occurred in the insulation film before annealing so as to render the elastic film side concave. Although the amount of warpage of this insulation film varied largely for an annealing time period of about 15 min, the amount of warpage also continued to vary gradually in a negative direction thereafter. After a lapse of 60 min from annealing, the insulation film caused warpage in a maximum amount of warpage equal to about −40 μm so as to render the elastic film side convex. As is apparent from this result, the stress of insulation film 55 varies depending on the time period for annealing. Therefore, by controlling the time period for annealing the insulation film, it is possible to adjust the insulation film 55 to a desired stress condition. Of course, the stress of the insulation film can be adjusted not only by controlling the time period for annealing but also by controlling the temperature. Here, it is also conceivable to perform stress adjustment of the insulation film by annealing at the time of sintering the piezoelectric layer. For example, the stress of the insulation film can be adjusted by modifying conditions such as a sintering temperature for the piezoelectric layer 70. However, modification of the conditions such as the sintering temperature for the piezoelectric layer is not favorable because physical properties of the formed piezoelectric layer may be changed, and it may be difficult to obtain desired characteristics. Moreover, it is also possible to reduce unevenness in the adhesion of the insulation film in an in-plane direction of the passage-forming substrate wafer by annealing as described above. Here, unevenness in the adhesion was investigated with reference to the insulation films of Comparative Examples without annealing and with reference to the insulation films of Examples which are subjected to annealing. To be more precise, a plurality of samples (Comparative Examples 1A, 1B, and 1C) in which the insulation films were formed on the elastic films by thermal oxidation under the above-described conditions, and a plurality of samples (Examples 1A, 1B, and 1C) in which the insulation films were further subjected to annealing after thermal oxidation were fabricated. Then, a scratch test was performed on the insulation film with reference to each of the samples according to the respective Examples and Comparative Examples. Here, as described previously, the scratch test was performed with reference to the three points on the passage-forming substrate wafer 110 (see FIG. 11). The result is shown in FIG. 15 and FIG. 16. As shown in FIG. 15 and FIG. 16, in the samples of Comparative Examples 1A to 1C, there was a difference in the adhesion of the insulation films, which was approximately equivalent to 30 mN at the maximum. On the contrary, in the samples of Examples 1A to 1C, there was very little difference in the adhesion of the insulation films. As it is apparent from this result, it is possible to prevent unevenness in the adhesion of the insulation film with reference to the in-plane direction of the passage-forming substrate wafer by forming the insulation film by thermal oxidation and further subjecting the insulation film to annealing. Moreover, it is also possible to minimize unevenness in the adhesion of the insulation films among the respective passage-forming substrate wafers. (Other Embodiments) The embodiments of the present invention have been described above. It is to be noted, however, that the present invention is not limited only to the above-described embodiments. For example, the insulation film 55 is formed on the elastic film 50 in the above-described embodiments. However, the insulation film 55 only needs to be formed closer to the piezoelectric layer 70 than the elastic film 50. For example, another layer may be provided between the elastic layer 50 and the insulation layer 55. Moreover, in the above-described embodiments, the present invention has been described on the liquid-jet head or namely the inkjet recording head, which is configured to be mounted on the liquid-jet apparatus and to include the actuator device as the liquid ejecting means as an example. However, the present invention is targeted for a wide range of actuator devices at large, and is by all means applicable to liquid-jet heads for injecting liquids other than the ink. Here, other liquid-jet heads may include various recording heads used in image recording devices such as printers, color material injection heads used for manufacturing color filters of liquid crystal displays and the like, electrode material injection heads used for forming electrodes of organic EL displays, FEDs (plane emission displays), and the like, living organic material injection heads used for manufacturing biochips, for example. Moreover, the present invention is applicable not only to the actuator device to be mounted on the liquid-jet head, but also to actuator devices to be mounted on all kinds of devices. In addition to the above-described liquid-jet heads, other devices for mounting the actuator devices may include sensors, for example.

<SOH> BACKGROUND ART <EOH>An actuator device including a piezoelectric element configured to be displaced by application of a voltage is used as liquid ejecting means of a liquid-jet head mounted on a liquid-jet apparatus for injecting droplets, for example. As for the liquid-jet apparatus described above, there is known an ink-jet recording device including an ink-jet recording head, which is configured to construct part of a pressure generating chamber communicating with a nozzle orifice by use of a. vibration plate, to pressurize ink in the pressure generating chamber by deforming this vibration plate with a piezoelectric element, and thereby to eject ink droplets out of a nozzle orifice. Two types of inkjet recording heads are put into practical use, namely, one mounting an actuator device of a longitudinal vibration mode configured to expand and contract in an axial direction of a piezoelectric element, and one mounting an actuator device of a flexural vibration mode. Moreover, as the one applying the actuator device of the flexural vibration mode, there is one configured to form a uniform piezoelectric film across the entire surface of the vibration plate in accordance with a film forming technique, and to form piezoelectric elements independently of respective pressure generating chambers by cutting this piezoelectric layer into shapes corresponding to the pressure generating chambers in accordance with a lithography method, for example. As a material of a piezoelectric material layer constituting such piezoelectric elements, lead zirconate titanate (PZT) is used, for example. In this case, when sintering the piezoelectric material layer, a lead component of the piezoelectric material layer is diffused into a silicon oxide (SiO 2 ) film, which is provided on a surface of a passage-forming substrate made of silicon (Si) for constituting the vibration plate. Accordingly, there is a problem that the melting point of silicon oxide drops by diffusion of this lead component and silicon oxide melts away owing to the heat at the time of backing the piezoelectric material layer. To solve this problem, for example, there is a technique configured to construct a vibration plate on a silicon oxide film, to provide a zirconium oxide film having a predetermined thickness, to provide a piezoelectric material layer on this zirconium oxide layer, and thereby to prevent diffusion of a lead component from the piezoelectric material layer into the silicon oxide film (see Patent Document 1, for example). This zirconium oxide film is formed for instance by forming a zirconium film in accordance with a sputtering method and then subjecting this zirconium layer to thermal oxidation. For this reason, there is a problem of occurrence of defects, such as occurrence of cracks on the zirconium oxide film due to stress generated at the time of subjecting the zirconium film to thermal oxidation. Meanwhile, if a large difference in stress exists between the passage-forming substrate and the zirconium oxide film, there also occurs a problem that the zirconium film comes off after forming the pressure generating chambers on the passage-forming substrate, for example, due to deformation of the passage-forming substrate and the like. Patent Document 1: Japanese Unexamined Patent Publication No. 11(1999) - 204849 ( FIG. 1 , FIG. 2 , p. 5)

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is an exploded perspective view of a recording head according to Embodiment 1. FIG. 2 ( a ) is a plan view and FIG. 2 ( b ) is a cross-sectional view of the recording head according to Embodiment 1. FIGS. 3 ( a ) to 3 ( d ) are cross-sectional views showing a manufacturing process of the recording head according to Embodiment 1. FIGS. 4 ( a ) to 4 ( d ) are cross-sectional views showing the manufacturing process of the recording head according to Embodiment 1. FIGS. 5 ( a ) and 5 ( b ) are cross-sectional views showing the manufacturing process of the recording head according to Embodiment 1. FIG. 6 is a schematic drawing of a diffusion furnace used in the manufacturing process. FIG. 7 is a graph showing a relation between a boat load speed and adhesion. FIG. 8 is a graph showing a relation between a thermal oxidation temperature and stress. FIG. 9 is a graph showing a relation between the boat load speed and the stress. FIG. 10 is a schematic drawing of a recording device according to an embodiment of the present invention. FIG. 11 is a view for explaining positions of measurement of the adhesion. FIG. 12 is a graph showing a relation between a rate of temperature increase and the adhesion. FIGS. 13 ( a ) to 13 ( c ) are SEM images showing cross sections of insulation films. FIG. 14 is a graph showing a relation between elapsed time for annealing and stress of an insulation film. FIG. 15 is a graph showing unevenness in adhesion of insulation films according to comparative examples. FIG. 16 is a graph showing unevenness in adhesion of insulation films according to examples. detailed-description description="Detailed Description" end="lead"?

20060608

20090721

20070419

66287.0

H04R1700

NGUYEN, TAI V

METHOD OF MANUFACTURING ACTUATOR DEVICE FOR INK JET HEAD

UNDISCOUNTED

ACCEPTED

H04R

ACCEPTED

Flexible network security system and method for permitting trusted process

Disclosed herein is a flexible network security system and method for permitting a trusted process. The system includes a port monitoring unit for extracting information about a server port being used through a network communication program, an internal permitted program storage for extracting information about a program for which communication is permitted by the firewall, and registering the extracted information, an internal permitted by the firewall, and registering the extracted information, an internal permitted port storage, if the port monitoring unit extracts the information about the server port being used using the program registered in the internal permitted program storage, registering the extracted information about the server port; and a device for making the firewall flexible, determining whether a destination port of a packet of inbound traffic has been registered in the internal permitted port storage, and if the destination port has not been registered, transmitting the corresponding packet to the firewall, and if the destination port has been registered, allowing the corresponding packet to bypass the firewall.

1. A network security system for permitting a trusted process using a firewall, the firewall protecting a corresponding network connection of a computer to a network by setting restrictions on information communicated between networks, comprising: a port monitoring unit for extracting information about a server port being used through a network communication program; an internal permitted program storage for extracting information about a program for which communication is permitted by the firewall, and registering the extracted information; an internal permitted port storage, if the port monitoring unit extracts the information about the server port being used using the program registered in the internal permitted program storage, registering the extracted information about the server port; and a device for making the firewall flexible, determining whether a destination port of a packet of inbound traffic has been registered in the internal permitted port storage, and if the destination port has not been registered, transmitting the corresponding packet to the firewall, and if the destination port has been registered, allowing the corresponding packet to bypass the firewall. 2. The network security system as set forth in claim 1, wherein the information about the program, which is extracted and registered in the internal permitted program storage, includes information about a program name, an entire path of the program, and a program Message Digest 5 (MD5) hash value. 3. The network security system as set forth in claim 1, wherein the information about the server port, which is extracted and registered in the internal permitted port storage, includes information about an entire path of the program, a protocol, and a port. 4. A network security method of permitting a trusted process using a firewall, the firewall protecting a corresponding network connection of a computer to a network by setting restrictions on information communicated between networks, comprising: the first step of extracting information about a server port being used through a network communication program; the second step of extracting information about a program for which communication is permitted by the firewall, and registering the extracted information in an internal permitted program storage; the third step of, if information about the server port being used is extracted using the program registered in the internal permitted program storage at the first step, registering the information about the extracted server port in internal permitted port storage; the fourth step of determining whether a destination port of a packet of inbound traffic has been registered in the internal permitted port storage; the fifth step of, if, as a result of the determination at the fourth step, the destination port has not been registered, transmitting the packet of inbound traffic to the firewall; and the sixth step of, if, as a result of the determination at the fourth step, the destination port has been registered, allowing the corresponding packet to bypass the firewall. 5. (canceled) 6. (canceled) 7. (canceled) 8. The network security method as set forth in claim 4, wherein the information about the program, which is extracted and registered at the second step, includes information about a program name, an entire path of the program, and a program Message Digest 5 (MD5) hash value. 9. The network security method as set forth in claim 4, wherein the information of the server port, which is extracted and registered at the third step, includes information about an entire path of the program, a protocol, and a port. 10. A computer-readable recording medium for performing a network security method using a firewall, the medium storing a program for executing the method, the method comprising: the first step of extracting information about a server port being used through a network communication program; the second step of extracting information about a program for which communication is permitted by the firewall, and registering the extracted information in an internal permitted program storage; the third step of, if information about the server port being used is extracted using the program registered in the internal permitted program storage at the first step, registering the information about the extracted server port in an internal permitted port storage; the fourth step of determining whether a destination port of a packet of inbound traffic has been registered in the internal permitted port storage; the fifth step of, if, as a result of the determination at the fourth step, the destination port has not been registered, transmitting the packet of inbound traffic to the firewall; and the sixth step of, if, as a result of the determination at the fourth step, the destination port has been registered, allowing the corresponding packet to bypass the firewall.

TECHNICAL FIELD The present invention relates generally to a flexible network security system and method for permitting a trusted process and, more particularly, to a network security system and method, in which a port, which is used by a program for which communication is permitted, is automatically added to or removed from an internet connection firewall, thus allowing inexpert users to easily use the internet connection firewall having excellent functionality. BACKGROUND OF THE ART A firewall is a security system that forms a protection border between a network and the outside thereof. FIG. 1 is a view showing an Internet Connection Firewall (ICF) for protecting a computer and a network, which has been basically provided by Microsoft Inc. since the XP version of Windows. The ICF is software used to set restrictions on information communicated between a network or small-scale network and the Internet, and protects an Internet connection of a single computer to the Internet. Meanwhile, a conventional ICF is a stateful firewall. The term stateful firewall refers to a firewall which monitors all the communication passing through a corresponding path, and inspects the original of each message to be processed, a target address and a port. The ICF permits outbound traffic but blocks inbound traffic, so that a network inside the ICF is not seen from the outside. For this reason, in a Personal Computer (PC) firewall, this function is referred to as a “stealth function.” The operation of the ICF is described in brief below. The ICF keeps track of traffic originating from an ICF computer, and maintains a communication table, so that unwanted traffic does not enter through the personal connection. Further, all inbound traffic on the Internet is compared with the items in the table. Only in the case where it is proved that a matching item exists in the table and communication originated from the user's computer, inbound Internet traffic is connected to a network computer. In contrast, in the case where an Internet connection is not permitted on the basis of a firewall permission list, the ICF disconnects the connection. Accordingly, general hacking, such as port scanning, can be blocked by automatically canceling unwanted communication. For example, when an ICF computer is scanned using a linux nmap scanning tool in order to check such a case, the ICF computer does not respond to any scan operation, so that Network Mapper (Nmap) determines that a target computer does not exist on a network for every scan, and outputs the message “Host Seems Down.” As described above, the ICF blocks general hacking, such as port scanning, is performed by automatically canceling unwanted communication. Meanwhile, when the ICF is installed in a web service providing computer, the ICF blocks inbound traffic, so that the Internet connection is disconnected, and, therefore, normal web service cannot be offered. To solve this problem, the ICF permits inbound traffic to Port 80 used by service, thus being capable of allowing normal web service. As described above, the ICF allows normal service to be used by adding services and protocols, and the PC firewall also provides such functions. Meanwhile, the problem of the ICF is described below. Recent Internet software, such as a web server, a File Transfer Protocol (FTP) server, a telnet server, a peer-to-peer (P2P) program, a remote control program and a messenger program, operates as service providing servers. Furthermore, the amount of software operating as a server as described above is increasing remarkably, and such software trends toward being used by many general users. However, most users avoid using stealth function of the ICF or PC firewall because the above-described software operating as a server does not operate normally. In Windows XP shown in FIG. 2, the corresponding software can be normally used by adding a port, a protocol, and an Internet Protocol (IP) used by the software operating as a server uses. However, it is difficult for inexpert users to set them because the inexpert users have difficulty in finding a port operating as a server. Furthermore, since a port operating as a server may be changed when the version of the software is upgraded, normal service may be unexpectedly interrupted. For these reasons, there is a problem in that it is difficult for general users to use the stealth functions of the ICF and the PC firewall despite their desired characteristics. DISCLOSURE OF INVENTION Technical Problem Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a network security system and method, in which a port, which is used by a program for which communication is permitted, is automatically added to or removed from an internet connection firewall, thus allowing inexpert users to easily use a desired function of the internet connection firewall. Technical Solution In order to accomplish the above object, the present invention provides a network security system for permitting a trusted process using a firewall, the firewall protecting a corresponding network connection of a computer to a network by setting restrictions on information communicated between networks, including a port monitoring unit for extracting information about a server port being used through a network communication program; an internal permitted program storage for extracting information about a program for which communication is permitted by the firewall, and registering the extracted information; an internal permitted port storage, if the port monitoring unit extracts the information about the server port being used using the program registered in the internal permitted program storage, registering the extracted information about the server port; and a device for making the firewall flexible, determining whether a destination port of a packet of inbound traffic has been registered in the internal permitted port storage, and if the destination port has not been registered, transmitting the corresponding packet to the firewall, and if the destination port has been registered, allowing the corresponding packet to bypass the firewall. In addition, in order to accomplish the above object, the present invention provides a network security method of permitting a trusted process using a firewall, the firewall protecting a corresponding network connection of a computer to a network by setting restrictions on information communicated between networks, including the first step of extracting information about a server port being used through a network communication program; the second step of extracting information about a program for which communication is permitted by the firewall, and registering the extracted information in an internal permitted program storage; the third step of, if information about the server port being used is extracted using the program registered in the internal permitted program storage at the first step, registering the information about the extracted server port in an internal permitted port storage; the fourth step of determining whether a destination port of a packet of inbound traffic has been registered in the internal permitted port storage; the fifth step of, if, as a result of the determination at the fourth step, the destination port has not been registered, transmitting the packet of inbound traffic to the firewall and the sixth step of, if, as a result of the determination at the fourth step, the destination port has been registered, allowing the corresponding packet to bypass the firewall. Preferably, in the case of performing communication using Transmission Control Protocol (TCP), the first step is extracts a listen port through hooking when a socket performs listen to operate as a server. Preferably, in the case of communication using User Datagram Protocol (UDP), the first step extracts the server port by performing hooking in a user mode when a socketcalls a relevant function to receive a packet. Advantageous Effects As described above, in accordance with the present invention, a port which is used by a program for which communication is permitted is automatically added to or removed from the ICF, so that inexpert users are capable of easily using the ICF having excellent functionality. BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects, features and advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which: FIG. 1 is a view showing an ICF for protecting a computer and a network, which has basically been provided by Microsoft Inc. since the XP version of Windows; FIG. 2 is a view showing an interface screen that allows a port, a protocol, and an IP, which are used by software that operates as a server uses in Windows XP, to be added FIG. 3 is a block diagram showing the mode division of a Microsoft Windows operating system used in the present invention FIG. 4 is a schematic flow chart showing the operation of an ICF according to the present invention, which illustrates processes of installing a port monitoring unit and the ICF, and storing a permitted program list in an internal permitted program storage FIG. 5 is a view showing an interface screen that is displayed to allow a communication permitted program list to be stored in an internal permitted program storage in a flexible ICF in accordance with an embodiment of the present invention; FIG. 6 is a block diagram showing the operation of an entire firewall using a device for making an ICF flexible according to the present invention FIG. 7 is a flowchart showing a process of storing and deleting a server port in and from the internal permitted port storage of a flexible ICF according to an embodiment of the present invention and FIG. 8 is a flowchart showing a packet processing flow performed in front of an ICF in accordance with an embodiment of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION A flexible network security system and method for permitting a trusted process and method in accordance with an embodiment of the present invention is described in detail with reference to the accompanying drawings below. First, the related art corresponding to the background of the present invention is described in brief. FIG. 3 is a block diagram showing the mode division of a Microsoft Windows operating system used in the present invention. Referring to FIG. 3, Windows XP, which is provided by Microsoft Inc., provides a kernel mode and a user mode. In the kernel mode, an operating system kernel and various kinds of device drivers are driven, and in the user mode, applications are mainly driven. Programs which operate in the kernel mode exist in the form of device drivers. A kernel mode network structure supported by the Microsoft Windows operating system includes afd.sys (AFD), that is, the kernel of a Windows socket, a Network Driver Interface Specification (NDIS), and a Transport Driver Interface (TDI). The afd.sys which exists at the uppermost layer in the kernel mode communicates with msafd.dll, that is, a Dynamic link library (DLL) which exists at the lowermost layer in the user mode Windows socket, and constitutes an interface with TDI existing at the lower layer thereof. The TDI defines a kernel mode interface which exists above a protocol stack. The NDIS provides a standard interface for Network Interface Card Device Drivers (NICDDs). A method of constructing a firewall in the user mode of the Microsoft Windows operating system is described below in brief. Hooking refers to a widely known programming method that stores the address of a original function intended to be hooked, and replaces the address of the original function with the address of a function made by the user, thus allowing the original function to be executed afterward through the execution of the function made by the user. 1) Winsock Layered Service Provider (LSP) This method is a method provided by Microsoft Inc., which is based on a Service Provider Interface (SPI) that is a component existing in Microsoft networking widely used in Quality Of Service (QOS), URL filtering, and the encryption of a data stream. 2) Windows 2000 Packet Filtering Interface Windows 2000 uses a method of installing a filter descriptor so that an application program in the user mode can perform permission and blocking on the basis of an IP address and port information. 3) Winsock Dll replacement This method is based on a method of filtering by replacing the Winsock DLL of Microsoft Windows with a DLL made by the user. 4) Global Function Hooking This method is based on a method of hooking the socket functions in Windows, such as Connect, listen, Send, Recv, Sendto, and Recvfrom, or a DeviceIoControl( ) function that application in the user mode uses to communicate with a driver in the kernel mode. A method of constructing a firewall in the kernel mode of the Microsoft Windows operating system is described in brief below. 1) Kernel Mode Socket Filter This scheme is based on a method of hooking all the Inputs/Outputs (I/Os) in which msafd.dll, which is a DLL existing at the lowermost layer below a Windows socket in the user mode, communicates with afd.sys, which is a kernel mode Windows socket. 2) TDI filter driver This scheme is based on a method of utilizing a filter driver produced by applying an IoAttackDevice( ) API to a device created by a tcpip.sys driver, such as \Device\RawIp, \Device\Udp, \Device\Tcp, \Device\Ip, \Device\MULTICAST. Alternatively, this method is based on a method of hooking all I/Os by replacing a dispatch table existing in the driver object of tcpip.sys. 3) NDIS InterMediate (IM) driver This scheme is a method, which is provided to users by Microsoft Inc., and allows a firewall and a Network Address Translation (NAT) to be developed through insertion between a protocol driver, such as TCP/IP, and an MC driver. 4) NDIS hooking filter driver This scheme is a method of hooking the functions of a NDIS library, which is based on a method of hooking functions, such as NdisRegisterProtocol, NdisDeregisterProtocol, NdisOpenAdapter, NdisCloseAdapter and NdisRegisterProtocol, or a method of hooking the I/Os of a Protocol driver and an MC driver in communication with the NDIS after finding an existing registered protocol driver link on the basis of a returned NdisProtocolHandle, such as TCP/IP, using an NdisRegisterProtocol function that registers the Protocol driver thereof. The ICF according to the present invention may be implemented in the above-described kernel mode socket filter, TDI filter driver, NDIS IM driver and NDIS hooking filter, and is generally implemented in the NDIS IM driver or NDIS hooking filter driver. The ICF maintains the entire communication table of EPs and ports by keeping track of traffic originating from an ICF computer. All inbound traffic from the Internet is compared with items existing in this communication table. Only when it is proved that a matching item exists in the table and, therefore, communication originated from the user's computer, inbound Internet traffic is permitted; otherwise the traffic is blocked. Granting permission to the inbound traffic is performed by calling the address of a hooked original function. In contrast, blocking to the inbound traffic is performed by sending a false return indicating that the call to the original function succeeded or failed without calling the original function, or providing false information so that the original function is called but the performance of the function is not performed normally. A flexible network security system and method for permitting a trusted process according to the present invention is described based on the above-described basic description related to the firewall. FIG. 4 is a schematic flowchart showing the operation of an ICF according to the present invention, which illustrates processes of installing a port monitoring unit and the ICF, and storing a permitted program list in an internal permitted program storage. First, at step S410, a port monitoring unit and an ICF are installed. In the case of TCP, when a socket performs listen to operate as a server, the port monitoring unit extracts a listen port through Winsock hooking. Furthermore, when a corresponding operation is performed in msafd.dll, a corresponding operation in a kernel is performed in the AFP, that is, the socket part of the kernel, or TDI_EVENT_CONNECT is called through TdiSetEvent( ) in the TDI, the port monitoring unit extracts the listen port. In the case of User Datagram Protocol (UDP), when a socket calls recvfrom to receive a packet, a server port for receiving the packet is extracted by Winsock hooking in the user mode. Furthermore, when a successive operation in the AFD exists in the kernel mode, or when TDI_EVENT_RECEIVE_DATAGRAM is created through corresponding TdiSetEvent( ), a server port for receiving a packet is extracted. The port monitoring unit is installed by Winsock hooking in the user mode, or by the kernel mode socket filter and the TDI filter driver in the kernel mode, and functions to extract server port information, protocol information (TCP, UDP, etc.), and OPEN/CLOSE information. Thereafter, the ICF is installed. Such an ICF may be implemented in a kernel mode socket filter, a TDI filter driver, an NDISIM driver, a Windows 2000 filter hook driver and an NDIS hooking filter driver, and is generally installed through the NDIS IM driver or the NDIS hooking filter driver in the same manner as described above. Then, at step S420, a permitted program list is stored in an internal permitted program storage. FIG. 5 is a view showing an interface screen that is displayed to allow a communication permitted program list to be stored in an internal permitted program storage in the flexible ICF in accordance with an embodiment of the present invention. As shown in FIG. 5, when a program to be permitted by the ICF is selected, a program name, the entire path of a program, and, the Message Digest algorithm 5 (MD5) hash value of a corresponding program file for checking, and the integrity of the program are obtained. The program name, the entire path of a program, and the program MD5 hash value obtained as described above are stored in the internal permitted program storage. The internal permitted program storage stores data in the form of the following Table 1, and in the form of a file or a database including information about the program name, the entire path of a program, and the program MD5 hash value. TABLE 1 Entire path of program Program MD5 hash value 1 D:\Program Files\MSN 0x832764827648273686823764826 Messenger\msnmsgr.exe 37872 2 D:\Program Files\ Ox938472938742983794279739284 PcAnywhere.exe 79374 3 . . . FIG. 6 is a block diagram showing the operation of an entire firewall using a device for making an ICF flexible device according to the present invention, which is described in detail below. When an Internet use program 610 opens a server port to operate as a server, a device for making an ICF flexible 620 determines whether a program, which opened the corresponding server port, has been registered in an internal permitted program storage 650. When the corresponding program has been registered, the device for making an ICF flexible 620 registers the opened server port in an internal permitted port storage 660. Meanwhile, when inbound traffic is transmitted from the outside, the inbound traffic reaches an ICF 630 after passing through a network card 640. The device for making an ICF flexible 620 determines whether a destination port has been registered in the internal permitted port storage 660 by examining the packets of the inbound traffic. If, as a result of the determination, the corresponding port has not been registered, a packet is transmitted to the ICF 630 and the packet is blocked. However, if the corresponding port has been registered, a packet is not permitted to pass through the ICF 630, and a hooked original function is called to bypass the packet to the device for making an ICF flexible 620 registers. The following Table 2 is an example showing ports registered in the internal permitted port storage. TABLE 2 Entire path of program Protocol Port 1 D:\Program Files\MSN TCP 1863 Messenger\msnmsgr.exe 2 D:\Program Files\MSN TCP 6891 Messenger\msnmsgr.exe 3 D:\Program TCP 5631 Files\PcAnywhere\PcAnywhere.exe 4 D:\Program UDP 5632 Files\PcAnywhere\PcAnywhere.exe . . . As shown in Table 2, the internal permitted port storage includes information about the entire path of a program, the protocol and the port, and may exist in the forms of an array or connection list in memory, or in the form of a file or a database. FIG. 7 is a flowchart showing a process of storing and deleting a server port in and from the internal permitted port storage of a flexible ICF according to an embodiment of the present invention, which is described in detail below. First, at step S701, information about a server port, OPEN/CLOSE information, and information about protocol are extracted from the port monitoring unit, and then, at step S703, the port monitoring unit determines whether a current program, which opened the server port, has been registered in the internal permitted program storage. Meanwhile, a method of obtaining information about a current process that is using a network is performed in such a way that the port monitoring unit extracts the ID information of the current process using a PsGetCurrentProcessId( ) function, and acquires the entire path of the current program through the process ID. The MD5 hash value of the corresponding program is extracted through the entire path of the program obtained as described above, and it is determined whether the current program exists in the internal permitted program storage using the MD5 hash value and the entire path of the program. If, as a result of the determination at step S703, the current program has not been registered, the process ends. In contrast, if the current program has been registered, at step 705, it is determined whether the server port is opened or closed using the extracted OPEN/CLOSE information. If, as a result of the determination at step S705, the server port has been opened, the information about the entire path of the program, the protocol and the server port is registered at step S709, and the process ends. In contrast, if, as a result of the determination at step S705, the server port has not been opened, the items of the permitted port storage matched with the information about the entire path of the program, the protocol and the server port are searched for and then deleted at steps S706 and S707, and the process ends. FIG. 8 is a flowchart showing a packet processing flow performed in front of an ICF in accordance with an embodiment of the present invention, which is described in detail below. First, at step S801, a packet is extracted from inbound traffic before being processed by the ICF and, then, at step S805, information about a corresponding destination (local) port and a protocol is extracted from the extracted packet. Thereafter, at step S805, it is determined whether information about a corresponding destination (local) port and a protocol has been registered in the internal permitted port storage. If, as a result of the determination at step S805, the information has not been registered, the corresponding packet is transmitted to the ICF at step S807. In contrast, if the information has been registered, the destination port must be a permitted port, so that the inbound traffic is allowed to bypass the ICF by calling a hooked original function. MODE FOR THE INVENTION Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, it will be apparent to those skilled in the art that various modifications, additions and substitutions thereof are possible, without departing from the spirit of the invention. Accordingly, the scope of the invention will be limited only by the accompanying claims, in which it will be appreciated that the examples of the modifications, additions and substitutions are all included. INDUSTRIAL APPLICABILITY As described above, in accordance with the present invention, a port which is used by a program for which communication is permitted is automatically added to or removed from the ICF, so that inexpert users are capable of easily using the ICF having excellent functionality.

<SOH> TECHNICAL FIELD <EOH>The present invention relates generally to a flexible network security system and method for permitting a trusted process and, more particularly, to a network security system and method, in which a port, which is used by a program for which communication is permitted, is automatically added to or removed from an internet connection firewall, thus allowing inexpert users to easily use the internet connection firewall having excellent functionality. BACKGROUND OF THE ART A firewall is a security system that forms a protection border between a network and the outside thereof. FIG. 1 is a view showing an Internet Connection Firewall (ICF) for protecting a computer and a network, which has been basically provided by Microsoft Inc. since the XP version of Windows. The ICF is software used to set restrictions on information communicated between a network or small-scale network and the Internet, and protects an Internet connection of a single computer to the Internet. Meanwhile, a conventional ICF is a stateful firewall. The term stateful firewall refers to a firewall which monitors all the communication passing through a corresponding path, and inspects the original of each message to be processed, a target address and a port. The ICF permits outbound traffic but blocks inbound traffic, so that a network inside the ICF is not seen from the outside. For this reason, in a Personal Computer (PC) firewall, this function is referred to as a “stealth function.” The operation of the ICF is described in brief below. The ICF keeps track of traffic originating from an ICF computer, and maintains a communication table, so that unwanted traffic does not enter through the personal connection. Further, all inbound traffic on the Internet is compared with the items in the table. Only in the case where it is proved that a matching item exists in the table and communication originated from the user's computer, inbound Internet traffic is connected to a network computer. In contrast, in the case where an Internet connection is not permitted on the basis of a firewall permission list, the ICF disconnects the connection. Accordingly, general hacking, such as port scanning, can be blocked by automatically canceling unwanted communication. For example, when an ICF computer is scanned using a linux nmap scanning tool in order to check such a case, the ICF computer does not respond to any scan operation, so that Network Mapper (Nmap) determines that a target computer does not exist on a network for every scan, and outputs the message “Host Seems Down.” As described above, the ICF blocks general hacking, such as port scanning, is performed by automatically canceling unwanted communication. Meanwhile, when the ICF is installed in a web service providing computer, the ICF blocks inbound traffic, so that the Internet connection is disconnected, and, therefore, normal web service cannot be offered. To solve this problem, the ICF permits inbound traffic to Port 80 used by service, thus being capable of allowing normal web service. As described above, the ICF allows normal service to be used by adding services and protocols, and the PC firewall also provides such functions. Meanwhile, the problem of the ICF is described below. Recent Internet software, such as a web server, a File Transfer Protocol (FTP) server, a telnet server, a peer-to-peer (P2P) program, a remote control program and a messenger program, operates as service providing servers. Furthermore, the amount of software operating as a server as described above is increasing remarkably, and such software trends toward being used by many general users. However, most users avoid using stealth function of the ICF or PC firewall because the above-described software operating as a server does not operate normally. In Windows XP shown in FIG. 2 , the corresponding software can be normally used by adding a port, a protocol, and an Internet Protocol (IP) used by the software operating as a server uses. However, it is difficult for inexpert users to set them because the inexpert users have difficulty in finding a port operating as a server. Furthermore, since a port operating as a server may be changed when the version of the software is upgraded, normal service may be unexpectedly interrupted. For these reasons, there is a problem in that it is difficult for general users to use the stealth functions of the ICF and the PC firewall despite their desired characteristics.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The above and other objects, features and advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which: FIG. 1 is a view showing an ICF for protecting a computer and a network, which has basically been provided by Microsoft Inc. since the XP version of Windows; FIG. 2 is a view showing an interface screen that allows a port, a protocol, and an IP, which are used by software that operates as a server uses in Windows XP, to be added FIG. 3 is a block diagram showing the mode division of a Microsoft Windows operating system used in the present invention FIG. 4 is a schematic flow chart showing the operation of an ICF according to the present invention, which illustrates processes of installing a port monitoring unit and the ICF, and storing a permitted program list in an internal permitted program storage FIG. 5 is a view showing an interface screen that is displayed to allow a communication permitted program list to be stored in an internal permitted program storage in a flexible ICF in accordance with an embodiment of the present invention; FIG. 6 is a block diagram showing the operation of an entire firewall using a device for making an ICF flexible according to the present invention FIG. 7 is a flowchart showing a process of storing and deleting a server port in and from the internal permitted port storage of a flexible ICF according to an embodiment of the present invention and FIG. 8 is a flowchart showing a packet processing flow performed in front of an ICF in accordance with an embodiment of the present invention. detailed-description description="Detailed Description" end="lead"?

20060607

20130924

20070927

73261.0

G06F1516

KHOSHNOODI, NADIA

Flexible network security system and method for permitting trusted process

SMALL

ACCEPTED

G06F

ACCEPTED

Melt Filter for Purifying Plastic Melts

The invention relates to a melt filter (1) for purifying, in particular, plastic melts leaving extruders, comprising a filter disk (3), which is provided between two plates (5, 5′) that form a housing equipped with a filter element changing station (7), and which can be rotationally driven by means of a power-operated pawl-type drive (4). Said filter disk has recesses, which are separated by webs (11) along a circular path and which serve to accommodate filter elements (8) that, by means of perforated disks, are supported against the forces arising due to the drop in pressure occurring therein in the flowing direction of the plastic melt. The inventive melt filter also comprises a melt channel (9), which passes through the plates in the area of the circular path, feeds the melt to the filter elements, and which widens up to the filter elements. The aim of the invention is to design the smallest possible melt filter with which, during operation, few unwanted changes occur in the plastic, and which ensures, even in the event of high pressures, a filter element exchange with nearly a constant pressure while remaining cost-effective. To this end, the invention provides that the plates completely cover the filter disk, whereby at least one of the plates is interrupted by the filter element changing station, and that the filter changing station is designed such that it is larger than a filter element and smaller than or the same size of two filter elements.

1. Melt filter (1) for purifying especially plastic melts discharged by extruders, with a filter disk (3), which is installed between two plates (5, 5′) that form a housing [2] equipped with a filter element changing station (7), can be rotationally driven by a power-driven ratchet drive (4), and has recesses that are separated by webs (11) and arranged along a circular path for holding exchangeable filter elements (8), which are supported by means of perforated disks against the forces that arise due to the pressure drop that occurs in them in the direction of flow of the plastic melt, and with a melt channel (9), which passes through the plates (5, 5′) in the area of the circular path, feeds the melt to the filter elements (8), and widens towards the filter elements (8), wherein the plates (5, 5′) completely cover the filter disk (3), with at least one of the plates (5, 5′) being interrupted by the filter element changing station (7), and that the filter element changing station (7) is designed to be larger than one filter element (8) and smaller than or the same size as two filter elements (8, 8′). 2. Melt filter in accordance with claim 1, wherein at least one of the plates (5, 5′) has a reversibly movable region that covers the filter element changing station (7), that the filter disk (3) is completely covered during the operation of the filter and is closed snugly towards the filter disk, and that the filter element changing station (7) is uncovered for the filter element change. 3. Melt filter in accordance with claim 1, wherein the given distance between filter elements (8) against which the melt is flowing and the filter element changing station (7) is larger than or the same size as the width of one filter element (8) and a web (11) and smaller than the width of two filter elements (8, 8′) and a web (11). 4. Melt filter in accordance with claim 3, wherein the ratio of the web area against which the melt is flowing to the area of the filter disk (3) through which melt is flowing is less than 18% and greater than 12%. 5. Melt filter in accordance with claim 4, wherein the ratio of the web area against which the melt is flowing to the area of the filter disk (3) through which melt is flowing is 14% to 16%. 6. Melt filter in accordance with claim 3, wherein, for each stroke of the ratchet drive (4), a maximum of 10% of the area of the filter disk (3) against which the plastic melt flows can be exchanged for a corresponding filter disk area with unused filter elements (8). 7. Melt filter in accordance with claim 6, wherein, for each stroke of the ratchet drive (4), 5% to 7% of the area of the filter disk (3) against which the plastic melt flows can be exchanged for a corresponding filter disk area with unused filter elements (8).

The invention concerns a melt filter for purifying especially plastic melts discharged by extruders, with a filter disk, which is installed between two plates that form a housing equipped with a filter element changing station, can be rotationally driven by a power-driven ratchet drive, and has recesses that are separated by webs and arranged along a circular path for holding exchangeable filter elements, which are supported by means of perforated disks against the forces that arise due to the pressure drop that occurs in them in the direction of flow of the plastic melt, and with a melt channel, which passes through the plates in the area of the circular path, feeds the melt to the filter elements, and widens towards the filter elements. Prior-art melt filters are described, for example, in EP 0 114 651 B1. However, the previously known melt filter has a very large and thus expensive filter disk, whose filter element changing station is also very large, but the surface of the filter disk against which the melt flows is very small, so that extremely poor efficiency results. EP 0 569 866 A1 has already proposed that the melt channel be widened towards the filter elements, so that the melt to be filtered can flow against two filter elements at the same time, but here again, there is no flow against large areas of the filter elements, so that similarly poor efficiency is obtained. In addition, the teeth on the filter disk have a relatively large pitch, so that when the filter disk is rotated further, large surfaces of the dirty filter elements are exchanged for correspondingly large surfaces of clean filter elements. This results in pressure differences in the cleaned melt which are unacceptable during further processing of the melt, so that additional pumps are often needed to guarantee a constant pressure of the cleaned melt. It has already been proposed that gear drives that produce smaller steps be used instead of the sturdy, inexpensive ratchet drive in order to exchange only small filter disk areas with dirty filter elements for filter disk areas with clean filters at any given time and thus to ensure pressure constancy. However, expensive rotational drives of this type constitute an immense cost factor. DE 42 12 928 A1 has already disclosed a large-surface cover for a filter disk, but large areas of the filter disk are still exposed to ambient air when the filter disk is rotated, so that undesired changes in the plastic can occur. The objective of the invention is to specify a melt filter that is as small as possible, with which hardly any changes occur in the plastic during operation, which guarantees filter element exchange at more or less constant pressure, even at high pressures, and which is nevertheless inexpensive to produce. To this end, it is proposed that the plates completely cover the filter disk, with at least one of the plates being interrupted by the filter element changing station, and that the filter element changing station be designed larger than one filter element and smaller than or the same size as two filter elements. This results in the formation of a housing which encloses, if possible, the whole filter disk and is better able to withstand the high pressures that are required. It has been found to be effective for at least one of the plates to have a reversibly movable region that covers the filter element changing station, for the filter disk to be completely covered during the operation of the filter and closed snugly towards the filter disk, and for the filter element changing station to be uncovered for the filter element change to be carried out during the operation of the filter. On the one hand, the complete covering of the filter disk makes it possible to realize higher pressures, and, on the other hand, it is guaranteed that during the operation no plastic melt adhering to the filter disk comes into contact with the ambient air. It is advantageous that the given distance between filter elements against which the melt is flowing and the filter element changing station is larger than or the same size as the width of one filter element and a web, and smaller than the width of two filter elements and a web. This guarantees that melt flows against the largest possible surface area of the filter disk with the smallest possible filter changing station without it being possible for melt to be pressed out of the filter element changing station. Due to these optimum relationships between the size of the filter element changing station and the surface of the filter disk against which melt is flowing, the filter disk can be made more compact than the prior-art filter disks and yet make a larger effective filter surface available. It is advantageous if the ratio of the web area against which the melt is flowing to the area of the filter disk through which melt is flowing is less than 18% and greater than 12%. This guarantees that the webs are provided with dimensions that still enable them to withstand the high pressures but oppose the melt to be filtered with the least possible surface areas that cannot be used for filtration, so that the greatest possible filter surface area can be effectively realized. In this connection, it has been found to be effective if the ratio of the web area against which the melt flows, to the area through which the melt flows, is 15±1%. To be able to guarantee constant pressure during the filter change, it is advantageous that, for each stroke of the ratchet drive, a maximum of 10% of the area of the filter disk against which the plastic melt flows can be exchanged for corresponding filter disk areas with unused filter elements. In this connection, it has been found to be effective if 6±1% of the filter area can be exchanged per stroke of the ratchet drive. The exchange of a maximum of 10% of the area of the filter disk, i.e., of the filter elements and the webs, against which the plastic melt flows guarantees that approximately constant pressure is present in the filtered melt, and this allows trouble-free further processing of the melt in the downstream machines. The invention will now be explained in greater detail with reference to the drawing, which shows a melt filter 1 that consists of a housing 2, a filter disk 3, and a ratchet drive 4. The housing 2 is formed by a plate 5, which is connected by fastening devices 6 with another plate 5′, whose outline is indicated by a broken line. The plates 5, 5′ enclose the filter disk 3 between them. A filter element changing station 7 is indicated in the plate 5. It is essentially the same size as a filter element 8. In addition, the plate 5 has a melt channel 9, which widens towards the filter disk 3 in the form of an annular segment 10. In addition to the filter elements 8, the filter disk 3 has webs 11. Teeth 12, which interact with the ratchet drive 4, are arranged along the periphery of the filter disk. The webs 11 are connected by a wheel rim 13. Due to the fact that the filter element changing station 7 is selected to be as small as possible, most of the filter disk 3 can be enclosed by the plates 5. This makes it possible to handle the largest possible pressure prevailing in the melt channel without the occurrence of clogging of the filter disk 3 in the housing 2. The webs 11 and the peripheral wheel rim 13 of the filter disk 3 are supported on the plates 5, 5′ and seal the melt channel 9 and the annular segment 10 towards the outside. The annular segment 10 spans the webs 11′ to 11′″″ and the filter elements 8′ to 8″″″. In this regard, as a result of the relationships, in accordance with the invention, between the size of the surface against which the melt is flowing, the distance to the filter element changing station, and the size of the filter element changing station, an optimum condition is achieved, so that even with a small filter disk 3 at high pressures, the melt can be optimally filtered with good pressure constancy. LIST OF REFERENCE NUMBERS 1. melt filter 2. housing 3. filter disk 4. ratchet drive 5. plate 6. fastening device 7. filter element changing station 8. filter element 9. melt channel 10. annular segment 11. webs 12. teeth 13. wheel rim

20080912

20120619

20081225

82252.0

B01D25164

CLEMENTE, ROBERT ARTHUR

MELT FILTER FOR PURIFYING PLASTIC MELTS

SMALL

ACCEPTED

B01D

ACCEPTED

Two-part curing high-durable polyurethane elastomer composition

A two-part curing high-durable polyurethane elastomer composition having excellent heat resistance and wet heat resistance, and excellent workability such that a viscosity after two-part mixing is suitable for casting workability which comprises (i) a polyisocyanate component, and (ii) an active hydrogen-containing compound comprising (A) a polyol having a hydroxyl value of from 25 to 55 obtained by reacting a castor oil fatty acid, 12-hydroxystearic acid, or a condensate of their fatty acids, with a polyol (X) having a molecular weight of from 400 to 1,500, and (B) a polyol having a hydroxyl value of from 100 to 500 obtained by ring opening an epoxidized fatty acid ester with a polyhydric alcohol.

1. A two-part curing high-durable polyurethane elastomer composition comprising (i) a polyisocyanate component and (ii) an active hydrogen-containing compound, the active hydrogen-containing compound (ii) comprising (A) a polyol having a hydroxyl value of from 25 to 55 obtained by reacting a castor oil fatty acid, 12-hydroxystearic acid, or a condensate of their fatty acids, with a polyol (X) having a molecular weight of from 400 to 1,500, and (B) a polyol having a hydroxyl value of from 100 to 500 obtained by ring opening an epoxidized fatty acid ester with a polyhydric alcohol, wherein the proportion of the polyol (B) is from 5 to 50 parts by weight per 100 parts by weight of the polyol (A). 2. The two-part curing high-durable polyurethane elastomer composition as claimed in claim 1, wherein the polyol (X) is a polyester polyol obtained by condensing adipic acid and a dihydric alcohol with trimethylolpropane. 3. (canceled) 4. The two-part curing high-durable polyurethane elastomer composition as claimed in claim 2, having hardness at 23° C. of JIS A 90 or lower, and elongation at break of 50% or higher. 5. The two-part curing high-durable polyurethane elastomer composition as claimed in claim 1, having hardness at 23° C. of JIS A 90 or lower, and elongation at break of 50% or higher.

TECHNICAL FIELD The present invention relates to a two-part curing high-durable polyurethane elastomer composition. More particularly, the invention relates to a two-part curing high-durable polyurethane elastomer composition having excellent heat resistance and wet heat resistance, and low viscosity after two-part mixing, thereby having good casting workability. BACKGROUND ART A two-part curing polyurethane elastomer composition has excellent physical properties of a cured product, such as strength, elongation, elastic modulus and the like, and therefore is widely used in applications such as a water-proof material, a floor material, a pavement material, an adhesive, a sealing material and the like. The two-part curing polyurethane elastomer composition is cured by stirring and mixing a curing agent comprising an active hydrogen-containing compound as a main component and a base resin comprising a polyisocyanate component as a main component, and executing with a trowel, a spatula, a roller or the like, or casting in a mold. Therefore, where the viscosity after two-part mixing is high, bubbles are liable to be included when executing with a trowel, a spatula, a roller or the like, resulting in deterioration of appearance and performance. Further, where casting in a mold, inclusion of bubbles is large, and casting workability deteriorates such that fine spaces cannot be filled with a composition. Conventionally, a production method of a two-part curing polyurethane elastomer composition comprising an active hydrogen-containing compound and a polyisocyanate component is generally a prepolymer method using an isocyanate-terminated urethane polymer obtained by reacting an organic polyisocyanate and a polyol with an equivalent ratio of an isocyanate group to an active hydrogen group being 2.0 or less. Other methods are a semi-one shot method using a partial prepolymer obtained by reacting an organic polyisocyanate as a polyisocyanate component and a polyol with an equivalent ratio of an isocyanate group to an active hydrogen group exceeding 2.0, and a one shot method using an organic polyisocyanate alone. Examples of the active hydrogen-containing compound to be reacted with the polyisocyanate component include a polyether polyol such as a polytetramethylene ether glycol obtained by ring opening polymerization of tetrahydrofuran, and a polyoxyalkylene polyol obtained by addition polymerizing at least one of alkylene oxides such as ethylene oxide, propylene oxide and butylene oxide, with a polyhydric alcohol such as propylene glycol, dipropylene glycol, glycerin and trimethylol propane; a polyester polyol obtained by condensation polymerization of at least one polyhydric alcohol such as ethylene glycol, propylene glycol, diethylene glycol, butanediol, pentanediol and hexanediol, and at least one of malonic acid, maleic acid, succinic acid, adipic acid, glutaric acid, sebacic acid, phthalic acid, isophthalic acid, terephthalic acid, and the like; and a polyester polyol obtained by ring opening polymerization of caprolactone or the like. However, where a polyether polyol is used as the active hydrogen-containing compound, a cured product has relatively good wet heat resistance, but has poor heat resistance. On the other hand, where a polyester polyol is used, heat resistance is relatively good, but wet heat resistance is poor. As a method for improving heat resistance and wet heat resistance, it is proposed to use a hydride of a hydroxyl group-containing liquid polyisoprene as the active hydrogen-containing compound (JP-A-63-57626, JP-A-1-203421, JP-A-6-220157, JP-A-7-102033, and the like). However, when the hydride of a hydroxyl group-containing liquid polyisoprene proposed in those patent publications is used, a composition has high viscosity, and when executing with a trowel, a spatula, a roller or the like after two-part mixing, bubbles are liable to be included, resulting in deterioration of appearance and performance. Further, in the case of casting in a mold, there are the disadvantages that inclusion of bubbles is large, and fine spaces cannot be filled with a composition. The prior art information of this invention is as follows; JP-A-63-57626, JP-A-1-203421, JP-A-6-220157 and JP-A-7-102033. DISCLOSURE OF THE INVENTION An object of the invention is to provide a two-part curing high-durable polyurethane elastomer composition that has improved heat resistance and wet heat resistance, and also has improved the viscosity after two-part mixing to the viscosity suitable for casting workability. In particular, it provides a polyol suitable for the objective composition, and the above composition having excellent heat resistance, wet heat resistance and casting workability using the same. As a result of intensive investigations to solve the above problems, the present inventors have found that a two-part curing high-durable polyurethane elastomer composition having excellent heat resistance and wet heat resistance, and low viscosity after two-part mixing, thereby having good casting workability is obtained by using, as an active hydrogen-containing compound, (A) a polyol having a hydroxyl value of from 25 to 55 obtained by reacting a castor oil fatty acid, 12-hydroxystearic acid, or a condensate of their fatty acids, with a polyol (X) having a molecular weight of from 400 to 1,500, and (B) a polyol having a hydroxyl value of from 100 to 500 obtained by ring opening an epoxidized fatty acid ester with a polyhydric alcohol, and have reached the invention. That is, the invention provides a two-part curing high-durable polyurethane elastomer composition comprising (i) a polyisocyanate component and (ii) an active hydrogen-containing compound, the active hydrogen-containing compound (ii) comprising (A) a polyol having a hydroxyl value of from 25 to 55 obtained by reacting a castor oil fatty acid, 12-hydroxystearic acid, or a condensate of their fatty acids, with a polyol (X) having a molecular weight of from 400 to 1,500, and (B) a polyol having a hydroxyl value of from 100 to 500 obtained by ring opening an epoxidized fatty acid ester with a polyhydric alcohol. The invention preferably provides the two-part curing high-durable polyurethane elastomer composition having excellent heat resistance and wet heat resistance, and low viscosity after two-part mixing, thereby having good casting workability, wherein the polyol (X) is a polyester polyol obtained by condensing adipic acid and a dihydric alcohol with trimethylolpropane, and the proportion of the polyol (B) is from 5 to 50 parts by weight per 100 parts by weight of the polyol (A). The invention further preferably provides the two-part curing high-durable polyurethane elastomer composition having hardness at 23° C. of JIS A 90 or lower, and elongation at break of 50% or higher. EFFECT OF THE INVENTION The two-part curing high-durable polyurethane elastomer composition of the invention has low viscosity after two-part mixing. Therefore, when the composition is executed with a trowel, a spatula, a roller or the like after two-part mixing, inclusion of bubbles does not involve, and even when casting in a mold, inclusion of bubbles does not involve. As a result, fine spaces can be filled with the composition. Further, a cured product of the composition has low hardness and large elongation at break. As a result, the cured product has excellent physical properties, and therefore has excellent heat resistance and wet heat resistance. BEST MODE FOR CARRYING OUT THE INVENTION In the two-part curing high-durable polyurethane elastomer composition of the invention, the active hydrogen-containing compound which is the main component of a curing agent comprises (A) a polyol having a hydroxyl value of from 25 to 55 obtained by reacting a castor oil fatty acid, 12-hydroxystearic acid, or a condensate of their fatty acids, with a polyol (X) having a molecular weight of from 400 to 1,500, and (B) a polyol having a hydroxyl value of from 100 to 500 obtained by ring opening an epoxidized fatty acid ester with a polyhydric alcohol. In the polyol (A) used in the invention, the polyol (X) is preferably a polyester polyol obtained by condensing adipic acid and a dihydric alcohol with trimethylolpropane. Examples of the dihydric alcohol used include ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, butanediol, pentanediol, and hexanediol. The polyol (X) obtained has a molecular weight of from 400 to 1,500, and preferably from 500 to 1,000. Where the polyol (A) obtained using the polyol (X) having a molecular weight of less than 400 is used, the polyurethane elastomer composition obtained does not have sufficient heat resistance. Where the polyol (A) obtained using the polyol (X) having a molecular weight exceeding 1,500 is used, the composition obtained has high viscosity, which is not preferable in the point of casting workability. The polyol (A) is obtained by reacting a castor oil fatty acid, 12-hydroxystearic acid, or a condensate of their fatty acids, with the polyol (X), if necessary, by adding a catalyst such as paratoluenesulfonic acid, under a nitrogen gas stream at a reaction temperature of from 150 to 250° C. for several hours while distilling off by-product water outside the reaction system (for example, the method described in JP-A-11-50086). The polyol (A) has a hydroxyl value of from 25 to 55, and preferably from 30 to 50. Where the hydroxyl value is less than 25, when a polyurethane elastomer composition is prepared, the composition does not cure completely, and necessary physical properties of the cured product are not obtained. Where the hydroxyl value exceeds 55, when a polyurethane elastomer composition is prepared, the hardness at 23° C. by JIS A exceeds 90. As a result, elongation at break decreases less than 50%, and physical properties of the cured product are not preferable. The polyol (B) used in the invention is a polyol having a hydroxyl value of from 100 to 500 obtained by ring opening an epoxidized fatty acid ester with a polyhydric alcohol. The starting material of this polyol is a fatty acid ester, and can preferably obtained by ester interchange of vegetable oils and animal oils containing unsaturated fatty acid with an aliphatic alcohol having from 1 to 10 carbon atoms. Examples of the vegetable oils and animal oils used include soybean oil, coconut oil, palm oil, castor oil, linseed oil, cotton seed oil, rapeseed oil, China wood oil, sunflower oil, safflower oil, rice bran oil, olive oil, camellia oil, corn oil, beef tallow, lard, fish oil, and whale oil. Examples of the aliphatic alcohol used include methanol, ethanol, propanol, butanol, hexanol, heptanol, octanol, nonanol, and decanol. Methanol, ethanol and propanol are preferable. The fatty acid ester can also be obtained by direct esterification of an unsaturated fatty acid such as oleic acid, linoleic acid, linolenic acid and recinoleic acid, and the aliphatic alcohol. The epoxidized fatty acid ester is obtained by, for example, reacting an unsaturated bond with the fatty acid ester by the conventional method of reaction of formic acid/hydrogen peroxide, thereby forming an epoxide. Ring opening of the epoxidized fatty acid ester uses a polyhydric alcohol having from 2 to 12, and preferably from 2 to 6, carbon atoms. Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, butylene glycol, glycerin, and trimethylolpropane. The ring opening reaction is conducted at a reaction temperature in a range of from 80 to 120° C. with an equivalent ratio of an epoxy group to a hydroxyl group being 5:1 to 1:5, preferably 2:1 to 1:2. An inorganic acid or an organic carboxylic acid is used as a catalyst. Examples of the preferable catalyst include sulfuric acid, phosphoric acid, formic acid and acetic acid. The polyol (B) has a hydroxyl value of from 100 to 500, and preferably from 150 to 400. Where the hydroxyl value is less than 100, the polyol has high viscosity, resulting in deterioration of casting workability. Where it exceeds 500, when a polyurethane elastomer composition is prepared, hardness at 23° C. by JIS A exceeds 90. As a result, elongation at break decreases less than 50%, and physical properties of the cured product deteriorate. The proportion of the polyol (B) is from 5 to 50 parts by weight, and preferably from 7.5 to 40 parts by weight, per 100 parts by weight of the polyol (A). Where the proportion of the polyol (B) is less than 5 parts by weight, when a polyurethane elastomer composition is prepared, the composition does not have sufficient wet heat resistance. Where the proportion exceeds 50 parts by weight, when a polyurethane elastomer composition is prepared, the composition has hardness at 23° C. by JIS A exceeding 90. As a result, elongation at break decreases less than 50%, resulting in deterioration of physical properties of the cured product. Examples of the polyisocyanate used in the invention include an aromatic polyisocyanate such as 4,4′-dipheylmethane diisocyanate (MDI-PH), polymeric MDI (MDI-CR), carbodiimide-modified MDI (liquid MDI), and tolylene diisocyanate containing 65% or more of 2,4-isomers (TDI); and an aliphatic polyisocyanate such as norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), hexamethylene diisocyanate (HDI), 4,4′-dicyclohexylmethane diisocyanate (hydrogenated MDI), and xylene diisocyanate (XDI). Of those polyisocyanates, MDI-PH, MDI-CR and liquid MDI are preferable. The polyisocyanate used in the invention can be used alone or as mixtures thereof, and also can use a prepolymer obtained by heating a part of isocyanate groups together with a polyol in a nitrogen stream at from 60 to 100° C. for several hours. Examples of the polyol include polyol (A), caster oil polyol, and polybutadiene polyol. Further, if necessary, a low molecular weight polyhydric alcohol may be used. Examples of the low molecular weight polyhydric alcohol include ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1,4-butanediol, 1,3-butanediol, pentanediol, hexanediol, glycerin and trimethylolpropane. If necessary, the two-part curing high-durable polyurethane elastomer composition of the invention may contain an organic solvent such as toluene, xylene, methyl ethyl ketone and acetic ester; a plasticizer such as dibutyl phthalate, dioctyl adipate, dioctyl phthalate, diisononyl adipate and diisononyl phthalate; a high-boiling solvent such as a chlorinated paraffin and a petroleum hydrocarbon oil; a phosphoric ester flame retardant; an inorganic filler such as calcium carbonate, talc, clay, titanium oxide, carbon black and silica; a stabilizer such as an antioxidant and an ultraviolet absorber; and a water absorber such as molecular sieves, as a viscosity-reducing agent, and an organic lead oxide such as lead octylate and lead naphthenate; and an organic tin oxide such as dibutyltin dilaurate, as a curing agent. The production method of the two-part curing high-durable polyurethane elastomer composition of the invention is not particularly limited, and the composition is obtained by uniformly mixing the active hydrogen component and the polyisocyanate component in a certain ratio with a stirrer, a low pressure casting machine, a spray machine or the like, and curing the resulting mixture in a range of from room temperature to 120° C. EXAMPLES The invention is specifically described below by referring to the Examples and the Comparative Examples, but the invention is not construed as being limited thereto. In the Examples and the Comparative Examples, “part” shows part by weight, and “%” shows wt %. In the Examples and the Comparative Examples, the following polyol component and polyisocyanate component were used. Polyol (B): Sovamol 750: Polyol having a hydroxyl value of 315 (mgKOH/g) and a viscosity of 1,000 (mPa·s) (fat and oil-based polyol: a product of Cognis Japan Ltd.) Polyoxypropylene Glycol: D-3000: Diol having a hydroxyl value of 38 (mgKOH/g) (a product of Mitsui Takeda Chemicals, Inc.) MN-300: Triol having a hydroxyl value of 300 (mg/KOH) (a product of Mitsui Takeda Chemicals, Inc.) Hydride of Hydroxyl Group-Containing Polyisoprene: Epol: Polyol having a number average molecular weight of 1,400, and a viscosity of 110,000 ((mPa·s) (a product of Idemitsu Petrochemical Co.) Polyisocyanate Component: Cosmonate PH: MDI-PH (a product of Mitsui Takeda Chemicals, Inc.) Cosmonate LL: Liquid MDI (a product of Mitsui Takeda Chemicals, Inc.) Cosmonate M-200: MDI-CR (a product of Mitsui Takeda Chemicals, Inc.) Test of Physical Properties: An active hydrogen-containing compound and a polyisocyanate compound in a predetermined ratio were uniformly stirred and mixed for 3 minutes. After defoaming, the mixture was flow cast on a slate plate equipped with a spacer so as to obtain a thickness of 2 mm, and cured at 80° C. for 10 hours. After aging at 23° C. for 7 days, test of physical properties was conducted. Mixing Viscosity (25° C.): An active hydrogen-containing compound and a polyisocyanate compound in a predetermined ratio, adjusted to 25° C. were uniformly stirred and mixed for 3 minutes, and a viscosity of the resulting mixture was measured with a B-type viscometer. Casting Workability: An active hydrogen-containing compound and a polyisocyanate compound were stirred in the same manner as in the preparation of 2 mm thick sheet, and the resulting mixture was cast in a mold of 100 mm×100 mm×3 mm. After curing, the resulting cured product was taken out of the mold, and the cast workability was judged by an appearance of the cured product. ◯: Bubbles are not included, and the mixture flows in up to the bottom. X: Bubbles are largely included, or the mixture does not flow in up to the bottom. Initial Hardness of Cured Product: Five 2 mm thick sheets were piled, and hardness at 23° C. was measured according to JIS K6253. Elongation at Break of Cured Product: Measured according to JIS K6251 Heat Resistance of Cured Product: The 2 mm thick sheet after measurement of the initial hardness was allowed to stand under an atmosphere at 150° C. for 2,000 hours, and then allowed to stand in a thermostat chamber at 23° C. for 7 days. Hardness of the sheet was measured according to JIS K6253. Wet Heat Resistance of Cured Product: The 2 mm thick sheet after measurement of the initial hardness was allowed to stand under an atmosphere at 121° C., 100% RH and steam pressure of 2 atm for 100 hours, and then allowed to stand in a thermostat chamber at 23° C. for 7 days. Wet heat resistance of the sheet was judged by appearance change. ◯: Shape of 2 mm thick sheet is maintained. X: Shape of 2 mm thick sheet is not maintained, and the sheet dissolved. Synthesis Example 1 1,000 parts of a polyester polyol having a molecular weight of 1,000 obtained by condensing trimethylolpropane, ethylene glycol and adipic acid, 2,384 parts of 12-hydroxystearic acid, and 3 parts of paratoluenesulfonic acid were charged in a reaction vessel equipped with a stirrer, a thermometer, a condenser, a water separator and a nitrogen gas introduction pipe, and were reacted at a reaction temperature of from 160 to 200° C. for 8 hours under nitrogen gas stream. By-product water was distilled off outside the system through a distillation-off pipe. The reaction product was cooled, washed with water and dehydrated to obtain Polyol (A-1). Polyol (A-1) obtained had a hydroxyl value of 34 and a viscosity of 5,000 (mPa·s/25° C.). Synthesis Example 2 500 parts of a polyester polyol having a molecular weight of 500 obtained by condensing trimethylolpropane, ethylene glycol and adipic acid, and 2,384 parts of 12-hydroxystearic acid were reacted in the same manner as in Synthesis Example 1. Polyol (A-2) obtained had a hydroxyl value of 40 and a viscosity of 3,700 (mPa·s/25° C.). Synthesis Example 3 300 parts of a polyester polyol having a molecular weight of 300 obtained by condensing trimethylolpropane, ethylene glycol and adipic acid, and 2,384 parts of 12-hydroxystearic acid were reacted in the same manner as in Synthesis Example 1. Polyol (A-3) obtained had a hydroxyl value of 46 and a viscosity of 2,100 (mPa·s/25° C.). Synthesis Example 4 5,000 parts of a polyester polyol having a molecular weight of 5,000 obtained by condensing trimethylolpropane, ethylene glycol and adipic acid, and 2,384 parts of 12-hydroxystearic acid were reacted in the same manner as in Synthesis Example 1. Polyol (A-4) obtained had a hydroxyl value of 16 and a viscosity of 71,800 (mPa·s/25° C.). Synthesis Example 5 213 parts of Polyol (A-1), 394 parts of Cosmonate PH, and 394 parts of Cosmonate M-200 were charged in a reaction vessel equipped with a stirrer, a thermometer and a nitrogen gas introduction pipe, and reacted at 80° C. for 3 hours under nitrogen stream, thereby obtaining a polyisocyanate component having a terminal NCO group content of 25% and a viscosity of 300 (mPa·s/25° C.). Example 1 100 parts of Polyol (A-1) obtained in Synthesis Example 1 and 10 parts of Sovamol 750 (a product of Cognis Japan Ltd.) were uniformly mixed to prepare an active hydrogen-containing compound component. 100 parts of the active hydrogen-containing compound component thus prepared and 14.3 parts of Cosmonate M-200 as a polyisocyanate component were uniformly stirred and mixed for 3 minutes, and the resulting mixture was cast on a slate plate to prepare a 2 mm thick sheet. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 1. Example 2 A 2 mm thick sheet was obtained in the same manner as in Example 1, except for using 25 parts of Sovamol 750 and 21.7 parts of Cosmonate M-200. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 1. Example 3 A 2 mm thick sheet was obtained in the same manner as in Example 1, except for using 40 parts of Sovamol 750 and 27.5 parts of Cosmonate M-200. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 1. Example 4 A 2 mm thick sheet was obtained in the same manner as in Example 2, except for using 100 parts of Polyol (A-1) obtained in Synthesis Example 2 in place of Polyol (A-1) and 22.9 parts of Cosmonate M-200. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 1. Example 5 A 2 mm thick sheet was obtained in the same manner as in Example 2, except for using 23.7 parts of Cosmonate LL in place of Cosmonate M-200. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 1. Example 6 A 2 mm thick sheet was obtained in the same manner as in Example 2, except for using 27.0 parts of the polyisocyanate component obtained in Synthesis Example 5 in place of Cosmonate M-200. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 1. TABLE 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Active hydrogen compound Polyol (A-1) 100 parts 100 parts 100 parts — 100 parts 100 parts Polyol (A-2) — — — 100 parts — — Sovamol 750 10 parts 25 parts 40 parts 25 parts 25 parts 25 parts Polyisocyanate component Cosmonate M-200 14.3 parts 21.7 parts 27.5 parts 22.9 parts — — Cosmonate LL — — — — 23.7 parts Prepolymer of — — — — — 27.0 parts Synthesis Example 5 Mixing viscosity 4600 3800 3000 2800 3700 3000 (mPa · s/25° C.) Casting workability ◯ ◯ ◯ ◯ ◯ ◯ Initial hardness (JIS A) 28 57 84 60 52 45 Elongation at break (%) 100 80 62 75 105 98 Heat resistance (JIS A) 26 61 88 63 55 47 Wet heat resistance ◯ ◯ ◯ ◯ ◯ ◯ Comparative Example 1 A 2 mm thick sheet was obtained in the same manner as in Example 2, except for using 100 parts of Polyol (A-3) obtained in Synthesis Example 3 in place of Polyol (A-1) and 24.0 parts of Cosmonate M-200. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet-heat resistance were measured. The test results are shown in Table 2. Comparative Example 2 A 2 mm thick sheet was obtained in the same manner as in Example 2, except for using 100 parts of Polyol (A-4) obtained in Synthesis Example 4 in place of Polyol (A-1) and 18.3 parts of Cosmonate M-200. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 2. Comparative Example 3 A 2 mm thick sheet was obtained in the same manner as in Example 1, except for using 2.5 parts of Sovamol 750 and 9.8 parts of Cosmonate M-200. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 2. Comparative Example 4 A 2 mm thick sheet was obtained in the same manner as in Example 1, except for using 70.0 parts of Sovamol 750 and 36.0 parts of Cosmonate M-200. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 2. Comparative Example 5 A 2 mm thick sheet was obtained in the same manner as in Example 1, except for using 100 parts of Epol as the active hydrogen-containing compound and 12.2 parts of Cosmonate M-200 as the polyisocyanate compound. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 2. Comparative Example 6 100 parts of D-300 and 25 parts of MN-300, as a polyol, were uniformly mixed to prepare an active hydrogen-containing compound. Using 100 parts of the active hydrogen-containing compound thus prepared and 21.8 parts of Cosmonate M-200 as the polyisocyanate component, a 2 mm thick plate was obtained in the same manner as in Example 1. Mixing viscosity, workability, hardness of a cured product, elongation at break, heat resistance and wet heat resistance were measured. The test results are shown in Table 2. TABLE 2 Comparative Comparative Comparative Comparative Comparative Comparative Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Active hydrogen compound Polyol (A-1) — — 100 parts 100 parts — — Polyol (A-3) 100 parts — — — — — Polyol (A-4) — 100 parts — — — — Epol — — — — 100 parts — D-3000 — — — — — 100 parts MN-300 — — — — — 25 parts Sovamol 750 25 parts 25 parts 2.5 parts 70 parts — — Polyisocyanate component Cosmonate M-200 24.0 parts 18.3 parts 9.8 parts 36.0 parts 12.2 parts 21.8 parts Mixing viscosity 2000 48000 4900 2100 70000 600 (mPa · s/25° C.) Casting workability ◯ X ◯ ◯ X ◯ Initial hardness (JIS A) 30 18 12 96 52 70 Elongation at break (%) 65 110 160 35 140 70 Heat resistance (JIS A) 10 22 8 99 or more 48 Dissolved Wet heat resistance ◯ Dissolved Dissolved ◯ ◯ Dissolved As is apparent from the results shown in Table 1, the polyurethane elastomer compositions obtained in Examples 1 to 6 have characteristics that heat resistance and wet heat resistance of a cured product are excellent, and a viscosity after two-part mixing is low, thereby casting workability is good, and physical properties of a cured product are excellent. Contrary to this, from the results of Table 2, in Comparative Example 1, hardness according to JIS A of a cured product after wet heat resistance test decreases from 30 to 10, and thus heat resistance is poor. In Comparative Example 2, viscosity after mixing is high, and casting workability is poor. Further, wet heat resistance deteriorates. In Comparative Example 3, wet heat resistance is poor. In Comparative Example 4, hardness of a cured product is high, and elongation at break is decreased. In Comparative Example 5, viscosity after mixing is high, and casting workability is poor. In Comparative Example 6, heat resistance and wet heat resistance are poor. INDUSTRIAL APPLICABILITY The two-part curing high-durable polyurethane elastomer composition of the invention has low viscosity after two-part mixing. Therefore, when the composition is executed with a trowel, a spatula, a roller or the like, inclusion of bubbles does not involve, and even when casting in a mold, inclusion of bubbles does not involve. As a result, fine spaces can be filled with the composition. Further, a cured product of the composition has low hardness and large elongation at break. As a result, the cured product has excellent physical properties. Further, a high-durable polyurethane elastomer composition having excellent heat resistance and wet heat resistance is provided, and industrial applicability is extremely high.

<SOH> BACKGROUND ART <EOH>A two-part curing polyurethane elastomer composition has excellent physical properties of a cured product, such as strength, elongation, elastic modulus and the like, and therefore is widely used in applications such as a water-proof material, a floor material, a pavement material, an adhesive, a sealing material and the like. The two-part curing polyurethane elastomer composition is cured by stirring and mixing a curing agent comprising an active hydrogen-containing compound as a main component and a base resin comprising a polyisocyanate component as a main component, and executing with a trowel, a spatula, a roller or the like, or casting in a mold. Therefore, where the viscosity after two-part mixing is high, bubbles are liable to be included when executing with a trowel, a spatula, a roller or the like, resulting in deterioration of appearance and performance. Further, where casting in a mold, inclusion of bubbles is large, and casting workability deteriorates such that fine spaces cannot be filled with a composition. Conventionally, a production method of a two-part curing polyurethane elastomer composition comprising an active hydrogen-containing compound and a polyisocyanate component is generally a prepolymer method using an isocyanate-terminated urethane polymer obtained by reacting an organic polyisocyanate and a polyol with an equivalent ratio of an isocyanate group to an active hydrogen group being 2.0 or less. Other methods are a semi-one shot method using a partial prepolymer obtained by reacting an organic polyisocyanate as a polyisocyanate component and a polyol with an equivalent ratio of an isocyanate group to an active hydrogen group exceeding 2.0, and a one shot method using an organic polyisocyanate alone. Examples of the active hydrogen-containing compound to be reacted with the polyisocyanate component include a polyether polyol such as a polytetramethylene ether glycol obtained by ring opening polymerization of tetrahydrofuran, and a polyoxyalkylene polyol obtained by addition polymerizing at least one of alkylene oxides such as ethylene oxide, propylene oxide and butylene oxide, with a polyhydric alcohol such as propylene glycol, dipropylene glycol, glycerin and trimethylol propane; a polyester polyol obtained by condensation polymerization of at least one polyhydric alcohol such as ethylene glycol, propylene glycol, diethylene glycol, butanediol, pentanediol and hexanediol, and at least one of malonic acid, maleic acid, succinic acid, adipic acid, glutaric acid, sebacic acid, phthalic acid, isophthalic acid, terephthalic acid, and the like; and a polyester polyol obtained by ring opening polymerization of caprolactone or the like. However, where a polyether polyol is used as the active hydrogen-containing compound, a cured product has relatively good wet heat resistance, but has poor heat resistance. On the other hand, where a polyester polyol is used, heat resistance is relatively good, but wet heat resistance is poor. As a method for improving heat resistance and wet heat resistance, it is proposed to use a hydride of a hydroxyl group-containing liquid polyisoprene as the active hydrogen-containing compound (JP-A-63-57626, JP-A-1-203421, JP-A-6-220157, JP-A-7-102033, and the like). However, when the hydride of a hydroxyl group-containing liquid polyisoprene proposed in those patent publications is used, a composition has high viscosity, and when executing with a trowel, a spatula, a roller or the like after two-part mixing, bubbles are liable to be included, resulting in deterioration of appearance and performance. Further, in the case of casting in a mold, there are the disadvantages that inclusion of bubbles is large, and fine spaces cannot be filled with a composition. The prior art information of this invention is as follows; JP-A-63-57626, JP-A-1-203421, JP-A-6-220157 and JP-A-7-102033.

20060609

20091006

20070412

73695.0

C08G1800

SERGENT, RABON A

TWO-PART CURING HIGH-DURABLE POLYURETHANE ELASTOMER COMPOSITION

UNDISCOUNTED

ACCEPTED

C08G

ACCEPTED

Process For The Preparation Of Anhydrous And Hydrated Active Pharmaceutical Ingredients (Apis); Stable Pharmaceutical Compositions Prepared From The Same And Uses Of Said Compositions

This invention describes a process for the production of ANHYDROUS active pharmaceutical ingredients (APIs); a process for the preparation of HYDRATED active pharmaceutical ingredients, a process for the preparation of sterile and stable injectable solutions, and their use, more specifically, APIs which are taxane derivatives, especially (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I); 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1, 7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II), and particularly 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate tri-hydrate (III).

1. A process for the preparation of anhydrous active pharmaceutical ingredients (API's), which are taxane derivatives, solubilizing a hydrated taxane derivative in a solvent that is chemically inert and forms an azeotrope with water, removing the water of hydration by azeotropic distillation at a temperature between −20 and 200° C. and at a pressure between <0.001 and 780 mm Hg, resulting in the anhydrous compound with an amount of water less than 1.0% w/w. 2. The process according to claim 1 in which anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) is obtained as a product. 3. (canceled) 4. The process according to claim 2, in which the solvent used in step a) is a mixture of solvents. 5. The process according to claim 4 in which the solvent employed is an alcohol, an organic acid, a halogenated solvent, an aromatic solvent or other solvent, of sufficient polarity, to effect the solubilization of the hydrated product. 6. The process according to claim 5 in which the solvent employed is a linear or branched chain alcohol. 7. The process according to claim 3 in which in steps a) and b) the (2R,3S) 4-acetoxy-2-αbenzoyloxy-5β-20-epoxy-1,7-β-10-R-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) is hydrated with between 1 to 20% water and the solvents employed are absolute ethanol and toluene in a relative proportion close to 1:9, at a temperature between 10 and 70° C. and at a pressure between 10 and 100 mm Hg. 8. A process for the preparation of anhydrous (2R,3S)4acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate (I) reacting di-tertbutyl-dicarbonate (>99% purity) and N-desacetyl-N-debenzoyl paclitaxel (>98% purity), in equimolar quantities, employing an anhydrous solvent, and directly isolating in a pure and anhydrous form, (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate (I). 9. The process according to claim 8 in which the anhydrous solvent employed to an aliphatic or cyclic ether. 10. The process according to claim 9 the solvent employed is anhydrous tetrahydrofuran. 11. A process for the preparation of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate (I) comprising purifying impure (2R,3S)4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) by chromatography. 12. The process according to claim 11 in which the chromatographic technique employed is normal or reverse phase. 13. The process according to claim 11 the chromatography is conducted using gradient elution with a solvent or a mixture of solvents. 14. The process according to claim 11 in which a mixture of alkane and ester solvents is used, and that the stationary phase employed is either SiO2 or Al2O3. 15. The process according to claim 14 in which the mixture of solvents used consists of ethyl acetate and hexane in a proportion close to 20:80, changing gradually to a proportion of 80:20 and the stationary phase employed is either SiO2 or A12O3. 16. The process according to claim 12 or 13 in which the mixture of solvents employed is a mixture of methanol or acetonitrile and water or an aqueous buffer solution in the proportion close to 85:15, gradually changing to a proportion close to 75:25 and the stationary phase employed is a chemically modified silica gel. 17. A process for the preparation of the stable hydrates of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (III), comprising solubilizing (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2hydroxy-3-phenylpropionate (I) in a solvent selected from the group consisting of a polar aprotic solvent, a cyclic ether and a polyethoxylated sorbitol and mixing the solution thus obtained with water or a mixture of water and a co-solvent, to induce crystallization, and isolating washing and drying the crystals of (2R,3S) 4-acetoxy-2α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.3 H2O (III). 18. The process, according to claim 17 in which the polar aprotic solvent employed is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, the cyclic ether is dioxane or tetrahydrofuran, and the polyethoxylated sorbitol employed is polysorbate 80. 19. The process, according to claim 17 in which the solvent employed to solubilize the (2R,3S)4acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) is capable of solubilizing, or is miscible with, between 3 and 200,000 molar equivalents of water. 20. The process, according to claim 17 in which the solvent used to solubilize the (2R,3S) 4acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate (I) is polysorbate 80 and the water for inducing crystalization is mixed with an alcohol containing between 1 and 8 carbons as a co-solvent. 21. The process, according to claim 20 in which the solvent employed is polysorbate 80, and the water for inducing crystallization is mixed with ethanol as a co-solvent 22. The process, according to claim 20 in which the solvent employed is polysorbate 80, and the water crystalization is mixed with n-butanol as a co-solvent. 23. The process, according to claim 17 characterized by the fact that the quantity of water employed is approximately 2,000 molar equivalents relative to the quantity of the (2R,3S) 4acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3 tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate (I). 24. The process, according to claim 23 in which the quantity of alcohol employed as a co-solvent is approximately 60 molar equivalents relative to the quantity of the (2R,3S) 4acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3 tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate (I). 25. The process, according to any one of claims 17 to 24 in which the final concentration of the (2R,3S) 4-acetoxy-2-α-benzoyloxy-50-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I), in polysorbate 80 is in the range of 0.025 to 0.067 mg/mL, before admixture with water or water and co-solvent. 26. The process, according to claim 17 in which the product (III) obtained is dried over a dessicant at ambient temperature. 27. A process, according to claim 17 in which the product (III) obtained is dried over P2O5 at ambient temperature. 28. A process, for the preparation of concentrated, sterile solutions of active pharmaceutical ingredients (API's), which are taxane derivatives, comprising adding to said API a solvent or mixture of solvents of sufficient polarity to effect complete solubilization of the active principle, said solvent being selected from the group consisting of water, ethanol, polyethoxylated sorbitol, lecithin, vegetable oils, and mixtures thereof, and adding a stabilizing agent such as an acid and/or antioxidant, to obtain a solution stable for greater than or equal to 24 months when stored under an inert atmosphere at between 2 and 8° C. 29. The process, according to claim 28 in which the API is anhydrous (2R,3S) 4acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I). 30. The process, according to claim 28 in which the API is (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.3 H2O (III). 31. The process, according to claim 28 in which the API is 4-acetoxy-2-α-benzoyloxy-5-αβ-20-epoxy- 1,7-β-10-β-tri-hidroxy-9-oxo-tax-11-25-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II). 32. The process, according to claim 28 a polyethoxylated sorbitol is employed as the vehicle. 33. The process, according to claim 32 in which the API is either anhydrous (2R,3S) 4acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-phenylpropionate (I), (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.3 H2O (III), or 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13a-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) and the API is slowly added with agitation under an inert atmosphere to the vehicle, to which has been previously added a stabilizing agent, until complete solubilization of the API is achieved; and the solution thus obtained is filtered through a sterilizing membrane having a porosity less than or equal to 0.45 μm. 34-39. (canceled) 40. The process, according to claim 28 or 37 whereby the solvent employed is polysorbate 80 and the stabilizing agent is either acetic or ascorbic acid, or a combination thereof, added in sufficient quantity such that the pH of the resulting solution is between 3.5 to 4.5. 41. An article of manufacture comprising a pharmaceutical composition comprising one or more anhydrous or hydrated taxane derivatives, which is sterile and is stable for greater than or equal to 24 months when stored under an inert atmosphere at between 2 and 8° C. and filled in sterile, pyrogen free recipients for single or multiple use. 42-44. (canceled) 45. The process, according to claim 33, in which the stabilizing agent is an organic or inorganic acid selected from the group consisting of aspartic acid, acetic acid, citric acid, ascorbic acid, phosphoric acid, pyrophosphoric acid, hypophosphoric acid, hydrochloric acid, sulfuric acid, propionic acid, sorbic acid, erythorbic acid, caprylic acid, gallic acid, gluconic acid, benzoic acid, thiodipropionic acid, sulfurous (H2SO3) acid, a saturated fatty acid and an unsaturated fatty acid. 46. The process according to claim 45 in which a combination of two or more stabilizing agents is employed. 47. The process, according to claim 24 or 33 in which the solvent employed is polysorbate 80 and the stabilizing agent is acetic acid, citric acid, ascorbic acid, or a combination thereof, added in sufficient quantity such that the pH of the resulting solution is between 3.5 to 4.5. 48. A pharmaceutical composition comprising anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-phenylpropionate (I), (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.3 H2O (III), or 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13a-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) and one or more polyethoxylated sorbitol(s). 49. A method for treating a neoplastic tumor that is responsive to treatment with an agent that inhibits the depolymerization of tubulin comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 48.

SCOPE OF THE INVENTION The present invention relates to a process for the preparation of API's, more specifically, taxane derivatives, especially (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) and 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II). One innovative aspect of the present invention refers to a process particularly useful for obtaining anhydrous compounds which form stable hydrates and are thermolabile, which prevents the removal of water by conventional processes such as drying under vacuum at elevated temperatures. Another innovative aspect of the present invention refers to a process for the preparation of hydrated API's, more specifically taxane derivatives, especially the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (III). Yet another innovative aspect of the present invention is with respect to a process for the preparation of injectable solutions, which are sterile and stable, from the API's according to the processes herein described, which are useful in the treatment of disease or infirmity, including, but not limited to, neoplastic tumors and other conditions which respond to treatment with agents that inhibit the depolymerization of tubulin, for example, cancers of the breast, ovaries, lungs and others. The solutions are obtained by way of dissolution of the active principle I, II or III indicated above, in an appropriate biocompatible vehicle, followed by filtration through a membrane having a porosity less than or equal to 0.45 μm; or, dissolution of the active principle I, II or III in an appropriate biocompatible vehicle, previously acidified with an organic or inorganic acid, followed by filtration through a membrane having a porosity less than or equal to 0.45 μm; or, dissolution of the active principle I, II or III in an appropriate biocompatible vehicle, posteriorly acidified, with an organic or inorganic acid followed by filtration through a membrane having a porosity less than or equal to 0.45 μm. Lastly, the invention is also with respect to the stable pharmaceutical compositions thus obtained and the use of these compostions in the treatment of disease or infirmity, including, but not limited to, neoplastic tumors and other conditions which respond to treatment with agents that inhibit the depolymerization of tubulin, for example, cancers of the breast, ovaries, lungs and others. PRIOR ART The active principle (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I), a taxane derivative obtained by chemical semi-synthesis, which presents anti-cancer and anti-leukemic properties. There are various synthetic methods which lead to compound (I) as well as its tri-hydrate (III), for example, those cited in patent PCT—WO 92/09589 issued to Rhone-Poulenc Rorer S.A, U.S. Pat. No. 5,808,113 issued to Hauser Inc., and patent PCT—WO 96/01815, also issued to Rhone-Poulenc Rorer S.A. The above mentioned compounds have demonstrated pharmacological activity against acute leukemia and solid tumors. U.S. Pat. No. 5,504,102 issued to Bristol-Myers Squibb describes a process for the preparation of polyethoxylated castor oil with low alkalinity and the use of this medium for the preparation of solutions containing antineoplastic agents. Additionally, U.S. Pat. No. 5,698,582 issued to Rhone-Poulenc Rorer S.A. describes a process for the preparation of compositions containing taxane derivatives in a surfactant and the utility of these compositions for preparing perfusions. Nonetheless, neither of these patents describe, nor do they suggest specifically, the use of anhydrous active principles in conjunction with polyethoxylated sorbitols which have been previously or posteriorly acidified for the preparation of sterile, injectable solutions, which confers additional stability to the compositions. Brazilian patent application PI 9508789-3A, whose priority is French patent FR 94 08479 issued to Rhone-Poulenc Rorer S.A., describes a process for the preparation of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (III), employing recrystallization from “a mixture of water and an aliphatic alcohol containg between 1 and 3 carbons, followed by drying the product obtained under pre-determined conditions of temperature, pressure and humidity.” This process presents various disadvantages. We call attention to the fact that this process suggests the prior purification of the (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate by chromatography. Another disadvantage of this process resides in the fact that it is recommended that the solvents used in the cromatographic purification be removed by co-distillation with alcohol under reduced pressure which results in a “thick syrup whose agitation is difficult”. Yet another disadvantage of this invention lies in the fact that the process recommends refrigeration of the solution to 0° C. in order to obtain the best results. Lastly, the cited process requires drying under vacuum at elevated temperatures in an atmosphere with controlled humidity, which requires costly and sophisticated equipment. The patent in question also maintains that the tri-hydrate (III) obtained “presents clearly superior stability relative to the anhydrous product”. However, comparative studies realized in our laboratories have demonstrated that, when stored under adequate and controlled conditions, the anhydrous product (I) obtained by the processes claimed herein demonstrates a stability equal or superior to the tri-hydrate and, that under these conditions of storage, the product does not re-hydrate to a significant degree. It has been observed that utilization of the anhydrous product (I), cited above, confers an equal or superior stability to the pharmaceutical finished dosage form, which can be illustrated by stability studies of solutions of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) in polyethoxylated sorbitol which has been previously or posteriorly acidified. Brazilian patent application PI 9508789-3 cites as an example the addition of ascorbic acid in the preparation of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, via recrystallization, which involves a laborious and multi-step process, to confer additional stability to the API. Therefore, patent application PI 9508789-3, cited here as a reference, neither describes nor anticipates in a manner obvious to a person skilled in the art, the process for the preparation of the anhydrous product (I), as claimed in the present invention, which may be obtained directly and with fewer experimental steps. Furthermore, patent application PI 9508789-3 does not anticipate nor suggest in a manner obvious to a person skilled in the art, the additional stability conferred to pharmaceutical formulations by addition of an organic or inorganic acid as claimed in the present invention. On the other hand, U.S. Pat. No. 5,698,582 describes a process for the preparation of solutions containing taxane derivatives in surfactants and the utilization of the same to prepare perfusions. This process requires that the active principle be first dissolved in ethanol, folowed by addition of a surfactant and subsequent removal of the ethanol under vacuum. This process involves several steps and manipulations which makes it complex, laborious and lengthy. The process claimed in the present invention overcomes these disadvantages. DETAILED DESCRIPTION OF THE INVENTION In a first embodiment, the present invention is advantageous with respect to the state of the art in that it is not necessary to recrystallize the active principle (III), with the concommitant reduction in the overall yield of the process. The anhydrous active principle (I) may be obtained directly, in a single production step, resulting in considerable economy and a reduction in the number of steps. In a second embodiment, the present invention also permits that, by use of the process described, (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I), of high purity, may be obtained in the form of an amorphous powder, which greatly facilitates its solubilization in biocompatible excipients. This results in the formation of solutions appropriate to be used directly in the confection of injectable pharmaceutical finished dosage forms without the addition of ethanol or other complementary excipients. In a third embodiment, while the state of the art mentions that the addition of ascorbic acid during the recrystallization of the active principle (III) confers additional stability to it, an innovation particular to the present invention lies in the fact that it is advantageous to add a weak acid during the preparation of pharmaceutical solutions of (I) and (III). This is niether mentioned nor suggested by the state of the art. As such, additional stability may be conferred to the finished dosage forms by addition of a weak acid to the solution. Acids which may be employed include, but are not limited to: ascorbic, phosphoric, acetic, citric or tartaric acid. A fourth embodiment of the present invention lies in the fact that it is not necessary to first solubilize the active principle in ethanol followed by the subsequent removal of the ethanol as described in U.S. Pat. No. 5,698,582. As proposed herein, the compounds (I) and (II) may be solubilized directly in the vehicle utilized in the formulation without the necessity of adding a co-solvent. In a fifth embodiment of the present invention, it is possible to obtain stable, sterile pharmaceutical presentations, absent of pyrogens, of small, medium and large volume, which are appropriate for administration after dilution, or for filling in ampuoles, vials or other suitable recipients which may be transported under adequate conditions for direct use in clinics and hospitals specialized in the treatment of cancer which posess installations for the dilution of cytostatic drugs. The installations for the dilution of cytostatic drugs serve as a means to ensure the individualization of the treatment for the cancer patient and offer an economy in the administration of the prescribed medication. In this context, it is indispensable that sterile, stable and apyrogenic injectectable formulations be available, ready for administration in large volumes, ideally between 50 and 5,000 mL. The solutions thus obtained may also be transported under adequate contions and be filled into smaller recipients at another location. In a sixth embodiment, the present invention also describes a process for the preparation of concentrated solutions of 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate, (II) in polyethoxylated sorbitols. The state of the art utilizes as a vehicle for the formulation of (II) a mixture of polyethoxylated castor oil, for example, Cremophoro® EL or ELP and ethanol. It is well known that Cremophor® is responsible for various adverse reactions which requires premedication with anti-histamines, corticosteroids and/or H2 antagonists). Known commercial formulations also utilize considerable amounts of ethanol, which is responsible on many occasions for ethanol intoxication of the patient due to the large volume of product administered to achieve the desired therapeutic effect. As such, the exclusion of polyethoxylated castor oil and ethanol from the compositions of the present invention presents considerable advantages from the patient point of view, and greatly reduce or eliminate the side-effects associated with these vehicles. The process for the preparation of anhydrous API's according to the present invention, more specifically taxane derivatives, and especially (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) and 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) may be realized according to various procedures as will become evident. In a seventh embodiment of the present invention, an hydrated sample of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) is solubilized in a chemically inert solvent which forms an azeotrope with water. This solvent may be a linear or branched alcohol, an organic acid, a halogenated solvent, an aromatic solvent or another solvent of sufficient polarity capable of solubilizing the hydrated product. Preferably the solvent employed in the present invention is a short chain linear or branched alcohol. The solution thus obtained is subjected to azeotropic distillation at a temperature between −20 and 200° C., and at a pressure between 1 and 800 mm Hg to remove the water of hydration. In the case of hydrated (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, the temperature is, preferably, below 40° C. In an eighth embodiment of the present invention, the hydrated (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate may also be solubilized in a combination of two or more of the aforementioned solvents. For example, these solvents may be a combination of a linear or branched alcohol, an organic acid, a halogenated solvent, an aromatic solvent or another solvent of sufficient polarity capable of solubilizing the hydrated product and capable of forming a binary, ternary or quarternary azeotrope with water. In the case of hydrated (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, the proportion between the first and second solvent is on the order of between 1:2 to 1:90. Afterwards, the azeotropic distillation may be carried out at a pressure between <0.001 and 780 mmHg. In the case of hydrated (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, the pressure is preferentially between 0.1-100 mm Hg. In a ninth embodiment of the present invention, impure (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) may be subjected to normal or reverse phase chromatography, employing a solvent or mixture of solvents among those routinely employed in the technique. In the case of impure (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I), the stationary phase may be silica gel, alumina or cellulose, or chemically modified versions thereof, including but not limited to RP-C18, RP-C8, RP-pentafluorophenyl or RP-phenyl. The stationary phase employed is preferencially silica gel or RP-pentafluorophenyl. In the case of normal phase chromatography, the solvents employed are esters, alcohols, alkanes, alkenes, alkynes, ethers, halogenated solvents, nitrites or mixtures thereof. It is understood that the technique of gradient elution may also be employed. In the present case concerning taxane derivatives, the solvents employed are preferentially mixtures of alkanes and esters. In the case of reverse phase chromatography, the solvents employed are esters, alcohols, alkanes, alkenes, alkynes, ethers, halogenated solvents, nitriles, water, aqueous buffer solutions or mixtures thereof. It is understood that the technique of gradient elution may also be employed. In the present case concerning taxane derivatives, the solvents employed are preferentially mixtures of nitrites or a short chain linear alcohol and water in an acidic buffer. After removal of the solvents, the anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate obtained may be used directly or submitted to one of the aforementioned processes for further purification and/or removal of water of hydration. In a tenth embodiment of the present invention, a process for the formation of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is described employing an anhydrous solvent, under controlled conditions, utilizing one or more of the processes cited in the state of the art, with reagents and raw materials of sufficient purity so as to lead directly to the formation of pure, anhydrous (I), after removal of the solvents. In the case of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I), it is paricularly advantageous to conduct the reaction in anhydrous tetrahydrofuran or anhydrous dioxane employing equimolar amounts of N-debenzoyl-10-desacetoxy paclitaxel >98 purity and di-tertbutyl-dicarbonate of >99% purity. Removal of the solvent and drying under vacuum affords directly anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 98% yield. In an eleventh embodiment of the present invention, we describe a process for the preparation of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (III), which may be realized via a simple and efficient technique. To begin, (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino2-hydroxy-3-phenylpropionate (I) is solubilized in a solvent which is chemically inert. This solvent may be a linear or branched alcohol containing between 1 and 8 carbons, an organic acid, an aliphatic or cyclic ether, a polar, aprotic solvent, a halogentated solvent, an aromatic solvent, a polyethoxylated sorbitol, lecithin or castor oil, or another solvent of adequate polarity to effect the complete solubilization of (I) and is capable of solubilizing, or is miscible with, at least 3 molar equivalents of water. The solution so obtained is admixed with an amount of distilled water between 3 and 200,000 molar equivalents relative to (I). Crystallization is induced and the tri-hydrate (III) is isolated by means of conventional processes such as filtration, decantation or centrifugation. As such, the steps necessary to realize the process according to the present invention are as follow: a) (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (I) is solubilized in polyethoxylated sorbitol at a temperature between 1 and 60° C. with agitation. The quantity of polyethoxylated sorbitol employed is on the order of between 15 to 40 mL per gram of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. The polyethoxylated sorbitol employed is, preferably, but not exclusively, polysorbate 80. b) The solution thus obtained is added to a quantity of distilled water and a co-solvent at ambient temperature to form a homogeneous mixture. The co-solvent employed is a linear alcohol containing between 1 and 8 carbons. The proportion of distilled water:alcohol is in the range of between 30 mL:1 mL to 300 mL:50 mL relative to each gram of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate present in the solution obtained in step a). c) The mixture obtained is left to stand at room temperature during 48-240 h to permit the formation of crystals of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (III). d) The crystals thus obtained are isolated by known techniques and washed with distilled water to remove vestiges of the solvents employed. Among the known techniques which can be used are filtration, decantation and centrifugation. e) The crystals are then dried at ambient temperature in a dessicator over a dessicant, such as P2O5, concentrated H2SO4, NaOH, Na2SO4 MgSO4 or CaCl2, until reaching constant weight. In relation to the state of the art, the present invention posesses diverse advantages which will be evident to persons skilled in the art, among which we may cite as most relevant, but not limited to: a) the present invention avoids previous purification of the (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate by chromatography, the same being commercially available; b) the process does not involve evaporation of solvents and avoids working at pressures below atmospheric; c) the process does not result in the formation of a “thick syrup, whose stirring is difficult”, which greatly facilitates the manipulation and handling of the solutions and simplifies the types of equipment required; d) All of the steps of the process can be conducted at ambient temperatures, contrary to the state of the art which requires heating and refrigeration; e) the process does not require vacuum drying niether control of humidity nor temperature during the drying operation. In a twelfth embodiment of the present invention, there is also described the preparation of sterile, stable solutions of anhydrous or tri-hydrated, (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, (I) or (III), and also, 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II), in a biocompatible vehicle. Appropriate vehicles include, but are not limited to, polyethoxylated sorbitols, and, preferentially polysorbate 80. The solutions are prepared by the slow addition of anhydrous or tri-hydrated (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, (I) or (III), or, 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) to the vehicle with agitation, preferably, in an inert atmosphere, at a concentration between 1 and 100 mg of active ingredient on an anhydrous basis per mL polysorbate 80. As an illustrative point, schematic figures of the present invention are presented in which: FIG. 1- refers to a schematic representation of the filtration process, as constituted in “Scheme 1”; FIG. 2- refers to a schematic representation of the dissolution and filtration process as constituted in “Scheme 2”. With respect to the elements depicted in FIG. 1, number (1) represents a sterilizing membrane employed in the filtration with a porosity of 0.22 μm. The pressurized vessel is represented by number (2) and the receipient for the sterilized filtrate is represented by number (3). N2 represents the pressure inlet for an inert gas such as nitrogen. The combination of these elements constitues “Scheme 1”. With respect to FIG. 2, the following elements are depicted: reactor (4), temperature control (5), control for agitation (6), sterilizing filtration membrane (7), and the receipient for the sterilized filtrate (8). N2 represents the pressure inlet for an inert gas such as nitrogen. The combination of these elements constitues “Scheme 2”. According to scheme 1, FIG. 1, after complete solubilization of the active principle, the solution is transferred to a pressure vessel (2), filtered through the sterilizing membrane with a porosity of less than 0.45 μm, preferably 0.22 μm and filled into pyrogen free, sterile recipient(s) (3) in a sterile environment. The products thus obtained are stable for at least 18 months when stored between 2-8° C. The preparation of sterile, stable solutions of anhydrous or tri-hydrated (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, (I) or (III), and also, 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II), in a biocompatible vehicle, may also be conducted in an alternative manner. Appropriate vehicles include, but are not limited to, polyethoxylated sorbitols, and, preferably, polysorbate 80. The solution is prepared directly in a stainless steel reactor (4), as shown in FIG. 2, by way of slow addition of the active principle (I), (II) or (III) to the vehicle with internal agitation, preferably under an inert atmosphere, at a concentration between 1 and 100 mg of active principle (on an anhydrous basis)/mL polysorbate 80. According to scheme 2 after complete solubilization of the active principle, the solution is filtered directly through the sterilizing membrane (7) with a porosity of less than 0.45 μm, preferably 0.22 μm and collected in a sterile recipient (8) in a sterile environment. The solution thus obtained may be filled into pyrogen free, sterile vials, ampuoles or other suitable recipient. The products thus obtained are stable for at least 18 months when stored between 2-8° C. In a thirteenth embodiment of the present invention, the aforementioned vehicles may be previously or posteriorly acidified. It is advantageous to acidify the polysorbate 80 prior to the addition of the active principle with an organic, inorganic or mixture of acids, chemically compatible with the vehicle and active principle (I, II or III), including, but not limited to, phosphoric, acetic, citric, tartaric or ascorbic acids. It is also advantageous to acidify the solution of the active principle in polysorbate 80 after the complete dissolution of the active principle (I), (II) or (III) with an organic, inorganic or mixture of acids, chemically compatible with the vehicle and active principle (I, II or III), including, but not limited to, phosphoric, acetic, citric, tartaric or ascorbic acids. The solutions thus obtained are more stable than solutions which are not acidified. For the purpose of the present invention, the preferable acids to be employed are acetic or ascorbic. The pH may be adjusted between 3.0-6.5, preferably, between 3.5 and 4.5. Solutions prepared in this manner are stable for at least 24 months when stored between 2 and 8° C. (Tables 1 and 2). TABLE 1 Comparative stability study of solutions of the tri-hydrate and anhydrous forms of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β- 20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3- tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in polysorbate 80 with and without the addition of acid A % A % Docetaxel A % Docetaxel Docetaxel A % (anhydrous) (anhydrous) Time (tri- Docetaxel with acetic with ascorbic (months) hydrate) (anhydrous) acid acid 0 100.10 99.87 100.04 99.98 3 100.07 99.72 99.89 99.72 6 99.23 99.02 99.03 99.34 12 97.41 97.21 98.98 98.79 18 96.23 96.09 98.13 98.02 24 94.14 90.09 97.67 97.48 Note 1: All solutions were prepared at a concentration of 40 mg/mL, on an anhydrous basis, followed by filtration through a sterilizing mambrane. Note 2: The acidified solutions were prepared from polysorbate 80 whose pH had been previously adjusted to between 3.5 and 4.5 by addition of the respective acids. Note 3: Samples were stored between 2 and 8° C. Note 4: Assay of docetaxel was performed by HPLC. TABLE 2 Comparative stability study of 4-acetoxy-2-α-benzoyloxy-5-β- 20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) in Cremophor EL and polysorbate 80 with and without addition of ascorbic acid A % Paclitaxel A % Paclitaxel Anhydrous Anhydrous Time A % Paclitaxel (polysorbate (polysorbate 80 (months) (Cremophor EL) 80) W/ascorbic acid) 0 100.08 100.55 100.30 3 99.46 100.10 100.20 6 99.04 99.81 99.99 12 96.46 97.02 97.90 18 92.10 93.05 97.01 24 85.16 89.84 94.97 Note 1: All solutions were prepared at a concentration of 6 mg/mL on an anhydrous basis, followed by filtration through a sterilizing membrane. Note 2: The acidified solutions were prepared from polysorbate 80 whose pH had been previously adjusted to between 3.5 and 4.5 by addition of the respective acids. Note 3: Samples were stored between 2 and 8° C. Note 4: Assay of paclitaxel was performed by HPLC In a fourteenth and final embodiment of the present invention, the solutions obtained by the processes heretofore described are useful in the treatment of disease or infirmity, including, but not limited to, neoplastic tumors and other conditions which respond to treatment with agents that inhibit the depolymerization of tubulin, for example, cancers of the breast, ovaries, lungs and others. EXAMPLE 1 Process for the Removal of Water of Hydration by Way of Azeotropic Distillation Under Vacuum A 1.00 g [1.16 mMol] sample of hydrated (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (6.27% water) was solubilized in 50 mL of reagent grade ethanol. The solution which was obtained was distilled under vacuum to remove the ethanol. The amorphous powder obtained was dried between 30 and 60° C. to constant weight, yielding 0.93 g of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate containing 0.10% water by KF titration. EXAMPLE 2 Process for the Removal of Water of Hydration by Way of Binary Azeotropic Distillation Under Vacuum A 1.00 g [1.16 mMol] sample of hydrated (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (6.27% water) was solubilized in 20 mL of ethanol. This was followed by the addition of 180 mL of toluene. The solution thus obtained was distilled under vacuum (20 mm Hg/40° C.) to remove, firstly the ethanol. The azeotrope formed between toluene and water was then distilled at 1 mm Hg/28° C. Finally, the remainder of the toluene was removed and the amorphous powder obtained was dried at a temperature around 50° C. until constant weight, yielding 0.92 g of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate ester containing 0.12% water by KF titration. EXAMPLE 3 Process for the Preparation of Anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate by Way of Purification of Impure (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate Using Column Chromatography A 1.00 g sample of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, with a chromatographic purity of 97.7% (1.1% H2O), prepared according to the method of Murray et. al., was solubilized in 2 mL of dichloromethane. The solution obtained was applied to a column of silica gel 60 previously activated at 150° C. and eluted with a gradient of hexane:EtOAc varying from 80:20 to 20:80. The fractions containing pure (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate were collected and pooled and the solvent removed on a rotary film evaporator at a temperature between 35 and 75° C. at a pressure between 10 and 40 mm Hg. After drying, there were obtained 0.85 g of with a chromatographic purity of 99.34% and a water content of 1.2%. EXAMPLE 4 Process for the Preparation of Anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate Using an Anhydrous Solvent as the Reaction Medium. (This Synthesis was Realized Utilizing a Variation of the Methodology Described by Murray et. al.). Under an atmosphere of nitrogen, a round bottom flask was charged with 500 mL THF, previously distilled over sodium. 10 g [14.14 mMol] of 10-desacetyl-N-debenzoyl-paclitaxel (>99% chromatographic purity, <0.1% water by KF) was added in one portion. This was followed by the addition of 3.08 g [14.14 mMol] of di-tert-butyl-dicarbonate (Aldrich >99%). The reaction was monitored by TLC and, after complete consumption of the starting materials, the solvent was removed under vacuum. After drying the product under vacuum, 11.42 g (100%) of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate was isolated with a chromatographic purity of 99.28% (HPLC) and a water content of 0.08% (KF). EXAMPLE 5 Preparation of the Tri-Hydrate (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate Employing Polysorbate 80, Ethanol and Water as Solvents. A 4.00 g sample of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (0.78% water, 98.8% chromatographic purity) was solubilized in 100 mL of polysorbate 80 with mechanical agitation. The solution thus obtained was added to a mixture containing 180 mL distilled water and 20 mL of absolute ethanol. The clear solution obtained was left at rest at ambient temperature. After two days, crystals (needles) began to form. After five days, the crystals that had formed were filtered, washed with distilled water, and dried between 20 and 30° C. in a dessicator over P2O5 until contant weight was obtained, yielding 3.97 g of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (III) (6.29% water by KF titration; the IR spectrum was identical to that of an authentic sample). EXAMPLE 6 Preparation of the Tri-Hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate Employing Polysorbate 80, n-butanol and Water as Solvents. A 4.00 g sample of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (0.78% water, 98.8% chromatographic purity) was solubilized in 100 mL of Polysorbate 80 with mechanical agitation. The solution thus obtained was added to a mixture containing 160 mL distilled water and 30 mL of n-propanol. The clear solution obtained was left at rest at ambient temperature. After two days, crystals (needles) began to form. After five days, the crystals that had formed were filtered, washed with distilled water, and dried between 20 and 30° C. in a dessicator over P2O5 until contant weight was obtained, yielding 3.67 g of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (III) (6.24% water by KF titration; the IR spectrum was identical to that of an authentic sample) EXAMPLE 7 Preparation of the Tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate Using the Washings of Production Equipment Used in the Manufacture of Sterile Injectable Solutions of (I) in Polysorbate 80. To the sterilizing filtration system, consisting of a stainless steel, pressurized reactor, silicone rubber hoses and sterilizing filtration capsule with a porosity of 0.22 μm, and containg approximately 1.50 g of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 36 mL of polysorbate 80, was added one liter of isopropanol. The resulting solution was collected and the alcohol removed under reduced pressure (20 mm Hg) at 40° C. The resulting solution was added to a mixture of 90 mL distilled water and 10 mL of ethanol with agitation. The clear solution which was obtained was left at rest at ambient temperature. After 2 days, crystals (needles) began to form. After 5 days, the crystals which had formed were filtered, washed with distilled water, and dried between 20 and 30° C. in a dessicator over P2O5 until constant weight, yielding 1.21 g of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (6.21% water by KF titration; the IR spectrum was identical to that of an authentic sample). EXAMPLE 8 Process for the Preparation of a Stable and Sterile Solution of Anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate Ester in Polysorbate 80 (with Compressed Air Agitation) In a beaker equipped with a helical compressed air agitator, under an atmosphere of N2 was added 100 mL of polysorbate 60. This was followed by the slow addition of 4.00 g of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was transferred to a pressurized vessel and filtered through a 0.22 μm sterilizing membrane, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 18 months when stored at temperatures between 2 and 8° C. EXAMPLE 9 Process for the Preparation of a Stable and Sterile Solution of Anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in Polysorbate 80 (Using a Stainless Steel Reactor) In a stainless steel reactor equipped with an internal agitation system, under an atmosphere of N2 was added 100 mL of polysorbate 80. This was followed by the slow addition of 4.00 g of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was filtered through a 0.22 μm sterilizing membrane coupled to the reactor, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 18 months when stored at temperatures between 2 and 8° C. EXAMPLE 10 Process for the Preparation of a Stable and Sterile Solution of Anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in Previously Acidified Polysorbate 80 (with Compressed Air Agitation) In a beaker equipped with a helical compressed air agitator, under an atmosphere of N2 was added 100 mL of polysorbate 80 which had been previous acidified with ascorbic acid to a pH of 3.9. This was followed by the slow addition of 4.00 g of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was transferred to a pressurized vessel and filtered through a 0.22 μm sterilizing membrane, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 24 months when stored at temperatures between 2 and 8° C. EXAMPLE 11 Process for the Preparation of a Stable and Sterile Solution of Anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in Previously Acidified Polysorbate 80 (Using a Stainless Steel Reactor) In a stainless steel reactor equipped with an internal agitation system, under an atmosphere of N2 was added 100 mL of polysorbate 80 which had been previous acidified with ascorbic acid to a pH of 3.9. This was followed by the slow addition of 4.00 g of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was filtered through a 0.22 μm sterilizing membrane coupled to the reactor, in a sterile environment under pressure , and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 24 months when stored at temperatures between 2 and 8° C. EXAMPLE 12 Process for the Preparation of a Stable and Sterile Solution of Anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in Posteriorly Acidified Polysorbate 80 (with Compressed Air Agitation) In a beaker equipped with a helical compressed air agitator, under an atmosphere of N2 was added 100 mL of polysorbate 80. This was followed by the slow addition of 4.00 g of anhydrous (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was then acidified with ascorbic acid to a pH of 4.0. The resulting solution was transferred to a pressurized vessel and filtered through a 0.22 μm sterilizing membrane, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 24 months when stored at temperatures between 2 and 8° C. EXAMPLE 13 Process for the Preparation of a Stable and Sterile Solution of the Tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in Previously Acidified Polysorbate 80 (with Compressed Air Agitation) In a beaker equipped with a helical compressed air agitator, under an atmosphere of N2 was added 100 mL of polysorbate 80 which had been previous acidified with ascorbic acid to a pH of 4.0. This was followed by the slow addition of 4.27 g of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was transferred to a pressurized vessel and filtered through a 0.22 μm sterilizing membrane, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 24 months when stored at temperatures between 2 and 8° C. EXAMPLE 14 Process for the Preparation of a Stable and Sterile Solution of the Tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in Previously Acidified Polysorbate 80 (Using a Stainless Steel Reactor) In a stainless steel reactor equipped with an internal agitation system, under an atmosphere of N2 was added 100 mL of polysorbate 80 which had been previous acidified with ascorbic acid to a pH of 3.9. This was followed by the slow addition of 4.27 g of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was filtered through a 0.22 μm sterilizing membrane coupled to the reactor, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 24 months when stored at temperatures between 2 and 8° C. EXAMPLE 15 Process for the Preparation of a Stable and Sterile Solution of the Tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in Posteriorly Acidified Polysorbate 80 (with Compressed Air Agitation) In a beaker equipped with a helical compressed air agitator, under an atmosphere of N2 was added 100 mL of polysorbate 80. This was followed by the slow addition of 4.27 g of the tri-hydrate of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was then acidified with ascorbic acid to a pH of 4.0 The resulting solution was transferred to a pressurized vessel and filtered through a 0.22 μm sterilizing membrane, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 24 months when stored at temperatures between 2 and 8° C. EXAMPLE 16 Process for the Preparation of a Stable and Sterile Solution of 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) in Polysorbate 80 (with Compressed Air Agitation) In a beaker equipped with a helical compressed air agitator, under an atmosphere of N2 was added 100 mL of polysorbate 80. This was followed by the slow addition of 0.6 g anhydrous 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II). Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was transferred to a pressurized vessel and filtered through a 0.22 μm sterilizing membrane, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 18 months when stored at temperatures between 2 and 8° C. EXAMPLE 17 Process for the Preparation of a Stable and Sterile Solution of 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) in Polysorbate 80 (Using a Stainless Steel Reactor) In a stainless steel reactor equipped with an internal agitation system, under an atmosphere of N2 was added 100 mL of polysorbate 80. This was followed by the slow addition of 0.6 g of anhydrous 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was filtered through a 0.22 μm sterilizing membrane coupled to the reactor, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 18 months when stored at temperatures between 2 and 8° C. EXAMPLE 18 Process for the Preparation of a Stable and Sterile Solution of 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7p-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) in Previously Acidified Polysorbate 80 (with Compressed Air Agitation) In a beaker equipped with a helical compressed air agitator, under an atmosphere of N2 was added 100 mL of polysorbate 80 which had been previous acidified with ascorbic acid to a pH between 3.5 and 4.5. This was followed by the slow addition of 0.60 g of 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was transferred to a pressurized vessel and filtered through a 0.22 μm sterilizing membrane, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 24 months when stored at temperatures between 2 and 8° C. EXAMPLE 19 Process for the Preparation of a Stable and Sterile Solution of 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) in Previously Acidified Polysorbate 80 (Using a Stainless Steel Reactor) In a stainless steel reactor equipped with an internal agitation system, under an atmosphere of N2 was added 100 mL of polysorbate 80 which had been previous acidified with ascorbic acid to a pH between 3.5 and 4.5. This was followed by the slow addition of 0.60 g of 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was filtered through a 0.22 μm sterilizing membrane coupled to the reactor, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 24 months when stored at temperatures between 2 and 8° C. EXAMPLE 20 Process for the Preparation of a Stable and Sterile Solution of 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate (II) in posteriorly acidified polysorbate 80 (with compressed air agitation) In a beaker equipped with a helical compressed air agitator, under an atmosphere of N2 was added 100 mL of polysorbate 80. This was followed by the slow addition of 0.60 g of 4-acetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,7β-10-β-tri-hidroxy-9-oxo-tax-11-en-13α-il (2R,3S) 3-benzoylamino-2-hydroxy-3-phenylpropionate. Agitation was maintained until complete solubilization of the active ingredient. The resulting solution was acidified with ascorbic acid to a pH between 3.5 and 4.5 and then transferred to a pressurized vessel and filtered through a 0.22 μm sterilizing membrane, in a sterile environment under pressure, and then filled in vials using customary procedures. The solution thus obtained was shown to be stable for 24 months when stored at temperatures between 2 and 8° C. EXAMPLE 21 Comparative Stability Study Between the Tri-hydrate and Anhydrous Forms of (2R,3S) 4-acetoxy-2-α-benzoyloxy-5β-20-epoxy-1,7-β-10-β-tri-hydroxy-9-oxo-tax-11-en-13α-il 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate A % Docetaxel A % A % Time (tri- A % Impurities Assay Docetaxel Impurities Assay (months) hydrate)1 (unknown) H2O2 (anhydrous)3 (unknown) H2O 0 99.51 0.49 6.32 99.28 0.72 0.10 3 99.23 0.77 6.35 99.21 0.79 0.11 6 99.30 0.70 6.21 99.26 0.73 0.12 12 98.91 1.09 6.42 98.93 1.07 0.09 18 98.72 1.28 6.31 98.65 1.35 0.12 24 98.21 1.79 6.29 98.29 1.71 0.13 Experimental data obtained in the laboratories of Quiral Química do Brasil S/A 1Prepared in the laboratories of Quiral Química do Brasil S/A. 2Water determined by Karl Fischer titration. 3Prepared according to EXAMPLE 2 Analysis was realized by HPLC using a Waters Spherisorb® C-18, 250×5 mm column, mobile phase MeOH: H2O 85:15, flow 1.5 mL/min. Related impurities reported as A % discounting the peak due to the dead volume. Samples were stored in amber glass vials under N2 in a dessicator over P2O5 maintained between =5 and 0° C. The examples given in the present patent application are for illustrative purposes only and should not be construed as limiting the scope of the invention. Variations of the heretofore described processes which produce similar results will be apparent to persons skilled in the art.

20070815

20101123

20080228

91976.0

A61K31337

MERCIER, MELISSA S

A PROCESS FOR THE PREPARATION OF CONCENTRATED, STERILE INJECTABLE SOLUTIONS CONTAINING DOCETAXEL

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Process for the synthesis of (2s, 3as, 7as)-1-[(s)-alanyl]-octahydro-1h-indole-2-carboxylic acid compounds and application in the synthesis of perindopril

Process for the synthesis of compounds of formula (I): wherein R represents a hydrogen atom or a protecting group for the amino function. Application in the synthesis of perindopril and pharmaceutically acceptable salts thereof.

1-6. (canceled) 7. A process for the synthesis of compounds of formula (I) wherein R represents a hydrogen atom or a protecting group for the amino function, wherein a benzyl ester of formula (IIIa) or (IIIb) or an addition salt of the ester of formula (IIIa) or (IIIb) with a mineral acid or organic acid, is reacted with an alanine compound of formula (IV): wherein R′ represents a protecting group for the amino function, in the presence of a coupling agent selected from: (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/1-hydroxybenzotriazole, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/1-hydroxy-7-azabenzotriazole, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/N-hydroxysuccinimide, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/N-hydroxyphthalimide, dicyclohexylcarbodiimide/1-hydroxy-7-azabenzotriazole, dicyclohexylcarbodiimide/N-hydroxysuccinimide, dicyclohexylcarbodiimide/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, dicyclohexylcarbodiimide/N-hydroxyphthalimide, O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate, O-(benzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)uronium hexafluorophosphate, chloro-tripyrrolidinophosphonium hexafluorophosphate, chloro-1,1,3,3-bis(tetramethylene)formamidinium hexafluorophosphate, chloro-1,1,3,3-bis(pentamethylene)formamidinium hexafluorophosphate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, O-[(ethoxycarbonyl)-cyanomethyleneamino]-1,1,3,3-tetramethyluronium tetrafluoroborate, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/N -methylmorpholine, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/collidine, O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate, O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole, O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate, O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate/1-hydroxy-benzotriazole, O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate, O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uronium tetrafluoroborate, O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uronium tetrafluoroborate/1-hydroxybenzotriazole, O-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate, propanephosphonic anhydride, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, and N-hydroxy-1,2-dihydro-2-oxo-pyridine, optionally in the presence of a base, to yield a compound of formula (Va) or (Vb), respectively, depending on whether the compound of formula (IIIa) or (IIIb) is used as starting material: which is subjected to a catalytic hydrogenation reaction in the presence of palladium to yield the product of formula (I). 8. The process of claim 7, wherein the compound of formula (IIIa) is used as starting material. 9. The process of claim 7, wherein the compound of formula (IIIb) is used as starting material. 10. The process of claim 8, wherein the hydrogenation reaction on the compound of formula (Va) is carried out under a hydrogen pressure of less than 10 bars. 11. The process of claim 9, wherein the hydrogenation reaction on the compound of formula (Vb) is carried out under a hydrogen pressure of from 10 to 35 bars. 12. A process for the synthesis of perindopril or pharmaceutically acceptable salts thereof starting from a compound of formula (I), wherein the compound of formula (I) is obtained by the synthesis process according to claim 7.

The present invention relates to a process for the synthesis of compounds of formula (I): wherein R represents a hydrogen atom or a protecting group for the amino function, and to their application in the synthesis of perindopril of formula (II): and pharmaceutically acceptable salts thereof. Perindopril and its pharmaceutically acceptable salts, and more especially its tert-butylamine salt, have valuable pharmacological properties. Their principal property is that of inhibiting angiotensin I converting enzyme (or kininase II), which allows, on the one hand, prevention of the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the other hand, prevention of the degradation of bradykinin (a vasodilator) to an inactive peptide. Those two actions contribute to the beneficial effects of perindopril in cardiovascular diseases, more especially in arterial hypertension and heart failure. Perindopril, its preparation and its use in therapeutics have been described in European patent specification EP 0 049 658. In view of the pharmaceutical value of this compound, it has been important to be able to obtain it by an effective synthesis process, readily transposable to an industrial scale, that leads to perindopril in a good yield and with excellent purity. Patent specification EP 0 308 341 describes the industrial synthesis of perindopril by the coupling of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester with N-[(S)-1-carboxybutyl]-(S)-alanine ethyl ester in the presence of dicyclohexylcarbodiimide, followed by deprotection of the carboxylic group of the heterocycle by catalytic hydrogenation. That process has disadvantages related to use of the dicyclohexylcarbodiimide. The Applicant has developed a process for the synthesis of perindopril that uses other coupling agents. More specifically, the present invention relates to a process for the synthesis of perindopril, which process is characterised in that the benzyl ester of formula (IIIa) or (IIIb): or an addition salt of the ester of formula (IIIa) or (IIIb) with a mineral acid or organic acid is reacted with the alanine compound of formula (IV): wherein R′ represents a protecting group for the amino function, in the presence of a coupling agent selected from the following reagents and pairs of reagents: (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/1-hydroxybenzotriazole, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/1-hydroxy-7-azabenzo-triazole, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/N-hydroxysuccinimide, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/N-hydroxyphthalimide, dicyclohexylcarbodiimide/1-hydroxy-7-azabenzotriazole, dicyclohexylcarbodiimide/N-hydroxysuccinimide, dicyclohexylcarbodiimide/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine, dicyclohexylcarbodiimide/N-hydroxyphthalimide, O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramnethyluronium hexafluorophosphate, O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate, O-(benzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)uronium hexafluorophosphate, chloro-tripyrrolidinophosphonium hexafluorophosphate, chloro-1,1,3,3-bis(tetramethylene)formamidinium hexafluorophosphate, chloro-1,1,3,3-bis(pentamethylene)formamidinium hexafluorophosphate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, O-[(ethoxycarbonyl)-cyanomethyleneamino]-1,1,3,3-tetramethyluronium tetrafluoroborate, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/N -methylmorpholine, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/collidine, O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate, O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole, O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate, O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate/1-hydroxy-benzotriazole, O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate, O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uronium tetrafluoroborate, O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uronium tetrafluoroborate/1-hydroxybenzotriazole, O-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate, propanephosphonic anhydride, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, and N-hydroxy-1,2-dihydro-2-oxo-pyridine, optionally in the presence of a base, to yield the compound of formula (Va) or (Vb), respectively, depending on whether the compound of formula (IIIa) or (IIIb) is used as starting material: wherein R′ is as defined hereinbefore, which is subjected to a catalytic hydrogenation reaction in the presence of palladium to yield the product of formula (I). Among the protecting groups for the amino function which can be used in the present invention, there may be mentioned, without implying any limitation, the tert-butyloxycarbonyl, benzyl and benzyloxycarbonyl groups. The catalytic hydrogenation of the compound of formula (Va) is preferably carried out under a hydrogen pressure of less than 10 bars. The catalytic hydrogenation of the compound of formula (Vb) is preferably carried out under a hydrogen pressure of from 10 to 35 bars. The compound of formula (I) thereby obtained is then subjected, if required, to a reaction deprotecting the amino function, followed by a coupling reaction either with ethyl 2-oxo-pentanoate under conditions of reductive amination or with a compound of formula (VI): wherein X represents a leaving group selected from halogen, to yield optically pure perindopril, which is converted, if desired, into a pharmaceutically acceptable salt such as the tert-butylamine salt. The Examples hereinbelow illustrate the invention. EXAMPLE 1 (2S,3aS,7aS)-1-{(2S)-2-[(tert-Butyloxycarbonyl)-amino]-propionyl}-octahydro-1H-indole-2-carboxylic acid/method 1 Step A: Benzyl (2S,3aS,7aS)-1-{(2S)-2-[(tert-butyloxycarbonyl)-amino]-propionyl}-octahydro-1H-indole-2-carboxylate 200 g of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester para-toluene-sulphonate, 65 ml of triethylamine and 1 litre of ethyl acetate are introduced into a stirred reactor, followed, after stirring for 10 minutes at ambient temperature, by 87 g of N-[tert-butyloxycarbonyl]-(S)-alanine and 175 g of O-(benzotriazol-1-yl)-1,1,3,3-bis(tetra-methylene)uronium hexafluorophosphate. The heterogeneous mixture is then heated at 30° C. for 3 hours whilst stirring well and is then cooled to 0° C. and filtered. The filtrate is then washed and subsequently evaporated to dryness to yield the expected product. Step B: (2S,3aS,7aS)-1-{(2S)-2-[(tert-Butyloxycarbonyl)-amino]-propionyl}-octahydro-1H-indole-2-carboxylic acid The residue obtained in the previous Step (200 g) is dissolved in 200 ml of methyl-cyclohexane and transferred to a hydrogenator; 26 g of 5% palladium-on-carbon suspended in 80 ml of methylcyclohexane are then added, followed by 640 ml of water. The mixture is then hydrogenated under a pressure of 0.5 bar at a temperature of from 15 to 30° C., until the theoretical amount of hydrogen has been absorbed. After filtering off the catalyst, the aqueous phase of the filtrate is washed with methylcyclohexane and then lyophilised to yield the expected product in a yield of 94%. EXAMPLE 2 (2S,3aS,7aS)-1-{(2S)-2-[(tert-Butyloxycarbonyl)-amino]-propionyl}-octahydro-1H-indole-2-carboxylic acid/method 2 Step A: Benzyl (2S)-1-{(2S)-2-[(tert-butyloxycarbonyl)-amino]-propionyl}-2,3-dihydro-1H-indole-2-carboxylate 200 g of benzyl 2,3-dihydro-1H-indole-2-carboxylate para-toluenesulphonate, 66 ml of triethylamine and 1 litre of ethyl acetate are introduced into a stirred reactor, followed, after stirring for 10 minutes at ambient temperature, by 89 g of N-[tert-butyloxycarbonyl]-(S)-alanine and 151 g of O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium tetrafluoroborate. The heterogeneous mixture is then heated at 30° C. for 3 hours whilst stirring well and is then cooled to 0° C. and filtered. The filtrate is then washed and subsequently evaporated to dryness to yield the expected product. Step B: (2S,3aS,7aS)-1-{(2S)-2-[(tert-Butyloxycarbonyl)-amino]-propionyl}-octahydro-1H-indole-2-carboxylic acid The residue obtained in the previous Step (200 g) is dissolved in 200 ml of methyl-cyclohexane and transferred to a hydrogenator; 26 g of 5% palladium-on-carbon suspended in 80 ml of methylcyclohexane are then added, followed by 640 ml of water. The mixture is then hydrogenated under a pressure of 0.5 bar at a temperature of from 15 to 30° C., until the theoretical amount of hydrogen required for debenzylation has been absorbed; the mixture is then heated to a temperature of from 50 to 100° C. and hydrogenated under a pressure of 30 bars until the theoretical amount of hydrogen required for hydrogenation of the ring has been absorbed. After filtering off the catalyst, the aqueous phase of the filtrate is washed with methylcyclohexane and then lyophilised to yield the expected product.

20060609

20071030

20070531

97224.0

A61K31405

BARKER, MICHAEL P

PROCESS FOR THE SYNTHESIS OF (2S, 3AS, 7AS)-1-[(S)-ALANYL]-OCTAHYDRO-1H-INDOLE-2-CARBOXYLIC ACID COMPOUNDS AND APPLICATION IN THE SYNTHESIS OF PERINDOPRIL

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Dosing Arrangement for Dispersion Paints

The invention relates to a dosing arrangement which is used to mix a dispersion paint. Said dosing arrangement comprises a mixing vessel and one container for the aqueous paint components. Each container is connected to a dosing valve, which is arranged in the supply area of the mixing vessel, by means of a supply line. The containers for the aqueous paint components are formed by waterproof bags.

1-8. (canceled) 9. A metering system for preparing an emulsion paint from two or more aqueous paint components in the desired composition, having a mixing vessel and a container for each paint component, each container being connected via a conveying line to a mixing head in the feed region of the mixing vessel, each conveying line having a metering valve in the feed region, and the metering valves being connected to a control apparatus in order to control the metering of the paint components in accordance with the desired composition, characterized in that the containers for the aqueous paint components are formed by watertight bags having a capacity of 200 l to 1500 l and whose internal volume contracts on discharge in accordance with the volume of the contents, the conveying lines are connected to the lower region of the respective bag, and in each conveying line a conveying pump is provided. 10. The metering system of claim 9, characterized by a balance for weighing the mixing vessel. 11. The metering system of claim 10, characterized in that beside the balance a shaker is disposed. 12. The metering system of claim 9, characterized in that the control apparatus is provided with a printer for a label to be applied to the mixing vessel. 13. The metering system of claim 12, characterized in that the printer prints the data for settlement at the till on the label. 14. The use of the system of claim 9, for preparing and dispensing aqueous emulsion paints to end customers.

The invention relates to a metering system for mixing an emulsion paint from two or more aqueous paint components in accordance with the preamble of claim 1. A system of this kind is known from DE 196 54 829 A1. Containers used for the individual paint components are in that case steel tanks. Aqueous paints which comprise fillers, pigments, polymers and the like are subject to microbial influences, such as bacterial or fungal infestation. Decomposition, discoloration, reduction in viscosity, and development of odor are the consequences. To protect paints against microbial infestation they are therefore admixed with a preservative in the tanks. Preservatives used are various biocides, examples being isothiazolines or formaldehyde donors. In order to get as close as possible to meeting customer wishes for a particular paint composition, metering systems are set up in home improvement stores and similar points of sale for end customers. With such systems, certain paint components which are less popular may often reside in the storage tank for months. The tanks with the individual components for aqueous emulsion paints must therefore be admixed with unusually large amounts of biocides in order to allow the microbial infestation to be durably prevented. In certain countries, such as Germany, however, only relatively low maximum concentrations of biocides in paints are permitted. In these countries, therefore, metering systems for aqueous emulsion paints cannot be set up at such points of sale. In those countries, instead, a large range of emulsion paints, dispensed into buckets, must be held ready at the points of sale in order to allow at least part of the possible color range to be covered. This results in a correspondingly complex and costly stock-keeping. It is an object of the invention to provide a metering system for mixing an emulsion paint from individual aqueous paint components in separate containers, with which there is no risk of microbial infestation of the paint components in the individual containers, even after months, without any biocide concentration or at any rate only with a very low biocide concentration. This object is achieved in accordance with the invention by the metering system characterized in claim 1. The dependent claims 2 to 7 provide advantageous embodiments of the system of the invention. The subject matter of claim 8 is the preferred use of the system of the invention for dispensing an aqueous emulsion paint in the desired composition, in buckets, to the end customers at the point of sale. The metering system of the invention is characterized in that the containers for the individual paint components, from which the emulsion paint is mixed together for the customers, is formed by a watertight bag. This allows microbial infestation of the aqueous paint components to be prevented. In storage tanks, indeed, the microbial infestation is primarily attributable to the gas space above the level of the liquid. This gas space leads, for example, to the drying of the paint on the inner wall. Beneath a dried-up paint layer of this kind, however, the development of the microorganisms is particularly rapid. As a result of the containers of the invention, formed as watertight and gastight bags, for the aqueous paint components, however, it is ensured that the formation of such a gas space is prevented, since the internal volume of the container contracts on discharge in accordance with the volume of the container contents. For this purpose the conveying line is preferably connected to the lower region of the bag. The bag may be composed of a polymeric film which shrinks as a result of the underpressure formed when the bag is discharged. It is also possible, however, to use a bag made from an elastomeric material. All that is important is that the baglike containers are watertight, gastight, and flexible. The components dispensed in accordance with the invention into containers in the form of watertight bags are aqueous dispersions made up of the various components which can be used to form an aqueous emulsion paint. Thus it is possible, for example, for there to be one or more containers for one or more polymer dispersions, one or more containers for one or more pigment dispersions, and one or more containers for one or more filler dispersions. The number of aqueous dispersions and hence containers is selected such that the emulsion paint range can be largely covered thereby. Of course, in one container, there may also be a mixture of, for example, two components, in other words, for example, a mixture of a pigment dispersion and a filler dispersion. The mixing container is generally formed by the bucket that forms the selling can for the customer. The amount of paint filled into the bucket is determined using a balance on which the bucket is disposed during dispensing. Beside the balance there may be a shaker provided for the homogeneous mixing of the dispensed paint. Between the balance and shaker there may be a transport apparatus located, a roller track for the bucket, for example. In order to allow precise metering there is preferably a conveying pump provided in the conveying line between the respective container and the feed region to the bucket. The metering of the paint from the individual components is controlled by means of a control apparatus, a PC for example, the control apparatus being connected to the metering valves at the feed region to the bucket and preferably also to the conveying pumps in the conveying lines, and to the balance. Connected to the PC is a keyboard or similar input device for controlling the metering valves and the conveying pumps for the individual paint components in accordance with the desired paint composition. Provided on the control apparatus there may be a printer for a label to be applied to the bucket, this printer printing the data onto the label in a way which, if desired, is also machine-readable, e.g., as a barcode, for settlement at the till of the emulsion paint dispensed into the bucket, after the label has been adhered. Computer-assisted advice and product selection give rise to a multiplicity of possible combinations. If, for example, a matt exterior paint of low hiding power is to be dispensed in the bucket, then, using the input device, a high proportion of polymer dispersions and fillers and a low proportion of pigment is set. The input device is also used to select the amount of paint to be dispensed into the bucket. Via the PC, in that case, the metering valves and conveying pumps for the individual paint components are controlled accordingly, with the metering valves being closed and the conveying pumps shut off when the amount of paint dispensed into the bucket reaches the predetermined level as measured by the balance. In order that the baglike, flexible containers for the individual aqueous paint components can be held and fully discharged, they may be disposed in or on a frame and/or suspended by their top end. The frame in this case may be formed by a pallet having at the side a support on which the container is suspended. Moreover, the container does not need to be of fully flexible design. Instead it is conceivable for the container to be composed of a rigid material, in the form for example of a shell, in the region of the outlet opening, to which the conveying line is connected. The invention is illustrated below with reference to the attached drawing, whose single figure shows in diagrammatic form a metering system according to one embodiment of the invention. According to said figure the metering system for mixing an aqueous emulsion paint has a bucket as mixing vessel 1 and two or more, five to eight for example, containers 2, 3 each for one paint component, from which the emulsion paint is mixed, only two of these containers being depicted in the drawing. The containers 2, 3, which are filled with an aqueous dispersion of the respective paint component, in other words, for example, with a polymer dispersion, a pigment dispersion or a filler dispersion, are composed in each case of a watertight bag comprising a polymeric film. The bags 2, 3, which can have a capacity of 200 to 1500 liters, for example, stand in each case on a pallet 4, 5. Each pallet 4, 5 is provided with a support 6, 7, from which the bag 2 or 3 is suspended. Each container 2, 3 has at the base an outlet opening 8, 9 to which a conveying line 11, 12 is connected, formed for example as a hose. The respective dispersion in the container 2, 3 is supplied using a pump 13, 14 in the conveying line 11, 12 to a filling head 15, which is located in the feed region above the bucket 1. Each conveying line 11, 12 has a metering valve 16, 17 connecting it to the filling head 15. The bucket 1 is placed on a balance 18. Beside the balance 18 there is a shaker 19 and, in between them, a roller track 21. The metering system is controlled by a PC 22 with monitor 23 and keyboard 24 or similar input device. From the PC 22 the pumps 13, 14 and the metering valves 16, 17 are driven. Furthermore, the balance 18 is connected to the PC 22. The keyboard 24 is used to input, in accordance with the predetermined formula, the nature and amount of the paint components in the containers 2, 3 that are to be mixed together in the bucket 1, and also the amount of emulsion paint to be filled into the bucket 1. Using the PC 22, the respective pump 13 or 14 in the respective conveying line 11 or 12 is actuated and the respective metering valve 16 or 17 is open in order to supply the relevant paint components from the individual containers 2, 3, in the desired amount, via the filling head 15, to the bucket 1. As soon as the predetermined amount of emulsion paint has been filled into the bucket 1, the pumps 13, 14 are switched off and the valves 16, 17 are closed. The bucket 1 filled with the emulsion paint is then sealed with a lid and pushed on the roller track 21 to the shaker 19, in order for the paint mixture in the bucket 1 to be homogenized. Furthermore, a printer 25 with which a label for the bucket 1 is printed is connected to the PC 22, and prints, for example, a barcode used for settlement of the purchased emulsion paint at the till of the point of sale.

20070312

20110517

20071101

71982.0

B01F1100

COOLEY, CHARLES E

METERING SYSTEM FOR PREPARING EMULSION PAINTS FROM MULTIPLE AQUEOUS PAINT COMPONENTS

UNDISCOUNTED

ACCEPTED

B01F

ACCEPTED

Optical Disk, Recording Method, Recording Medium, And Optical Disk Unit

A method of recording information using a laser on a multilayer optical disk having a plurality of recording layers is provided. The plurality of recording layers include a first recording layer and a second recording layer adjacent the first recording layer. The first recording layer is provided with a first test writing area to be used for calibration of write power, and the second recording layer is provided with a second test writing area to be used for calibration of write power. The disk is arranged so that a first region of the first test writing area is superposed with a second region of the second test writing area when considered in the direction in which the laser is arranged to irradiate. The method comprises, if the second region of the second test writing area is unrecorded, recording data in the second region of the second test writing area, thereby converting the second region of the second test writing area into a recorded state; and once the second region of the second test writing area has been converted into a recorded state, performing test writing in the first region of the first test writing area.

1. A method of recording information using a laser on a multilayer optical disk having a plurality of recording layers, the plurality of recording layers including a first recording layer and a second recording layer, the second recording layer being a recording layer adjacent the first recording layer, the first recording layer having a first test writing area to be used for calibration of write power and the second recording layer having a second test writing area to be used for calibration of write power, wherein a first region of the first test writing area is superposed with a second region of the second test writing area when considered in the direction in which the laser is arranged to irradiate, the method comprising: if the second region of the second test writing area is unrecorded, recording data in the second region of the second test writing area, thereby converting the second region of the second test writing area into a recorded state; once the second region of the second test writing area has been converted into a recorded state, performing test writing in the first region of the first test writing area. 2. A method according to claim 1, wherein the second recording layer is the next recording layer with respect to the first recording layer in the direction in which the laser is arranged to irradiate. 3. A method according to claim 2, wherein the optical disk includes a third recording layer, the third recording layer being the next recording layer with respect to the first recording layer in the opposite direction to that in which the laser is arranged to irradiate, the third recording layer having a third test writing area to be used for calibration of write power, wherein a third region of the third test writing area is superposed with the first region of the first test writing area when considered in the direction in which the laser is arranged to irradiate, the method comprising: if the third region of the third test writing area is unrecorded, recording data in the third region of the third test writing area, thereby converting the third region of the third test writing area into a recorded state; once the third region of the third test writing area has been converted into a recorded state, performing said test writing in the first region of the first test writing area. 4. A method according to any one of claims 1 to 3, wherein before performing the test writing in the first region of the first test writing area, if the first region of the first test writing area is unrecorded, the method comprises: recording data in the first region of the first test writing area, thereby converting the first region of the first test writing area into a recorded state; and then clearing the first region of the first test writing area. 5. A method according to any one of claims 1 to 3, wherein, before performing the test writing in the first region of the first test writing area, the method comprises clearing the first region of the first test writing area. 6. A method according to claim 4 or claim 5, wherein the clearing of the first region of the first test writing area comprises performing an erasure operation to make the first region unrecorded. 7. A method according to any one of claims 1 to 4, wherein for the first region of the first test writing area, or the second region of the second test writing area, or the third region of the third test writing area, the respective step of recording data in the region thereby converting the region into a recorded state comprises performing an operation to make the region logically zero. 8. Apparatus arranged to record information to a multilayer optical disk having a plurality of recording layers using a laser, the plurality of recording layers including a first recording layer and a second recording layer, the second recording layer being a recording layer adjacent the first recording layer, the first recording layer having a first test writing area to be used for calibration of write power and the second recording layer having a second test writing area to be used for calibration of write power, wherein a first region of the first test writing area is superposed with a second region of the second test writing area when considered in the direction in which the laser is arranged to irradiate, wherein if the second region of the second test writing area is unrecorded, the apparatus is arranged to record data in the second region of the second test writing area, thereby converting the second region of the second test writing area into a recorded state; once the second region of the second test writing area has been converted into a recorded state, the apparatus is arranged to perform test writing in the first region of the first test writing area. 9. Apparatus according to claim 8, wherein the second recording layer is the next recording layer with respect to the first recording layer in the direction in which the laser is arranged to irradiate. 10. Apparatus according to claim 9, wherein the optical disk includes a third recording layer, the third recording layer being the next recording layer with respect to the first recording layer in the opposite direction to that in which the laser is arranged to irradiate, the third recording layer having a third test writing area to be used for calibration of write power, wherein a third region of the third test writing area is superposed with the first region of the first test writing area when considered in the direction in which the laser is arranged to irradiate, wherein if the third region of the third test writing area is unrecorded, the apparatus is arranged to record data in the third region of the third test writing area, thereby converting the third region of the third test writing area into a recorded state; once the third region of the third test writing area has been converted into a recorded state, the apparatus is arranged to perform said test writing in the first region of the first test writing area. 11. Apparatus according to any one of claims 8 to 10, wherein before performing the test writing in the first region of the first test writing area, if the first region of the first test writing area is unrecorded, the apparatus is arranged to: record data in the first region of the first test writing area, thereby converting the first region of the first test writing area into a recorded state; and then to clear the first region of the first test writing area. 12. Apparatus according to any one of claims 8 to 10, wherein, before performing the test writing in the first region of the first test writing area, the apparatus is arranged to clear the first region of the first test writing area. 13. Apparatus according to claim 11 or claim 12, wherein the clearing of the first region of the first test writing area comprises performing an erasure operation to make the first region unrecorded. 14. Apparatus according to any one of claims 8 to 11, wherein for the first region of the first test writing area, or the second region of the second test writing area, or the third region of the third test writing area, the apparatus is arranged such that the respective recording of data in the region thereby converting the region into a recorded state comprises performing an operation to make the region logically zero. 15. A single-sided multilayer optical disk, comprising: a plurality of information rewritable recording layers each having a spiral track or concentric tracks formed thereon, wherein a test writing area to be used for calibration of write power is provided in each of the recording layers; and the test writing areas of adjacent two of the recording layers are superposed at least partly on each other in a view from a direction of incidence of a light beam. 16. A single-sided multilayer optical disk according to claim 15, wherein the test writing area of each of the recording layers is provided in at least one of a center part and a peripheral part of the recording layer. 17. A single-sided multilayer optical disk according to claim 15, wherein information to be used for the calibration of the write power is recorded in at least one of the recording layers in a process of manufacturing the single-sided multilayer optical disk. 18. A single-sided multilayer optical disk according to claim 17, wherein: the information to be used for the calibration of the write power includes a plurality of calibration information items each set independently for a corresponding one of the recording layers; and each of the calibration information items is recorded in the corresponding one of the recording layers. 19. The single-sided multilayer optical disk according to claim 17, wherein the information to be used for the calibration of the write power includes information set recording rate by recording rate. 20. A single-sided multilayer optical disk according to claim 17, wherein the information to be used for the calibration of the write power is recorded by performing phase modulation on a wobble shape of the spiral track or the concentric tracks in accordance with the information to be used for the calibration of the write power. 21. A single-sided multilayer optical disk according to claim 15, wherein optimum write strategy information for recording information in the recording layers is recorded in at least one of the recording layers in a process of manufacturing the single-sided multilayer optical disk. 22. A single-sided multilayer optical disk according to claim 21, wherein: the write strategy information includes a plurality of parameter information items each set independently for a corresponding one of the recording layers; and each of the parameter information items is recorded in the corresponding one of the recording layers. 23. A single-sided multilayer optical disk according to claim 21, wherein the write strategy information includes information set recording rate by recording rate. 24. A single-sided multilayer optical disk according to claim 21, wherein the write strategy information is recorded by performing phase modulation on a wobble shape of the spiral track or the concentric tracks in accordance with the write strategy information. 25. A method of recording information on the single-sided multilayer optical disk as set forth in claim 15, the method comprising the step of: before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer closest to a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on a light beam entrance surface side thereof, thereby converting the second one of the test writing areas into a recorded state. 26. A method of recording information on the single-sided multilayer optical disk as set forth in claim 15, the method comprising the step of: before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer most remote from a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on a side thereof opposite from the light beam entrance surface, thereby converting the second one of the test writing areas into a recorded state. 27. A computer-readable recording medium on which recorded is a program for causing a computer to execute a method of recording information on the single-sided multilayer optical disk as set forth in claim 15, the method comprising the step of: before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer closest to a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on a light beam entrance surface side thereof, thereby converting the second one of the test writing areas into a recorded state. 28. A computer-readable recording medium on which recorded is a program for causing a computer to execute a method of recording information on the single-sided multilayer optical disk as set forth in claim 15, the method comprising the step of: before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer most remote from a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on a side thereof opposite from the light beam entrance surface, thereby converting the second one of the test writing areas into a recorded state. 29. An optical disk unit capable of recording information on the single-sided multilayer optical disk as set forth in claim 15, the optical disk unit comprising: a memory; an optical pickup unit configured to emit a light beam onto the optical disk; a controlling computer; and a processing unit, wherein: the memory stores a program for causing the controlling computer to execute a method of recording the information on the optical disk, the method comprising the step of, before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer closest to a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on a light beam entrance surface side thereof, thereby converting the second one of the test writing areas into a recorded state; the controlling computer obtains an optimum recording condition for the optical disk in accordance with the program stored in the memory; and the processor unit records the information on the optical disk with the optimum recording condition through the optical pickup unit. 30. An optical disk unit capable of recording information on the single-sided multilayer optical disk as set forth in claim 15, the optical disk unit comprising: a memory; an optical pickup unit configured to emit a light beam onto the optical disk; a controlling computer; and a processing unit, wherein: the memory stores a program for causing the controlling computer to execute a method of recording the information on the optical disk, the method comprising the step of, before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer most remote from a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on a side thereof opposite from the light beam entrance surface, thereby converting the second one of the test writing areas into a recorded state; the controlling computer obtains an optimum recording condition for the optical disk in accordance with the program stored in the memory; and the processor unit records the information on the optical disk with the optimum recording condition through the optical pickup unit.

TECHNICAL FIELD The present invention relates generally to optical disks, recording methods, recording media, and optical disk units, and more particularly to an optical disk having multiple layers on which information is rewritable (information rewritable layers), a method of recording information on the optical disk, an optical disk unit capable of recording information on the optical disk, and a recording medium on which a program employed in the optical disk unit is recorded. BACKGROUND ART In recent years, with progress in digital technology and an improvement in data compression techniques, optical disks such as DVDs (digital versatile disks) have drawn attention as media for recording information such as music, movies, photographs, and computer software (hereinafter also referred to as “contents”). As optical disks have become lower in price, optical disk units employing optical disks as media for recording information have become widely used. In the optical disk unit, information is recorded on an optical disk by forming a minute laser light spot on the recording surface of the optical disk on which a spiral track or concentric tracks are formed, and information is reproduced from the optical disk based on reflected light from the recording surface. An optical pickup unit is provided in the optical disk unit in order to emit laser light onto the recording surface of the optical disk and receive reflected light from the recording surface. In general, the optical pickup unit includes an optical system, a photodetector, and a lens drive unit. The optical system includes an objective lens. The optical system guides a light beam emitted from a light source to the recording surface of the optical disk, and guides a returning light beam reflected from the recording surface to a predetermined light-receiving position. The photodetector is disposed at the light-receiving position. The lens drive unit drives the objective lens in the directions of its optical axis (hereinafter also referred to as “focus directions”) and in the directions perpendicular to the tangential directions of the tracks (hereinafter also referred to as “tracking directions”). The photodetector outputs a signal including not only the reproduced information of data recorded on the recording surface, but also information necessary to control the position of the objective lens (servo information). Information is recorded on the optical disk based on the length of each of a mark and a space different in reflectivity from each other, and their combination. For example, when a mark is formed in rewritable optical disks such as DVD-RW (DVD-rewritable) and DVD+RW (DVD+rewritable) disks including a special alloy in their recording layers, the special alloy is rapidly cooled after being heated to a first temperature so as to be in an amorphous state. On the other hand, when a space is formed, the special alloy is gradually cooled after being heated to a second temperature (lower than the first temperature) so as to be in a crystalline state. As a result, the reflectivity is lower in the mark than in the space. Such control of special alloy temperature is performed by controlling the light emission power of laser light. At the time of forming marks in particular, the pulse shape of light emission power is set based on a rule (method) concerning the pulse shape of light emission power, etc., called a write strategy, in order to reduce variation in heat distribution due to preceding and subsequent marks and spaces. In the optical disk unit, at the time of recording, an optimum write (recording) power is obtained by performing test writing in a preset test writing area called PCA (Power Calibration Area) before writing information in order that a mark and a space of target length are formed at a target position on the optical disk (see, for example, ECMA-337 Data Interchange on 120 mm and 80 mm Optical Disk using +RW Format-Capacity: 4.7 and 1.46 Gbytes per Side, December 2003). This operation is called OPC (Optimum Power Control). The contents tend to increase in quantity year by year, so that a further increase in the recording capacity of optical disks is expected. Providing multiple recording layers is considered as means for increasing the recording capacity of optical disks, and lots of efforts are being made to develop optical disks having multiple recording layers (hereinafter also referred to as “multilayer disks”) and optical disk units to access the multilayer disks. It is also important to obtain an appropriate write power in the multilayer disks, and a variety of proposals have been made regarding OPC (see, for example, Japanese Laid-Open Patent Application No. 2004-310995). However, in rewritable multilayer disks, which are not yet commercially available, for example, higher recording rates may cause variations in recording quality even when recording is performed with an optimum write power obtained by OPC. DISCLOSURE OF THE INVENTION Accordingly, it is a general object of the present invention to provide an optical disk in which the above-described disadvantages are eliminated. A more specific object of the present invention is to provide an optical disk with multiple rewritable recording layers on which disk recording can be stably performed. Another more specific object of the present invention is to provide a recording method and an optical disk unit that make it possible to perform recording on the optical disk with stable recording quality. Yet another more specific object of the present invention is to, provide a recording medium on which recorded is a program to be executed by the controlling computer of the optical disk unit, the program making it possible to perform recording on the optical disk with stable recording quality. According to a first aspect of the invention, there is provided a method of recording information using a laser on a multilayer optical disk having a plurality of recording layers, the plurality of recording layers including a first recording layer and a second recording layer, the second recording layer being a recording layer adjacent the first recording layer, the first recording layer having a first test writing area to be used for calibration of write power and the second recording layer having a second test writing area to be used for calibration of write power, wherein a first region of the first test writing area is superposed with a second region of the second test writing area when considered in the direction in which the laser is arranged to irradiate, the method comprising: if the second region of the second test writing area is unrecorded, recording data in the second region of the second test writing area, thereby converting the second region of the second test writing area into a recorded state; once the second region of the second test writing area has been converted into a recorded state, performing test writing in the first region of the first test writing area. The second recording layer can be the next recording layer with respect to the first recording layer in the direction in which the laser is arranged to irradiate. In addition, the optical disk can include a third recording layer, the third recording layer being the next recording layer with respect to the first recording layer in the opposite direction to that in which the laser is arranged to irradiate, the third recording layer having a third test writing area to be used for calibration of write power, wherein a third region of the third test writing area is superposed with the first region of the first test writing area when considered in the direction in which the laser is arranged to irradiate. In such embodiments, the method comprises: if the third region of the third test writing area is unrecorded, recording data in the third region of the third test writing area, thereby converting the third region of the third test writing area into a recorded state; once the third region of the third test writing area has been converted into a recorded state, performing said test writing in the first region of the first test writing area. In some embodiments, before performing the test writing in the first region of the first test writing area, if the first region of the first test writing area is unrecorded, the method comprises: recording data in the first region of the first test writing area, thereby converting the first region of the first test writing area into a recorded state; and then clearing the first region of the first test writing area. In some embodiments, before performing the test writing in the first region of the first test writing area, the method comprises clearing the first region of the first test writing area. The clearing of the first region of the first test writing area can comprise performing an erasure operation to make the first region unrecorded. For the first region of the first test writing area, or the second region of the second test writing area, or the third region of the third test writing area, the respective step of recording data in the region thereby converting the region into a recorded state comprises performing an operation to make the region logically zero. According to a second aspect of the invention, there is provided an apparatus arranged to record information to a multilayer optical disk having a plurality of recording layers using a laser, the plurality of recording layers including a first recording layer and a second recording layer, the second recording layer being a recording layer adjacent the first recording layer, the first recording layer having a first test writing area to be used for calibration of write power and the second recording layer having a second test writing area to be used for calibration of write power, wherein a first region of the first test writing area is superposed with a second region of the second test writing area when considered in the direction in which the laser is arranged to irradiate, wherein: if the second region of the second test writing area is unrecorded, the apparatus is arranged to record data in the second region of the second test writing area, thereby converting the second region of the second test writing area into a recorded state; once the second region of the second test writing area has been converted into a recorded state, the apparatus is arranged to perform test writing in the first region of the first test writing area. The second recording layer can be the next recording layer with respect to the first recording layer in the direction in which the laser is arranged to irradiate. In addition, the optical disk can include a third recording layer, the third recording layer being the next recording layer with respect to the first recording layer in the opposite direction to that in which the laser is arranged to irradiate, the third recording layer having a third test writing area to be used for calibration of write power, wherein a third region of the third test writing area is superposed with the first region of the first test writing area when considered in the direction in which the laser is arranged to irradiate, wherein: if the third region of the third test writing area is unrecorded, the apparatus is arranged to record data in the third region of the third test writing area, thereby converting the third region of the third test writing area into a recorded state; once the third region of the third test writing area has been converted into a recorded state, the apparatus is arranged to perform said test writing in the first region of the first test writing area. In some embodiments, before performing the test writing in the first region of the first test writing area, if the first region of the first test writing area is unrecorded, the apparatus is arranged to: record data in the first region of the first test writing area, thereby converting the first region of the first test writing area into a recorded state; and then to clear the first region of the first test writing area. In some embodiments, before performing the test writing in the first region of the first test writing area, the apparatus is arranged to clear the first region of the first test writing area. The clearing of the first region of the first test writing area can comprise performing an erasure operation to make the first region unrecorded. For the first region of the first test writing area, or the second region of the second test writing area, or the third region of the third test writing area, the apparatus is arranged such that the respective recording of data in the region thereby converting the region into a recorded state comprises performing an operation to make the region logically zero. One or more of the above objects of the present invention are achieved by a single-sided multilayer optical disk including a plurality of information rewritable recording layers each having a spiral track or concentric tracks formed thereon, wherein a test writing area to be used for calibration of write power is provided in each of the recording layers, and the test writing areas of adjacent two of the recording layers are superposed at least partly on each other in a view from a direction of incidence of a light beam. An optical disk according to one embodiment of the present invention allows an optical disk unit in which the optical disk is set to perform positioning swiftly at the time of performing test writing in one recording layer after another, and accordingly, to calibrate write power in each recording layer in a short period of time. As a result, it is possible to perform stable recording even if the optical disk has multiple rewritable recording layers. One or more of the above objects of the present invention are also achieved by a method of recording information on a single-sided multilayer optical disk according to one embodiment of the present invention, the method including the step of, before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer closest to a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on a light beam entrance surface side thereof, thereby converting the second one of the test writing areas into a recorded state. According to one embodiment of the present invention, before performing test writing in a first one of the test writing areas of recording layers in an optical disk except the recording layer closest to a light beam entrance surface, a second one of the test writing areas adjacent to the first one of the test writing areas on its light beam entrance surface side is converted into a recorded state. Accordingly, it is possible to determine an optimum write power matching a situation where user data is actually recorded, so that it is possible to perform recording with stable recording quality. One or more of the above objects of the present invention are also achieved by a method of recording information on a single-sided multilayer optical disk according to one embodiment of the present invention, the method including the step of, before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer most remote from a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on a side thereof opposite from the light beam entrance surface, thereby converting the second one of the test writing areas into a recorded state. According to one embodiment of the present invention, before performing test writing in a first one of the test writing areas of recording layers in an optical disk except the recording layer most remote from a light beam entrance surface, a second one of the test writing areas adjacent to the first one of the test writing areas on the opposite side from the light beam entrance surface is converted into a recorded state. Accordingly, it is possible to suppress the adverse effect of so-called interlayer crosstalk, so that it is possible to perform recording with stable recording quality. One or more of the above objects of the present invention are also achieved by a computer-readable recording medium on which recorded is a program for causing a computer to execute any of the above-described methods of recording information on a single-sided multilayer optical disk according to one embodiment of the present invention. According to one embodiment of the present invention, when a program is loaded into a predetermined memory, and its start address is set in a program counter, the controlling computer of an optical disk unit, before performing test writing in a first one of the test writing areas of recording layers in an optical disk except the recording layer closest to a light beam entrance surface, changes a second one of the test writing areas adjacent to the first one of the test writing areas on its light beam entrance surface side into a recorded state. Alternatively, the controlling computer, before performing test writing in a first one of the test writing areas of the recording layers except the recording layer most remote from a light beam entrance surface, may change a second one of the test writing areas adjacent to the first one of the test writing areas on the opposite side from the light beam entrance surface into a recorded state. Thus, it is possible to cause the controlling computer of the optical disk unit to execute any of the above-described recording methods of recording information on the optical disk, so that it is possible to perform recording with stable recording quality. One or more of the above objects of the present invention are also achieved by an optical disk unit capable of recording information on a single-sided multilayer optical disk according to one embodiment of the present invention, the optical disk unit including a memory, an optical pickup unit configured to emit a light beam onto the optical disk, a controlling computer, and a processing unit, wherein the memory stores a program for causing the controlling computer to execute any of the above-described methods of recording information on the optical disk; the controlling computer obtains an optimum recording condition for the optical disk in accordance with the program stored in the memory; and the processor unit records the information on the optical disk with the optimum recording condition through the optical pickup unit. According to one embodiment of the present invention, the controlling computer of an optical disk unit executes a program, recorded in a memory, for causing the controlling computer to execute any of the above-described methods of recording the information on the optical disk, so that an optimum recording condition is obtained. A processing unit records the information on the optical disk with the optimum recording condition through an optical pickup unit. In this case, the controlling computer obtains an optimum recording condition whichever recording layer of the optical disk is to have information recorded therein. As a result, it is possible to perform recording on the optical disk with stable recording quality. BRIEF DESCRIPTION OF THE DRAWINGS Other objects, features and advantages of the present invention will become more apparent from the following detailed description when read in conjunction with the accompanying drawings, in which: FIG. 1 is a block diagram showing an optical disk unit according to an embodiment of the present invention; FIG. 2 is a diagram for illustrating a structure of an optical disk according to the embodiment of the present invention; FIGS. 3A and 3B are diagrams for illustrating a write strategy according to the embodiment of the present invention; FIGS. 4A and 4B are additional diagrams for illustrating the write strategy according to the embodiment of the present invention; FIG. 5 is another diagram for illustrating the write strategy according to the embodiment of the present invention; FIG. 6 is a table showing parameters of the write strategy according to the embodiment of the present invention; FIG. 7 is a diagram for illustrating a disk layout of the optical disk of FIG. 2 according to the embodiment of the present invention; FIG. 8 is a diagram for illustrating PCA in the optical disk of FIG. 2 according to the embodiment of the present invention; FIG. 9 is another diagram for illustrating the PCA in the optical disk of FIG. 2 according to the embodiment of the present invention; FIG. 10 is a diagram for illustrating an optical pickup unit of the optical disk unit of FIG. 1 according to the embodiment of the present invention; FIG. 11 is a flowchart for illustrating a recording operation according to the embodiment of the present invention; FIG. 12 is a graph for illustrating the effect of the recording state of a layer L0 on the degree of modulation of a layer L1 according to the embodiment of the present invention; FIG. 13 is a graph for illustrating the effect of the recording state of the layer L0 on the jitter of the layer L1 according to the embodiment of the present invention; and FIG. 14 is a graph for illustrating the effect of the write power of the layer L0 on the degree of modulation of the layer L1 according to the embodiment of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION A description is given below, with reference to the accompanying drawings, of an embodiment of the present invention. FIG. 1 is a block diagram showing an optical disk unit 20 according to the embodiment of the present invention. The optical disk unit 20 includes a spindle motor 22 to rotate an optical disk 15 according to the embodiment of the present invention; an optical pickup unit 23; a seek motor 21 to drive the optical pickup unit 23 in the radial directions of the optical disk 15; a laser control circuit 24, an encoder 25, a drive control circuit 26, a reproduced signal processing circuit 28, a buffer RAM 34, a buffer manager 37, an interface 38, a flash memory 39, a CPU 40, and a RAM 41. The arrows in FIG. 1 represent typical information and signal flows, and do not represent all the interconnections of the blocks. Further, in this embodiment, the optical disk unit 20 supports multilayer disks. [Structure of Optical Disk 15] A light beam is made incident on or enters the optical disk 15 through one side thereof. By way of example, the optical disk 15 includes two rewritable recording layers. That is, the optical disk 15 is a single-sided double-layer disk. By way of example, as shown in FIG. 2, the optical disk 15 includes a substrate 1a, a layer L0, an adhesive layer 7, a layer L1, and a substrate 1b in this order of closeness to the light beam entrance surface. The incident light beam reaches the layer L1 through the substrate 1a, the layer L0, and the adhesive layer 7. Accordingly, the substrate 1a, the layer L0, and the adhesive layer 7 should have a predetermined transparency in the wavelength range of the incident light beam. The layer L0 has a lower protection layer 2a, a recording layer 3a, an upper protection layer 4a, a semi-transparent layer 5, and an intermediate layer 6 in this order of closeness to the light beam entrance surface. Further, the layer L1 has a lower protection layer 2b, a recording layer 3b, an upper protection layer 4b, and a reflective layer 8 in this order of closeness to the light beam entrance surface. By way of example, the optical disk 15 is a disk of 120 mm in diameter. Further, by way of example, the optical disk 15 is an information recording medium belonging to the DVD system. The substrate 1a is 0.565 mm in thickness. By way of example, polycarbonate is employed as the material of the substrate 1a. The lower protection layer 2a has a film thickness of 200 nm. By way of example, a mixture of ZnS and SiO2 is employed as the material of the lower protection layer 2a. Here, by way of example, the mixture ratio of ZnS to SiO2 is 80:20 (molar ratio). The recording layer 3a has a film thickness of 8 mm. By way of example, an In—Sb—Ge alloy is employed as the material of the recording layer 3a. The upper protection layer 4a has a film thickness of 20 nm. By way of example, SiO2 is employed as the material of the upper protection layer 4a. The lower protection layer 2a and the upper protection layer 4a are provided in order to prevent thermal deformation and diffusion of the recording layer 3a. The semi-transparent layer 5 has a film thickness of 8 nm. By way of example, Cu is employed as the material of the semi-transparent layer 5. The intermediate layer 6 has a film thickness of 150 nm. By way of example, ITO is employed as the material of the intermediate layer 6. The intermediate layer 6 has the function of diffusing heat around the recording layer 3a with efficiency and of correcting light absorptance. That is, the layer L0 is 386 nm in thickness. The adhesive layer 7 is 50 μm in thickness. By way of example, an acryl-based UV-curable adhesive agent is employed as the material of the adhesive layer 7. The lower protection layer 2b has a film thickness of 100 nm. By way of example, the same ZnS—SiO2 mixture as that of the lower protection layer 2a is employed as the material of the lower protection layer 2b. The recording layer 3b has a film thickness of 12 nm. That is, the recording layer 3b is thicker than the recording layer 3a. By way of example, a Ge—In—Sb—Te alloy is employed as the material of the recording layer 3b. The upper protection layer 4b has a film thickness of 20 nm. By way of example, SiO2 is employed as the material of the upper protection layer 4b. The reflective layer 8 has a film thickness of 140 nm. By way of example, Ag is employed as the material of the reflective layer 8. That is, the layer L1 is 272 nm in thickness. The substrate 1b is 0.6 mm in thickness. By way of example, polycarbonate is employed as the material of the substrate 1b. Part of a light beam incident on the optical disk 15 is reflected from the layer L0, and the remaining part of the light beam passes through the layer L0. The light beam passing through the layer L0 is reflected from the layer L1. Further, a spiral guide groove is formed in each of the layers L0 and L1. [Method of Manufacturing Optical Disk 15] (a) A spiral groove of a track pitch of 0.74 μm is formed on a first polycarbonate board of 0.565 mm in thickness serving as the substrate 1a. This groove wobbles at a period of 4.7 μm so that the period of a wobble signal is 1.22 μs at the reference velocity of 3.83 m/s. The wobble shape is partially phase-modulated. Address information, calibration information used to calibrate write (recording) power for writing onto the layer L0, and information on write power recommended for writing onto the layer L0 are stored in the phase-modulated part of the wobble shape. (b) A film of a mixture of ZnS and SiO2 to serve as the lower protection layer 2a is formed on the groove formed on the first polycarbonate board using a magnetron sputtering device. The mixture film is 200 nm in thickness. The film thickness is measured using ellipsometry and the fluorescent X-ray method together. (c) In the same manner, an In—Sb—Ge alloy film to serve as the recording layer 3a is formed on the mixture film. The In—Sb—Ge alloy film is 8 nm in thickness. (d) In the same manner, a SiO2 film to serve as the upper protection layer 4a is formed on the In—Sb—Ge alloy film. The SiO2 film is 20 nm in thickness. (e) In the same manner, a Cu film to serve as the semi-transparent layer 5 is formed on the SiO2 film. The Cu film is 8 nm in thickness. (f) In the same manner, an ITO film to serve as the intermediate layer 6 is formed on the Cu film. The ITO film is 150 nm in thickness. For convenience, the first polycarbonate board and these stacked layers of the ZnS—SiO2 mixture film, the In—Sb—Ge alloy film, the SiO2 film, the Cu film, and the ITO film on the first polycarbonate board are collectively referred to as an L0 substrate. (g) The same groove as in (a) is formed on a second polycarbonate board of 0.6 mm in thickness serving as the substrate 1b. Here, address information, calibration information used to calibrate write (recording) power for writing onto the layer L1, and information on write power recommended for writing onto the layer L1 are stored in the phase-modulated part. (h) A Ag film to serve as the reflective layer 8 is formed on the groove formed on the second polycarbonate board using a magnetron sputtering device. The Ag film is 140 nm in thickness. (i) In the same manner, a SiO2 film to serve as the upper protection layer 4b is formed on the Ag film. The SiO2 film is 20 nm in thickness. (j) In the same manner, a Ge—In—Sb—Te alloy film to serve as the recording layer 3b is formed on the SiO2 film. The Ge—In—Sb—Te alloy film is 12 nm in thickness. (k) In the same manner, a film of a mixture of ZnS and SiO2 to serve as the lower protection layer 2b is formed on the Ge—In—Sb—Te alloy film. The mixture film is 100 nm in thickness. For convenience, the second polycarbonate board and these stacked layers of the Ag film, the SiO2 film, the Ge—In—Sb—Te alloy film, and the ZnS—SiO2 mixture film on the second polycarbonate board are collectively referred to as an L1 substrate. (l) A commercially available adhesive agent for DVDs is applied to the intermediate layer 6 of the L0 substrate and the lower protection layer 2b of the L1 substrate, and the L0 substrate and the L1 substrate are stuck together. (m) The stuck L0 and L1 substrates are irradiated with ultraviolet rays from the L0 substrate side so that the adhesive agent is hardened. The layer of the adhesive agent is approximately 50 μm in thickness. The thickness of the adhesive agent layer is measured by a so-called interference method using a spectrophotometer. That is, here, the optical disk 15 is manufactured by the so-called inverted stack method. [Initialization of Recording Layers] Laser light of 810 nm wavelength is emitted onto and scans the recording layers 3a and 3b, so that each of the recording layers 3a and 3b is initialized. Here, by way of example, the light emission power is 700 mW for the recording layer 3a and 1600 mW for the recording layer 3b. A light spot in the recording layers 3a and 3b is shaped as an ellipse of 1 (μm)×75 (μm), and the scanning velocity is 3.5 m/s. The directions of the shorter axis of the light spot coincide with the tangential directions of a track. Before initialization, the recording layers 3a and 3b are in an amorphous state and have high transmittance. Accordingly, in order to reduce time required for initialization, first, the recording layer 3b is initialized, and thereafter, the recording layer 3a is initialized. In this case, for example, the reflectance after initialization is 8.5% in the layer L0 and 7.5% in the layer L1. [Calibration Information] Calibration information employed to calibrate write power includes Pind, ρ, and γtarget (for example, see ECMA-337). Here, by way of example, Pind=33.6 mW, ρ=1.25, and γtarget=1.4 in the layer L0, and Pind=40 mW, ρ=1.25, and γtarget=1.5 in the layer L1. [Write Strategy Information] Write strategy information includes a variety of parameters defining a light emission waveform according to mark length nT (n=3 through 11, T is the period of a write channel clock). Here, by way of example, so-called 2T write strategy is employed as shown in FIGS. 3A through 6. FIG. 3A shows a light emission waveform at the time of formation of a 3T mark. FIG. 3B shows a light emission waveform at the time of formation of a 4T mark. FIG. 4A shows a light emission waveform at the time of formation of a 5T mark. FIG. 4B shows a light emission waveform at the time of formation of a 6T mark. For the marks of even multiples of T greater than the 6T mark, the same parameters as for the 6T mark are employed, and only the number of pulses of a pulse width Tmp (so-called intermediate heating pulses) is different. FIG. 5 shows a light emission waveform at the time of formation of a 7T mark. For the marks of odd multiples of T greater than the 7T mark, the same parameters as for the 7T mark are employed, and only the number of pulses of the pulse width Tmp (so-called intermediate heating pulses) is different. FIG. 6 is a table showing a value of each parameter. [Disk Layout of Optical Disk 15] By way of example, the optical disk 15 supports a standard called opposite track path (OTP) as shown in FIG. 7. That is, in the layer L0, a lead-in zone, a data zone, and a middle zone are provided in this order from the center to the edge of the optical disk 15. Meanwhile, in the layer L1, a middle zone, a data zone, and a lead-out zone are provided in this order from the edge to the center of the disk. The layer L0 is assigned physical addresses to successively increase from the lead-in zone to the middle zone. The layer L1 is assigned physical addresses to successively increase from the middle zone to the lead-out zone. Here, the start address and the end address of the data zone of the layer L0 are 030000h and 22D7FFh, respectively, and the start address and the end address of the data zone of the layer L1 are DD2800h and FCFFFFh, respectively. The data zone is provided between radial positions of 24.0 mm and 58.0 mm in each of the layers L0 and L1. By way of example, as shown in FIG. 8, a drive test zone that is the test writing area of the layer L0 is provided in the lead-in zone, and a drive test zone that is the test writing area of the layer L1 is provided in the lead-out zone. Each drive test zone is provided between radial positions of 23.4 mm and 23.75 mm, and the drive test zones are superposed on each other when viewed from the direction of incidence of a light beam. Further, by way of example, as shown in FIG. 9, a drive test zone that is the test writing area of the layer L0 is provided in the middle zone of the layer L0, and a drive test zone that is the test writing area of the layer L1 is provided in the middle zone of the layer L1. Each drive test zone is provided between radial positions of 58.1 mm and 58.25 mm, and the drive test zones are superposed on each other when viewed from the direction of incidence of a light beam. That is, here, the test writing area is provided in the center part and the peripheral part of each of the recording layers 3a and 3b. Hereinafter, the drive test zones are also referred to as “PCA (Power Calibration Area)” for convenience. The optical pickup unit 23 is a device for focusing laser light on one of the two recording layers 3a and 3b of the optical disk 15 which one is a target of access, and receiving reflected light from the optical disk 15. Hereinafter, the one of the two recording layers 3a and 3b of the optical disk 15 which one is a target of access is abbreviated as “target recording layer.” By way of example, as shown in FIG. 10, the optical pickup unit 23 includes a light source unit 51, a coupling lens 52, a polarization beam splitter 54, a ¼ wave plate 55, an objective lens 60, a collective lens (detection lens) 58, a light receiver PD serving as a photodetector, and a drive system AC for driving the objective lens 60. The light source unit 51 includes a semiconductor laser LD serving as a light source to emit laser light of a wavelength corresponding to the optical disk 15 (in this case, approximately 660 nm). In this embodiment, the direction of maximum intensity emission of laser light emitted from the light source unit 51 is a positive (+) X direction indicated by the arrow X in FIG. 10. Further, by way of example, a light beam of polarization parallel to the plane of incidence of the polarization beam splitter 54 (p-polarization) is emitted from the light source unit 51. The coupling lens 52 is disposed on the positive X side of the light source unit 51 so as to convert the light beam emitted from the light source unit 51 into a substantially parallel beam. The polarization beam splitter 54 is disposed on the positive X side of the coupling lens 52. The reflectance of the polarization beam splitter 54 differs depending on the polarization state of a light beam made incident thereon. Here, by way of example, the polarization beam splitter 54 is set so as to have low reflectance for p-polarized light and high reflectance for s-polarized light. That is, most of the light beam emitted from the light source unit 51 is allowed to pass through the polarization beam splitter 54. The ¼ wave plate is disposed on the positive X side of the polarization beam splitter 54. The ¼ wave plate 55 provides a light beam made incident thereon with an optical phase difference of a ¼ wavelength. The objective lens 60 is disposed on the positive X side of the ¼ wave plate, and focuses a light beam passing through the ¼ wave plate on the target recording layer. Here, the NA (numerical aperture) is 0.60. The collective lens 58 is disposed on the negative (−) Z side of the polarization beam splitter 54 so as to focus a returning light beam diverging in the negative Z direction in the polarization beam splitter 54 on the light-receiving surface of the light receiver PD. The light receiver PD includes multiple light-receiving elements (or light-receiving areas) for generating optimum signals (photoelectrically converted signals) for detecting an RF signal, a wobble signal, and servo signals in the reproduced signal processing circuit 28. The drive system AC includes a focusing actuator for driving the objective lens 60 minutely in the focus directions, or the optical axis directions of the objective lens 60, and a tracking actuator for driving the objective lens 60 minutely in the tracking directions. Here, for convenience, the optimum position of the objective lens 60 with respect to the focus directions at a time when the target recording layer is the recording layer 3a is referred to as “first lens position,” and the optimum position of the objective lens 60 with respect to the focus directions at a time when the target recording layer is the recording layer 3b is referred to as “second lens position.” A description is given of the operation of the optical pickup unit 23 having the above-described structure. A linearly polarized (p-polarized in this case) light beam emitted from the light source unit 51 is converted into a substantially parallel light beam in the coupling lens 52 and enters the polarization beam splitter 54. Most of the light beam passes as it is through the polarization beam splitter 54 to be circularly polarized in the ¼ wave plate 55, and is focused into a fine spot on the target recording layer of the optical disk 15 through the objective lens 60. Reflected light from the optical disk 15 is circularly polarized in the opposite direction from that of the light beam incident on the optical disk 15 so as to be converted again into a substantially parallel beam in the objective lens 60 as a returning light beam. The returning light beam is converted into a linearly polarized (s-polarized in this case) light beam perpendicular to that emitted from the light source unit 51 in the ¼ wave plate 55. Then, this returning light beam enters the polarization beam splitter 54. The returning light beam 54 is reflected in the negative Z direction in the polarization beam splitter 54, and is received by the light receiver PD through the collective lens 58. In the light receiver PD, photoelectric conversion is performed in each light-receiving element (or light-receiving area), and each photoelectrically converted signal is output to the reproduced signal processing circuit 28. Referring back to FIG. 1, the reproduced signal processing circuit 28 obtains servo signals (such as a focus error signal and a tracking error signal), address information, synchronization information, and an RF signal based on the output signals (photoelectrically converted signals) of the light receiver PD. The obtained servo signals are output to the drive control circuit 26. The obtained address information is output to the CPU 40. The obtained synchronization signal is output to the encoder 25, the drive control circuit 26, etc. Further, the reproduced signal processing circuit 28 performs decoding and error detection on the RF signal. In the case of detecting error, the reproduced signal processing circuit 28 performs error correction, and thereafter, stores the RF signal in the buffer RAM 34 through the buffer manager 37 as reproduced data. Further, the address information included in the reproduced data is output to the CPU 40. The drive control circuit 26, based on the tracking error signal fed from the reproduced signal processing circuit 28, generates a tracking actuator driving signal for correcting the position offset of the objective lens 60 with respect to the tracking directions. Further, the drive control circuit 26, based on the focus error signal fed from the reproduced signal processing circuit 28, generates a focusing actuator driving signal for correcting the focus error of the objective lens 60. The generated driving signals are output to the optical pickup unit 23 so that tracking control and focus control are performed. Further, the drive control circuit 26, based on instructions from the CPU 40, generates a driving signal for driving the seek motor 21 and a driving signal for driving the spindle motor 22. The driving signals are output to the seek motor 21 and the spindle motor 22, respectively. The buffer RAM 34 temporarily stores data to be recorded on the optical disk 15 (recording data) and data reproduced from the optical disk 15 (reproduced data). The buffer manager 37 manages data input to and data output from the buffer RAM 34. The encoder 25, based on an instruction from the CPU 40, extracts recording data stored in the buffer RAM 34 through the buffer manager 37, performs modulation on the data, and adds an error correction code to the data, thereby generating a write signal for writing onto the optical disk 15. The generated write signal is output to the laser control circuit 24. The laser control circuit 24 controls the light emission power of the semiconductor laser LD. For example, in the case of recording, a signal to drive the semiconductor laser LD is generated in the laser control circuit 24 based on the write signal, write (recording) conditions, and the light emission characteristics of the semiconductor laser LD. The interface 38 is a bidirectional communications interface with a host apparatus 90 such as a personal computer, and is compliant with standard interfaces such as ATAPI (AT Attachment Packet Interface), SCSI (Small Computer System Interface), and USB (Universal Serial Bus). The flash memory 39 stores a variety of programs including one coded in a code decodable by the CPU 40 according to the embodiment of the present invention, and a variety of data including the light emission characteristics of the semiconductor laser LD. The CPU 40 controls the operation of each of the above-described parts of the optical disk unit 20 in accordance with the programs stored in the flash memory 39, and stores data necessary for the control in the RAM 41 and the buffer RAM 34. [Recording Operation] Next, a description is given, with reference to FIG. 11, of an operation in the optical disk unit 20 at the time of receiving a recording request from the host apparatus 90. The flowchart of FIG. 11 corresponds to a series of processing algorithms executed by the CPU 40. When a recording request (command) is received from the host apparatus 90, the start address of a program stored in the flash memory 39 and corresponding to the flowchart of FIG. 11 (hereinafter referred to as “recording operation algorithm”) is set in the program counter of the CPU 40, and a recording operation is started. First, in step S401, an instruction is given to the drive control circuit 26 so that the optical disk 15 rotates at a predetermined linear velocity (or angular velocity), and the reproduced signal processing circuit 28 is notified of reception of the recording request (command) from the host apparatus 90. By way of example, the write (recording) scanning velocity is 9.19 m/s (2.4 times that in a DVD). Next, in step S403, calibration conditions and write strategy information recorded on the optical disk 15 are obtained through the reproduced signal processing circuit 28. Here, the reproduced signal processing circuit 28 performs phase demodulation on a wobble signal detected in each layer, and extracts calibration conditions and write strategy information layer by layer. Next, in step S405, the recording state of PCA in each layer is obtained. Here, detection as to whether the PCA of the layer L0 is recorded or unrecorded (whether recording has been performed on the layer L0) and whether the PCA of the layer L1 is recorded or unrecorded (whether recording has been performed on the layer L1) is performed based on, for example, the intensity of reflected light from each PCA. Next, in step S407, it is determined whether the PCA of the layer L0 is recorded. If the PCA of the layer L0 is unrecorded (NO in step S407), the operation proceeds to step S411. In step S411, write conditions are set based on the write strategy information in the layer L0 obtained in step S403. Parameters defining the light emission waveform of the semiconductor laser LD are set in a register (not graphically illustrated) of the laser control circuit 24. Next, in step S413, an optimum write power (Pw0) is determined by performing OPC based on the calibration information in the layer L0 obtained in step S403. Here, by way of example, Pw0=42 mW is obtained. Next, in step s415, dummy data is recorded in the PCA of the layer L0 with the optimum write power Pw0 determined in step S413. Next, in step S421, it is determined whether the PCA of the layer L1 is recorded. If the PCA of the layer L1 is unrecorded (NO in step S421), the operation proceeds to step S423. In step S423, write conditions are set based on the write strategy information in the layer L1 obtained in step S403. Next, in step S425, an optimum write power (Pw1) is determined by performing OPC based on the calibration information in the layer L1 obtained in step S403. Here, by way of example, Pw1=50 mW is obtained. Next, in step S427, dummy data is recorded in the PCA of the layer L1 with the optimum write power Pw1 determined in step S425. Next, in step S431, the target recording layer is specified from a specified address included in the recording request (command). Next, in step S433, the PCA of the target recording layer is made “unrecorded.” Specifically, laser light of erase power is emitted from the semiconductor laser LD onto the PCA of the target recording layer. That is, so-called DC erasure is performed. Next, in step S435, write conditions are set based on the write strategy information in the target recording layer obtained in step S403. Next, in step S437, an optimum write power Pw is determined by performing OPC based on the calibration information in the target recording layer obtained in step S403. Next, in step S439, dummy data is recorded in the PCA of the target recording layer with the optimum write power Pw determined in step S437. Next, in step S441, user data is recorded at the requested address of the target recording layer with the optimum write power Pw determined in step S437. When the recording of the user data is completed, the host apparatus 90 is notified of the completion, and the recording operation ends. In step S407, if the PCA of the layer L0 is recorded (YES in step S407), the operation proceeds to step S421. In step S421, if the PCA of the layer L1 is recorded (YES in step S421), the operation proceeds to step S431. When recording was performed with the write conditions shown in FIG. 6, with ten overwrite operations (DOW 10), jitter was 8.6% and the degree of modulation was 0.60 in the layer L0, and jitter was 8.2% and the degree of modulation was 0.68 in the layer L1. Further, with one hundred overwrite operations (DOW 100), jitter was 9.6% in the layer L0 and jitter was 8.5% in the layer L1. In each case, the jitter of each of the layers L0 and L1 was at a level causing no problem in reproduction, being less than 10%. Here, the evaluations were performed using ODU-1000, a DVD evaluation apparatus of Pulstec Industrial Co., Ltd., with a read power of 1.4 mW and a read (reproduction) scanning velocity of 3.83 m/s. The details of jitter and the degree of modulation are described in ECMA-337. By way of example, as shown in FIG. 12, the write power for obtaining a predetermined degree of modulation in the layer L1 differs depending on the recording state of the layer L0. If the layer L0 is unrecorded, a higher write power is required than in the case where the layer L0 is recorded. This is because T<T′, where T is a transmittance in the case where the layer L0 is unrecorded, and T′ is a transmittance in the case where the layer L0 is recorded. The write power differs depending on the number of times of overwrite even though the layer L0 is recorded. However, the difference is small. By way of example, as shown in FIG. 13, the write power for maintaining good jitter in the layer L1 also differs depending on the recording state of the layer L0. If the layer L0 is unrecorded, a higher write power is required than in the case where the layer L0 is recorded. The minimum value of jitter is smaller in the case where the layer L0 is recorded than in the case where the layer L0 is unrecorded. From these, letting the optimum write power in the layer L1 in the case where the layer L0 is unrecorded be P0, and letting the optimum write power in the layer L1 in the case where the layer L0 is recorded be P0′, P0 is greater than P0′ (P0>P0′). Further, letting the intensity of reflected light from the layer L1 in the case where the layer L0 is unrecorded be R, and letting the intensity of reflected light from the layer L1 in the case where the layer L0 is recorded be R′, R is less than R′ (R<R′). Further, by way of example, as shown in FIG. 14, the degree of modulation in the layer L1 varies also because of write power in the layer L0. This is because the size of an amorphous area in the layer L0 differs depending on write power. In the case of FIG. 14, recording is performed in the layer L1 with a constant write power (write power level) after performing recording in the layer L0 with various write powers (write power levels). That is, it is possible to maintain high degrees of modulation in the layer L1 if recording is performed in the layer L0 with high write power. According to this embodiment, first, OPC is performed on the layer L0 so that dummy data is recorded in the PCA of the layer L0 with optimum write power, and then, OPC is performed on the layer L1 so that dummy data is recorded in the PCA of the layer L1 with optimum write power. Thereafter, optimum write power is determined with respect to the target recording layer by performing OPC thereon. Accordingly, it is possible to determine optimum write power that matches an actual situation of user data recording. As a comparative example, when OPC was performed in the layer L1 in the same manner as described above with the PCA of the layer L0 being unrecorded, the obtained optimum write power was 55 mW. Then, recording was performed in the layer L0 with a write power of 42 mW, and overwriting was performed 100 times on the layer L1 with a write power of 55 mW. This resulted in a jitter value of 11%. This corresponds to a level more than 100 times of so-called PI error, and may cause reproduction error. As is apparent from the above description, in the optical disk unit 20 according to this embodiment, the flash memory 39 forms memory, and the encoder 25 and the laser control circuit 24 form a processing unit. Further, the CPU 40 forms a computer for control (controlling computer). Further, according to this embodiment, of the programs stored in the flash memory 39, the program of the above-described recording operation includes a program according to this embodiment of the present invention. In the above-described recording operation, a recording method according to this embodiment of the present invention is performed. As described above, according to the optical disk unit 20 according to this embodiment, at the time of recording user data on the optical disk 15, which is a rewritable single-sided double-layer disk where a test writing area is provided in each recording layer and the test writing areas of the adjacent recording layers are superposed on each other when viewed from the direction of incidence of a light beam, first, OPC is performed on the layer L0 so that dummy data is recorded in the PCA of the layer L0 with optimum write power, and then, OPC is performed on the layer L1 so that dummy data is recorded in the PCA of the layer L1 with optimum write power. Thereafter, OPC is performed on the target recording layer, so that optimum write power is determined with respect to the target recording layer. As a result, it is possible to determine optimum write power whichever of the two recording layers of the optical disk 15 is to have user data recorded therein. As a result, it is possible to perform recording with stable recording quality. Further, according to the optical disk 15 according to this embodiment, the test writing areas of the adjacent recording layers are superposed on each other in a view from the direction of incidence of a light beam. Accordingly, an optical disk unit in which the optical disk 15 is set can easily determine optimum write power matching an actual situation of user data recording. As a result, it is possible to perform stable recording. Further, according to the optical disk 15 according to this embodiment, calibration information and write strategy information are “pre-formatted.” Accordingly, an optical disk unit in which the optical disk 15 is set can obtain optimum write power swiftly. In this embodiment, the above description is given of the case where the optical disk 15 is manufactured by the inverted stack method. The manufacturing method of the optical disk 15 is not limited to this, and the optical disk 15 may be manufactured by the so-called 2P method. Further, in this embodiment, the above description is given of the case where the optical disk 15 has two recording layers. However, the present invention is not limited to this, and the optical disk 15 may have three or more recording layers. In this case, at the time of recording information in, for example, the Nth closest recording layer to the light beam entrance surface, OPC is performed in the Nth recording layer after converting at least one of the PCA of the (N−1)th recording layer and the PCA of the (N+1)th recording layer into a recorded state (that is, after recording data in at least one of the PCA of the (N−1)th recording layer and the PCA of the (N+1)th recording layer). Further, in this embodiment, the above description is given of the case where the optical disk 15 is 120 mm in diameter. However, the present invention is not limited to this, and the optical disk 15 may be, for example, 80 mm or 30 mm in diameter. Further, in this embodiment, the above description is given of the case where each recording layer independently stores calibration information and write strategy information corresponding thereto. However, the present invention is not limited to this, and the calibration information and the write strategy information corresponding to all recording layers may be recorded in one of the recording layers. Further, in this embodiment, the above description is given of the case where the calibration information and the write strategy information are set recording layer by recording layer. However, the present invention is not limited to this. For example, if the difference in calibration information and write strategy information between recording layers is small, the average calibration information and write strategy information may be set and recorded in one of the recording layers. Further, in this embodiment, for example, if the range of supportable recording rates is wide, the calibration information may be set recording rate by recording rate. Further, in this embodiment, for example, if the range of supportable recording rates is wide, the write strategy information may be set recording rate by recording rate. Further, in this embodiment, the above description is given of the case where the test writing areas of adjacent recording layers are superposed on each other in a view from the direction of incidence of a light beam. Alternatively, the test writing areas of adjacent recording layers may be superposed partly on, or overlap with, each other. In this case, the overlap is preferably at least 50%, and more preferably 70%, of the entire area. In the case of overlapping (partial superposition), it is preferable to perform OPC in the overlapping area. Further, in this embodiment, the above description is given of the case where the test writing area is provided in each of the center part and the peripheral part of the optical disk 15. However, the present invention is not limited to this, and the test writing area may be provided in one of the center part and the peripheral part of the optical disk 15. Further, in this embodiment, the above description is given of the case where the test writing area of the center part of the optical disk 15 is provided between radial positions of 23.4 mm and 23.75 mm. However, the present invention is not limited to these radial positions. Further, in this embodiment, the above description is given of the case where the test writing area of the peripheral part of the optical disk 15 is provided between radial positions of 58.1 mm and 58.25 mm. However, the present invention is not limited to these radial positions. Further, in this embodiment, the above description is given of the case where 2T write strategy is employed. However, the present invention is not limited to this, and so-called 1T write strategy may be employed. Further, in this embodiment, the above description is given of the case where the disk layout supports OTP. However, the present invention is not limited to this, and the disk layout may support parallel track path (PTP). Further, the material and the thickness of each layer of the optical disk 15 may be, but are not limited to, those described above in this embodiment. (a) As the material of the substrate 1a, other resins such as polyolefin-based and acryl-based resins, and glass may also be employed. That is, materials for the substrate 1a have high transmittance with respect to a light beam emitted from the optical pickup unit 23. In terms of processability and manufacturing cost, however, it is preferable to employ resin. (b) Inorganic material is preferable as the material of each of the protection layers 2a, 4a, 2b, and 4b. For example, metal or alloy oxides, and simple substances or mixtures of sulfides, nitrides, and carbides may be employed. Further, each of the protection layers 2a, 4a, 2b, and 4b may have a multilayer structure. The material of each of the protection layers 2a, 4a, 2b, and 4b is required to have a melting point higher than that of the material of the recording layer 3a, and at the same time, appropriate toughness. Further, the material of each of the protection layers 2a, 4a, 2b, and 4b is required to have transparency in the wavelength range of an incident light beam. Materials satisfying these conditions include, in addition to ZnS and SiO2, MgO, Al2O3, SiO, ZnO2, InO2, SnO2, TiO2, ZrO2, Y2O3, AlN, Si3N4, GaN, GeN, SiC, TiC, and TaC. (c) The optimum film thickness of the lower protection layer 2a, which is determined by reflectance and recording sensitivity, preferably falls within the range of 40 nm to 300 nm. (d) Since it is necessary to ensure a predetermined transmittance in the recording layer 3a, the recording layer 3a should be reduced in film thickness compared with the case of a single-layer disk having one recording layer. In general, however, a thinner phase change material tends to have a lower rate of crystallization. Accordingly, phase change materials employed in high-speed compliant optical disks such as 8× (scanning velocity: 27.9 m/s) single-layer DVD+RWs are preferable. Specifically, an In—Sb alloy, Ga—Sb alloy, and Ge—Sb alloy with a third metal added thereto may be used. (e) The optimum film thickness of the upper protection layer 4a, which is determined by thermal design, preferably falls within the range of 4 nm to 50 nm. (f) The material of the semi-transparent layer 5 may also be an alloy whose principal component is Au, Ag, Al, or Cu. Alternatively, the material of the semi-transparent layer 5 may also be a simple substance of Au, Ag, or Al. (g) The optimum film thickness of the semi-transparent layer 5, which is determined from transmittance and reflectance, preferably falls within the range of 2 nm to 50 nm. More preferably, the optimum film thickness of the semi-transparent layer 5 falls within the range of 5 nm to 15 nm particularly in order to ensure transmittance. If the semi-transparent layer 5 exceeds 50 nm in film thickness, it becomes difficult to ensure reflectance in the layer L1. If the semi-transparent layer 5 is less than 2 nm in film thickness, insufficient thermal diffusion results, so that rapid cooling of the recording layer 3a is hindered. This increases the possibility of a decrease in recording sensitivity and deterioration of jitter. (h) Materials for the intermediate layer 6 have transparency in the wavelength range of an incident light beam and high thermal conductivity. For example, a simple substance or mixture of In2O3, SnO2, ZnO2, or Ga2O3 with a dopant added thereto is usually employed. The dopant may be Al, Ga, B, In, Y, Sc, F, V, Si, Ge, Ti, Zr, Hf, Sb, Mo, etc. (i) The optimum film thickness of the intermediate layer 6, which is determined by thermal design and optical design, preferably falls within the range of 10 nm to 300 nm, more preferably, the range of 50 nm to 200 nm. (j) The material of the reflective layer 8 may also be an alloy whose principal component is Ag, Au, Cu, or Al. Alternatively, the material of the reflective layer 8 may be a simple substance of Au, Cu, or Al. (k) Materials for the adhesive layer 7 do not corrode an adjacent layer and have transparency in the wavelength range of an incident light beam. (l) The optimum thickness of the adhesive layer 7, which is determined so that interlayer crosstalk and wave front aberration are at or below predetermined levels, preferably falls within the range of 40 nm to 70 nm. Further, in this embodiment, the program according to the present invention is recorded in the flash memory 39. Alternatively, the program may be recorded in other recording media such as a CD, magneto-optical disk, DVD, memory card, USB memory, and flexible disk. In this case, the program is loaded into the flash memory 39 through a reproduction apparatus (or dedicated interface) corresponding to a recording medium in which the program is recorded. The program may be forwarded to the flash memory 39 through a network such as a LAN, an intranet, or the Internet. That is, the program according to the present invention is stored in the flash memory 39. Further, in this embodiment, the above description is given of the case where the optical disk 15 is a DVD-type information recording medium. However, the present invention is not limited to this, and the optical disk 15 may be, for example, a CD-type rewritable single-sided multilayer disk or a rewritable single-sided multilayer disk corresponding to a light beam of 405 nm wavelength. In this case, for example, the track pitch is 1.6 μm for a CD for which NA=0.5 and λ (wavelength)=780 nm, and is 0.4 μm for an HD DVD for which NA=0.65 and λ=405 nm. Further, in this embodiment, the above description is given of the case where the optical pickup unit 23 has one semiconductor laser. However, the present invention is not limited to this, and for example, the optical pickup unit 23 may have multiple semiconductor lasers emitting respective light beams different in wavelength from each other. In this case, the optical pickup unit 23 may include at least one of, for example, a semiconductor laser emitting a light beam of a wavelength of approximately 405 nm, a semiconductor laser emitting a light beam of a wavelength of approximately 660 nm, and a semiconductor laser emitting a light beam of a wavelength of approximately 780 nm. That is, the optical disk unit 20 may support multiple types of optical disks compliant with respective standards different from each other. In this case, at least one of the multiple types of optical disks may be a rewritable single-sided multilayer disk. As described above, the optical disk 15 according to this embodiment has multiple rewritable recording layers, and is suitable for stable recording and reproduction. Further, the recording method and the optical disk unit 20 according to this embodiment are suitable for performing recording on the optical disk 15 of this embodiment with stable recording quality. Further, the program and the recording medium according to this embodiment are suitable for causing the optical disk unit 20 to perform recording on the optical disk 15 of this embodiment with stable recording quality. According to one embodiment of the present invention, a single-sided multilayer optical disk including multiple information rewritable recording layers each having a spiral track or concentric tracks formed thereon is provided, wherein a test writing area to be used for calibration of write power is provided in each of the recording layers, and the test writing areas of adjacent two of the recording layers are superposed at least partly on each other in a view from the direction of incidence of a light beam. This optical disk allows an optical disk unit in which the optical disk is set to perform positioning swiftly at the time of performing test writing in one recording layer after another, and accordingly, to calibrate write power in each recording layer in a short period of time. As a result, it is possible to perform stable recording even if the optical disk has multiple rewritable recording layers. According to one embodiment of the present invention, a method of recording information on a single-sided multilayer optical disk is provided that includes the step of, before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer closest to a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on its light beam entrance surface side, thereby converting the second one of the test writing areas into a recorded state. According to this method, before performing test writing in a first one of the test writing areas of recording layers in an optical disk except the recording layer closest to a light beam entrance surface, a second one of the test writing areas adjacent to the first one of the test writing areas on its light beam entrance surface side is converted into a recorded state. Accordingly, it is possible to determine an optimum write power matching a situation where user data is actually recorded, so that it is possible to perform recording with stable recording quality. According to one embodiment of the present invention, a method of recording information on a single-sided multilayer optical disk is provided that includes the step of, before performing test writing in a first one of the test writing areas of the recording layers in the optical disk except the recording layer most remote from a light beam entrance surface, recording data in a second one of the test writing areas adjacent to the first one of the test writing areas on the opposite side from the light beam entrance surface, thereby converting the second one of the test writing areas into a recorded state. According to this method, before performing test writing in a first one of the test writing areas of recording layers in an optical disk except the recording layer most remote from a light beam entrance surface, a second one of the test writing areas adjacent to the first one of the test writing areas on the opposite side from the light beam entrance surface is converted into a recorded state. Accordingly, it is possible to suppress the adverse effect of so-called interlayer crosstalk, so that it is possible to perform recording with stable recording quality. According to one embodiment of the present invention, a computer-readable recording medium on which recorded is a program for causing a computer to execute any of the above-described methods of recording information on a single-sided multilayer optical disk is provided. According to this computer-readable recording medium, when the program is loaded into a predetermined memory, and its start address is set in a program counter, the controlling computer of an optical disk unit, before performing test writing in a first one of the test writing areas of recording layers in an optical disk except the recording layer closest to a light beam entrance surface, changes a second one of the test writing areas adjacent to the first one of the test writing areas on its light beam entrance surface side into a recorded state. Alternatively, the controlling computer, before performing test writing in a first one of the test writing areas of the recording layers except the recording layer remotest from a light beam entrance surface, may change a second one of the test writing areas adjacent to the first one of the test writing areas on the opposite side from the light beam entrance surface into a recorded state. Thus, it is possible to cause the controlling computer of the optical disk unit to execute any of the above-described recording methods of recording information on the optical disk, so that it is possible to perform recording with stable recording quality. According to one embodiment of the present invention, an optical disk unit capable of recording information on a single-sided multilayer optical disk is provided that includes a memory, an optical pickup unit configured to emit a light beam onto the optical disk, a controlling computer, and a processing unit, wherein the memory stores a program for causing the controlling computer to execute any of the above-described methods of recording information on the optical disk; the controlling computer obtains an optimum recording condition for the optical disk in accordance with the program stored in the memory; and the processor unit records the information on the optical disk with the optimum recording condition through the optical pickup unit. According to this optical disk unit, the controlling computer executes a program, recorded in the memory, for causing the controlling computer to execute any of the above-described methods of recording the information on the optical disk, so that an optimum recording condition is obtained. The processing unit records the information on the optical disk with the optimum recording condition through an optical pickup unit. In this case, the controlling computer obtains an optimum recording condition whichever recording layer of the optical disk is to have information recorded therein. As a result, it is possible to perform recording on the optical disk with stable recording quality. The present invention is not limited to the specifically disclosed embodiment, and variations and modifications may be made without departing from the scope of the present invention. The present application is based on Japanese Priority Patent Application No. 2005-153872, filed on May 26, 2005, the entire contents of which are hereby incorporated by reference.

<SOH> BACKGROUND ART <EOH>In recent years, with progress in digital technology and an improvement in data compression techniques, optical disks such as DVDs (digital versatile disks) have drawn attention as media for recording information such as music, movies, photographs, and computer software (hereinafter also referred to as “contents”). As optical disks have become lower in price, optical disk units employing optical disks as media for recording information have become widely used. In the optical disk unit, information is recorded on an optical disk by forming a minute laser light spot on the recording surface of the optical disk on which a spiral track or concentric tracks are formed, and information is reproduced from the optical disk based on reflected light from the recording surface. An optical pickup unit is provided in the optical disk unit in order to emit laser light onto the recording surface of the optical disk and receive reflected light from the recording surface. In general, the optical pickup unit includes an optical system, a photodetector, and a lens drive unit. The optical system includes an objective lens. The optical system guides a light beam emitted from a light source to the recording surface of the optical disk, and guides a returning light beam reflected from the recording surface to a predetermined light-receiving position. The photodetector is disposed at the light-receiving position. The lens drive unit drives the objective lens in the directions of its optical axis (hereinafter also referred to as “focus directions”) and in the directions perpendicular to the tangential directions of the tracks (hereinafter also referred to as “tracking directions”). The photodetector outputs a signal including not only the reproduced information of data recorded on the recording surface, but also information necessary to control the position of the objective lens (servo information). Information is recorded on the optical disk based on the length of each of a mark and a space different in reflectivity from each other, and their combination. For example, when a mark is formed in rewritable optical disks such as DVD-RW (DVD-rewritable) and DVD+RW (DVD+rewritable) disks including a special alloy in their recording layers, the special alloy is rapidly cooled after being heated to a first temperature so as to be in an amorphous state. On the other hand, when a space is formed, the special alloy is gradually cooled after being heated to a second temperature (lower than the first temperature) so as to be in a crystalline state. As a result, the reflectivity is lower in the mark than in the space. Such control of special alloy temperature is performed by controlling the light emission power of laser light. At the time of forming marks in particular, the pulse shape of light emission power is set based on a rule (method) concerning the pulse shape of light emission power, etc., called a write strategy, in order to reduce variation in heat distribution due to preceding and subsequent marks and spaces. In the optical disk unit, at the time of recording, an optimum write (recording) power is obtained by performing test writing in a preset test writing area called PCA (Power Calibration Area) before writing information in order that a mark and a space of target length are formed at a target position on the optical disk (see, for example, ECMA-337 Data Interchange on 120 mm and 80 mm Optical Disk using +RW Format-Capacity: 4.7 and 1.46 Gbytes per Side, December 2003). This operation is called OPC (Optimum Power Control). The contents tend to increase in quantity year by year, so that a further increase in the recording capacity of optical disks is expected. Providing multiple recording layers is considered as means for increasing the recording capacity of optical disks, and lots of efforts are being made to develop optical disks having multiple recording layers (hereinafter also referred to as “multilayer disks”) and optical disk units to access the multilayer disks. It is also important to obtain an appropriate write power in the multilayer disks, and a variety of proposals have been made regarding OPC (see, for example, Japanese Laid-Open Patent Application No. 2004-310995). However, in rewritable multilayer disks, which are not yet commercially available, for example, higher recording rates may cause variations in recording quality even when recording is performed with an optimum write power obtained by OPC.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Other objects, features and advantages of the present invention will become more apparent from the following detailed description when read in conjunction with the accompanying drawings, in which: FIG. 1 is a block diagram showing an optical disk unit according to an embodiment of the present invention; FIG. 2 is a diagram for illustrating a structure of an optical disk according to the embodiment of the present invention; FIGS. 3A and 3B are diagrams for illustrating a write strategy according to the embodiment of the present invention; FIGS. 4A and 4B are additional diagrams for illustrating the write strategy according to the embodiment of the present invention; FIG. 5 is another diagram for illustrating the write strategy according to the embodiment of the present invention; FIG. 6 is a table showing parameters of the write strategy according to the embodiment of the present invention; FIG. 7 is a diagram for illustrating a disk layout of the optical disk of FIG. 2 according to the embodiment of the present invention; FIG. 8 is a diagram for illustrating PCA in the optical disk of FIG. 2 according to the embodiment of the present invention; FIG. 9 is another diagram for illustrating the PCA in the optical disk of FIG. 2 according to the embodiment of the present invention; FIG. 10 is a diagram for illustrating an optical pickup unit of the optical disk unit of FIG. 1 according to the embodiment of the present invention; FIG. 11 is a flowchart for illustrating a recording operation according to the embodiment of the present invention; FIG. 12 is a graph for illustrating the effect of the recording state of a layer L 0 on the degree of modulation of a layer L 1 according to the embodiment of the present invention; FIG. 13 is a graph for illustrating the effect of the recording state of the layer L 0 on the jitter of the layer L 1 according to the embodiment of the present invention; and FIG. 14 is a graph for illustrating the effect of the write power of the layer L 0 on the degree of modulation of the layer L 1 according to the embodiment of the present invention. detailed-description description="Detailed Description" end="lead"?

20060821

20110222

20080320

69856.0

G11B500

FISCHER, MARK L

OPTICAL DISK, RECORDING METHOD, RECORDING MEDIUM, AND OPTICAL DISK UNIT, FOR RECORDING INFORMATION ON MULTILAYER OPTICAL DISK

UNDISCOUNTED

ACCEPTED

G11B

ACCEPTED

Biomaterial Measuring Device and Manufacturing Method Thereof

A method of producing a biomaterial measuring device is disclosed. The method includes forming a plurality of reactions elements, to which an assay reagent is applied, on a first substrate, cutting the resulting first substrate in a unit of individual reaction element, and attaching a first substrate piece, which is formed by cutting the resulting first substrate in the unit of individual reaction element, to a predetermined portion of a second substrate. In the biomaterial measuring device, since a material cost in minimized and it is easy to automate production, it is possible to reduce a production, it is possible to reduce a production cost.

1. A method of producing a biomaterial measuring device, comprising: forming a plurality of reaction elements, to which an assay reagent is applied, on a first substrate; cutting the resulting first substrate in a unit of individual reaction element; and attaching a first substrate piece, which is formed by cutting the resulting first substrate in the unit of individual reaction element, to a predetermined portion of a second substrate. 2. The method as set forth in claim 1, wherein a plurality of first substrate pieces, which are formed by cutting the resulting first substrate in the unit of individual reaction element, is attached to the second substrate. 3. The method as set forth in claim 1, wherein the assay reagent is used to measure a biomaterial through an optical assay, and light penetrates through the portion of the second substrate, to which the first substrate piece is attached. 4. The method as set forth in claim 3, wherein the assay reagent is layered on a membrane so as to be applied to a first substrate, or is directly applied to the first substrate. 5. The method as set forth in claim 3, further comprising forming means for focusing or defocusing light, on the portion of the second substrate, to which the first substrate piece is attached. 6. The method as set forth in claim 1, wherein the second substrate is made of any one selected from the group consisting of plastic, glass, and semiconductor wafer. 7. The method as set forth in claim 1, wherein the assay reagent is used to measure a biomaterial through an electrochemical assay, and the formation of the plurality of reaction elements comprises: forming at least two first electrodes on a first side of the first substrate; and applying the assay reagent through the first electrodes. 8. The method as set forth in claim 7, further comprising: forming a second electrode on a second side of the first substrate, which is opposite to the first side; and electrically connecting at least one of the first electrodes on the first side to the second electrode on the second side. 9. The method as set forth in claim 1, further comprising mounting a dehumidifying agent for removing moisture, which is introduced from an environment to the assay reagent, on a predetermined portion of the biomaterial measuring device while the dehumidifying agent is isolated from the environment. 10. A method of producing a biomaterial measuring device, comprising: forming a plurality of first reaction elements, to which a first assay reagent is applied, on a first substrate; forming a plurality of second reaction elements, to which a second assay reagent is applied, on a second substrate; cutting the first and second substrates in a unit of individual reaction element; and attaching first and second substrate pieces, which are formed by cutting the first and second substrates in the unit of individual reaction element, to predetermined portions of a third substrate. 11. A biomaterial measuring device, comprising: a first substrate; an assay reagent which is applied on an entire first side of the first substrate to form a reaction element; and a second substrate, on which the first substrate is mounted to enable the assay reagent to form a path for introducing a biomaterial therethrough. 12. The biomaterial measuring device as set forth in claim 11, wherein the assay reagent is used to measure the biomaterial through an optical assay, and light penetrates through a portion of the second substrate, to which the first substrate is attached. 13. The biomaterial measuring device as set forth in claim 12, wherein the assay reagent is layered on a membrane so as to be applied to the first substrate, or is directly applied to the first substrate. 14. The biomaterial measuring device as set forth in claim 12, further comprising means for focusing or defocusing light, which is formed on the portion of the second substrate, to which the first substrate is attached. 15. The biomaterial measuring device as set forth in claim 11, wherein the second substrate is made of any one selected from the group consisting of plastic, glass, and semiconductor wafer. 16. The biomaterial measuring device as set forth in claim 11, wherein the reaction element includes at least two first electrodes formed on the first side of the first substrate, and the assay reagent is used to measure the biomaterial through an electrochemical assay and is applied through the first electrodes. 17. The biomaterial measuring device as set forth in claim 16, further comprising a second electrode which is formed on a second side of the first substrate, opposite to the first side, and which is electrically connected to at least one of the first electrodes on the first side. 18. The biomaterial measuring device as set forth in claim 17, wherein the first electrodes on the first side are electrically connected to the second electrode on the second side through a via hole which is formed through the first substrate, a wall of which is coated with a conductor. 19. The biomaterial measuring device as set forth in claim 11, further comprising a dehumidifying agent which is mounted on a predetermined portion of the biomaterial measuring device so that the dehumidifying agent is isolated from an environment and which removes moisture introduced from the environment to the assay reagent.

TECHNICAL FIELD The present invention relates, in general, to a biomaterial measuring device and a method of producing the same and, more particularly, to a biomaterial measuring device and a method of producing the same, in which a plurality of reaction elements is formed on a substrate, the resulting substrate is cut in a reaction element unit, and the resulting elements are attached to another substrate acting as a mechanical supporter. BACKGROUND ART A biosensor, in which a biomaterial is used as a tracing device and which has excellent sensitivity and reaction specificity, is expected to be applied to various fields, such as medical/pharmaceutical fields (clinical chemical assay and remedy), and process and environmental monitoring and chemical stability evaluation in the bio-industry. Particularly, a chemical composition assay in vivo is medically very important, and recently, the biosensor has been frequently used to assay a biomaterial sample containing blood in a medical diagnosis field. Of various biosensors, a biosensor, which employs an enzyme assay method using a characteristic reaction of an enzyme to a matrix or of an enzyme to an inhibitor, is most frequently used in hospitals and clinical chemical assays because ease of application is assured, measurement sensitivity is excellent, and the results are rapidly obtained. The enzyme assay method, which is applied to the biosensor, may be classified into an optical method, in which light transmittance is measured through a spectroscopic assay before and after an enzyme reaction, and an electrode method, in which an electrochemical signal is measured. Compared to the electrode method, the optical method is difficult to use assay of critical biomaterial because the measuring time is long, a great amount of blood is required, and measurement error occurs due to turbidity of a biomaterial sample. Accordingly, recently, the electrode method has been frequently applied to a biosensor using an enzyme. In the electrode method, after an electrode system is formed on a plastic film, an assay reagent is applied to an electrode, a sample is introduced, and specific components of the sample are quantitatively measured using a predetermined electric potential. U.S. Pat. Nos. 5,120,420, 5,395,504, 5,437,999, and 5,997,817 are patent literatures of a biosensor, which disclose embodied operations and effects of the biosensor in detail. The disclosures of the above patents are incorporated herein by reference as follows. FIG. 1 illustrates the production of a strip using a conventional optical method. Holes 104 are formed through a substrate 102 to allow light to penetrate therethrough, and a membrane 106, to which a biochemical reaction reagent is applied, is attached thereto. Subsequently, the resulting structure is cut into strips 108. In the method, since the strips must be produced in a handy size, the strips are formed so as to be a few cm long. Hence, the size of a production device increases and the device costs a great deal. Since the strip is typically provided in a roll form, the substrate 102 is made of a flexible material. Accordingly, a process error occurs in the course of forming the holes by punching or of forming the strips by cutting, and thus, the uniformity of measurements is undesirably reduced. Furthermore, there is a limit that only one reaction element can be produced using one strip. FIG. 2 illustrates the production of a biosensor strip using a conventional electrochemical method. FIG. 3 is a sectional view of the biosensor strip of FIG. 2. For convenience of understanding, thicknesses of layers are exaggerated in FIG. 3. After an operation electrode 204, a standard electrode 206, and an auxiliary electrode (not shown), on which a redox reaction occurs, are formed on an insulator 202, an insulator 210, which is processed in a predetermined shape to form a capillary 208 for feeding a sample therethrough and which acts as a spacer, is attached to the resulting insulator 202. Subsequently, a biochemical reagent 212 is applied to the electrodes, and an insulator 214 is attached thereto to form a cover, thereby completing the biosensor, in which the biochemical reagent 212 is contained in the capillary 208, through the electrochemical method. Finally, the resulting structure is cut into strips 216. As in the production of the strips using the conventional optical method, the strips must be produced in a handy size, thus the strips are formed so as to be a few cm long. Since the electrodes must be formed on every strip, it is difficult to implement the production in a roll form, and thus, the production is typically carried out in a sheet form. When the production is conducted in the sheet manner, it is necessary to carefully handle the entire surface of a sheet because each strip is large. To produce the strips having uniform performance using a wide sheet, it is necessary to take a care in the formation of the electrodes. Additionally, since application of a solution must be conducted throughout the wide area, it is difficult to assure uniformity during a drying process. Therefore, a production device is large and costly, it is difficult to implement the production, and the production cost is high. The insulator 202 is made of a relatively thin plastic material so as to be cut into strips. When using glass or silicon wafer, the material cost of the substrate increases per strip, thus the price of the strip increases. As well, there is a limit that only one reaction element can be produced using one strip. Furthermore, a capillary having one structure can be formed in one process. If capillaries having two structures are formed, the production cost doubles. DISCLOSURE OF THE INVENTION Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a biomaterial measuring device and a method of producing the same, in which a material cost is minimized and it is easy to automate the production, thereby reducing a production cost. Another object of the present invention is to provide a biomaterial measuring device and a method of producing the same, in which it is possible to attach a plurality of reaction elements to one substrate, thereby reducing a price per reaction element. A further object of the present invention is to provide a biomaterial measuring device, in which, since a substrate is made of plastic, silicone, or glass, according to the type of reactant and a characteristic of a reaction, process compatibility is improved, and which can be applied to the expanded range of biochemical assay, and a method of producing the same. Yet another object of the present invention is to provide a biomaterial measuring device, in which, since a plurality of reaction elements for measuring the same object material (or assay material) is attached to one substrate, or a plurality of reaction elements for measuring different object materials is attached to the one substrate, various applications are possible, usability is maximized, and sequential measurement is possible, and a method of producing the same. Still another object of the present invention is to provide a biomaterial measuring device, which is packaged in a magazine manner, thus reducing inconvenience when a user must exchange it every measurement, and a method of producing the same. Still another object of the present invention is to provide a biomaterial measuring device, in which the amount of sample needed during measurement is minimized, and a method of producing the same. In order to accomplish the above objects, the present invention provides a method of producing a biomaterial measuring device. The method comprises forming a plurality of reaction elements, to which an assay reagent is applied, on a first substrate, cutting the resulting first substrate into individual reaction elements, and attaching a first substrate piece, which is formed by cutting the resulting first substrate into individual reaction elements, to a predetermined portion of a second substrate. The method may further comprise mounting a dehumidifying agent for removing moisture, which is fed from the environment to the assay reagent, on a predetermined portion of the biomaterial measuring device while the dehumidifying agent is isolated from the environment. Preferably, a plurality of first substrate pieces, which are formed by cutting the resulting first substrate into individual reaction elements, is attached to the second substrate. The second substrate is made of any one selected from the group consisting of plastic, glass, and semiconductor wafer. When the biomaterial measuring device employs an optical assay, light may penetrate through the portion of the second substrate, to which the first substrate piece is attached. The assay reagent may be layered on a membrane so as to be applied to the first substrate, or be directly applied to the first substrate. Furthermore, means may be additionally formed on the portion of the second substrate, to which the first substrate piece is attached, to focus or defocus light. When the biomaterial measuring device employs an electrochemical assay, the formation of the plurality of reaction elements comprises forming at least two first electrodes on a first side of the first substrate, and applying the assay reagent through the first electrodes. The method may further comprise forming a second electrode on a second side of the first substrate, which is opposite to the first side, and electrically connecting at least one of the first electrodes on the first side to the second electrode on the second side. The first electrodes on the first side may be electrically connected to the second electrode on the second side through a via hole which is formed through the first substrate, a wall of which is coated with a conductor. Additionally, the present invention provides another method of producing the biomaterial measuring device. The method comprises forming a plurality of first reaction elements, to which a first assay reagent is applied, on a first substrate, forming a plurality of second reaction elements, to which a second assay reagent is applied, on a second substrate, cutting the first and second substrates into individual reaction elements, and attaching first and second substrate pieces, which are formed by cutting the first and second substrates into individual reaction elements, to predetermined portions of a third substrate. As well, the present invention provides a biomaterial measuring device. The device comprises a first substrate, an assay reagent, which is applied on an entire first side of the first substrate to form a reaction element, and a second substrate, on which the first substrate is mounted to enable the assay reagent to form a path for feeding a biomaterial therethrough. In a biomaterial measuring device according to the present invention, since a material cost is minimized and it is easy to automate production, it is possible to reduce a production cost. Further, it is possible to attach a plurality of reaction elements to one substrate, thereby reducing the price per reaction element. Furthermore, since the substrate is made of plastic, silicone, or glass according to the type of reactant and a characteristic of a reaction, process compatibility is improved, and the device can be applied to an expanded range of biochemical assays. Additionally, since a plurality of reaction elements for measuring the same object material is attached to one substrate, or a plurality of reaction elements for measuring different object materials is attached to one substrate, various applications are possible, usability is maximized, and sequential measurement is possible. As well, the biomaterial measuring device is packaged in a magazine manner, thus reducing inconvenience when a user must exchange a strip every measurement. Furthermore, if using an optical method, it is possible to install a lens to focus light, thus reducing a reaction area, thereby minimizing the amount of sample needed during measurement. This has very important significance when blood-gathering is repeatedly conducted for a regular medical examination. Additionally, if using an electrochemical method, since; it is possible to freely control the shape of a capillary, the amount of sample needed during measurement is reduced. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates the production of a strip using a conventional optical method; FIG. 2 illustrates the production of a biosensor strip using a conventional electrochemical method; FIG. 3 is a sectional view of the biosensor strip of FIG. 2; FIG. 4 illustrates the production of a chip using an optical method according to the present invention; FIG. 5 illustrates the chip using the optical method according to an embodiment of the present invention; FIG. 6 is a sectional view of the chip of FIG. 5; FIGS. 7 to 13 are sectional views of various attachment substrates of chips using the optical method according to the present invention; FIG. 14 illustrates a chip using an optical method according to another embodiment of the present invention; FIG. 15 illustrates the production of a biosensor chip using an electrochemical method according to the present invention; FIG. 16 illustrates a biosensor chip using an electrochemical method according to an embodiment of the present invention; FIG. 17 is a partial sectional view of the biosensor chip of FIG. 16; and FIG. 18 illustrates a biosensor chip using an electrochemical method according to another embodiment of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a detailed description will be given of embodiments of the present invention with reference to the drawings. In the drawings, the same reference numerals are used throughout the different drawings to designate the same or similar components. FIG. 4 illustrates the production of a chip using an optical method according to the present invention. The procedure of producing a reaction element is the same as a conventional procedure. In other words, holes 304 are formed through a substrate 302 to allow light to penetrate therethrough, and a membrane 306, to which a biochemical reagent is applied, is attached thereto. Subsequently, the resulting structure is cut into reaction elements 308. Next, the cut reaction elements 308 are attached to separate attachment substrates 310, 312. If holes are already formed through the substrates 310, 312, it is possible to attach the reaction elements 308 to the attachment substrates 310, 312 while the membrane 306 is not attached to the substrate 302. In this case, the preparation of the substrate 302 and the formation of the holes through the substrate 302 may be omitted. In the present invention, the biochemical reagent is applied to the substrate 302 after it is layered on the membrane 306. However, it may be directly applied to the substrate 302 without being layered on the membrane 306. The attachment substrates 310, 312 may be made of any one selected from rigid plastic, glass, or silicon wafer. In consideration of processability, it is preferable to use a plastic substrate, such as a polycarbonate, used as the material for a compact disk. Since the plastic substrate may be produced through an injection molding process, a process error of the hole is insignificant, and the plastic substrate may be processed into various shapes, such as a circle, triangle, or square, and thus, it is applied to various fields. If the attachment substrates 310, 312 are made of glass or silicon wafer, it is possible to form a structure using anisotropic etching or isotropic etching. If using the attachment substrate 310, the attachment of the reaction element 308 to the attachment substrate is implemented in such a way that only the one reaction element 314 is attached to the attachment substrate. On the other hand, if using the attachment substrate 312, since it is possible to attach two or more reaction elements 316a, 316b, 316c, 316d to the attachment substrate, the production cost per reaction element is reduced. When the attachment of the four reaction elements is conducted, the four reaction elements for measuring the same object may be attached, or alternatively, the four reaction elements for measuring different objects may be attached. For example, the four reaction elements for measuring glucose may be attached, or alternatively, the reaction elements for measuring different objects of glucose, cholesterol, HDL, and LDL may be attached to the attachment substrate 312 to produce a chip. If the objects, which must be clinically measured together, such as glucose, glycated hemoglobin (HbAlc), and hemoglobin (Hb), are analyzed, availability is improved and it is possible to produce goods having high added value. FIG. 5 illustrates a chip using an optical method according to the present invention, and FIG. 6 is a sectional view of the chip of FIG. 5. In FIGS. 5 and 6, reference numerals 302, 304, 306, 310, and 402 denote a substrate, a hole, a membrane to which a biochemical reagent is applied, an attachment substrate, and a lens integrated with the attachment substrate 310, respectively. Since light is focused using the lens 402, it is possible to reduce a reaction area so as to minimize the amount of sample needed during measurement. FIGS. 5 to 13 are sectional views of various attachment substrates of the chips using the optical method according to the present invention. As described above, when the attachment substrates 310, 312 are produced through an injection molding process using plastic as a material, it is possible to produce them in a predetermined shape. FIG. 7 illustrates an attachment substrate, which is not processed, except that a groove 502 for receiving the reaction element 308 is formed on the substrate. FIG. 8 illustrates an attachment substrate through which a hole is already formed. In this case, it is unnecessary to use a transparent material, but it is preferable to use a black or opaque material which does not reflect light. In particular, it is possible to use reused plastic, contributing to the reduction of environmental pollution. FIGS. 9 and 10 illustrate an attachment substrate on which a convex lens is formed, FIGS. 11 and 12 illustrate an attachment substrate on which a concave lens is formed, and FIG. 13 illustrates an attachment substrate on which convex and concave lenses are formed simultaneously. Meanwhile, since the attachment substrate is thicker than a conventional strip-type plastic film and it is possible to produce the attachment substrate through an injection molding process, various functions may be additionally provided. FIG. 14 illustrates a chip using an optical method, on which a dehumidifying agent is mounted. It is very important for a biochemical reagent to be dehumidified so as to assure stability for a long time. As shown in FIG. 14, a space 604 for storing a dehumidifying agent 602 is formed on the attachment substrate 310. A cover 606, which forms the top of the resulting attachment substrate, is provided so as to isolate the space 604 for the dehumidifying agent and a membrane 306, to which a biochemical reagent is applied, from the environment. The dehumidifying agent 602 may be produced in a predetermined shape, such as circular or granular shape, and thus, it is preferable to form the space 604 for the dehumidifying agent so as to correspond in shape to the dehumidifying agent 602. Other components are the same as those of FIG. 4. FIG. 15 illustrates the production of a biosensor chip using an electrochemical method according to the present invention. As shown in FIG. 15, after an electrode 704 and a via hole 706 are formed on an insulator 702, a biochemical reagent (not shown) is applied on the resulting insulator through a dot dispensing process or a spin coating process. The resulting structure is cut into reaction elements 708, and they are attached to separate attachment substrates 710, 712 on which capillaries are already formed. The via hole 706 electrically connects the electrode 704, formed on an upper side of the insulator 702, to an electrode (not shown) formed on a lower side, that is, an opposite side of the upper side. A conductor is applied on a wall of the via hole. In the specification, the via hole is used as a comprehensive notion, and includes a conductive rod. The insulator 702 may be made of any one selected from rigid plastic, glass, or silicon wafer. In consideration of processability, it is preferable to use a plastic substrate, such as polycarbonate, used as a material for compact disks, or to use a printed circuit board (PCB). Particularly, when employing the PCB frequently used in the industrial world, the formation of the via hole 706 is very easily conducted because it is possible to automatically form the via hole using existing facilities. A portion of the electrode 704 on the upper side of the insulator 702, to which the biochemical reagent is applied, may be made of a predetermined electrode material. Any material, which is used as an electrode material in electrochemistry, may be used, and the electrode material may be exemplified by carbon, carbon paste (carbon containing Au, Ag, or the like), Ag/AgCl, gold, platinum, and palladium. The electrode (not shown), which is formed on the lower side of the insulator 702, transfers an electric signal, which is formed by a reaction between the biochemical reagent and an object, to a measuring device. Hence, the electrode may be made of a wiring material, such as copper having excellent electric conductivity, which is typically used in the PCB because it has no connection with a biochemical reaction. The attachment substrates 710, 712 may be made of any one selected from rigid plastic, glass, or silicon wafer. In consideration of processability, it is preferable to use a plastic substrate, such as polycarbonate, used as a material for compact disks, or to use a PCB. Particularly, since the plastic substrate may be produced through an injection molding process, it is possible to form a capillary through one process and to process the capillary in various shapes. Furthermore, since a plurality of capillaries having different shapes is formed on one attachment substrate, it is possible to analyze the different objects using one attachment substrate. As well, the attachment substrate may be formed in various shapes, such as a circle, triangle, or square, and thus, it may be applied to various fields. If using the attachment substrate 710, the attachment of the reaction element 708 to the attachment substrate is implemented in such a way that only one reaction element 714 is attached to the attachment substrate. On the other hand, if using the attachment substrate 712, since it is possible to attach two or more reaction elements 716a, 716b, 716c, 716d to the attachment substrate, the production cost per reaction element is reduced. When four reaction elements are attached, four reaction elements for measuring the same object may be attached, or alternatively, four reaction elements for measuring different objects may be attached. For example, four reaction elements for measuring glucose may be attached, or alternatively, reaction elements for measuring different objects, such as glucose, cholesterol, HDL, and LDL may be attached to the attachment substrate 312 to produce a chip. If the objects, which must be clinically measured together, such as glucose, glycated hemoglobin (HbAlc), and hemoglobin (Hb), are analyzed, availability is improved and it is possible to produce goods having high added value. In the biosensor chip using the conventional electrochemical method as shown in FIG. 2, a reaction between the object and the biochemical reagent mostly occurs in the reaction element, which includes the capillary, in practice, and the performance of a product depends on the application of the biochemical reagent to the electrode therein. The remaining portion of the electrode serves only to transfer an electric signal, and thus, it need not be carefully produced. Accordingly, in the present invention, after the reaction elements are precisely produced, they are attached to a substrate which is capable of transferring an electric signal therethrough. This is the core characteristic of the present invention. In a process of forming the electrode, the electrode must be formed in an area of an A4-sized paper (210 mm×297 mm) in order to produce two hundred conventional biosensors having a size of 7.5 mm×35 mm. On the other hand, in the present invention, the electrode is formed in an area (100 mm×100 mm) that is smaller than half a sheet of A4-sized paper. Therefore, since an operation area, required by a screen printer and a sputter used to produce the electrode, is reduced, device expenses are reduced and it is possible to gain high uniformity. As well, application of a solution is easily implemented, and uniformity of application of the reagent is improved because an area to be dried after the application is reduced. Furthermore, it is possible to employ a spin coating process instead of a dot dispensing process, thus improving productivity. FIG. 16 illustrates a biosensor chip using an electrochemical method according to an embodiment of the present invention, and FIG. 17 is a partial sectional view of the biosensor chip of FIG. 16. FIG. 16 shows the attachment of one reaction element to an attachment substrate. FIG. 18 illustrates a biosensor chip using an electrochemical method according to another embodiment of the present invention, in which a plurality of reaction elements is attached to one attachment substrate. Constitutions of the above biosensor chips are shown in FIG. 15. The present invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described. INDUSTRIAL APPLICABILITY As described above, in a biomaterial measuring device according to the present invention, since a material cost is minimized and it is easy to automatize production, it is possible to reduce a production cost. Further, it is possible to attach a plurality of reaction elements to one substrate, thereby reducing the price per reaction element. Furthermore, since the substrate is made of plastic, silicone, or glass according to the type of reactant and a characteristic of a reaction, process compatibility is improved, and the device can be applied to an expanded range of biochemical assays. Additionally, since a plurality of reaction elements for measuring the same object material is attached to one substrate, or a plurality of reaction elements for measuring different object materials is attached to one substrate, various applications are possible, usability is maximized, and sequential measurement is possible. As well, the biomaterial measuring device is packaged in a magazine manner, thus reducing inconvenience when a user must exchange a strip every measurement. Furthermore, if using an optical method, it is possible to install a lens to focus light, thus reducing a reaction area, thereby minimizing the amount of sample needed during measurement. This has very important significance when blood-gathering is repeatedly conducted for a regular medical examination. Additionally, if using an electrochemical method, since it is possible to freely control a capillary shape, the amount of sample needed during measurement is reduced.

<SOH> BACKGROUND ART <EOH>A biosensor, in which a biomaterial is used as a tracing device and which has excellent sensitivity and reaction specificity, is expected to be applied to various fields, such as medical/pharmaceutical fields (clinical chemical assay and remedy), and process and environmental monitoring and chemical stability evaluation in the bio-industry. Particularly, a chemical composition assay in vivo is medically very important, and recently, the biosensor has been frequently used to assay a biomaterial sample containing blood in a medical diagnosis field. Of various biosensors, a biosensor, which employs an enzyme assay method using a characteristic reaction of an enzyme to a matrix or of an enzyme to an inhibitor, is most frequently used in hospitals and clinical chemical assays because ease of application is assured, measurement sensitivity is excellent, and the results are rapidly obtained. The enzyme assay method, which is applied to the biosensor, may be classified into an optical method, in which light transmittance is measured through a spectroscopic assay before and after an enzyme reaction, and an electrode method, in which an electrochemical signal is measured. Compared to the electrode method, the optical method is difficult to use assay of critical biomaterial because the measuring time is long, a great amount of blood is required, and measurement error occurs due to turbidity of a biomaterial sample. Accordingly, recently, the electrode method has been frequently applied to a biosensor using an enzyme. In the electrode method, after an electrode system is formed on a plastic film, an assay reagent is applied to an electrode, a sample is introduced, and specific components of the sample are quantitatively measured using a predetermined electric potential. U.S. Pat. Nos. 5,120,420, 5,395,504, 5,437,999, and 5,997,817 are patent literatures of a biosensor, which disclose embodied operations and effects of the biosensor in detail. The disclosures of the above patents are incorporated herein by reference as follows. FIG. 1 illustrates the production of a strip using a conventional optical method. Holes 104 are formed through a substrate 102 to allow light to penetrate therethrough, and a membrane 106 , to which a biochemical reaction reagent is applied, is attached thereto. Subsequently, the resulting structure is cut into strips 108 . In the method, since the strips must be produced in a handy size, the strips are formed so as to be a few cm long. Hence, the size of a production device increases and the device costs a great deal. Since the strip is typically provided in a roll form, the substrate 102 is made of a flexible material. Accordingly, a process error occurs in the course of forming the holes by punching or of forming the strips by cutting, and thus, the uniformity of measurements is undesirably reduced. Furthermore, there is a limit that only one reaction element can be produced using one strip. FIG. 2 illustrates the production of a biosensor strip using a conventional electrochemical method. FIG. 3 is a sectional view of the biosensor strip of FIG. 2 . For convenience of understanding, thicknesses of layers are exaggerated in FIG. 3 . After an operation electrode 204 , a standard electrode 206 , and an auxiliary electrode (not shown), on which a redox reaction occurs, are formed on an insulator 202 , an insulator 210 , which is processed in a predetermined shape to form a capillary 208 for feeding a sample therethrough and which acts as a spacer, is attached to the resulting insulator 202 . Subsequently, a biochemical reagent 212 is applied to the electrodes, and an insulator 214 is attached thereto to form a cover, thereby completing the biosensor, in which the biochemical reagent 212 is contained in the capillary 208 , through the electrochemical method. Finally, the resulting structure is cut into strips 216 . As in the production of the strips using the conventional optical method, the strips must be produced in a handy size, thus the strips are formed so as to be a few cm long. Since the electrodes must be formed on every strip, it is difficult to implement the production in a roll form, and thus, the production is typically carried out in a sheet form. When the production is conducted in the sheet manner, it is necessary to carefully handle the entire surface of a sheet because each strip is large. To produce the strips having uniform performance using a wide sheet, it is necessary to take a care in the formation of the electrodes. Additionally, since application of a solution must be conducted throughout the wide area, it is difficult to assure uniformity during a drying process. Therefore, a production device is large and costly, it is difficult to implement the production, and the production cost is high. The insulator 202 is made of a relatively thin plastic material so as to be cut into strips. When using glass or silicon wafer, the material cost of the substrate increases per strip, thus the price of the strip increases. As well, there is a limit that only one reaction element can be produced using one strip. Furthermore, a capillary having one structure can be formed in one process. If capillaries having two structures are formed, the production cost doubles.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 illustrates the production of a strip using a conventional optical method; FIG. 2 illustrates the production of a biosensor strip using a conventional electrochemical method; FIG. 3 is a sectional view of the biosensor strip of FIG. 2 ; FIG. 4 illustrates the production of a chip using an optical method according to the present invention; FIG. 5 illustrates the chip using the optical method according to an embodiment of the present invention; FIG. 6 is a sectional view of the chip of FIG. 5 ; FIGS. 7 to 13 are sectional views of various attachment substrates of chips using the optical method according to the present invention; FIG. 14 illustrates a chip using an optical method according to another embodiment of the present invention; FIG. 15 illustrates the production of a biosensor chip using an electrochemical method according to the present invention; FIG. 16 illustrates a biosensor chip using an electrochemical method according to an embodiment of the present invention; FIG. 17 is a partial sectional view of the biosensor chip of FIG. 16 ; and FIG. 18 illustrates a biosensor chip using an electrochemical method according to another embodiment of the present invention. detailed-description description="Detailed Description" end="lead"?

20081125

20120508

20100311

96672.0

C12M134

RUFO, LOUIS J

BIOMATERIAL MEASURING DEVICE AND MANUFACTURING METHOD THEREOF

SMALL

ACCEPTED

C12M

ACCEPTED

Quick-Connect Coupling

A quick-connect coupling has a retainer for retaining a tube in a coupling body. The retainer is pressed in the coupling body so as to lock the tube in place in the coupling body. The retainer cannot be fully pressed in the coupling body and projects from the coupling body to indicate that the tube is not properly connected to the coupling body unless the tube is inserted completely in the coupling body. The retainer is combined with complete connection verifying legs that enables the retainer to be able to be pressed in the coupling body when an annular ridge formed in an end part of a tube inserted in the coupling body is advanced beyond a position where the retainer is able to engage with the annular ridge.

1. A quick-connect coupling comprising: a coupling body in which an end part, provided with an annular ridge, of a tube is inserted, and a retainer to be inserted through a window into the coupling body in a direction perpendicular to the axis of the coupling body so as to engage with the annular ridge to retain the end part of the tube in the coupling body; wherein the retainer engages with the annular ridge to retain the tube in the coupling body, complete connection verifying members are formed in combination with the retainer to enable the retainer to be pressed through the window into the coupling body only after the annular ridge of the end part of the tube inserted in the coupling body has advanced beyond a position where the retainer is able to engage with the annular ridge. 2. The quick-connect coupling according to claim 1, wherein the complete connection verifying members are formed integrally with the retainer. 3. The quick-connect coupling according to claim 2, wherein the coupling body has a blocking part that engages with the complete connection verifying members to restrain the complete connection verifying members from being pressed into the coupling body in a state where the tube is improperly inserted in the coupling body. 4. The quick-connect coupling according to claim 3, wherein the retainer has a rib having an inner end surface that engages with the annular ridge of the tube to retain the annular ridge in place and locking legs respectively having locking hooks that engage with side walls of the coupling body, respectively, and the complete connection verifying members extend along the locking legs of the retainer and are provided at their free ends with hooks capable of coming into contact with the blocking part, respectively. 5. The quick-connect coupling according to claim 4, wherein the hooks of the complete connection verifying members are provided with notches in which ends of the blocking part engage. 6. The quick-connect coupling according to claim 4, wherein the coupling body has backup parts for supporting the rib when a pulling force is exerted on the tube connected to the coupling body in a direction to pull the tube off the coupling body and an outer end surface opposite the inner end surface in engagement with the annular ridge to retain the tube in the coupling body is pressed against thereto. 7. The quick-connect coupling according to claim 4, wherein the complete connection verifying members have a strength such that the hooks of the complete connection verifying members cannot be separated from the blocking part by a pressure not higher than a predetermined reference threshold force to make the retainer unable to be pressed in the coupling body unless the tube is inserted in the coupling body so that the annular ridge of the tube is advanced clear of the rib into the coupling body beyond a position corresponding to the inner end surface of the rib. 8. The quick-connect coupling according to claim 7, wherein the retainer has a strength enough to make the retainer unable to be removed from the coupling body by a tensile force not higher than the predetermined reference threshold force in a state where the tube is retained normally in the coupling body by the retainer. 9. The quick-connect coupling according to claim 7, wherein the reference threshold force is 80N. 10. The quick-connect coupling according to claim 2, wherein a slit is formed between each of the locking legs and the complete connection verifying member adjacent to the locking leg. 11. The quick-connect coupling according to claim 2, wherein the retainer is a thin, substantially U-shaped member. 12. The quick-connect coupling according to claim 8, wherein the reference threshold force is 80N. 13. The quick-connect coupling according to claim 10, wherein the retainer is a thin, substantially U-shaped member.

TECHNICAL FIELD The present invention relates to a quick-connect coupling for coupling tubes of an automotive fuel system. BACKGROUND ART Quick-connect couplings are used prevalently for connecting fuel tubes of automotive fuel systems. The quick-connect coupling is capable of simply and quickly connecting tubes without using any fastening means, such as bolts. The quick-connect coupling has a coupling body and a retainer. An end part of a tube is inserted in the coupling body, and the retainer is pressed in the coupling body to retain the tube in the coupling body. Representative techniques related with quick-connect couplings are disclosed in U.S. Pat. No. 5,542,716 and JP 2002-206683 A. Referring to FIG. 12, an annular ridge 3 is formed on the outer circumference of an end part of a tube 2 fitted in a coupling body 4. A slide retainer 5 is pressed radially in a window formed in the coupling body 4. An end edge 6a of a rib 6 formed in the retainer engages with the annular ridge 3 to retain the end part of the tube 2 in the coupling body 4. A correct method of connecting the tube 2 and the quick-connect coupling fits the end part of the tube in the coupling body 4 first, and then the retainer 5 is pushed in the window of the coupling body 4. However, it often occurs that the retainer 5 is pressed in the window of the coupling body 4 as shown in FIG. 13 before fitting the end part of the tube 2 in the coupling body 4. If the tube 2 is applied to the coupling body 4 in an effort to fit the end part of the tube 2 into the coupling body 4 after pressing the retainer 5 in the window of the coupling body 4, the other end edge 6b of the rib 6 stops the annular ridge 3 and obstructs the further insertion of the tube 2 in the coupling body 4. Consequently, the quick-connect coupling and the tube 2 are connected incompletely. The appearance of the incomplete connection of the quick-connect coupling and the tube 2 cannot be discriminated from that of the complete connection of the quick-connect coupling and the tube 2. Therefore, the known quick-connect coupling is designed such that the end part of the tube 2 is unable to engage with O rings when the quick-connect coupling and the tube 2 are connected incompletely, and the incomplete connection can be found by the detection of the leakage of a fluid in a leakage test. A quick-connect coupling disclosed in JP 11-230456 A is designed so that the incomplete connection of the quick-connect coupling and a tube can be noticed at a glance. The quick-connect coupling has, in addition to a coupling body and a retainer, complete connection verifying legs. The complete connection verifying legs cannot be easily separated from the coupling body unless the tube is inserted in the coupling body to a coupling position and the retainer is engaged normally with the tube. Although this quick-connect coupling is capable of indicating incomplete connection, the quick-connect coupling is unable to prevent incomplete connection. DISCLOSURE OF THE INVENTION Accordingly, it is an object of the present invention to solve the foregoing problems and to provide a quick-connect coupling capable of preventing the incomplete connection of the quick-connect coupling and a pipe by making a retainer unable to lock a pipe unless the pipe is inserted fully in the quick-connect coupling to a complete connection position. A quick-connect coupling according to the present invention includes: a coupling body in which an end part, provided with an annular ridge, of a tube is inserted; and a retainer to be inserted through a window into the coupling body in a direction perpendicular to the axis of the coupling body so as to engage with the annular ridge to retain the end part of the tube in the coupling body; wherein the retainer engages with the annular ridge to connect the tube and the coupling body, and complete connection verifying legs are formed in combination with the retainer to enable the retainer to be pressed through the window into the coupling body only after the annular ridge of the end part of the tube inserted in the coupling body has advanced beyond a position where the retainer is able to engage with the annular ridge. According to the present invention, the insertion of the complete connection verifying legs in the coupling body is obstructed by blocking parts and the retainer cannot be pressed in the coupling body unless the tube is inserted in the coupling body beyond the position where the retainer is able to engage with the annular ridge. Thus the incomplete engagement of the retainer and the tube can be surely prevented. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an exploded perspective view of a quick-connect coupling in a preferred embodiment according to the present invention; FIG. 2 is a side elevation of the quick-connect coupling shown in FIG. 1; FIG. 3 is a front view of the quick-connect coupling shown in FIG. 1; FIGS. 4(a) and 4(b) are longitudinal sectional views of the quick-connect coupling shown in FIG. 1 in a state where an annular ridge formed on a tube is in contact with complete connection verifying legs and a state where the annular ridge of the tube has not yet passed a locking point where a retainer engages with the annular ridge, respectively; FIG. 5 is a longitudinal sectional view of the quick-connect coupling shown in FIG. 1 in a state where a tube is inserted in the quick-connect coupling to a position where the retainer is able to exercise its function; FIG. 6 is a cross-sectional view of the quick-connect coupling shown in FIG. 1 in a state where the annular ridge is at a position shown in FIG. 5 and the complete connection verifying legs is expanded; FIG. 7 is a longitudinal sectional view of the quick-connect coupling shown in FIG. 1 in a state where the annular ridge of the tube is securely retained by the retainer; FIG. 8 is an end view of the quick-connect coupling in a state shown in FIG. 7; FIG. 9 is a front view of a retainer in a modification of the retainer included in the quick-connect coupling shown in FIG. 1; FIG. 10 is a view of assistance in explaining the operation of complete connection verifying legs shown in FIG. 9; FIG. 11 is a front view of a coupling body in a modification of a coupling body included in the quick-connect coupler shown in FIG. 1; FIG. 12 is a longitudinal sectional view of a prior art quick-connect coupling; and FIG. 13 is a longitudinal sectional view of the quick-connect coupling shown in FIG. 12 in a state where a tube and the quick-connect coupling are incompletely connected. BEST MODE FOR CARRYING OUT THE INVENTION A quick-connect coupling in a preferred embodiment according to the present invention will be described with reference to the accompanying drawings. Referring to FIG. 1 showing a quick-connect coupling 10 in an exploded perspective view, the quick-connect coupling 10 has a coupling body 12 and a retainer 16. FIG. 2 is a side elevation of the quick-connect coupling 10. FIG. 3 is a front view of the quick-connect coupling 10. FIGS. 4(a) and 4(b) are longitudinal sectional views of the quick-connect coupling 10 in a state where an end part of a tube 14 is inserted in the quick-connect coupling 10. The coupling body 12 of the quick-connect coupling 10 is a female fitting having a tube entrance 20 and integrally provided with a male fitting 18 to be forced into a resin tube 17. An end part of the tube 14 is inserted through the tube entrance 20 in the coupling body 12 and the resin tube 17 is joined to the male fitting 18. A stepped passage 21 is formed axially through the coupling body 12 as shown in FIG. 4. A tangential retainer guide slot 22 is formed in a front end part of the coupling body 12. Locking legs 31a and 31b of the retainer 16 is inserted in the retainer guide slot 22 in a direction perpendicular to the axis of the coupling body 12. The coupling body 12 has side walls 23a and 23b, a first cylindrical part 25a, a reduced second cylindrical part 25b continuous with the first cylindrical part 25a, and the male fitting 18 continuous with the second cylindrical part 25b. An O ring 27 is fitted in the first cylindrical part 25a and is retained in place by an O ring retainer 28. Referring to FIGS. 1 and 4, the tube 14 in this embodiment is a metal or resin tube. An annular ridge 30 is formed in a part of the tube 14 in a part at a predetermined distance from the free end of the tube 14. When the retainer is inserted in the retainer guide slot 22, the retainer 16 engages with the annular ridge 30 to restrain the tube 14 from coming off the coupling body 12. The retainer 16 is a generally U-shaped plastic or metal member having the parallel locking legs 31a and 31b. The retainer 16 is thin as compared with conventional retainers of this kind. The thickness of the retainer 16 corresponds to the width of the retainer guide slot 22. Referring to FIGS. 1 and 3, a substantially U-shaped rib 32 is formed integrally with the locking legs 31a and 31b of the retainer 16. The U-shaped rib 32 has a curved inner surface of a curvature substantially equal to the curvature of the outer surface of the tube 14. The tube 14 inserted in the coupling body 12 is fitted closely in the rib 32. The locking legs 31a and 31b of the retainer 16 are provided in their end parts with locking hooks 34a and 34b, respectively. When the locking legs 31a and 31b of the retainer 16 are inserted in the retainer guide slot 22 to predetermined locking positions, the locking hooks 34a and 34b engage with the lower edges of the side walls 23a and 23b of the coupling body 12, respectively, as shown in FIG. 8 to retain the retainer 16 in the coupling body 12. When the retainer 16 is thus locked in place, an inner end surface 32a of the U-shaped rib 32 of the retainer 16 engages with the annular ridge 30 to make the tube 14 inseparable from the coupling body 12 as shown in FIG. 7. The quick-connect coupling 10 is designed such that the retainer 16 retained in place in the coupling body 12 cannot be pulled out of the coupling body 12 until a pulling force applied to the retainer 16 exceeds a reference threshold force of about 80N even if the retainer 16 is pulled to extract the retainer 16 forcibly from the coupling body 12 in a state where the locking hooks 34a and 34b of the retainer 16 are engaged with the lower edges of the side walls 23a and 23b. The retainer 16 is integrally provided with complete connection verifying legs 36a and 36b in combination with the locking legs 31a and 31b, respectively. The complete connection verifying legs 36a and 36b verifies a condition where the retainer 16 and the tube 14 are in a positional relation that enables the complete connection of the quick-connect coupling 10 and the tube 14. The bar-shaped complete connection verifying legs 36a and 36b extend parallel to the locking legs 31a and 31b, respectively, such that narrow slits 35 are formed between the locking leg 31a and the complete connection verifying leg 36a and between the locking leg 31b and the complete connection verifying leg 36b, respectively. Hooks 37a and 37b are formed on the free ends of the complete connection verifying legs 36a and 36b, respectively. The coupling body 12 is provided with a blocking part 38 that interferes with the hooks 37a and 37b of the complete connection verifying members 36a and 36b when the retainer 16 is inserted in the coupling body 12. As shown in FIGS. 1 and 3, the blocking part 38 has a crescent shape and extends along the edge of the open end of the passage formed in the first cylindrical part 25a. The blocking part 38 has opposite ends serving as blocking edges 39a and 39b. The hooks 37a and 37b of the complete connection verifying legs 36a and 36b come into contact with the blocking edges 39a and 39b. The distance A between the hooks 37a and 37b when the complete connection verifying legs 36a and 36b are in a free state is shorter than the diameter B of the annular ridge 30 of the tube 14. When the tube 14 is inserted in the coupling body 12, the annular ridge 30 comes into contact necessarily with the hooks 37a and 37b of the complete connection verifying legs 36a and 36b. The distance between the blocking edges 39a and 39b of the blocking part 38 is determined such that the blocking edges 39a and 39b are directly below the hooks 37a and 37b when the complete connection verifying legs 36a and 36b are in a free state. The retainer cannot be pressed into the coupling body 12 even if a force is exerted on the retainer 16 to press the retainer into the coupling body 12 in this state unless the force exceeds a fixed threshold force. In this embodiment, the threshold force is about 80N. The strength of the complete connection verifying legs 36a and 36b are designed so that the retainer 16 cannot be pressed into the coupling body 12 unless a force exceeding the threshold force is applied thereto. The annular ridge 30 has a U-shaped cross section. The hooks 37a and 37b of the complete connection verifying legs 36a and 36b are able to slide along the surface of the annular ridge 30. As the hooks 37a and 37b slide down along the surface of the annular ridge 30, the complete connection verifying legs 36a and 36b are bent outward. When the tube 14 is inserted in the coupling body 12 deep enough to set the annular ridge 30 in a plane containing the complete connection verifying legs 36a and 36b as shown in FIG. 5, the space between the complete connection verifying legs 36a and 36b is increased to a maximum as shown in FIG. 6. Consequently, the hooks 37a and 37b are separated from the blocking edges 39a and 39b of the blocking part 38 and the retainer 16 can be pressed into the coupling body 12. The operation of the quick-connect coupling 10 will be described. First, the temporary assembly of the coupling body 12 and the retainer 16 will be described. Referring to FIG. 1, the retainer 16 is inserted lightly in the retainer guide slot 22 formed in the coupling body 12. Then, the locking hooks 34a and 34b of the locking legs 31a and 31b of the retainer 16 engages in grooves 40a and 40b formed in the inner surface of the side walls 23a and 23b of the coupling body 12 as shown in FIG. 3. When the coupling body 12 and the retainer 16 are thus temporarily assembled, the complete connection verifying legs 36a and 36b are at positions shown in FIG. 3 and the hooks 37a and 37b are spaced the distance A apart. When the quick-connect coupling 10 in this embodiment is shipped, the coupling body 12 and the retainer 16 are temporarily assembled and the resin tube 17 is connected to the quick-connect coupling 10 by forcing the male fitting 18 into the resin tube 17. When the user uses the quick-connect coupling for connecting a fuel pipe for supplying fuel to an engine at an automobile assembling plant, the metal tube 14 can be connected to the quick-connect coupling 10 simply by inserting the metal tube 14 in the coupling body 12 and pressing the retainer 16 into the coupling body 12. As shown in FIG. 4(a), the annular ridge 30 of the tube 14 engages the hooks 37a and 37b of the complete connection verifying legs 36a and 36b when an end part of the tube 14 is inserted through the tube entrance 20 in the coupling body 12. If the end part of the tube 14 is inserted deep enough in the coupling body 12 the annular ridge 30 is at a position shown in FIG. 4(a) and hence the retainer 16 cannot be fully pressed into the retainer guide slot 22 because the advancement of the hooks 37a and 37b is blocked by the blocking edges 39a and 39b of the blocking part 38. When the tube 14 is pressed further into the coupling body 12, the annular ridge 30 bends the complete connection verifying legs 36a and 36b so as to move the hooks 37a and 37b away from each other, and the operator feels a sensation of resistance. When the tube 14 is pressed into the coupling body 12 until the annular ridge 30 comes into engagement with the O ring retainer 28, the annular ridge 30 and the hooks 37a and 37b of the complete connection verifying legs 36a and 36a are contained in a plane. FIG. 6 shows the positional relation between the hooks 37a and 37b of the connection verifying legs 36a and 36b and the blocking edges 39a and 39b in a state where the annular ridge 30 and the hooks 37a and 37b of the complete connection verifying legs 36a and 36a are contained in a plane. In this state, the hooks 37a and 37b are able to advance further without being interfered with by the blocking edges 39a and 39b, so that the retainer 16 can be fully pressed into the coupling body 12. When the retainer 16 is pressed deep into the coupling body 12, the locking hooks 34a and 34b engage with the lower edges of the side walls 23a and 23b of the coupling body 12, respectively, as shown in FIGS. 7 and 8. FIG. 8 is an bottom view of the quick-connect coupling taken from the side of the tube entrance 20. When a force is exerted on the tube 14 in a direction to pull the tube 14 off the coupling body 12, the inner end surface 32a of the rib 32 of the retainer 16 engages with the annular ridge 30 to restrain the tube 14 from axial, outward movement of the tube 14 relative to the coupling body 12. Thus the quick-connect coupling 10 and the tube 14 are firmly connected and locked together. Needless to say, the joint of the coupling body 12 and the tube 14 is sealed by the O rings 27. The locking legs 34a and 34b of the retainer 16 are strong enough to withstand a destructive force not higher than the predetermined reference threshold force. Preferably, the locking legs 34a and 34b do not yield to and cannot be removed from the coupling body 12 by a tensile force not higher than 80N at a minimum. If the tube 14 is not inserted sufficiently deep into the coupling body 12 as shown in FIG. 4(b), an end surface of the annular ridge 30 of the tube 14 is substantially at a position corresponding to the inner end surface 32a, namely, stopping surface, of the rib 32, namely, a locking point where the annular ridge 30 can be engaged with the retainer 16. However, in the state shown in FIG. 4(b), the distance between the hooks 37a and 37b of the complete connection verifying legs 36a and 36b is not increased properly. Consequently, the hooks 37a and 37b are in contact with the blocking edges 39a and 39b and the further insertion of the retainer 16 into the coupling body 12 is obstructed by the blocking edges 39a and 39b. Since the retainer 16 cannot be further inserted in the coupling body 12 by a considerably high pressure, the insufficient insertion of the tube 14 in the coupling body 12 can be intuitively recognized by the sense of touch. The complete connection verifying legs 36a and 36b are strong enough not to be broken or chipped unless a high force exceeding a predetermined reference threshold force, preferably, 80N, is applied thereto. Thus the retainer 16 cannot be further inserted into the coupling body 12 unless the complete connection verifying legs 39a and 39b are broken by a high force exceeding the predetermined reference threshold force. The hooks 37a and 37b are not separated from the blocking edges 39a and 39b until the tube 14 is inserted so that the annular ridge 30 of the tube 14 is advanced beyond the locking point. Thus the advancement of the annular ridge 30 beyond the locking point can be verified by the agency of the complete connection verifying legs 36a and 36b. The distance of advancement of the annular ridge 30 beyond the locking point necessary for the separation of the hooks 37a and 37b from the blocking edges 39a and 39b is dependent on the thickness of the slits 35 between the locking leg 31a and the complete connection verifying leg 36a and between the locking leg 31b and the complete connection verifying leg 36b. Since the complete connection verifying legs 36a and 36b are necessarily subject to the blocking action of the blocking edges 39a and 39b and the retainer 16 cannot be further inserted in the coupling body 12 until the tube 14 is properly inserted in the coupling body 12, the incomplete engagement of the tube 14 and the retainer 16 can be surely prevented. Referring to FIG. 9, a retainer 16 in a modification has complete connection verifying legs 36a and 36b having hooks 37a and 37b provided with notches 42a and 42b, respectively. The notches 42a and 42b facilitate the engagement of the blocking edges 39a and 39b with the hooks 37a and 37b. The hooks 37a and 37b of the complete connection verifying legs 36a and 36b collide against the blocking edges 39a and 39b, respectively, if the tube 14 is inserted improperly into the coupling body 12. The notches 42a and 42b of the hooks 37a and 37b make the separation of the hooks 37a and 37b from the blocking edges 39a and 39b more difficult. As shown in FIG. 10, pressure (insertion force) P presses the notches 42a and 42b against the blocking edges 39a and 39b. Consequently, the complete connection verifying legs 36a and 36b have difficulty in shifting in the directions of the arrows A and B, and the complete connection verifying legs 36a and 36b never separate from the blocking edges 39a and 39b unless the blocking edges 39a and 39b break. After the tube 14 has been properly inserted in the coupling body 12, there is no problem in the movement of the hooks 37a and 37b of the complete connection verifying legs 36a and 36b in the direction of the arrow A even if the hooks 37a and 37b are provided with the notches 42a and 42b, respectively. Referring to FIG. 11, a coupling body 12 in a modification is provided with backup walls 44a and 44b protruding toward a tube entrance 20 so that the backup walls 44a and 44b may not interfere with the annular ridge 30 of the tube 14. The backup walls 44a and 44b engage with the rib 32 to support the rib 32. FIG. 11(a) shows the retainer 16 not pressed fully into the coupling body 12 and FIG. 11(b) shows the retainer 16 pressed fully into the coupling body 12. In the state shown in FIG. 11(b) the opposite ends 45a and 45b of the rib 32 overlap the backup walls 44a and 44b, respectively. When a pulling force is applied to the tube 14 in a direction to pull the tube 14 off the coupling body 12 in the state shown in FIG. 7, the annular ridge 30 of the tube 14 exerts a pressure on the inner end surface 32a of the rib 32. If the pressure is excessively high, it is possible that the rib 32 is deformed and the tube 14 comes off the coupling body 12. When parts, corresponding to the ends 45a and 45b overlapping the backup walls 44a and 44b, of the outer end surface opposite the inner end surface 32a of the rib 32 is in contact with the backup walls 44a and 44b as shown in FIG. 11(b), the backup walls 45a and 45b supports the rib 32 to prevent the deformation of the rib 32 and, consequently, the tube 14 cannot be pulled off the coupling body 12. The slits 35 are formed between the locking leg 31a and the complete connection verifying leg 36a and between the locking leg 31b and the complete connection verifying leg 36b, respectively, in the retainer 16. The slits 35 may be of a very small thickness. Since the retainer 16 of the present invention is very thin as compared with conventional retainers, the coupling body 12 can be formed in a length shorter than that of the conventional coupling body shown in FIG. 12. The quick-connect coupling 10 of the present invention facilitates the discrimination of a state of complete connection from a state of incomplete connection. Although the retainer 16 of the quick-connect coupling 10 of the present invention has both the locking legs 31a and 31b and the complete connection verifying legs 36a and 36b, a quick-connect coupling in a modification may include a retainer provided with only locking legs, and a separate complete connection verifying member. Although the invention has been described in its preferred embodiment with a certain degree of particularity, obviously many changes and variations are possible therein. It is therefore to be understood that the present invention may be practiced otherwise than as specifically described herein without departing from the scope and spirit thereof.

<SOH> BACKGROUND ART <EOH>Quick-connect couplings are used prevalently for connecting fuel tubes of automotive fuel systems. The quick-connect coupling is capable of simply and quickly connecting tubes without using any fastening means, such as bolts. The quick-connect coupling has a coupling body and a retainer. An end part of a tube is inserted in the coupling body, and the retainer is pressed in the coupling body to retain the tube in the coupling body. Representative techniques related with quick-connect couplings are disclosed in U.S. Pat. No. 5,542,716 and JP 2002-206683 A. Referring to FIG. 12 , an annular ridge 3 is formed on the outer circumference of an end part of a tube 2 fitted in a coupling body 4 . A slide retainer 5 is pressed radially in a window formed in the coupling body 4 . An end edge 6 a of a rib 6 formed in the retainer engages with the annular ridge 3 to retain the end part of the tube 2 in the coupling body 4 . A correct method of connecting the tube 2 and the quick-connect coupling fits the end part of the tube in the coupling body 4 first, and then the retainer 5 is pushed in the window of the coupling body 4 . However, it often occurs that the retainer 5 is pressed in the window of the coupling body 4 as shown in FIG. 13 before fitting the end part of the tube 2 in the coupling body 4 . If the tube 2 is applied to the coupling body 4 in an effort to fit the end part of the tube 2 into the coupling body 4 after pressing the retainer 5 in the window of the coupling body 4 , the other end edge 6 b of the rib 6 stops the annular ridge 3 and obstructs the further insertion of the tube 2 in the coupling body 4 . Consequently, the quick-connect coupling and the tube 2 are connected incompletely. The appearance of the incomplete connection of the quick-connect coupling and the tube 2 cannot be discriminated from that of the complete connection of the quick-connect coupling and the tube 2 . Therefore, the known quick-connect coupling is designed such that the end part of the tube 2 is unable to engage with O rings when the quick-connect coupling and the tube 2 are connected incompletely, and the incomplete connection can be found by the detection of the leakage of a fluid in a leakage test. A quick-connect coupling disclosed in JP 11-230456 A is designed so that the incomplete connection of the quick-connect coupling and a tube can be noticed at a glance. The quick-connect coupling has, in addition to a coupling body and a retainer, complete connection verifying legs. The complete connection verifying legs cannot be easily separated from the coupling body unless the tube is inserted in the coupling body to a coupling position and the retainer is engaged normally with the tube. Although this quick-connect coupling is capable of indicating incomplete connection, the quick-connect coupling is unable to prevent incomplete connection.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is an exploded perspective view of a quick-connect coupling in a preferred embodiment according to the present invention; FIG. 2 is a side elevation of the quick-connect coupling shown in FIG. 1 ; FIG. 3 is a front view of the quick-connect coupling shown in FIG. 1 ; FIGS. 4 ( a ) and 4 ( b ) are longitudinal sectional views of the quick-connect coupling shown in FIG. 1 in a state where an annular ridge formed on a tube is in contact with complete connection verifying legs and a state where the annular ridge of the tube has not yet passed a locking point where a retainer engages with the annular ridge, respectively; FIG. 5 is a longitudinal sectional view of the quick-connect coupling shown in FIG. 1 in a state where a tube is inserted in the quick-connect coupling to a position where the retainer is able to exercise its function; FIG. 6 is a cross-sectional view of the quick-connect coupling shown in FIG. 1 in a state where the annular ridge is at a position shown in FIG. 5 and the complete connection verifying legs is expanded; FIG. 7 is a longitudinal sectional view of the quick-connect coupling shown in FIG. 1 in a state where the annular ridge of the tube is securely retained by the retainer; FIG. 8 is an end view of the quick-connect coupling in a state shown in FIG. 7 ; FIG. 9 is a front view of a retainer in a modification of the retainer included in the quick-connect coupling shown in FIG. 1 ; FIG. 10 is a view of assistance in explaining the operation of complete connection verifying legs shown in FIG. 9 ; FIG. 11 is a front view of a coupling body in a modification of a coupling body included in the quick-connect coupler shown in FIG. 1 ; FIG. 12 is a longitudinal sectional view of a prior art quick-connect coupling; and FIG. 13 is a longitudinal sectional view of the quick-connect coupling shown in FIG. 12 in a state where a tube and the quick-connect coupling are incompletely connected. detailed-description description="Detailed Description" end="lead"?

20070419

20090728

20071129

68507.0

F16L3714

BOCHNA, DAVID

QUICK-CONNECT COUPLING

UNDISCOUNTED

ACCEPTED

F16L

ACCEPTED

Optical disc for storing both data requiring defect management and real-time av data

An optical disc (1) for storing digital data, comprising a first storage area (10) for storing a first type of digital data and a second storage area (20) for storing a second type of digital data. Each of the first and second areas comprises a user-data area (11, 21). Furthermore, the storage areas (10, 20) are logically independent. The second storage area (20) has a defect management area (22a, 22b) associated with the user-data area (21) of the second storage area (20) for storing defect management data.

1. An optical disc (1) for storing digital data, comprising a first storage area (10) for storing a first type of digital data and a second storage area (20) for storing a second type of digital data, each of the first and second areas comprising a user-data area (11, 21), wherein the first and the second storage area (10, 20) are logically independent, and wherein said first storage area has reading/writing capabilities for high-speed data without defect management, and said second storage area (20) has reading/writing capabilities for data requiring defect management support and comprises at least one defect management area (22a, 22b) associated with said user data area (21) of the second storage area (20) for storing defect management data. 2. The optical disc according to claim 1, wherein the first type of data is real-time audio/video data incompatible with defect management, and the second type of data is digital data requiring defect management support. 3. The optical disc according to claim 1, wherein each of the first and second areas has a logical zero, or its own address space. 4. The optical disc according to claim 1, wherein the first and second areas of the disc are independently accessible. 5. The optical disc according to claim 1, wherein the first and second storage areas are fixedly defined. 6. The optical disc according to claim 5, wherein the first and second storage areas can be altered during use. 7. The optical disc according to claim 1, wherein the disc has a nominal data transfer rate of 36 Mbs. 8. A method of reading digital data from or writing digital data to an optical disc comprising a first storage area (10) for storing a first type of digital data and a second storage area (20), which is logically independent of the first storage area (10), for storing a second type of digital data requiring support for defect management, each of the first and second areas comprising a user-data area, comprising the steps of: accessing the first storage area (19) when digital data of the first type are to be read from or written to the first storage area, accessing the second storage area (20) when digital data of the second type are to be read from or written to the second storage area. 9. An optical disc drive (30) comprising an optical reader/writer (31), a drive controller (33), means for receiving digital data (34, 35), and means for receiving (36) an optical disc, wherein the drive controller comprises: first access means for accessing a first storage area (10) of an optical disc (1) received in the means for receiving the optical disc in response to receiving instructions to read a first type of data from or write data of the first type to the first storage area (10); and second access means for accessing a second storage area (20) of the optical disc (1) in response to receiving instructions to read a second type of data from or write data of the second type to the second storage area (20), the second type of data requiring support for defect management. 10. A computer system comprising a disc drive according to claim 9. 11. A computer program product embodied on a computer-readable medium comprising computer-readable instructions to carry out the method according to claim 7 when executed by said computer.

FIELD OF THE INVENTION This invention relates in general to the field of optical discs for storing digital data and more particularly to the field of optical discs for storing both digital data requiring support for defect management and digital real-time audio/video data. BACKGROUND OF THE INVENTION Optical discs of today may e.g. be a CD-ROM (Compact Disc Read Only Memory) disc, a CD-R (Recordable) disc, or a DVD (Digital Versatile Disc) for storing digital information. The discs may have different storing capacity and data transfer rates for transferring data to or reading data from the disc. Providing audio/video data for real time recording/reading requires a high data transfer rate. One optical disc supporting real-time recording/reading of audio/video data is the Blu-ray disc. Using a short-wavelength blue-violet laser, the Blu-ray disc successfully minimizes its beam spot size by making the numerical aperture (NA) on a field lens that converges the laser 0.85. In addition, by using a disc structure with a 0.1 mm optical transmittance protection layer, the Blu-ray disc diminishes aberration caused by disc tilt. This also provides a better disc readout and an increased recording density. The tracking pitch of the Blu-ray disc is reduced to 0.32 μm, almost half that of a regular DVD, achieving up to 27 GB high-density recording on a single-sided disc. Since the Blu-ray disc utilizes global standard MPEG-2 transport stream compression technology, it is highly compatible with digital broadcasting for real-time audio/video recording, and a wide range of contents can be recorded. It is possible for the Blu-ray disc to record digital high-definition broadcasting while maintaining high-quality and other data simultaneously with video data if they are received together. To read/write digital data on an optical disc by a drag and drop functionality, it is preferred that physical defect management in the drive is provided. Thus, the optical disc has to have a dedicated area of the recordable area wherein defect management data may be provided. The Blu-ray video real-time requirements, i.e. 36 Mb/s read/write and 800 ms seek, match the maximum read-write speed of the Blu-ray disc and device. However, the requirements are incompatible with defect management. This means that there is currently no room for the extra delay caused by defect management while playing or recording digital real-time Blu-Ray video data. In the Blu-ray standard a disc is a single partition containing either a continuous area without defect management or an area with defect management. The standard also requires a certain file system: BDFS (Blu-Ray Disc File System). UDF (Universal Disc Format) is a file system for optical discs. BDFS cannot administer as many files as UDF can, which makes BDFS impractical for PC data use, in which tens of thousands of files on a 27 GB disc can be expected. BDFS is an integral part of the Blu-ray disc and is highly capable of storing data with real-time requirement. UDF, on the other hand, may be used on a Blu-Ray disc in the PC environment. UDF may be used with a Blu-ray disc in which defect management is switched on and can hold tens of thousands of files. The Blu-ray disc standard makes it impossible to have defect management switched on and use it for BDFS at the same time because the logical to physical relationship, i.e. the logical zero point, is at a different location of the disc, is different in the two cases. Thus, separate discs have to be provided in order to meet the conflicting requirements of reading/writing both digital data with support for defect management and read/write real-time audio/video data according to the Blu-ray standard. SUMMARY OF THE INVENTION The present invention overcomes the above-identified deficiencies in the art and solves the above problems by providing an optical disc having at least two storage areas, which are logically separate. Accordingly, according to a first aspect of the invention, there is provided an optical disc, wherein a first storage area is dedicated to storing a first type of digital data, such as audio/video data having a real-time requirement incompatible with defect management. A second storage area is dedicated to storing a second type of digital data, such as data having a requirement for defect management support, e.g. data supporting a drag and drop function. Only the second storage area has associated defect management areas for storing defect management data. Each of the first and second areas of the disc is accessible separately and independently of the other. According to a second aspect of the invention, a method for reading digital data from or writing digital data to the optical disc is provided. According to the method, the first storage area is accessed by a first access means when digital data of the first type are to be read from or written to the first storage area. The second storage area is accessed by a second access means when digital data requiring defect management are to be read from or written to the second storage area. According to a third aspect of the invention, an optical disc drive comprising an optical reader/writer, a drive controller, means for receiving digital data, and means for receiving an optical disc is provided. The drive controller is adapted to access the first storage area of the optical disc in response to receiving instructions to read a first type of data from or write the first type of data to the first storage area. Furthermore, the drive controller is adapted to access the second storage area of the optical disc in response to receiving instructions to read a second type of data from or write the second type of data to the second storage area, the second type of data requiring support for defect management. According to a fourth aspect of the invention, a computer system comprising a disc drive according to the invention is provided. Separate drive letters within the operating system of the computer may provide separate and independent access to the first and second storage areas of the disc. Alternatively, the first storage area is directly accessible via an application program comprising software-readable instructions to access the first storage area. It is an advantage of the invention that digital data of separate types can be provided on a high-speed and high-capacity optical disc, such as a Blu-ray disc. Furthermore, it is an advantage that digital data incompatible with defect management and digital data requiring defect management support can be stored on the same disc. With a disc drive capable of accessing the separate storage areas of the disc in a computer system, the data may be read/written independently by means of the computer system. Another advantage of the invention is that, if the storage area dedicated to real-time data is provided as the first storage area of the disc, the disc is compatible with disc recorders known in the art, which do not expect any defect management in the first area. BRIEF DESCRIPTION OF THE DRAWINGS Further objects, features and advantages of the invention will appear from the following detailed description of the invention, reference being made to the accompanying drawings, in which: FIG. 1 is a schematic view of a portion of the optical disc according to the invention; FIG. 2 is a plan view of the optical disc according to the invention; FIG. 3 is a block diagram of a disc drive connected to a computer system; and FIG. 4 is a flowchart of a method according to the invention. DETAILED DESCRIPTION OF EMBODIMENTS FIG. 1 illustrates in a first embodiment of the invention in a schematic view of a section of an optical disc 1. A plan view of the disc 1 is illustrated in FIG. 2. The disc 1 has a first storage area 10 for storing digital data relating to a first type of data. A second storage area 20 is provided for storing digital data relating to a second type of digital data. As shown in FIGS. 1 and 2, the disc 1 comprises two physically separate partitions, comprising two logically independent areas. However, the disc may equally well comprise more than two partitions, as long as at least one area is dedicated to digital data of a first type and at least one area is dedicated to digital data of a second type. The disc 1 has a large storing capacity and a high data transfer rate. Thus, the disc is suitable for storing audio/video data, which may be read from or written to the disc 1 in real time. With the use of a 405-nm blue-violet semiconductor laser, with a 0.85 NA field lens and a 0.1 mm optical transmittance protection disc layer structure, the disc 1 can record up to 27 GB video data on a single-sided 12-cm phase change disc. The data transfer rate of the Blu-ray disc is nominally 36 Mbps. The highest transfer rate is only limited by the disc's highest rotational speed and the lowest transfer rate is zero. Thus read/write of real-time data is supported. According to the invention, the first type of data is digital data having a real-time constraint, such as 36 Mbs read/write and 800 ms seek, which do not support defect management, e.g. real-time audio/video data. Thus the first type of data may be read/written in real time. The second type of digital data is any type not having any real-time constraint, such as digital data requiring defect management, e.g. data readable/writable by means of a drag and drop function. According to the invention, the first storage area 10 may be provided as the first, i.e. the innermost, storage area of the disc 1. Thus the disc 10 is useable together with a Blu-ray reader/writer known in the art, as such readers/writers expect to see no defect management. However, the second storage area 20 will not be accessed by the readers/writers known in the art. However, the use of a recorder/writer according to the invention has the advantage that either of the storage areas 10, 20 may be provided as the first storage area of the disc 1. The first storage area 10 comprises a user-data area 11, which has read/write capabilities for high-speed data without defect management. The data recorded in the first storage area are written/read randomly. A track, or a number of consecutively tracks, may be written randomly, hence not continuously. The real-time constraint specifies the minimum size of these tracks to be 12 MB, the maximum access time to be 800 ms, and the nominal read/write rate 36 Mbps. The second storage area 20 may support defect management in the disc drive, as is preferred for drag and drop support. When used in a computer, a file may be transferred or copied from e.g. the hard disc drive to the optical disc simply be dragging a link in the operating system to a drive letter referring to the second storage area, or vice versa. To support the defect management, the second storage area 20 comprises at least one user-data area 21 and at least one defect management area 22a. In FIGS. 1 and 2, a second defect management area 22b is also provided, the defect management data being divided between them. However, one large defect management area may be provided instead of two. If two defect management areas are provided, one is the “main-data area” and the other area is where the replacements of faulty locations in the main-data area are stored. The defect area with replacement locations may either be continuous or fragmented. The “main-data” area may also be continuous or fragmented. Hence, these two areas may also be interleaved, using e.g. Mt Rainier interleaving. In the user-data area 21 of the second storage area the data are fragmented. Thus, the data may be stored consecutively or randomly in different locations of the user-data area. The disc 1 is partitioned such that each storage area 10, 20 may be separately and independently accessed. The size of each partition may either be predetermined or determined by the user. Furthermore, the size of each partition may also be changed by the user by studying the BDFS and UDF file system by means of a software tool, such as Partition Magic from Norton Utilities. Such a software tool can re-allocate the partitions if needed and change the border position of the two partitions. The partitions are each addressed logically by the user. Each partition may be viewed as two separate discs, wherein each partition has a logical zero. Alternatively, each partition has its own address space, the first space starting at zero and having a maximum of M−1 addresses 0<=M<=22.27 GB), and the second address space starting at M and continuing to N−1 (N is the size of the disc: 22.27 GB, i.e. 0<=M<=N<=22.27 GB). FIG. 3 is a schematic diagram of a disc drive 30 according to the invention. The disc drive 30 comprises means 36 for receiving a disc 1 when it is inserted into the drive 30. The drive 30 also comprises means for rotating the disc (not shown), such as an electric motor, and means for optically reading/writing the digital data 31, such as an optical pick-up, to transfer data to/from the disc 1. A digital signal processor (DSP) 32 may be provided to process the data received from or transmitted to the read/write means 31. The DSP 32 may e.g. comprise a controller for controlling the motor, a demodulator, one or several memories, such as a RAM (Random Access Memory) and a ROM (Read Only Memory), a defect management controller for executing defect management, and an interleaver/deinterleaver. A drive controller 33 is adapted to control the disc drive 30. The drive controller is adapted to detect whether data received through an interface 37 having a first and a second input 34, 35 has a real-time restriction or constraint. This may be detected in that a read/write instruction is received through the first input 34 from a first access means, such as a first drive letter (e.g. D:) 40 of a computer 41, to which the disc drive 30 is connected. When it is detected that a read/write instruction relates to the first type of data, such as an instruction received from the first drive-letter, the read/write means 31 is directed to the first storage area 10. Alternatively, the read/write instruction may relate to the second type of data, e.g. the instruction is received from a second access means, such as a second drive-letter (e.g. E:) 42 of the computer 41. Then, the read/write means is directed to the second storage area 20. The computer system 41 comprises a controller 43, such as a central processing unit (CPU) to execute computer-readable instructions embodied on the hard disc. The invention is not only usable together with computer systems. It is usable together with any other device having a controller for providing instructions regarding the first and the second type of data to the disc drive 30. To read/write a digital data file, a user of the computer 41 may simply drag a link to a file from a drive-letter of the computer 41, such as the drive-letter C: commonly used as the drive-letter of the hard-disc drive, and drop the file at the second drive letter 42 indicated by the operating system of the computer. Alternatively, the user may prefer to access a real-time audio/video file of the disc 1. Then the first drive letter 41 is entered, whereupon the drive controller 33 will direct the read/write means 31 towards the first storage area 10. The first storage area may also only be accessible from an application run by the computer. Then, the application program will have computer-readable instructions which will access the first storage area 10 of the disc 1, whereupon the real-time data will automatically be read to/written from the first storage area 10. FIG. 4 illustrates the steps to be carried out according to the method of the invention for accessing the first or the second storage area 10, 20. In a first step 100, instructions to read data from or write data to the first or the second storage area 10, 20 are received from the computer 41. Then, in step 110 it is determined whether the read/write instruction was executed by the first or the second access means of the computer 41, i.e. which type of data the instruction relates to. If the instruction relates to the first type of data, the procedure continues to step 120 wherein the first storage area 10 is accessed for reading data from or writing data to the disc 1. Alternatively, if the instruction relates to the second type of data, the procedure continues from step 110 to step 130, wherein the second storage area 20 is accessed for reading data requiring support for defect management from or writing such data to the disc 1. Then, in step 140 the digital data in question may be read from or written to the disc 1, whereupon the procedure is ended. The present invention has been described above with reference to specific embodiments. However, embodiments other than those described above are equally possible within the scope of the appended claims, e.g. performing the above method by hardware or software. Furthermore, the term “comprising” does not exclude other elements or steps, the terms “a” and “an” do not exclude a plurality and a single processor or other unit may fulfil the functions of several of the units or circuits recited in the claims. The invention is only limited by the appended patent claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>Optical discs of today may e.g. be a CD-ROM (Compact Disc Read Only Memory) disc, a CD-R (Recordable) disc, or a DVD (Digital Versatile Disc) for storing digital information. The discs may have different storing capacity and data transfer rates for transferring data to or reading data from the disc. Providing audio/video data for real time recording/reading requires a high data transfer rate. One optical disc supporting real-time recording/reading of audio/video data is the Blu-ray disc. Using a short-wavelength blue-violet laser, the Blu-ray disc successfully minimizes its beam spot size by making the numerical aperture (NA) on a field lens that converges the laser 0.85. In addition, by using a disc structure with a 0.1 mm optical transmittance protection layer, the Blu-ray disc diminishes aberration caused by disc tilt. This also provides a better disc readout and an increased recording density. The tracking pitch of the Blu-ray disc is reduced to 0.32 μm, almost half that of a regular DVD, achieving up to 27 GB high-density recording on a single-sided disc. Since the Blu-ray disc utilizes global standard MPEG-2 transport stream compression technology, it is highly compatible with digital broadcasting for real-time audio/video recording, and a wide range of contents can be recorded. It is possible for the Blu-ray disc to record digital high-definition broadcasting while maintaining high-quality and other data simultaneously with video data if they are received together. To read/write digital data on an optical disc by a drag and drop functionality, it is preferred that physical defect management in the drive is provided. Thus, the optical disc has to have a dedicated area of the recordable area wherein defect management data may be provided. The Blu-ray video real-time requirements, i.e. 36 Mb/s read/write and 800 ms seek, match the maximum read-write speed of the Blu-ray disc and device. However, the requirements are incompatible with defect management. This means that there is currently no room for the extra delay caused by defect management while playing or recording digital real-time Blu-Ray video data. In the Blu-ray standard a disc is a single partition containing either a continuous area without defect management or an area with defect management. The standard also requires a certain file system: BDFS (Blu-Ray Disc File System). UDF (Universal Disc Format) is a file system for optical discs. BDFS cannot administer as many files as UDF can, which makes BDFS impractical for PC data use, in which tens of thousands of files on a 27 GB disc can be expected. BDFS is an integral part of the Blu-ray disc and is highly capable of storing data with real-time requirement. UDF, on the other hand, may be used on a Blu-Ray disc in the PC environment. UDF may be used with a Blu-ray disc in which defect management is switched on and can hold tens of thousands of files. The Blu-ray disc standard makes it impossible to have defect management switched on and use it for BDFS at the same time because the logical to physical relationship, i.e. the logical zero point, is at a different location of the disc, is different in the two cases. Thus, separate discs have to be provided in order to meet the conflicting requirements of reading/writing both digital data with support for defect management and read/write real-time audio/video data according to the Blu-ray standard.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention overcomes the above-identified deficiencies in the art and solves the above problems by providing an optical disc having at least two storage areas, which are logically separate. Accordingly, according to a first aspect of the invention, there is provided an optical disc, wherein a first storage area is dedicated to storing a first type of digital data, such as audio/video data having a real-time requirement incompatible with defect management. A second storage area is dedicated to storing a second type of digital data, such as data having a requirement for defect management support, e.g. data supporting a drag and drop function. Only the second storage area has associated defect management areas for storing defect management data. Each of the first and second areas of the disc is accessible separately and independently of the other. According to a second aspect of the invention, a method for reading digital data from or writing digital data to the optical disc is provided. According to the method, the first storage area is accessed by a first access means when digital data of the first type are to be read from or written to the first storage area. The second storage area is accessed by a second access means when digital data requiring defect management are to be read from or written to the second storage area. According to a third aspect of the invention, an optical disc drive comprising an optical reader/writer, a drive controller, means for receiving digital data, and means for receiving an optical disc is provided. The drive controller is adapted to access the first storage area of the optical disc in response to receiving instructions to read a first type of data from or write the first type of data to the first storage area. Furthermore, the drive controller is adapted to access the second storage area of the optical disc in response to receiving instructions to read a second type of data from or write the second type of data to the second storage area, the second type of data requiring support for defect management. According to a fourth aspect of the invention, a computer system comprising a disc drive according to the invention is provided. Separate drive letters within the operating system of the computer may provide separate and independent access to the first and second storage areas of the disc. Alternatively, the first storage area is directly accessible via an application program comprising software-readable instructions to access the first storage area. It is an advantage of the invention that digital data of separate types can be provided on a high-speed and high-capacity optical disc, such as a Blu-ray disc. Furthermore, it is an advantage that digital data incompatible with defect management and digital data requiring defect management support can be stored on the same disc. With a disc drive capable of accessing the separate storage areas of the disc in a computer system, the data may be read/written independently by means of the computer system. Another advantage of the invention is that, if the storage area dedicated to real-time data is provided as the first storage area of the disc, the disc is compatible with disc recorders known in the art, which do not expect any defect management in the first area.

20060612

20100406

20070614

65202.0

G06F1300

CHOW, VAN NGUYEN

OPTICAL DISC FOR STORING BOTH DATA REQUIRING DEFECT MANAGEMENT AND REAL-TIME AV DATA

UNDISCOUNTED

ACCEPTED

G06F

ACCEPTED

Method for protection switching of geographically separate switching systems

A protocol is provided being executed with a redundancy of 1:1. As a result, an identical clone, with identical hardware, identical software and an identical data base, is allocated to each switching system to be protected, as a redundancy partner. Switching is carried out in a quick, secure and automatic manner by a superordinate, real-time enabled monitor which establishes communication with the switching systems which are arranged in pairs. In the event of communication loss with respect to the active communication system, real-time switching to the redundant switching system is carried out.

1.-10. (canceled) 11. A method for protection switching of geographically separate switching systems arranged in pairs, comprising: providing a first switching system in an active operating state; providing a redundant switching system as a pair to the first switching system, the redundant switching system in a hot-standby operating state; providing a monitor that communicates with the first and the redundant switching systems; controlling the communication between the first switching system and the monitor in accordance with the active operating state; controlling the communication between the first switching system and the monitor in accordance with the hot-standby operating state; when a loss of the communication to the first switching system occurs: deactivating the first switching system by the monitor, and activating the redundant switching system to be in the active operating state by the monitor within 2 seconds. 12. The method as claimed in claim 11, wherein an operating state selected from the group consisting of active and hot-standby has a pre-definable number of packet-based interfaces. 13. The method as claimed in claim 11, further comprising periodically sending IP requests to the monitor by packet-based interfaces of the switching system in the hot-standby operating state, the interfaces in an inactive state. 14. The method as claimed in claim 13, wherein the monitor does not respond the requests. 15. The method as claimed in claim 13, further comprising changing the packet based interface from the inactive state to an active state in response to receiving an IP response. 16. The method as claimed in claim 15, wherein the response from the monitor contains an IP address of the requesting packet-based interface. 17. The method as claimed in claim 13, further comprising suppressing sending IP requests to the monitor by packet-based interfaces of the switching system in the active operating state, the interfaces in an active operating state. 18. The method as claimed in claim 13, further comprising: receiving a monitoring message from the monitor by the interfaces in the active state; and acknowledging the message by the interface. 19. The method as claimed in claim 18, further comprising: determining by the monitor a fault condition when an acknowledgement is not received from the interface in the active state; and sending a IP response to the switching system in the hot-standby operating state. 20. The method as claimed in claim 19, further comprising changing the packet based interface from the inactive state to an active state in response to receiving an IP response. 21. The method as claimed in claim 20, wherein the response from the monitor contains an IP address of the requesting packet-based interface. 22. The method as claimed in claim 18, further comprising changing the packet based interface from the inactive state to an active state in response to receiving an IP response. 23. The method as claimed in claim 18, further comprising changing the operating state from hot-standby to active in response to receiving an IP response. 24. The method as claimed in claim 18, wherein the response from the monitor contains an IP address of the requesting packet-based interface. 25. The method as claimed in claim 19, further comprising changing the operating state of the switching system having the communication loss to a hot-standby operation state. 26. The method as claimed in claim 18, wherein the operating state of the switching system having the communication loss changes to a hot-standby operation state and remains defined as the hot-standby switching system until a new fault situation forces a new switchover. 27. The method as claimed in claim 18, further comprising: determining by the monitor a fault condition when an acknowledgement is not received from the interface in the active state; and sending a message to the switching system in the hot-standby operating state a message indicating to change over to the active operating state.

CROSS REFERENCE TO RELATED APPLICATIONS This application is the US National Stage of International Application No. PCT/EP2004/051925, filed Aug. 26, 2004 and claims the benefit thereof. The International Application claims the benefits of German application No. 10358344.0 DE filed Dec. 12, 2003, both of the applications are incorporated by reference herein in their entirety. FIELD OF INVENTION The present invention relates to a method for protection switching of geographically separate switching systems. BACKGROUND OF INVENTION Contemporary switching systems (switches) possess a high degree of internal operational reliability owing to the redundant provision of important internal components. This means that a very high level of availability of the switching-oriented functions is achieved in normal operation. If, however, external influencing factors occur on a massive scale (e.g. fire, natural disasters, terrorist attacks, consequences of war, etc.), the precautionary measures taken to increase operational reliability are generally of little use, since the original and replacement components of the switching system are located at the same place and so in a disaster scenario of said kind there is a high probability that both components have been destroyed or rendered incapable of operation. SUMMARY OF INVENTION A 1:1 redundancy has been proposed as a solution. Accordingly it is provided to assign each switching system requiring protection an identical clone as a redundancy partner having identical hardware, software and database. The clone is in the powered-up state, but is nonetheless not active in terms of switching functions. Both switching systems are controlled by a realtime-capable monitor, ranked at a higher level in the network hierarchy, which controls the switchover operations. An object underlying the invention is to specify a method for protection switching of switching systems which ensures an efficient switchover of a failed switching system to a redundancy partner in the event of a fault. According to the invention a protocol is proposed which is executed between a higher-level realtime-capable monitor and the active switching system on the one side, and the hot-standby switching system on the other side. The protocol is based on the standard IP protocols BOOTP/DHCP which are usually supported by every IP implementation. This solution can therefore be implemented in any switching system with IP-based interfaces with minimal implementation overhead. The solution is comprehensively deployable and cost-effective, because essentially only the outlay for the monitor is incurred. Furthermore, it is extremely robust thanks to the use of simple, standardized IP protocols. Control errors due to temporary outages in the IP core network are rectified automatically after the outage has been terminated. A dual monitor failure likewise represents no problem in this variant. A significant advantage of the invention is to be seen in the fact that in the course of the switchover operation from an active switching system to a hot-standby switching system no network management and no form of central control unit to support the switchover operations are required in the participating switching systems. To that extent it is irrelevant whether the switching system has a central control unit or not. This means that the invention is also applicable to routers, which—in contrast to the traditional switching system—generally have no central control unit of said kind. BRIEF DESCRIPTION OF THE DRAWING The invention is explained in more detail below with reference to a schematically represented exemplary embodiment. According to the invention it is provided to assign each switching system requiring protection (e.g. S1) an identical clone as a redundancy partner (e.g. S1b) with identical hardware, software and database. The clone is in the powered-up state, but is nonetheless not active in terms of switching functions (“hot standby” operating state). In this way a highly available 1:1 redundancy of switching systems distributed over a plurality of locations is defined. DETAILED DESCRIPTION OF INVENTION The two switching systems (switching system S1 and the clone or redundancy partner S1b) are controlled by a network management system NM. The control is implemented in such a way that the current status of the database and the software of the two switching systems S1, S1b is kept identical. This is achieved in that every operation-oriented command, every configuration command and every software update including patches is delivered in identical fashion to both partners. In this way a physically remote clone identical to a switch that is in operation is defined with identical database and identical software revision level. The database basically contains all semi-permanent and permanent data. In this context permanent data is understood to mean the data which is stored as code in tables and which can only be changed by means of a patch or software update. Semi-permanent data refers to the data which enters the system e.g. via the user interface and which is stored there for a relatively long period in the form of the input. Except for the configuration statuses of the system, this data is generally not modified by the system itself. The database does not contain the transient data accompanying a call, which data the switching system stores only temporarily and which generally has no significance beyond the duration of a call, or status information which consists of transient overlays/supplements to configuratively predetermined basic states. (For example, although a port could be active in the basic state, it may not be accessible at the present time due to a transient (transitory) fault). In addition, the switching systems S1, S1b both have at least one active, packet-oriented interface to the common network management system NM. According to the present exemplary embodiment these are to be the two interfaces IF1. In this case the two interfaces IF1 assume an active operating state (“act”). However, whereas in the case of switching system S1 all the remaining packet-oriented interfaces IF2 . . . IFn are also active, in the case of switching system S1b, in contrast, the remaining interfaces are in the operating state “idle”. The state “idle” means that the interfaces permit no exchange of messages, but can be activated from an external point, i.e. by a higher-level, realtime-capable monitor located outside of switching system S1 and switching system S1b. The monitor can be implemented in hardware or software and in the event of a fault switches over in real time to the clone. Real time, in this case, means a time span of 1 to 2 seconds. According to the present exemplary embodiment the monitor is embodied as control device SC and duplicated for security reasons (local redundancy). The interfaces In are packet-based and so represent communication interfaces to packet-based peripheral devices (such as e.g. IAD, MG, SIP proxy devices), remote packet-based switches, packet-based media servers. They are controlled indirectly by the monitor which is embodied as a control device SC (Switch Controller). This means that the control device SC can activate and deactivate the interfaces IFn and therefore switch back and forth at will between the operating states “act” and “idle”. The configuration according to the figure is to be regarded as a default configuration. This means that switching system S1 is active in terms of switching functions, while switching system S1b is in a “hot standby” operating state. This state is characterized by an up-to-date database and full activity of all components except for the packet-based interfaces (and possibly the processing of switching-oriented events). The (geographically redundant) switching system S1b can therefore be switched over quickly (in real time) by the control device SC into the active state in terms of switching-oriented functions by activation of the interfaces IF2 . . . IFn. The interface IF1 is also active on the hot standby switching system, because it describes the interface to the network management, which interface must always be active. It is to be regarded as a significant aspect that the two geographically redundant switching systems S1, S1b as well as the network management NM and the duplicated control device SC must each be clearly separated geographically. The control device SC transmits the current operating state of the switching systems S1 and S1b (act/hot-standby, status of the interfaces) as well as its own operating state to the network management NM s. The functions of the control device SC can optionally be performed partially or in full by the network management NM. For security reasons the network management NM should have the functionality to be able also to effect the above described switchovers manually. Optionally, the automatic switchover can be blocked so that the switchover can only be performed manually. The switching systems S1 and S1b can also perform their own regular checks to determine whether their packet-based interfaces are active. If this is not the case for the interfaces IF2 . . . IFn, it can be concluded that they are in the “hot standby” state and certain alarms which are produced as a result of the non-availability of the interfaces IF2 . . . IFn can be selectively blocked. The transition of a switch from “hot standby” to “active” can also be detected in this way. This enables targeted measures to be taken if necessary at the start of the switching operations. The packet addresses (IP addresses) of the interfaces I2 . . . n of switching system S1 and their respective partner interfaces of switching system S1b can be identical, but do not have to be. If they are identical, the switchover is noticed only by the front-end router. For the partner application in the network, on the other hand, it is completely transparent. This is a new application and generalization of the IP failover function. If the protocol which serves an interface permits a switchover of the communication partner to a different packet address, as is the case, for example, with the H.248 protocol (a media gateway can independently establish a new connection to another media gateway controller with a different IP address), the IP addresses can also be different. In an embodiment of the invention it is provided to use the central computer of a further switching system as the control device SC. As a result there then exists a control device with maximum availability. In a development of the invention consideration is given to the establishment of a direct communication interface between switching system S1 and switching system S1b. This can be used for updating the database e.g. with regard to SCI (Subscriber Controlled Input) and charge data as well as for exchanging transient data of individual connections or important further transient data (e.g. H.248 Association Handle). In this way the disruptions to operation can be minimized from the subscriber and operator perspective. The semi-permanent and transient data can then be transferred from the respective active switching system into the redundant hot-standby switching system in a cyclical time frame (update). The update of the SCI data has the advantage that the cyclical restore on the hot-standby system is avoided and SCI data in the hot-standby system is always up-to-date. As a result of the update of stack-relevant data, such as the H.248 Association Handle, the takeover by a standby system can be hidden from the peripherals and the downtimes can be reduced even more considerably. Essentially, the IP addresses of all network components must be known in the network. The allocation of the IP addresses is controlled when the entire IP network device is powered up. For this purpose there is provided in the network a server (BOOTP server) which communicates via a BOOTP protocol with the clients that are to be powered up. At startup the network components (client), such as, for example, the switching systems S1, S1b, request the IP addresses from the BOOTP server with the aid of the BOOTP protocol. Once these IP addresses have been received, the respective component's own MAC address (network-wide hardware address) and own IP address are thus known in all network components. Since this assignment is not yet known in the network, this information is communicated by the network components to other network components (client, router) in the course of a broadcast message. A separate protocol (ARP protocol, Address Resolution Protocol) is used for this purpose. According to the invention a protocol, referred to in the following as the HSCB protocol (HSCB: Hot-Standby Control Protocol), is proposed for monitoring and for switching over from an active switching system to a redundantly arranged switching system. Said HSCB protocol is executed between the control device SC and the switching system S1 as well as between the control device SC and the switching system S1b. It is essential that the protocol is able to bring the switching system S1 into an active (“act”) or a “hot standby” operating state after startup (recovery). In addition the switching system in the active (and optionally also the system in the “hot standby”) operating state has to be monitored and the necessary switchovers have to be initiated in the event of a fault (active switching system goes to hot-standby/hot-standby switching system goes to active). Optionally, it can be explicitly communicated to switching systems S1 and S1b whether they are in the active or hot-standby state. The following rules are specified in the HSCB protocol between the control device SC and the switching system S1 or, as the case may be, S1b: If a packet-based interface of a switching system is in the operating state “IDLE”, it sends IP address requests (“BOOTP request”) to the control device SC at regular intervals. In this case it is not necessary for the control device SC to answer these BOOTP requests of the interfaces of the switching system: this is done only for the address requests from the switching system that is identified as active to the control device SC. In the case of a positive response from the control device SC, the packet-based interface is placed into the active operating state (“act”). If there is no (or a negative) response from the control device SC, the packet-based interfaces that are in the inactive operating state remain in the inactive operating state (“IDLE”). After the booting sequence all the packet-based interfaces are in the inactive operating state (“IDLE”). An interface in the active operating state does not need to send any address requests (“IP Request”) to the control device SC. The control device SC, for its part, sends monitoring messages at regular intervals to the packet-based interfaces, which must respond to these messages only if they are active. By means of a special message the control device SC can bring a packet-based interface from the active operating state into the inactive operating state (“IDLE”). The startup of the network configuration is described below. After startup, all the interfaces of switching systems S1 and S1b are always in the inactive operating state “IDLE”. The control device SC is now to be the BOOTP server for switching systems S1 and S1b. This means that at startup time the IP interfaces of switching system S1 and/or switching system S1b fetch their IP addresses via BOOTP request from the control device SC. The control device SC is aware of the existence of both switching systems as well as of the operating state (act/hot-standby) still to be assumed by these. The control device SC implicitly communicates to the two switching systems S1, S1b the operating state that they have to assume after startup. On the one hand this is effected for the switching system S1b that is to be defined as hot-standby in that the control device SC does not respond to the BOOTP requests of the interfaces IF2 . . . IFn. Consequently, these interfaces have no IP addresses and remain in the inactive operating state (“IDLE”). However, they continue sending BOOTP requests at regular intervals to the control device SC, which in the normal state continues not to respond to these requests. On the other hand this is effected for the switching system S1 that is to be defined as active in that the control device SC responds to all BOOTP requests (through communication of the IP address), as a result of which all interfaces are activated. DHCP requests can also be taken instead of BOOTP requests. The system consisting of active switching system and clone thus assumes the state provided (in the control device SC), which is defined as the fault-free normal state. In this state the cyclical BOOTP requests of the interfaces of the clone continue not to be answered, as a result of which these also continue not to have their IP addresses. The active interfaces of switching system S1 send no BOOTP requests. In this normal state the control device SC now sends monitoring messages cyclically to the interfaces of the active switching system, which messages have to be answered by the active interfaces. If this is the case, it can be assumed that the active switching system also continues to be in a fault-free operating state, as a result of which the active operating state is maintained. Since the cyclical BOOTP requests from the clone also continue to arrive (and also continue not to be answered), it can likewise be assumed that the clone too is in a fault-free operating state (still “IDLE”, as previously). The control device SC has therefore stored the knowledge of the functional integrity of the active switching system and also of the clone. This knowledge is always kept at the latest level by means of the acknowledgement of the cyclical monitoring messages and the cyclical BOOTP requests of the clone. In the scenario described below let a serious failure of switching system S1 be assumed. Owing to the geographical redundancy there is a high probability that the clone (switching system S1b), like the control device SC, is also unaffected. The failure of switching system S1 is identified by the control device SC, which also controls the corresponding switchover operations to switching system S1b: The failure of switching system S1 is detected by the control device SC due to the fact that the monitoring messages are no longer acknowledged. However, a predefinable number of interfaces (configurable, optionally also all) should apply as the failure criterion, and not simply a loss of communication with all the interfaces. Thus, if no acknowledgements for this predefinable number of interfaces of switching system S1 arrive at the control device SC for a relatively long period (e.g. 1 min.), it is concluded that a serious failure of switching system S1 has occurred. This criterion is sufficient to initiate a switchover from switching system S1 to switching system S1b. In this case the control device SC initially places still active interfaces of switching system S1 into the inactive operating state (“IDLE”) with the aid of a special message. This message is embodied such that the interfaces of switching system S1 are prompted to release their IP addresses. To be on the safe side, the message is supplied to all the interfaces of switching system S1 (i.e. also to those that have failed) and cyclically repeated until the BOOTP requests from the now inactive interfaces arrive at the control device SC. Switching system S1 is therefore in the inactive operating state. The BOOTP requests still cyclically arriving as previously from S1b are now answered by the control device SC in that the interfaces of the hitherto inactive clone are notified of their IP addresses. As a result switching system S1b assumes an active operating state. Switching system S1b is thus ready for switching operation and can take over the functions of switching system S1. The advantage of this approach lies in the avoidance of the “split brain” scenario. The interfaces of switching system S1 are to remain in the inactive operating state even after the recovery of switching system S1. Switching system S1 is therefore deactivated in terms of switching functions until the next switchover. In order to keep the time interval of inconsistent interface states in switching system S1b as short as possible, the requests could be triggered in switching system S1b. Several failure scenarios are discussed below: For the solution according to the invention, a total failure of the control device SC (dual failure of the two halves) represents no problem, in particular since such a case is extremely unlikely. In this embodiment variant this does not disrupt normal switching operation. Only the automatic switchover function of the control device SC is no longer present. Should a switchover become necessary during this time, it can be performed manually by the network management NM. Similarly, a disruption to the communication between switching system S1 and control device SC can be intercepted. In this case there is a very small probability that the “split brain” scenario can occur. This means that the two switching systems S1, S1b simultaneously assume an active operating state and both also use the same IP addresses. In order to rule out this complete scenario it is proposed to introduce a mutual monitoring for act/stb between switching system S1 and switching system S1b. The monitoring can use the same mechanisms as described above. Thus, for example, a dedicated IP interface of switching system S1b (hot standby) can send BOOTP requests to its partner interfaces in switching system S1 at regular intervals and monitor whether its partner interface is active. If switching system S1b is now to go from hot-standby to active, a check can first be carried out to determine whether the partner interface has failed (i.e. is no longer sending any responses). If it is still active (which must not be the case if the switchover has been performed correctly and would lead to the “split brain”), the switchover stb->act in switching system S1b is prevented—and consequently also the “split brain”. In this case there is a high probability that switching system S1 is still active. If a “split brain” scenario should still nonetheless occur at some point, there is still a simple possibility of correction from the network management NM side. According to this, one of the two switching systems is once again placed into the stb operating state and if necessary executes a recovery

<SOH> BACKGROUND OF INVENTION <EOH>Contemporary switching systems (switches) possess a high degree of internal operational reliability owing to the redundant provision of important internal components. This means that a very high level of availability of the switching-oriented functions is achieved in normal operation. If, however, external influencing factors occur on a massive scale (e.g. fire, natural disasters, terrorist attacks, consequences of war, etc.), the precautionary measures taken to increase operational reliability are generally of little use, since the original and replacement components of the switching system are located at the same place and so in a disaster scenario of said kind there is a high probability that both components have been destroyed or rendered incapable of operation.

<SOH> SUMMARY OF INVENTION <EOH>A 1:1 redundancy has been proposed as a solution. Accordingly it is provided to assign each switching system requiring protection an identical clone as a redundancy partner having identical hardware, software and database. The clone is in the powered-up state, but is nonetheless not active in terms of switching functions. Both switching systems are controlled by a realtime-capable monitor, ranked at a higher level in the network hierarchy, which controls the switchover operations. An object underlying the invention is to specify a method for protection switching of switching systems which ensures an efficient switchover of a failed switching system to a redundancy partner in the event of a fault. According to the invention a protocol is proposed which is executed between a higher-level realtime-capable monitor and the active switching system on the one side, and the hot-standby switching system on the other side. The protocol is based on the standard IP protocols BOOTP/DHCP which are usually supported by every IP implementation. This solution can therefore be implemented in any switching system with IP-based interfaces with minimal implementation overhead. The solution is comprehensively deployable and cost-effective, because essentially only the outlay for the monitor is incurred. Furthermore, it is extremely robust thanks to the use of simple, standardized IP protocols. Control errors due to temporary outages in the IP core network are rectified automatically after the outage has been terminated. A dual monitor failure likewise represents no problem in this variant. A significant advantage of the invention is to be seen in the fact that in the course of the switchover operation from an active switching system to a hot-standby switching system no network management and no form of central control unit to support the switchover operations are required in the participating switching systems. To that extent it is irrelevant whether the switching system has a central control unit or not. This means that the invention is also applicable to routers, which—in contrast to the traditional switching system—generally have no central control unit of said kind.

20060609

20120103

20070621

61420.0

H04J314

BROCKMAN, ANGEL T

METHOD FOR PROTECTION SWITCHING OF GEOGRAPHICALLY SEPARATE SWITCHING SYSTEMS

UNDISCOUNTED

ACCEPTED

H04J

ACCEPTED

Isolated cytotoxic factor associated with multiple sclerosis and method of detecting said cytotoxic factor

The invention relates to an isolated cytotoxic factor which is associated with multiple sclerosis and which is selected from the heterocomplex GM2AP/GM2/MRP14 and mutated GM2AP/GM2/MRP14, and to the method of detecting said factor in a biological sample to be tested. The inventive method comprises the following steps consisting in: (i) bringing the biological sample into contact with at least one capture antibody selected from antibodies that bind specifically to the GM2AP protein, to the mutated GM2AP protein, to the MRP14 protein, to the complex GM2AP/GM2, to the complex mutated GM2AP/GM2 and to the complex MRP14/GM2, and with at least one labeled detection antibody selected from antibodies that bind specifically to the GM2AP protein, to the mutated GM2AP protein, to the MRP14 protein, to the complex GM2AP/GM2, to the complex mutated GM2AP/GM2 and to the complex MRP14/GM2, and (ii) detecting and/or quantifying the cytotoxic factor by detecting and/or quantifying the labeled detection antibody.

1. An isolated cytotoxic factor, associated with multiple sclerosis, said cytotoxic factor being chosen from the heterocomplex GM2AP/GM2/MRP14 and mutated GM2AP/GM2/MRP14 in which mutated GM2AP corresponds to the sequence SEQ ID No. 2. 2. A method for detecting and/or quantifying a cytotoxic factor, associated with multiple sclerosis, in a biological sample, according to which a heterocomplex chosen from the heterocomplex GM2AP/GM2/MRP14 and mutated GM2AP/GM2/MRP14, in which mutated GM2AP corresponds to the sequence SEQ ID No. 2, is isolated from said biological sample. 3. The method as claimed in claim 2, according to which the heterocomplex is isolated by means of at least one antibody that binds specifically to the heterocomplex, and said cytotoxic factor is detected and/or quantified by demonstrating the formation of a complex consisting of the heterocomplex and the antibody. 4. The method as claimed in claim 3, according to which the heterocomplex is isolated by means of at least two antibodies that bind specifically to the heterocomplex, and said cytotoxic factor is detected and/or quantified by demonstrating the formation of a complex consisting of the heterocomplex and the two antibodies. 5. The method as claimed in claim 4, according to which at least one of said antibodies is a capture antibody and at least the other of said antibodies is a detection antibody. 6. The method as claimed in claim 2, according to which the heterocomplex is isolated by means of at least two antibodies, at least one of which binds specifically to GM2AP or mutated GM2AP of the heterocomplex, and at least the other of which binds specifically to MRP14 of the heterocomplex, and said cytotoxic factor is detected and/or quantified by demonstrating the formation of a complex consisting of the heterocomplex and the two antibodies. 7. The method as claimed in claim 6, according to which at least one of said antibodies is a capture antibody and at least the other said antibody is a detection antibody. 8. The method as claimed in claim 2, according to which the biological sample is subjected to a prior treatment comprising: digesting the proteins of the sample with proteinase K, inactivating the proteinase K, and neutralizing the pH. 9. The method as claimed in claim 8, wherein inactivating the proteinase K is carried out by precipitation with trichloroacetic acid, and wherein neutralizing the pH is carried out by the addition of a tris-maleate buffer. 10. The method as claimed in claim 2, in which the biological sample is selected from the group consisting of serum, plasma, urine and cerebrospinal fluid. 11. A composition for detecting and/or quantifying a cytotoxic factor associated with multiple sclerosis, said cytotoxic factor being chosen from the heterocomplex GM2AP/GM2MRP 14 and mutated GM2AP/GM2/MRP14 in which mutated GM2AP corresponds to the sequence SEQ ID No. 2, wherein the composition comprises at least one antibody that binds specifically to the heterocomplex. 12. The composition as claimed in claim 11, comprising at least two antibodies that bind specifically to the heterocomplex. 13. A reaction mixture for detecting and/or quantifying a cytotoxic factor associated with multiple sclerosis, said cytotoxic factor being chosen from the heterocomplex GM2AP/GM2/MRP14 and mutated GM2AP/GM2/MRP14 in which mutated GM2AP corresponds to the sequence SEQ ID No. 2, wherein the reaction mixture comprises at least two antibodies, at least one of which binds specifically to GM2AP or mutated GM2AP of the heterocomplex, and at least the other of which binds specifically to MRP14 of the heterocomplex. 14. The reaction mixture as claimed in claim 13, wherein at least one of said antibodies is a capture antibody and at least the other of said antibodies is a detection antibody. 15. A complex comprising the heterocomplex GM2AP/GM/MRP 14 or mutated GM2AP/GM2/MRP14, said heterocomplex being bound to at least two antibodies, at least one of the antibodies of which is specific for GM2AP or for mutated GM2AP, and at least the other antibody of which is specific for MRP 14.

Multiple sclerosis is a chronic disease of the central nervous system in humans, which evolves through a succession of remission and exacerbation phases or according to a regular progression, and the anatomopathological characteristic of which consists of the formation of clearly delimited areas of demyelination in the white substance of the brain and of the spinal cord. At the histological level, these areas exhibit, at the early stage of the lesional process, degradation of the peri-axonal myelin associated with damage to the glial cells responsible for this demyelination. An inflammatory macrophage activation involving microglial cells (resident tissue macrophages of the central nervous system), and also, probably, macrophages originating from infiltrated blood monocytes, is associated with this demyelination process and contributes to the destruction of the myelinated sheets. A relative depletion of glial cells is found at the center of the demyelinated area, whereas a proliferation of astrocytes develops at the periphery and can invade the demyelinated plaque to generate a fibrous or gliotic plaque. These sclerotic structures are the reason for the name given to the disease. Another characteristic of these plaques is their virtually systematic association with a vascular element around which they develop. At the histological level, a frequent impairment of the blood-brain barrier (BBB) consisting of the capillary endothelium is observed. One of the determining elements in the maintenance of the BBB consists of the underlying presence of cytoplasmic extensions of astrocytes, called astrocytic end-feet. The astrocytic end-feet probably induce the formation or allow the maintenance of tight junction structures which ensure the cohesion of the capillary endothelial barrier giving concrete expression to the BBB. Now, various pathological models refer to the impairment of the BBB and to a depletion of the astrocytic end-feet. Moreover, in the lesional process of MS, the impairment of the BBB contributes to amplifying the associated inflammatory response, through the influx of lymphoid cells originating from the bloodstream. The contribution of the inflammation associated with the immune cells is considerable in MS and participates in the lesional process. The etiology of MS is a source of current debate because the disease could have various causes. Hypotheses have been put forward regarding a bacterial and/or viral origin. Moreover, as described in patent application WO 95/21859, H. Perron et al. were led to search for one or more effecter agents of the pathogenic process resulting in the typical formation of demyelination plaques and in astrocytic gliosis. In the context of this study, they demonstrated the presence, in the cerebrospinal fluid (CSF) and the serum of MS patients, of at least one factor which exhibits toxic activity with respect to human or animal astrocyte or oligodendrocyte cells. This toxic activity is characterized by a cytomorphological disorganization of the network of intermediate filaments and/or a degradation of the proteins of said filaments and/or cell death by apoptosis of glial cells. They established a significant correlation between the in vitro detection of this toxic activity in CSF and serum samples from MS patients and multiple sclerosis, by means of a quantitative colorimetric assay with methyltetrazolium bromide (MTT) of living cells, as described in patent application WO 95/21859. Moreover, C. Malcus-Vocanson et al.1,4 have shown that urine is a biological fluid very favorable for detecting the activity of this toxic factor and have developed a method using flow cytometry for detecting and/or quantifying adherent glial cells that are dead through apoptosis. All the information concerning this method is described in patent application WO 98/11439. Assays were carried out using a protein fraction of CSF and of urine from MS patients in order to attempt to identify this toxic factor. The protein content of each fraction was separated on an SDS-PAGE 12% gel and observed after silver staining of the gel. Among the proteins observed, a protein fraction centered on an apparent molecular weight of approximately 21 kD was found as a minor component associated with the toxic activity detected in vitro and a fraction centered on an apparent molecular weight of approximately 17 kD was found as a predominant component associated with this toxic activity. Injection of the fraction originating from CSF from MS patients, into the brain of Lewis rats, and post-mortem histological observation of brain sections from the rats made it possible to observe, three months after the injection, apoptosis of the astrocyte population and the formation of demyelination plaques. All the information is contained in patent application WO 97/33466. These observations are in accordance with those which could be made on brain sections from patients suffering from MS, after biopsy5. Proteins potentially associated with this toxic activity with respect to glial cells in biological samples from MS patients have been studied as described in patent application WO 01/05422. The proteins GM2AP (GM2 ganglioside activator precursor) and saposin B have thus been assayed in the urine of MS and non-MS patients. The results presented in patent application WO 01/05422 showed that GM2AP and saposin B were present at high concentrations in the urine of MS patients compared with the concentrations found in non-MS individuals, and that these two proteins which are codetected in the urine of MS patients could represent a marker for the pathology. The inventors had also established a correlation between the detection of the GM2AP and saposin B proteins in the urine and the gliotoxicity measured in this urine by means of the MTT assay and shown that a correlation existed between high urine concentration and gliotoxicity for these two proteins. The inventors concluded therefrom that the GM2AP and/or saposin B proteins were involved in the mechanism of gliotoxicity and that they could probably act in combination to induce gliotoxicity. The present inventors have now wanted to determine the activity of the proteins identified in patent application WO 01/05422 using the MTT assay, and to see whether the gliotoxicity discovered in the urine of patients suffering from multiple sclerosis is related to the proteins identified. Against all expectations, the present inventors have shown that it is neither the proteins identified in WO 01/05422 taken individually, nor the combination of the GM2AP/saposin B proteins which is involved in the gliotoxicity and that, entirely surprisingly, the agent responsible for the gliotoxic activity and involved in the cytotoxicity corresponds to a heterocomplex GM2AP/GM2/MRP14 (calgranulin B) or mutated GM2AP/GM2/MRP14, as described in the examples which follow. GM2 or ganglioside GM2 is a complex lipid present in cerebral tissue. Thus, a subject of the present invention is the purified isolated cytotoxic factor, associated with multiple sclerosis, said cytotoxic factor being the heterocomplex GM2AP/GM2/MRP14 or mutated GM2AP/GM2/MRP14, it being understood that mutated GM2AP corresponds to the sequence SEQ ID No. 2. These purified isolated heterocomplexes are useful as markers for the MS pathology, and more specifically for a form of the disease, for a stage of the disease or for a period of activity of the disease, and also in the follow-up of patients treated for this pathology. The present inventors have therefore developed a method, a composition and a reaction mixture for detecting and/or quantifying the heterocomplexes GM2AP/GM2/MRP14 and mutated GM2AP/GM2/MRP14 in samples from individuals liable to be suffering from multiple sclerosis or exhibiting clinical signs of this pathology. The method consists in detecting and/or quantifying the cytotoxic factor, associated with multiple sclerosis, in a biological sample, by isolating the heterocomplex GM2AP/GM2/MRP14 or mutated GM2AP/GM2/MRP14 from said biological sample. The expression “isolating the heterocomplex” is intended to mean all the conditions which allow the specific detection of the heterocomplex. The isolation of said heterocomplex can be carried out by any appropriate means. By way of example, mention may be made of nondenaturing electrophoreses, column chromatographies, methods for degrading the compounds of the biological medium, with the exception of the heterocomplex (such as, for example, a treatment with proteinase K), and also any other method for detecting a physicochemical characteristic of said heterocomplex, such as the molecular mass or the isoelectric point, or any other appropriate means. In one embodiment of the invention, use is made of at least one antibody or at least two antibodies that bind(s) specifically to the heterocomplex, and said cytotoxic factor is detected and/or quantified by demonstrating the formation of a complex consisting of the heterocomplex and the antibody or by demonstrating a complex consisting of the heterocomplex and the two antibodies. Preferably, at least one of said antibodies is a capture antibody and at least the other of the antibodies is a detection antibody. The capture antibody is chosen from antibodies that bind specifically to the complex GM2AP/GM2, to the complex mutated GM2AP/GM2, to the complex MRP14/GM2, to the complex GM2AP/MRP14 and to the complex mutated GM2AP/MRP14, and the detection antibody is chosen from antibodies that bind specifically to the complex GM2AP/GM2, to the complex mutated GM2AP/GM2, to the complex MRP14/GM2, to the complex GM2AP/MRP14 and to the complex mutated GM2AP/MRP14. In another embodiment, the heterocomplex is isolated by means of at least two antibodies, at least one of which binds specifically to GM2AP or mutated GM2AP of the heterocomplex, and at least the other of which binds specifically to MRP14 of the heterocomplex, and said cytotoxic factor is detected and/or quantified by demonstrating the formation of a complex consisting of the heterocomplex and the two antibodies. Preferably, at least one of said abovementioned antibodies is a capture antibody and at least the other said antibody is a detection antibody. In the abovementioned embodiments, the demonstration of the formation of the complex consisting of the heterocomplex and at least one antibody or of the heterocomplex and at least two antibodies can be carried out by any appropriate means, for example by screening as a function of size using a sorting device, by screening as a function of molecular mass using a separation column or by direct or indirect labeling of at least one antibody or by any other appropriate means. In one embodiment, the method consists in (i) providing a biological sample to be tested, (ii) bringing said biological sample into contact with at least one capture antibody, said capture antibody being chosen from antibodies that bind specifically to the GM2AP protein, to the mutated GM2AP protein, to the MRP14 protein, to the complex GM2AP/GM2, to the complex mutated GM2AP/GM2 and to the complex MRP14/GM2, and with at least one labeled detection antibody, said detection antibody being chosen from antibodies that bind specifically to the GM2AP protein, to the mutated GM2AP protein, to the MRP14 protein, to the complex GM2AP/GM2, to the complex mutated GM2AP/GM2 and to the complex MRP14/GM2, and (iii) detecting and/or quantifying the cytotoxic factor by detecting and/or quantifying the labeled detection antibody, it being understood that mutated GM2AP corresponds to the sequence SEQ ID No. 2. Preferably, the detection and/or the quantification of the cytotoxic factor is (are) carried out using various immunoassay principles which are well known to those skilled in the art, such as ELISA and ELFA, and use is advantageously made of a “sandwich” immunoassay. The “sandwich”—immunoassay can be carried out in one or more steps, i.e. without a washing step or with one or more washing steps. The detection antibody or antibodies is (are) labeled with any appropriate label. The labeling can thus be radioactive labeling, labeling with an enzyme, labeling with a fluorescent molecule, labeling with a vitamin, or colorimetric labeling. In the present invention, the label is preferably a vitamin, biotin, the detection is carried out by the addition of streptavidin coupled to horseradish peroxidase and the visualization is carried out by the addition of ortho-phenylenediamine dihydrochloride. The capture antibody or antibodies is (are) directly or indirectly immobilized on a solid phase. The term “antibody” used in the present invention encompasses monoclonal and polyclonal antibodies, fragments thereof and derivatives thereof. The term “antibody fragment” is intended to mean the F(ab)2, Fab, Fab′ and sFv fragments of a native antibody6,7, and the term “derivative” is intended to mean, inter alia, a chimeric derivative of a native antibody8,9. These antibody fragments and antibody derivatives conserve the ability to bind selectively to the target antigen. It may be advantageous to use humanized antibodies. “Humanized” forms of nonhuman, for example murine, antibodies are chimeric antibodies which comprise a minimum sequence derived from a nonhuman immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues of a hypervariable region of the recipient are replaced with residues of a hypervariable region of a nonhuman donor species (donor antibody), such as mouse, rat, rabbit or nonhuman primate, having the desired specificity, affinity and capacity. In certain cases, the residues (FR) of the Fv region of the human immunoglobulin are replaced with corresponding nonhuman residues. Furthermore, humanized antibodies can comprise residues which are not found in the recipient antibody or in the donor antibody. These modifications are made so as to improve the effectiveness of the antibody. In general, the humanized antibody will comprise at least and preferably two variable domains, in which all or virtually all of the hypervariable loops correspond to a nonhuman immunoglobulin and all or virtually all of the FR regions will be those of a human immunoglobulin. The humanized antibodies may optionally also comprise at least one part of a constant region (Fc) of an immunoglobulin, such as a human immunoglobulin10,11,12. Mention may in particular be made of the anti-GM2AP and anti-MRP14 antibodies described in application WO 01/05422. However, the surprising discovery that the agent responsible for the gliotoxic activity and involved in the cytotoxicity corresponds to the heterocomplex GM2AP/GM2/MRP14 or mutated GM2AP/GM2/MRP14 allows the production of anti-heterocomplex antibodies that are capable of binding specifically to the complex GM2AP/GM2, to the complex mutated GM2AP/GM2, to the complex MRP14/GM2, to the complex GM2AP/MRP14 or to the complex mutated GM2AP/MRP14. The production of such antibodies is well known to those skilled in the art. The heterocomplex GM2AP/GM2/MRP14 or mutated GM2AP/GM2/MRP14 is used as an immunogen for immunizing BALB/c mice by intraperitoneal injection. The first injection is given with complete Freund's adjuvant. The other injections are given at intervals of 4-8 weeks, with incomplete Freund's adjuvant. A final booster is given a few days before the fusion in physiological saline. After this booster, the spleens of the immunized mice are removed and the splenocytes are collected. The fusion of the spleen cells with cells of a myeloma line is then carried out and the cells secreting antibodies which recognize, in ELISA, the heterocomplex used for the immunization are selected. Finally, the clones producing antibodies specific for the immune heterocomplex, i.e. that recognize neither GM2AP, nor mutated GM2AP, nor MRP14, alone, are selected. The abovementioned antibodies can be used in the method for detecting and/or quantifying the cytotoxic factor, either alone or in combination. In a preferred embodiment of the method of the invention, the test sample is subjected to a prior treatment comprising: a step consisting in digesting the proteins of the sample with proteinase K; a step consisting in inactivating the proteinase K, for example by precipitation with trichloroacetic acid, and a step consisting in neutralizing the pH, for example by the addition of a tris-maleate buffer. The biological test sample is serum, plasma, urine or cerebrospinal fluid, preferably urine. Preferably, the antibodies used in the method of the invention are the following monoclonal and polyclonal antibodies: 10E11A11, 13D1E5, 13H9C9, 19C11C10, 2G12H5, 79, 2B9H2, 4A7B10, 5H7C10 and 196. However, it is quite obvious that any antibody that exhibits the characteristic of binding specifically to the GM2AP protein, to the mutated GM2AP protein, to the MRP14 protein, to the complex GM2AP/GM2, to the complex mutated GM2AP/GM2, to the complex MRP14/GM2, to the complex GM2AP/MRP14 or to the complex mutated GM2AP/MRP14 is part of the invention, the methods for obtaining such antibodies being well known to those skilled in the art, as described above. Preferably, the antibodies used in the sandwich ELISA detection and/or quantification assay of the invention are the following monoclonal and polyclonal antibodies: capture antibodies 10E11A11, 13D1E5, 2G12H5, 4A7B10, 5H7C10, 2B9H2, and 79; detection antibodies 10E11A11, 4A7B10, 5H7C10, 2B9H2, 13H9C9, 19C11C10, 13D1E5 and 2G12H5. The capture and detection antibodies are advantageously chosen from the pairs: 2B9H2/10E11A11, 10E11A11/4A7B10+5H7C10, 13D1E5+2G12H5/4A7B10+5H7C10, 79/4A7B10+5H7C10, 79/2B9H2, 4A7B10+5H7C10/10E11A11, 4A7B10+5H7C10/13H9C9+19C11C10, 2B9H2/100E11A11, 2B9H2/13H9C9+19C11C10, 13D1E5+2G12H5/4A7B10+5H7C10, 79/2B9H2, 4A7B10+5H7C10/10E11A11, 4A7B10+5H7C10/13D1E5+22G12H5, 2B9H2/13D1E5+22G12H5, 2B9H2/13H9C9+19C11C10. The abovementioned monoclonal and polyclonal antibodies are novel and are also part of the subjects of the present invention. The method of producing them will be described in greater detail in the experimental section. The selected and preferred capture and detection antibody pairs are also novel and are also part of the subjects of the present invention. A subject of the present invention is also a composition for detecting and/or quantifying the abovementioned cytotoxic (gliotoxic) factor in a biological-test sample, said composition comprising at least one antibody that binds specifically to the heterocomplex GM2AP/GM2/MRP14 or mutated GM2AP/GM2/MRP14. Preferably, said composition comprises at least two antibodies that bind specifically to the heterocomplex. A subject of the present invention is also a composition for detecting and/or quantifying the abovementioned cytotoxic (gliotoxic) factor in a biological test sample, said composition comprising, in a reaction mixture and simultaneously, at least one capture antibody and at least one labeled detection antibody, said antibodies being chosen from the antibodies that bind specifically to the GM2AP protein, to the mutated GM2AP protein and to the MRP14 protein of the heterocomplex. Preferably, the capture and detection antibodies are chosen from the following monoclonal and polyclonal antibodies: 10E11A11, 13D1E5, 13H9C9, 19C11C10, 2G12H5, 79, 2B9H2, 4A7B10, 5H7C10 and 196. Advantageously, said composition comprises at least one capture antibody chosen from the antibodies 10E11A11, 13D1E5, 2G12H5, 4A7B10, 5H7C10, 2B9H2 and 79; and at least one detection antibody chosen from the detection antibodies 10E11A11, 4A7B10, 5H7C10, 2B9H2, 13H9C9, 19C11C10, 13D1E5 and 2G12H5. The preferred compositions comprise the following capture and detection antibody pairs: 2B9H2/10E11A11, 10E11A11/4A7B10+5H7C10, 13D1E5+2G12H5/4A7B10+5H7C10, 79/4A7B10+5H7C10, 79/2B9H2, 4A7B10+5H7C10/10E11A11, 4A7B10+5H7C10/13H9C9+19C11C10, 2B9H2/10E11A11, 2B9H2/13H9C9+19C11C10, 13D1E5+2G12H5/4A7B10+5H7C10, 79/2B9H2, 4A7B10+5H7C10/10E11A11, 4A7B10+5H7C10/13D1E5+22G12H5, 2B9H2/13D1E5+22G12H5, 2B9H2/13H9C9+19C11C10. A subject of the invention is also a reaction mixture for detecting and/or quantifying the abovementioned cytotoxic (gliotoxic) factor, said mixture comprising at least two antibodies, at least one of which binds specifically to GM2AP or mutated GM2AP of the heterocomplex, and at least the other of which binds specifically to MRP14 of the heterocomplex. The term “reaction mixture” is intended to mean a homogeneous or heterogeneous medium which simultaneously comprises at least the abovementioned two antibodies. Preferably, at least one of said antibodies is a capture antibody and at least the other of said antibodies is a detection antibody. Another subject of the invention is a complex comprising the heterocomplex bound to at least two antibodies, at least one of the antibodies of which is specific for GM2AP or for mutated GM2AP, and at least the other antibody of which is specific for MRP14. The sequence SEQ ID No. 1 corresponds to the sequence of the GM2AP protein. The sequence SEQ ID No. 2 corresponds to the sequence of the GM2AP protein mutated in exon 2, at position 40 (replacement of an aspartic acid with a phenylalanine). The sequence SEQ ID No. 3 corresponds to the sequence of the mutated GM2AP protein exhibiting mutations both in exon 1, in exon 2 and in exon 4. In the detailed description which will follow, when reference is made to the GM2AP protein, the sequence to be taken into consideration is the sequence identified in the sequence identifier SEQ ID No. 1. Moreover, when reference is made to the mutated GM2AP protein, the sequence to be taken into consideration is the sequence identified in the sequence identifier SEQ ID No. 2; it being understood that, in the sequences SEQ ID No. 1 and SEQ ID No. 2, a valine or an alanine can be found without distinction at position 153, as explained in the experimental section in example 3. However, equivalent experiments can be carried out by taking into consideration the mutated GM2AP protein exhibiting mutations both in exon 1, in exon 2 and in exon 4, as identified in the sequence identifier SEQ ID No. 3. FIGURE The attached FIGURE represents the dose-response curve of the ternary complex GM2AP+MRP14+GM2 (GM2: 50 μg/ml final concentration). The amounts of MRP14 are represented along the x-axis (in ng) and the percentage cytotoxicity corresponding to the percentage of dead cells is represented along the y-axis. In the present FIGURE, the amounts of GM2AP in ng are, respectively, represented by the following symbols: φ:5 ng, π: 10 ng, ψ: 20 ng, υ: 50 ng and χ: 100 ng. A similar experiment was carried out with the mutated GM2AP protein instead of the GM2 protein. The results obtained are similar to those given in the attached FIGURE. EXAMPLES Example 1 MTT Assay Protocol (i) “Coating” of the Plates with poly-L-lysine 250 μl of sterile poly-L-lysine solution (12.5 μg/ml) are deposited into all the wells of 48-well plates (Falcon 3078). After incubation for 2 hours at 37° C., the solution is removed by suction and replaced with 250 μl of sterile water so as to wash the wells. Once the wells have been emptied by suction, they are dried under the airstream of a microbiological safety station. (ii) Cells Used CLTT1-1 cells are astrocytes derived from transgenic mice expressing the large T gene of the polyoma virus13. These cells are cultured at 37° C. under a humid atmosphere at 5% CO2, in Dubelcco's Modified Eagle's Medium (DMEM)/Ham's F12 medium (50/50), 4.5 g/l of D-glucose, supplemented with 10% of nondecomplemented fetal calf serum (FCS), glutamax (580 mg/l), penicillin (500 units/i) and streptomycin (500 μg/l). (iii) Cytotoxicity Assay The test samples are prepared 24 hours before deposit for the toxicity assay and incubated at 4° C. The 48-well plates “coated” with poly-L-lysine are seeded with CLTT 1-1 cells at a rate of 250 μl of cell suspension (6000 cells/ml) per well, i.e. 1500 cells/well. After incubation for 24 hours at 37° c, in the humid atmosphere at 5% CO2, the samples are deposited at the surface of the cell medium. Each sample is deposited in triplicate. Certain wells make it possible to evaluate cellular controls (C) (no deposit of sample) or “TUC” controls (deposit of 10 μl of TUC solution). The TUC reagent (20 mM Tris, 250 mM urea, 1 mM CaCl2) is a solution that mimics the chemistry of the urine. The deposit is homogenized and, in order to prevent any evaporation, a protective film is applied over the top of the plates. After incubation for 72 hours at 37° C., in a humid atmosphere at 5% CO2, the visualization by means of the MTT assay is carried out. The cell supernatant is removed by suction, taking care not to remove the cells from the bottom of the wells. 250 μl of MTT solution (0.5 mg/ml in culture medium) are deposited carefully onto the cells. After incubation for 3 hours at 37° C., the solution is removed by suction and the formazan crystals formed in the cells are solubilized with isopropanol, 1N HCl (40 μl/ml). Once homogeneous, 70 μl of solution of each well of the 48-well plate are transferred into the wells of a 96-well plate, in order to carry out an optical density reading. The absorbances are read at 570 nm/650 nm. The percentage cytotoxicity can be calculated: MeanC=mean of the absorbances of the controls σC =standard deviation of the absorbances of the controls CO=CutOff=MeanC=2 σC OD=mean absorbance of the samples % toxicity=(1-(OD/CO))×100 In order to be valid, the absorbances of each sample (in triplicate) must not have a standard deviation greater than 10% of the mean absorbance. Example 2 Preparation of Pools of Urine 100 liters-of MS urine (0.2-0.5 liter originating from the first morning micturition of patients) were collected. The urine from patients with a bacterial4 contamination or that from patients treated with drugs liable to interfere with the gliotoxicity bioassay4 were eliminated. The individual samples were tested for gliotoxicity and a final pool of 46 liters of urine with a significant gliotoxicity, by virtue of the MTT assay, was selected. In parallel, an equivalent volume of urine from normal donors with negative gliotoxicity, for each sample, was obtained. The steps consisting of concentration and purification of this material, the protein analysis and the identification strategy are presented below. Purification of Proteins in the Urine The MS positive and MS negative urine pools were purified so as to obtain a high concentration of proteins. (i) Precipitation: Precipitations with ammonium sulfate (Prolabo—ref. 21 333 365) were carried out on the MS positive and MS negative urine pools. The percentage of 60% saturated ammonium sulfate for 40% of urine, i.e. 390 grams of ammonium sulfate per liter of urine, was used. Each pool is dispensed, in fractions of 1.8 liters, into 2-liter bottles so as to improve the precipitation. The precipitation was carried out for 2×8 hours, at ambient temperature, with gentle stirring. After centrifugation of the urine pools at 3000 rpm for 10 min, at a temperature of 10° C., the pellet obtained is taken up in 20 mM Tris buffer containing 1 mM CaCl2 and 0.25 M urea. The mixture was then centrifuged at 3000 rpm for 10 min. The supernatant contains the concentrated proteins. It is either used immediately for the following step, or frozen if the following step cannot be carried out continuously. (ii) Ion Exchange Chromatography: The solution containing the proteins was then passed over a DEAE Fast Flow gel (trade name, sold by Pharmacia). This step is carried out at low pressure on a Pharmacia column packed with gel. The buffers are introduced onto the column via a peristaltic pump which allows an even flow rate. The column-equilibrating buffer is 20 mM Tris buffer, pH 7. The fraction corresponding to the precipitation supernatant and containing a too high amount of salts is dialyzed against this buffer before being loaded onto the column. A salt-gradient elution makes it possible to recover the proteins. The elution gradient is effected by steps of 100, 200, 300 and 500 mM NaCl in the column-equilibrating buffer. The elution fractions are tested by means of the MTT assay. Only the positive fractions, i.e. the fractions eluted at 200 mM NaCl, are conserved. These fractions are treated immediately or conserved in the lyophilized state. (iii) Purification: A steric exclusion chromatography based on the difference in size and in shape of the proteins to be eluted was used. The fraction corresponding to the 200 mM NaCl elution is loaded onto the column. In the course of the elution, the low molecular weight proteins are retained and therefore eluted later than the large molecules. The purifications were carried out on HPLC with a TosoHaas TSK Prep G 3000 SW column, 21.5 mm in diameter and 300 mm in length. The molecular mass exclusion limit is 500 000 daltons. The elution buffer used contains 100 mM phosphate, 100 mM sodium sulfate, at pH 6.8. The separation of the mixture of proteins was carried out in 60 min. Only the fraction corresponding to a mass of 15-20 000 daltons was conserved. This fraction was dialyzed in a 20 mM Tris buffer containing 0.2 mM CaCl2, pH 7.2, then lyophilized. At each step, only the fractions exhibiting a significant toxic activity were retained for the subsequent step. A control for the toxic activity of the proteins was carried out at each step, using the MTT assay. Only the fractions exhibiting a significant toxic activity were retained for the additional purification step. (iv) Additional Purification of the Proteins in the Urine by Reverse-Phase Chromatography: The pools of urine originating from MS patients (MS positive pool) and from non-MS patients (MS negative pool), obtained after purification, were taken up in distilled water, and then diluted with a 0.2% TFA/10% acetonitrile solution so as to obtain a final concentration of approximately 130 to 140 μg/ml. The separation by C8 reverse-phase HPLC was carried out on a Brownlee Aquapore column (trade name) sold by the company Perkin Elmer (column characteristics: 300 angstroms/7 μm/(100×4.6) mm). Two different columns were used respectively for the positive and negative pools. The injections were carried out by virtue of multi-injections of 250 μl. The proteins were eluted with a linear gradient of 5% to 15% of buffer A in 5 min, then of 15% to 100% of buffer B in 95 min, at a flow rate of 0.5 ml/min. The separation buffers A and B used are respectively the .0.1% TFA (Pierce No. 28904)/MilliQ water buffer and the 0.09% TFA/80% acetonitrile (Baker) buffer. The detection was carried out by measuring the UV absorbance at 205 and 280 nm. The fractions were collected as fractions of 1.5 ml and of 0.5-1 ml in the zone of interest. The fractions were frozen after collection, in dry ice. The fractions collected were then dried in a Speed Vac and taken up in 100 μl of 0.1% TFA/30% acetonitrile. 20 μl of the fractions were transferred into 500 μl eppendorfs, dried and washed twice with 100 μl of MilliQ water, and then dried again. The toxic activity of the proteins contained in each fraction collected after elution was determined using the MTT assay. Only the fraction X76/43 of the MS positive pool exhibits toxic activity in vitro. The number of this fraction corresponds to the order of the elution as a function of the elution conditions stated in the example. Its toxic activity was confirmed in vitro by FACS on murine astrocyte cells, as described in application WO 98/11439. Its profile on SDS-PAGE revealed protein bands at 55 kDa, 35 kDa, 20 kDa, 18 kDa, 14 kDa and 8 kDa. The corresponding fraction X76/43 of the MS negative pool, obtained from the control urine, did not exhibit any toxic activity by means of the MTT assay. Its profile on SDS-PAGE showed bands at 55 kDa, 35 kDa and 20 kDa. Analysis of the Proteins Obtained by Separation on HPLC on SDS-TRICINE Gel The protein content of the fraction X76/43 of the MS negative control pool and of the fraction X76/43 of the MS positive pool was observed after separation on SDS-TRICINE 16% gel and zinc/imidazole staining of the gel. The fraction X76/43 collection pool obtained by HPLC was loaded onto a pre-poured SDS-TRICINE 16% gel with 10 wells and 1 mm thick (sold by the company Novex). The conditions for using the gel correspond to those recommended by the supplier. The sample is taken up in 75 μl of once concentrated sample buffer (SDS-TRICINE No. LC 1676, 1 ml twice concentrated+50 μl of β-mercaptoethanol (Pierce) diluted to ½ in water) and 25 μl of the sample are loaded onto the gel in triplicate. The fraction X76/43 collection pool originating from the MS negative pool was loaded onto the gel under the same conditions as those described for the MS positive pool. The migration on the two gels was carried out in parallel in the same migration tank (XCELL II NOVEX (trade name)) at a constant voltage of 125 mV for 2 hours. The tank was placed in a container containing ice. The gels were stained directly after migration by zinc/imidazole staining (staining kit 161-0440 sold by the company Biorad) so as to obtain a reversible negative staining. Trypsin Digestion of the Gel Bands All the protein bands visualized in the loadings of the fraction X76/43 were cut out and subjected to proteolysis in a trypsin solution overnight. The gel bands were cut into slices of 1 mm with a scalpel and transferred into eppendorf tubes. The eppendorfs were subjected to a centrifugation spike so as to bring down the gel pieces and, after centrifugation, 100 μl of washing buffer (100 mM NH4CO3/50% CH3CN) were added to the gel pieces. After agitation for 30 min at ambient temperature, the supernatant was removed by 20 μl fractions and the washing step was repeated twice. The eppendorfs were dried for 5 min in a speed vac. 20 μg of trypsin (modified sequential grade PROMEGA V5111) (trade name) were taken up in 200 μl of digestion buffer (5 mM Tris, pH 8) and dissolved for 30 min at ambient temperature, with intermittent agitation, and 20 to 30 μl of resuspended trypsin were added to the gel pieces. The eppendorfs were centrifuged and stored in a warm room at 28° C. overnight. After digestion, the gel bands can be used immediately for the measurements of mass or frozen for subsequent use. Proteins of higher apparent molecular weights were found in the two fractions. On the other hand, the bands of apparent molecular weights 8, 14 and 18 kDa are visible only in the fraction X76/43 of the MS positive pool. Example 3 Mass Spectrometry and Sequencing of the Proteins Analysis by MALDI-TOF Mass Spectrometry of the Proteolytic Fragments 30 μl of extraction buffer (2% TFA/50% acetonitrile) are added to the samples. The eppendorfs to be analyzed are subjected to centrifugation for 5 min, and then to sonication for 5 min, and, finally, to centrifugation for 1 min. 14 deposits of 0.5 μl of matrix (α-cyano-4-hydroxy-trans-cinnamic acid at saturation in acetone) are made on a stainless steel disk. A thin uniform microcrystalline layer is obtained. 0.5 μl of a solution of 2% TFA/water is deposited onto this undercoat on the 14 deposits, and then 0.5 μl of sample to be analyzed is added. 0.5 μl of a saturated solution of α-cyano-4-hydroxy-trans-cinnamic acid in 50% acetonitrile/water is added to this drop thus formed. After drying at ambient temperature for 30 min, the crystalline deposits are washed with 2 μl of water, which are immediately removed with a blast of air. All the spectra are obtained on a BRUKER BIFLEX mass spectrometer (trade name) equipped with a reflectron. The measurements (90 to 120 firings of the laser over the entire deposit) are accumulated so as to obtain a mass spectrum which is the most representative of all the peptides present in the matrix-sample sandwich. For each deposit, a calibration with the trypsin autolysis peptides was carried out in order to be able to use a measuring accuracy of less than 100 ppm. The mass spectrometry results were searched in the databanks using the MS-FIT algorithm of the Protein Prospector-software (http://prospector.ucsf.edu). N-Terminal Sequencing of the Digestion Peptides (i) Extraction and Separation by HPLC of the Digestion Peptides The peptides obtained after digestion with trypsin were extracted in 3 times 30 min in a sonication bath with 0.1% TFA/60% acetonitrile. The extraction solutions were combined and dried to 20 μl in a speed vac. After dilution in 80 μl of buffer A (0.1% TFA/water), the extractions of the gel bands, digested with trypsin, were injected onto a C18/MZ-Vydac/(125×1.6) mm/5 μm column (trade name). The peptides were eluted at a flow rate of 150 μl/min and in a gradient ranging from 5% of buffer B (0.09% TFA/80% acetonitrile) to 40% of buffer B in 40 min, and then from 40% of buffer B to 100% of buffer B in 10 min. The detection was carried out by measuring the UV absorbance at 205 nm. The peaks were collected in 500 μl eppendorf tubes. The individual peptide peaks collected were then subjected to N-terminal amino acid sequence analysis. (ii) N-Terminal Sequencing: The fractions corresponding to a single mass peak were analyzed by Edman degradation on a sequencer (Perkin Elmer model 477A, Applied Biosystems). The sequencing conditions were those described by the constructor. A microcartridge was used for loading the samples and the PTH-amino acids were identified with an online HPLC system (Perkin Elmer model 120A, Applied Biosystems). Results The results of the analysis by mass spectrometry and of the sequencing are given in table 1 below. TABLE 1 IMS IS MW (kDa) MS Control MS Control 55 Human Human ND ND serum serum albumin albumin 35 Inter- Inter- ND ND alpha- alpha- trypsin trypsin inhibitor inhibitor 20 Perlecan* Perlecan* Perlecan* Perlecan 20 NI NI Retinol- Retinol- binding binding protein protein 20 NI NI GM2- Not activating present protein Not detected 18 GM2- No band GM2- No band activating on the activating on the protein gel protein gel 14 MRP14 No band MRP14 No band on the on the gel gel 8 Not No band Saposin B No band identified on the on the gel gel MW: average molecular weight IMS: identification by mass spectrometry IS: identification by sequencing NI: remaining peaks not identified ND: not determined *identical to the 20 kDa C-terminal fragment of perlecan probably resulting from prior proteolysis of the complete 467 kDa protein in the urine or during the purification process. A mixture of co-purified proteins was also present both in the final MS purification fraction and in the corresponding control fraction. The proteins identified in these two samples were considered to be irrelevant due to the absence of gliotoxic activity in these two fractions. Consequently, GM2AP (18 kDa), MRP14 or calgranulin B (14 kDa), and saposin B (10 kDa) were considered to be potential candidates for the gliotoxic activity. Moreover, the N-terminal sequencing of the trypsin-digested fragments of the 18 kDa band in the MS fraction showed the presence of polymorphism in various positions of GM2AP; a mutation in exon 1, at position 19 of the GM2AP amino acid sequence, where an alanine is replaced with a threonine; a mutation in exon 2, where an aspartic acid is replaced with a phenylalanine at position 40 of the GM2AP amino acid sequence. This mutation has never been found in the genomic DNA of normal or affected donors; two other mutations in exon 2, respectively at positions 59 and 69 of the GM2AP amino acid sequence, which correspond to the replacement of an isoleucine with a valine and of a methionine with a valine. A mutation in exon 4, which consists of a replacement of a valine with an alanine at position 153 of the GM2AP amino acid sequence, was found to be a new polymorphism that had not been described, after various rounds of sequencing of the genomic DNA of lymphocytes originating from normal individuals (blood donors) and from patients suffering from multiple sclerosis. This mutation in exon 4 was found in 3 out of 27 MS patients tested, and also in 8 out of 27 control individuals, suggesting a normal polymorphism. Another mutation is found in exon 4, at position 171 of the GMPA2 amino acid sequence, where a lysine is replaced with a glutamine. The amino acid sequences of GM2AP and of mutated GM2AP are respectively represented in the sequence identifier as SEQ ID No. 1 and SEQ ID No. 2, it being understood that, in these two sequences SEQ ID No. 1 and SEQ ID No. 2, a valine or an alanine can be found without distinction at position 153, since the mutation in exon 4 for this position suggests a normal polymorphism. Example 4 Recombinant Proteins Recombinant proteins (purchased or produced by transfection) were used to evaluate the gliotoxic potential of the candidate proteins. The following “nonhuman” proteins, i.e. recombinant proteins produced in a prokaryotic expression system (E. coli) by transformation with a plasmid containing the insert to be expressed, or in a eukaryotic expression system in yeast or insect cells infected with the baculovirus having integrated the insert to be expressed, were used: The MRP14 protein (or calgranulin B or S100A9) fused in the N-terminal position with a histidine tail and produced in E. coli; the MRP8 protein (or calgranulin A or S100A8) produced in E. coli; and the native human heterocomplex MRP14/MRP8 (or calprotectin), purchased from Dr C. Kerkhoff (University of Munster, Germany). The GM2AP protein (ganglioside GM2-activating precursor) fused in the N-terminal position with a histidine tail produced in baculoviruses and the Sap B (saposin B) protein produced in yeast, purchased from Professor K. Sandhoff (Institut Kekule, University of Bonn, Germany). These proteins have their own physiological activity described in the literature. The “human” proteins, i.e. recombinant proteins produced in a eukaryotic expression system in human cells transfected with an appropriate plasmid having integrated the insert to be expressed, were produced according to the protocol described below. 293T cells (primary human embryonic kidney cells transformed with an adenovirus type 5, expressing the large T antigen) were cultured at 37° C. in a humid atmosphere at 5% CO2, in DMEM, 4.5 g/l of D-glucose, supplemented with 10% of decomplemented fetal calf serum (FCS), glutamax (580 mg/l), penicillin (500 units/l) and streptomycin (550 μg/l). To carry out the transient transfection, appropriate plasmids containing the cDNA of the proteins of interest, MRP14, GM2AP and mutated GM2AP (aspartic acid/phenylalanine/position 40) preceded by a secretion peptide (IgK) in the N-terminal position, were used. The 293T cells were transfected with a “Transfectant” reagent composed of lipids which complex and transport the DNA into the cells. The 293T cells are trypsinized, seeded at 2 million cells per 75 cm2 flask, and incubated overnight at 37° C. in a humid atmosphere at 5% CO2 in 10 ml of culture medium (DMEM, 4.5 g/l of D-glucose, supplemented with 10% of decomplemented fetal calf serum (FCS), glutamax (580 mg/l), penicillin (100 units/ml) and streptomycin (100 μg/ml)). The transfection solution is prepared extemporaneously using the ratio 3/2 [volume of Transfectant (μl)/amount of plasmid DNA (μg)], qs 1 ml of FCS-free medium. After 45 minutes of contact at ambient temperature, the transfection solution is added dropwise to a nonconfluent cell layer. After incubation for 72 hours at 37° C., in a humid atmosphere at 5% CO2, the supernatants are recovered, and centrifuged for 10 minutes at 2500 rpm. The quantification of protein produced is then carried out either with the MRP Enzyme Immunoassay kit (trade name) sold by BMA Biomedicals AG, Augst, Switzerland, according to the information sheet for the human recombinant MRP14 protein, or by the semi-quantitative Western blotting technique with anti-GM2AP rabbit polyclonal antibodies. These techniques give indicative values for a relative comparison. The crude supernatants derived from this production will be used in particular for the toxic activity and detection assays. Example 5 Toxicity of the “Nonhuman” Proteins The toxicity of the “nonhuman” recombinant proteins MRP14, MRP8, GM2AP and SapB was evaluated by means of the MTT assay. The proteins were tested in a range defined from the evaluation of the concentration of each protein in various urines. The ranges are prepared in various buffers, either in the TUC solution, or in two types of urine: urine originating from patients suffering from multiple sclerosis and which was toxic with the MTT assay (MS urine), and urine originating from a recruitment of non-MS donors, which was not toxic with the MTT assay (normal urine). The urine was treated beforehand for 30 min at 56° C. and filtered. The results show that, taken individually, the proteins tested in the TUC solution and in the normal urine are not toxic with the MTT assay. No significant effect of the GM2AP, MRP14 and saposin B proteins is demonstrated in the MS urine with the MTT assay. An inhibition of the toxicity is noted with an MRP8 dose greater than or equal to 3-ng. These results are shown in table 2. TABLE 2A Range in the TUC solution Protein Amount in ng Cytotoxicity as % GM2AP 5 −48 2.5 −19 1.25 −122 0 −55 MRP14 10 −20 5 −22 2.5 −34 0 −11 Saposin B 50 −9 40 −8 30 −16 20 −3 10 −16 0 −18 MRP8 3 −18 1.5 −19 0.5 −14 0 −19 TABLE 2B Range in the urine MS urine Normal urine Cytotoxicity Cytotoxicity Protein Amount in ng as % as % GM2AP 5 34 −11 2.5 41 −7 1.25 32 −13 0 42 −4 MRP14 10 29 −8 5 29 10 2.5 33 9 0 37 7 Saposin B 100 44 ND 80 54 ND 50 58 ND 30 67 ND 20 70 ND 10 69 ND 0 62 ND MRP8 3 −18* 8 1.5 50 5 0.5 46 10 0 40 8 For MRP14 and MRP8, the percentage cytotoxicity is a mean percentage cytotoxicity over 2 assays ND: not determined *In another MS urine, the same inhibition of toxicity is observed. Combinations of GM2AP/MRP14, saposin B/MRP14 and saposin B/GM2AP/MRP14 proteins were then prepared in the TUC solution and in the two types of urine as described above. In “control” combinations, the heterocomplex MRP14/8 or the MRP8 protein replaced the MRP14 protein in the various GM2AP/MRP14/8, saposin B/GM2AP/MRP8 combinations. The “controI” combinations were prepared in the same manner. All the combinations were incubated overnight at 4° C. before being tested for their toxicity using the MTT assay. The results are given in table 3. TABLE 3A Range in the TUC solution % Combinations of proteins cytotoxicity GM2AP (ng) MRP14 (ng) 20 1 −12 20 0.5 −8 10 1 −9 10 0.5 18* 0 0 0 GM2AP (ng) MRP14/8 (ng) 20 20 −14 20 10 −21 10 20 −12 10 10 −16 0 0 0 Sap. B (ng) MRP14 (ng) 30 1 −17 30 0.5 −19 15 1 −9 15 0.5 −8 0 0 0 GM2AP (ng) MRP14 (ng) Sap. B (ng) 20 1 30 −11 20 1 15 −4 20 0.5 30 −15 20 0.5 15 −14 10 1 30 −9 10 1 15 −5 10 0.5 30 −21 10 0.5 15 −17 0 0 0 0 MRP14/8: human native heterocomplex Sap. B: saposin B *mean of two assays The results in table 3A show that the combinations GM2AP/MRP14, GM2AP/MRP14/8, saposin B/MRP14 and GM2AP/MRP14/saposin B have no toxic effect in the TUC, whatever the amount tested. Only the combination GM2AP (10 ng)/MRP14 (0.5 ng) appears to exhibit toxicity, but this toxic activity was not subsequently found in two additional comparable assays. Furthermore, additional assays were carried out with the combination GM2AP/MRP14 using various amounts of GM2AP and of MRP14. The results obtained confirmed that the combination GM2AP/MRP14 has no toxic effect in the TUC, whatever the amount tested. TABLE 3B Range in the normal urine % % Combination of proteins cytotoxicity cytotoxicity Amounts in ng Normal urine 1 Normal urine 2 GM2AP MRP14 20 1 −10 26 20 0.5 0 25 10 1 3 8 10 0.5 −6 20 0 0 −19 10 Sap. B MRP14 30 1 0 16 30 0.5 −4 15 15 1 −10 13 15 0.5 3 11 0 0 −19 10 GM2AP MRP14 Sap. B 20 1 30 −19 19 20 1 15 8 9 20 0.5 30 −27 25 20 0.5 15 16 13 10 1 30 7 17 10 1 15 5 32 10 0.5 30 14 23 10 0.5 15 4 22 0 0 0 −88 12 Sap. B: saposin B As emerges from table 3B, the combination GM2AP/MRP14 is toxic in the normal urine since the toxicity increases as a function of the increase in the amount of GM2AP protein. However, this toxicity appears to be relatively unstable and relatively unreproducible and seems to be dependent on the urine sample (see comparison of the percentage cytotoxicity between normal urine 1 and normal urine 2, in table 3B). The combination saposin B/MRP14 is at the limit of significance in the normal urine. The results obtained with the combination GM2AP/MRP14/saposin B are difficult to interpret. The toxicity of the combinations of GM2AP/MRP14 and saposin B/MRP14 proteins was also tested with respect to normal urine and toxic urine derived from patients suffering from multiple sclerosis (MS urine). The results are shown in table 3C. TABLE 3C Range in the non-MS urine and MS urine Combinations of % % % proteins (ng) cytotoxicity cytotoxicity cytotoxicity MRP14 Normal urine 1 Normal urine 2 MS urine GM2AP 20 1 −10 26 7 20 0.5 0 25 12 10 1 3 8 8 10 0.5 −6 20 9 0 0 −19 10 22 Sap. B 30 1 0 16 32 30 0.5 −4 15 28 15 1 −10 13 16 15 0.5 3 11 14 0 0 −19 10 22 Sap. B: saposin B The combination saposin B/MRP14 has no toxic effect in the normal urine and the MS urine, whatever the amount tested. The combination GM2AP/MRP14 does not exhibit any toxic effect with respect to normal urine 1, but exhibits a toxic effect with respect to norm,al urine 2 (when GM2AP increases, the toxicity of the urine increases). An inverse effect with respect to the MS urine is, moreover, noted. When the amount of MRP14 increases, the toxicity of the urine decreases. Example 6 Toxicity of the “Human” Proteins The proteins GM2AP, GM2AP mutated in exon 2 and MRP14 produced as described in example 3 were tested for their toxicity by means of the MTT assay, using the culture supernatants from the 293T cells containing them. The following combinations were also effected using the 293T cell culture supernatants: GM2AP/MRP14, mutated GM2AP/MRP14, GM2AP/MRP14/MRP8. The combinations prepared were subsequently incubated overnight at 4° C., and were then tested for their toxicity by means of the MTT assay. The results are shown in table 4. TABLE 4A % C % C % C % C GM2AP MRP14 Batch 1 Batch 1 Batch 2 Batch 2 (ng) (ng) Assay 1 Assay 2 Assay 1 Assay 2 20 1 4 23 11 12 20 0.5 31 29 20 20 20 0 −26 −26 8 8 10 1 −13 −13 0 8 10 0.5 −14 −11 6 24 10 0 −25 −25 0 0 0 1 −24 −24 ND ND 0 0.5 −8 −8 ND ND % C: percentage cytotoxicity ND: not determined Approximate concentrations of proteins in the supernatants: MRP14 batches 1 and 2: 350 ng/ml; GM2AP batch 1: 300 ng/ml, batch 2: 200 ng/ml For certain values, indicated in bold characters, some GM2AP/MRP14 combinations are weakly cytotoxic (from 20 to 30% cytotoxicity) with an optimum for the combination GM2AP (20 ng)/MRP14 (0.5 ng). MRP14 alone is not cytotoxic. GM2AP alone is not considered to be cytotoxic, even though a very weak toxicity is found in assays 1 and 2 carried out on batch 2. This is because the reproducibility cannot be perfect since it depends on the supernatant production batch. TABLE 4B % C % C Batch 3 Batch 3 GM2AP (ng) MRP14 (ng) Assay 1 Assay 2 100 100 29 41 100 50 36 17 100 10 10 8 100 5 31 1 100 1 rejection 9 100 0 18 2 50 100 rejection 28 50 50 31 16 50 10 21* −4 50 5 11 −6 50 1 −14 −7 50 0 2 −3 20 100 12* 13 20 50 rejection 22 20 10 −13 4 20 5 −30 4 20 1 −22 4 20 0 ND ND 10 100 29* 18 10 50 15 6 10 10 −2 −16 10 5 −22 −7 10 1 −21* −17 10 0 ND ND 5 100 22* 32 5 50 −9 9 5 10 −11 1 5 5 −29 −6 5 1 −18 −4 5 0 ND ND 0 100 31 33 0 50 41* 22 0 10 4 11 0 5 ND ND 0 1 ND ND % C: percentage cytotoxicity ND: not determined Approximate concentration of GM2AP and MRP14 in the supernatant: 2 μg/ml Rejection: % cytotoxicity rejected since the standard deviation of the OD values of the samples is greater than 50 *standard deviation of the OD values of the samples between 16 and 11 No comment: standard deviation of the OD values of the samples less than 10. The results show that the proteins alone, in the supernatants, are not toxic, except in a nonspecific manner at very high amounts (10.0 ng of MRP14). Only the combination GM2AP (100 ng)/MRP14 (100 ng) can be considered to exhibit a relative cytotoxicity. IF the GM2AP protein is replaced with the mutated GM2AP protein in this combination, the same type of toxicity is obtained for certain mixtures, as shown below. TABLE 4C Mutated % C % C % C GM2AP MRP 14 Batch 2 Batch 2 Batch 2 (ng) (ng) Assay 1 Assay 2 Assay 3 20 1 16 25 53 20 0.5 18* 18 50 10 1 12 15* 21 10 0.5 10 20 25* 10 0 −7 0 −7 0 1 −9 13 −16 % C: percentage cytotoxicity *standard deviation of the OD values of the samples between 14 and 11 No comment: standard deviation of the OD values of the samples less than 10 Approximate concentration of proteins in the supernatants: mutated GM2AP: 200 ng/ml; MRP14: 350 ng/ml. For many values, indicated in bold characters, the combination mutated GM2AP/MRP14 is toxic. The mutated GM2AP protein alone has no cytotoxic effect. MRP14 alone is not considered to exhibit any cytotoxic activity. The cytotoxicity of the combinations of supernatants containing the human recombinant proteins, GM2AP/MRP14 and mutated GM2AP/MRP14, is found to be in the same order of magnitude, with a greater stability, as a function of the protein production batch, than with the nonhuman recombinant proteins. However, this does not correspond to the stability, the reproducibility and the intensity of the gliotoxic activity found in the biological fluids of MS patients. TABLE 4D % C % C % C GM2AP MRP14/18 Batch 1 Batch 1 Batch 2 (ng) (ng) Assay 1 Assay 2 Assay 1 20 20 17 −13 16 20 10 6 −2 23 20 0 −26 −26 8 10 20 −14 −16 1 10 10 −15 −24 12 10 0 −25 −25 0 % C: percentage cytotoxicity Approximate concentration of proteins in the supernatants: GM2AP (batch 1): 300 ng/ml, GM2AP (batch 2): 200 ng/ml. Concentration of native MRP14/8: 1.3 mg/ml. It emerges from the results in table 4D that GM2AP alone has no cytotoxic activity and that, for certain values, indicated in bold characters, the combination GM2AP/MRP8 has a cytotoxic effect. This cytotoxicity is dependent on the supernatant batch used. TABLE 4E % C Mutated GM2AP MRP14/8 Batch 2 (ng) (ng) Assay 1 20 20 5 20 10 6 20 0 15 10 20 −18 10 10 4 10 0 −2 % C: percentage cytotoxicity Approximate concentration of proteins in the supernatants: mutated GM2AP: 200 ng/ml. Concentration of native MRP14/8: 1.3 mg/ml. It emerges from table 4E that the combination mutated GM2AP/MRP8 does not exhibit any cytotoxic activity. These studies show that none of the proteins identified in the gliotoxic fraction purified from MS urine reproduced, alone, the gliotoxic activity sought and that the combinations of proteins produced in the form of “nonhuman” or “human” recombinants reproduce only weakly, and relatively unreproducibly (even though an improvement is noted with the “human” recombinants), the gliotoxic activity. The results obtained do not meet all the criteria that characterize the gliotoxic activity (high activity, stability, reproducibility, dose-response effect). The results show that an essential component, which was not identified in the protein analysis, is lacking. The inventors then found, surprisingly, that lipids, in particular complex lipids, are advantageous candidates in this context. To this effect, ganglioside GM1, ganglioside GM2 and sulfatide were tested. Among these lipids, ganglioside GM2 proved to be the only one which was probative, as shown in the following examples. Example 7 Toxicity of the “Human” Recombinant Proteins in Combination with Ganglioside GM2 Ganglioside GM2 (provided by Professor J. Portoukalian (Lyon, France)) is added, at a final concentration of 50 μg/ml, to the combinations of “human” recombinant proteins already prepared, involving the MRP14, GM2AP and mutated GM2AP proteins. The combinations GM2AP/MRP14 and mutated GM2AP/MRP14 were tested in a protein range: 0, 5, 10, 20, 50, 100 ng for the GM2AP and mutated GM2AP recombinant proteins and up to 200 ng for the MRP14 protein. These ranges were prepared in combination or not in combination with ganglioside GM2. After mixing, the combinations are incubated overnight at 4° C., and their toxicity is then evaluated using the MTT assay. The results obtained are described in table 5 and in the attached FIGURE. TABLE 5A Measurement of the gliotoxic activity of the “human” proteins combined and associated with ganglioside GM2 (50 μg/ml final concentration) % C with gGM2 GM2AP (ng) MRP14 (ng) Batch 3 100 100 56* 100 10 58 100 5 71 100 1 49 100 0 20 50 100 64* 50 10 33 50 5 29 50 1 32* 50 0 17 20 100 56 20 10 14 20 5 6 20 1 6 20 0 −5 10 100 43 10 10 26 10 5 8 10 1 4 10 0 −15 5 100 13 5 10 7 5 5 −2 5 1 −16 5 0 −10 0 100 30 0 10 −23 0 5 −19 0 1 −8 0 0 8 % C: percentage cytotoxicity gGM2: ganglioside GM2 *standard deviation OD of the samples between 13 and 11 No comment: standard deviation OD of the samples less than 10 Approximate concentrations in the supernatants: GM2AP and MRP14: 2 μg/ml The combination GM2AP/MRP14 combined with a constant concentration of ganglioside exhibits a gliotoxic effect which increases in parallel with the amount of MRP14 protein. Furthermore, for increasing amounts of the GM2AP protein (20 and 10 ng), a typical dose-response effect increasing in steps is obtained. However, at the end points, when there is not enough GM2AP protein (5 ng), there is no toxicity. Conversely, if there is too much GM2AP protein (50 ng and 100 ng), there is saturation of the toxicity with a plateau around 60%. In fact, only the CLTT1-1 cells undergoing proliferation in the culture during exposure to the gliotoxic factor are sensitive. This explains why the gliotoxicity plateaus do not reach 100%. TABLE 5B Measurement of the gliotoxic activity of the combined “human” proteins, combined or not combined with the ganglioside GM2 (50 μg/ml final concentration) % C % C % C % C Batch 4 Batch 4 Batch 4 Batch 4 Mutated without without with with GM2AP MRP14 gGM2 gGM2 gGM2 gGM2 (ng) (ng) Assay 1 Assay 2 Assay 1 Assay 2 100 200 ND 10 ND 32 100 100 −15 −8 40 55 100 50 −5 −18 37 7 100 10 −8 −33 32 −19 100 5 −15 −33 20 −9 100 1 −5 −26 31 −14 100 0 −11 −44 11 −61 50 200 ND 19 ND 25 50 100 3 5 30 4 50 50 2 −1 18 −21 50 10 −10 −23 17 −28 50 5 −9 −15 −2 −21 50 1 −23 −11 12* −18 50 0 −7 −40 9 −57 20 200 ND 8 ND 5 20 100 −7 −3 32 −13 20 50 −18 −16 34 −15 20 10 −18 −19 19 −8 20 5 −23 −8 17 13 20 1 −12 −12 16 −20 20 0 −4 −26 1 −33 10 200 ND −2 ND 33 10 100 −10 −9 24 8 10 50 −12 −19 2 −8 10 10 −17 −16 −6 −34 10 5 −14 −13 −4 −11 10 1 −30 −37 −20 −12 10 0 ND ND ND ND 5 200 ND −10 ND 26 5 100 −5 −1 39 −17 5 50 −8 −3* 32 −18 5 10 −14 −7 12 −25 5 5 −27 −11 16 −29 5 1 −26 −15 15 −39 5 0 ND ND ND ND 0 200 ND 45 ND 72 0 100 16 12 32 21 0 50 −14 −8 24 −6 0 10 0 −5 8 −6 0 5 ND ND ND ND 0 1 ND ND ND ND 0 0 ND ND −21 −21 % C: percentage cytotoxicity gGM2: ganglioside GM2 *standard deviation OD of the samples between 13 and 11 No comment: standard deviation OD of the samples less than 10 Without ganglioside GM2, the combinations mutated GM2AP/MRP14 are not gliotoxic. An overall increase in the cytotoxicity of the mixture with ganglioside GM2 is observed compared with the combinations without ganglioside. The variability of the measurements is apparently greater with the use of the mutated GM2AP protein. Overall, the activity appears to be significant and reaches a maximum plateau (cf.: maximum reached on the pool of cells undergoing proliferation during the assay, as discussed above) for the highest concentrations, according to a dose-effect with two variables, mutated GM2AP and MRP14. In order to determine whether the action of ganglioside GM2 is indeed specific for the toxicity of the combinations of human recombinant proteins GM2AP/MRP14 (5 ng of MRP14 and 50 ng or 100 ng of GM2AP), other lipids were tested in parallel: ganglioside GM1 and sulfatide. The concentration ranges used are 0, 10, 20, 30 and 50-μg/ml final concentration. Once the lipids have been added, the combinations are incubated overnight at 4° C., and their toxicity is then evaluated in the MTT assay. The results, shown in tables 5C and 5D, show that only the combinations with ganglioside GM2 for the combinations GM2AP/MRP14 at the doses 30 μg/ml and 50 μ/ml are toxic for the glial cells (respectively 27% and 30%). The other lipids show no toxicity with the protein combinations. TABLE 5C Influence of ganglioside GM2 in the gliotoxic activity of the combined “human” recombinant proteins GM2AP/MRP14 Concentration of gGM2 % GM2AP (ng) MRP14 (ng) (μg/ml) cytotoxicity 100 5 0 −14 100 5 5 −1 100 5 10 4 100 5 20 15 100 5 30 28 100 5 50 34 50 5 0 10 50 5 5 12 50 5 10 21 50 5 20 24 50 5 30 25 50 5 50 37 — 5 — −26 100 — — −5 50 — — −10 100 — 0 −29 100 — 5 −91 100 — 10 −11 100 — 20 −18 100 — 30 −12 100 — 50 −9 — 5 0 −25 — 5 30 −29 — 5 50 −51 For the 100 ng GM2AP assay, this is a mean of two assays. gGM2: ganglioside GM2 TABLE 5D Influence of ganglioside GM2 in the gliotoxic activity of the combined “human” recombinant proteins GM2AP/MRP14 GM2AP (100 ng)/MRP14 (5 ng) % cytotoxicity Without lipid −12 With GM2 (10 μg/ml) −4 With GM2 (20 μg/ml) 2 With GM2 (30 μg/ml) 17 With GM2 (50 μg/ml) 25 With GM1 (10 μg/ml) −12 With GM1 (20 μg/ml) −4 With GM1 (30 μg/ml) −1 With GM1 (50 μg/ml) 2 With sulfatide (10 μg/ml) −12 With sulfatide (20 μg/ml) −19 With sulfatide (30 μg/ml) −13 With sulfatide (50 μg/ml) 5 GM2AP control (100 ng) −19 GM2AP control (50 ng) −32 MRP14 control (5 ng) −18 GM2 control 3 GM1 control rejection Sulfatide control −21 The results of the study show that: the activity is associated with a protein heterocomplex involving the GM2AP or mutated GM2AP and MRP14 proteins; it is the addition of a lipid, such as ganglioside GM2, which made it possible to obtain levels of activity, a reproducibility and dose-response effects that were compatible with the reproduction of the gliotoxic activity sought; the mutation found on the GM2AP protein is not essential to the determinism of the gliotoxin in vitro. However, in vivo, it may be determining if it is necessary for the process of bioavailability of the GM2AP protein (for example, in the extracellular medium of the central nervous system). These elements therefore demonstrate that a heterocomplex MRP14/GM2AP or MRP14/mutated GM2AP, combined with ganglioside GM2, is the main, or even sole, vector of the gliotoxic activity. Example 8 Development of an Immunoassay for the Gliotoxic Complex—Preparation of the Samples Before the ELISA Assay (i) Samples Tested The samples tested are: firstly, the human recombinant proteins in combination (GM2AP+MRP14), with or without ganglioside GM2, possibly diluted in normal urine, in order to detect the active recombinant complex, secondly, normal urine and MS urine for direct detection in the urine. The samples, once prepared, are incubated for 24 hours at 4° C. for the detection assay. The “human” recombinant proteins are used in the form of crude production supernatants, recovered after the transient transfection of 293T cells, with the appropriate negative controls in parallel. The systems used for assaying the MRP14 and GM2AP proteins are semi-quantitative and the amounts specified are indicative. The results are given in the examples which follow. (ii) Treatment of the Samples As is shown, in the following examples, the method of detection using the anti-MRP14 and anti-GM2AP antibodies in a “sandwich” ELISA format makes it possible to obtain positive results. However, the inventors optimized this method of detection by carrying out a prior treatment of the sample, comprising a step consisting in digesting the proteins in the presence of proteinase K, followed by a step consisting in inactivating this protease by means of an original method of precipitation with trichloroacetic acid, and then neutralizing the pH with a tris-maleate buffer, selected for its subsequent compatibility with a sandwich ELISA assay. This treatment of the sample, which is original in its various steps, was subsequently applied to the analyses which are presented in the following examples, and is described in detail below. The samples (mixture of recombinant proteins or urine) are treated with proteinase K before detection of the complex according to the following protocol: 0.3 mg of proteinase K is added per 100 μl of sample. After digestion for one hour at 37° C., a precipitation with trichloroacetic acid is carried out, in order to inhibit the action of the proteinase K. 90% trichloroacetic acid (90 g of trichloroacetic acid per 48 ml of distilled water) is added to the sample (15% of the initial volume of the sample). The mixture is incubated for 30 minutes at 4° C. After centrifugation for 30 minutes at 13 000 rpm, the pellet is taken up with a volume equal to the initial volume of the sample, with 0.2 M Tris maleate buffer, pH 6.2 (in the assays with no concentration factor) or any minimum volume (to carry out a concentration of the nondigested proteins in terms of volume). After verification of the proteinase K-treated samples by means of the Western blotting technique, an observation can be made and the treatment can be optimized by increasing the amount of proteinase K and the action time thereof. Example 9 Protocol for Detecting the Heterocomplex in a Sandwich ELISA Assay (i) Production of Antibodies: the Following Antibodies were Produced According to the Protocols Described Below: polyclonal antibodies (bioMérieux): rabbit polyclonal antibody 196 (anti-MRP14 peptide) rabbit polyclonal antibody 79 (anti-recombinant GM2AP protein) monoclonal antibodies (bioMérieux): 4A7B10 5H7C10 2B9H2 10E11A11 13H9C9 19C11C10 13D1E5 2G12H5. Anti-GM2AP monoclonal antibodies: 10E11A11, 13D1E5, 13H9C9, 19C11C10 and 2G12H5. The mice were immunized according to the following protocol: on day DO, intraperitoneal injection of 75 μg of the complex GM2AP-MRP14 in the presence of complete Freund's adjuvant. On days D23 and D37, a further intraperitoneal injection of the same amount of complex GM2AP-MRP14 in the presence of incomplete Freund's adjuvant. Four days before the fusion, give an intravenous injection of 50 μg of GM2AP antigen diluted in physiological saline. 1900 supernatants were screened by the indirect ELISA technique. The plates were “coated” with 100 μl of antigen (the complex GM2AP-MRP14) at 1 μg/ml in 0.05 M bicarbonate buffer, pH 9.6. The “coated” plates were incubated overnight at the temperature of 18-22° C. The plates were saturated with 200 μl of PBS-1% milk and subjected to incubation for 1 hour at 37°+/−2° C. 100 μl of supernatants or of ascites fluid in PBS buffer-0.05% tween 20 were added and the plates were incubated for 1 hour at 37°+/−2° C. 100 μl of goat anti-mouse Ig (H+L) polyclonal antibody conjugated to alkaline phosphatase (Jackson Immunoresearch ref: 115-055-062), diluted to 1/2000 in PBS buffer-1% BSA, were added and the plates were then incubated for 1 hour at 37°+/−2° C. 100 μl of PNPP (Biomérieux ref 60002990) at the concentration of 2 mg/ml in DEA-HCl (Biomérieux ref 60002989), pH=9.8, were added. The plates were subjected to incubation for 30 minutes at 37°+/−2° C. The reaction was blocked by adding 100 μl of 1N NaOH. Three washes were carried out between each step, with 300 μl of PBS-0.05% tween 20. An additional wash in distilled water was carried out before adding the PNPP. 150 supernatants were found to be positive by indirect ELISA with an OD>0.9. After the specificity assays, the abovementioned five antibodies are produced. Anti-MRP14 monoclonal antibodies: 2B9H2, 4A7B10 and 5H7C10. The mice were immunized according to the following protocol: on day DO, an intraperitoneal injection of 75 pg of the complex GM2AP-MRP14 in the presence of complete Freund's adjuvant. On days D23 and D37, intraperitoneal injection of the same amount of complex in the presence of incomplete Freund's adjuvant. Four days before the fusion, an intravenous injection of 50 μg of MRP14 antigen diluted in physiological saline. 1100 supernatants were tested and screened by the indirect ELISA technique, as described above. 300 supernatants were found to be positive with an OD>1. After the specificity assays, the abovementioned three antibodies were produced. Rabbit polyclonal antibody 79 (anti-recombinant GM2AP protein). The rabbits were immunized according to the following protocol: on day DO, the 1st blood sample of 10 ml was taken, and 75 μg of GM2AP were injected intraperitoneally in the presence of complete Freund's adjuvant (CFA) (75 μg of immunogen+qs 0.5 ml of 9‰ physiological saline+0.5 ml CFA). On days D28 and D56, the same amount of immunogen was injected intraperitoneally under the same conditions, in the presence of 0.5 ml of incomplete Freund's adjuvant (IFA). On day D63, a 2nd blood sample of 30 ml was taken from the ear without anticoagulant. A 3rd blood sample was taken under the same conditions on day D70. Rabbit polyclonal antibody 196 (anti-MRP14 peptide). The rabbits were immunized according to the following protocol: The rabbits were immunized according to the following protocol: on day DO, the 1st blood sample of 10 ml was taken, and 80 μg of immunogen were injected intraperitoneally in the presence of complete Freund's adjuvant (CFA) (80 μg of immunogen+qs 0.5 ml of 9‰ physiological saline+0.5 ml CFA). On days D28 and D56, the same amount of immunogen was injected intraperitoneally under the same conditions, in the presence of 0.5 ml of incomplete Freund's adjuvant (IFA). On day D63, a 2nd blood sample of 30 ml was taken from the ear without anticoagulant. A 3rd blood sample was taken under the same conditions on day D70. These antibodies are used for capture or for detection. When they are used for detection in the sandwich ELISA assay, the antibodies are biotinylated. (ii) Sandwich ELISA Assay: The treatment of the samples (proteinase K and TCA precipitation), if it takes place, is carried out after overnight incubation at 4° C. and before the sandwich ELISA detection assay. The capture antibody is “coated” at 1 μg in carbonate-bicarbonate buffer (50 mM), pH 9.5; 100 μl are deposited in the wells of a 96-well microplate. The plate is covered with a protective film and incubated overnight at ambient temperature. After 3 washes in PBS (Phosphate Buffered Saline)-0.05% Tween, the nonspecific sites are blocked with PBS-0.05% Tween, goat serum-( 1/10) for the monoclonal antibodies or 100 μl of casein hydrolyzate for the polyclonal antibodies. After 3 washes in PBS-0.05% Tween, the treated or nontreated samples are deposited at a rate of 100 μl per well and thus incubated for 1 hour 30 minutes at 37° C. with agitation. After 3 washes in PBS-0.05% Tween, 100 μl of biotinylated detection antibodies at 1 μg/ml are deposited into each well and incubated for 1 hour 30 minutes at 37° C. After 3 washes in PBS-0.05% Tween, 100 μl of streptavidin coupled to HRP (horseradish peroxidase) at 0.2 μg/ml are deposited into each well and incubated for 1 hour 30 minutes at 37° C. in order to amplify the signal. After 3 washes in PBS-0.05% Tween, 100 μl of OPD (ortho-phenylenediamine dihydrochloride) solution at 2 g/l are deposited into each well and incubated for 10 minutes at ambient temperature. The reaction is stopped with 100 μl of 1N H2SO4. The optical density is read at 492 nm. Similarly, for the production of anti-heterocomplex antibodies, the heterocomplex GM2AP/GM2/MRP14 or mutated GM2AP/GM2/MRP14 is used as immunogen for immunizing BALB/c mice by intraperitoneal injection. The first injection is given with complete Freund's adjuvant. The other injections are given at intervals of 4-8 weeks, with incomplete Freund's adjuvant. A final booster is given a few days before the fusion in physiological saline. After this booster, the spleens of the immunized mice are removed and the splenocytes are collected. The spleen cells are then fused with cells of a myeloma line and the cells secreting antibodies which recognize, by ELISA, the heterocomplex used for the immunization are selected. Finally, the clones producing antibodies specific for the immune heterocomplex, i.e. which recognize neither GM2AP, nor mutated GM2AP nor MRP14, alone, are selected. Example 10 Detection of the Human Recombinant Heterocomplex The enzymatic immunoassays for the gliotoxic activity characterized molecularly in the previous examples involve an antigen/antibody system using only the proteins involved (GM2AP, mutated GM2AP and MRP14 proteins), and antibodies (alone or in combination) capable of detecting this molecular complex. The recombinant complex corresponds to the combination of the supernatants of recombinant proteins GM2AP (1000 ng) and MRP14 (50 ng), combined with a final concentration of 50 μg/ml of ganglioside GM2. (i) Detection of the Recombinant Gliotoxic Heterocomplex Without Proteinase K Treatment In order to determine whether the toxic combinations were directly detectable, the “human” recombinant proteins MRP14 and GM2AP are combined with ganglioside GM2, incubated overnight at 4° C. and tested by means of the sandwich ELISA assay using the anti-MRP14 and anti-GM2AP antibodies. The combinations [MRP14, GM2AP and ganglioside GM2] are diluted in normal urine (not gliotoxic in the MTT toxicity assay). The results are shown in table 6. These results show that anti-GM2AP capture antibody/anti-MRP14 detection antibody pairs recognize the recombinant complex in an extremely reproducible manner. The results are shown in table 6. TABLE 6 Capture Detection Positive Assay antibody antibody assays total 4A7B10 + 5H7C10 10E11A11 0 3 13D1E5 + 2G12H5 0 1 13H9C9 + 19C11C10 0 3 79 0 1 2B9H2 10E11A11 1 3 13D1E5 + 2G12H5 0 1 13H9C9 + 19C11C10 0 3 79 0 2 10E11A11 4A7B10 + 5H7C10 2 1 2B9H2 0 2 196 0 1 13D1E5 + 2G12H5 4A7B10 + 5H7C10 1 2 2B9H2 0 2 196 0 2 13H9C9 + 19C11C10 4A7B10 + 5H7C10 0 1 2B9H2 0 1 196 0 1 79 4A7B10 + 5H7C10 2 2 2B9H2 2 2 196 0 1 Positive assays: number of positive assays Assay total: total number of assays (ii) Detection of the Recombinant Gliotoxic Heterocomplex After Proteinase K Treatment As described above, the gliotoxic activity withstands proteinase K. Thus, by treating the samples (combination GM2AP+MRP14+GM2) with proteinase K, the noncomplexed proteins are destroyed, and the background noise is decreased. As in the previous section, the combinations are incubated overnight at 4° C. However, before testing them, the samples are treated with proteinase K and precipitated with TCA (trichloroacetic acid), according to the protocol described in example 8 (ii). The results are shown in table 7. These results show in particular that the anti-MRP14 capture antibody/anti-GM2AP detection antibody pairs [4A7B10+5H7C10]/[13H9C9+19C11C10], [4A7B10+5H7C10]/10E11A11, 2B9H2/10E11A11 and 2B9H2/[13H9C9+19C11C10] detect the recombinant complex in the supernatants diluted in the urine, after proteinase K treatment, in an extremely reproducible manner. The background noise is significantly reduced. TABLE 7 Capture Detection Positive Assay antibody antibody assays total 4A7B10 + 5H7C10 10E11A11 2 3 13D1E5 + 2G12H5 0 1 13H9C9 + 19C11C10 2 3 79 0 1 2B9H2 10E11A11 2 3 13D1E5 + 2G12H5 0 1 13H9C9 + 19C11C10 2 3 79 0 2 10E11A11 4A7B10 + 5H7C10 0 2 2B9H2 0 1 196 0 1 13D1E5 + 2G12H5 4A7B10 + 5H7C10 1 2 2B9H2 0 2 196 0 2 13H9C9 + 19C11C10 4A7B10 + 5H7C10 0 1 2B9H2 0 1 196 0 1 79 4A7B10 + 5H7C10 0 2 2B9H2 1 2 196 0 1 Positive assays: number of positive assays Assay total: total number of assays Example 11 Detection of the Heterocomplex in the Urine of Patients The direct detection of the complex in the urine of patients was tested on two representative urines: an MS urine and a normal urine. The results are described in table 8. These results show that the anti-MRP14 capture antibody/anti-GM2AP detection antibody pairs [4A7B10+5H7C10]/[13D1E5+2G12H5], [4A7B10+5H7C10]/10E11A11, 2B9H2/[13D1E5+2G12H5] and 2B9H2/[13H9C9+19C11C10] detect the complex. TABLE 8 Capture Detection Assay antibody antibody number MS Normal Urine without proteinase K treatment 2B9H2 13H9C9 + 19C11C10 1 0 0 2 0 0 4A7B10 + 5H7C10 10E11A11 1 0.102 0.067 2 0.030 0.011 4A7B10 + 5H7C10 13D1E5 + 2G12H5 1 0.117 0 2B9H2 13D1E5 + 2G12H5 1 0.152 0.006 Urine after proteinase K treatment 2B9H2 13H9C9 + 19C11C10 1 0.149 0.060 2 0.141 0.020 4A7B10 + 5H7C10 10E11A11 1 0.130 0.087 2 0.741 0.563 4A7B10 + 5H7C10 13D1E5 + 2G12H5 1 0.467 0.328 2B9H2 13D1E5 + 2G12H5 1 0.111 0.12 For the urine treated with proteinase K, there is no concentration with TCA The methods described in the examples are useful as diagnostic tools for assaying a biological marker for multiple sclerosis, since the correlations between the gliotoxic activity and the clinical situation have proved to be very good1,3,4. BIBLIOGRAPHICAL REFERENCES 1. Malcus-Vocanson, C. et al. (1998) A urinary marker for multiple sclerosis (letter]. Lancet 351, 1330. 2. Menard, A. et al. (1997) Gliotoxicity, reverse transcriptase activity and retroviral RNA in monocyte/macrophage culture supernatants from patients with multiple sclerosis. FEBS Lett 413, 477-85. 3. Menard, A. et al. (1998) Detection of gliotoxic activity in the cerebrospinal fluid from multiple sclerosis patients. Neurosci Lett 245, 49-52. 4. Malcus-Vocanson, C. et al. (2001) Glial Toxicity in urine and Multiple Sclerosis. Multiple Sclerosis 7, 383-388. 5. N. Benjelloun et al. Cell. Mol. Biol., 1998, 44(4), 579-583. 6. Blazar et al., (1997) Journal of Immunology 159: 5821-5833. 7. Bird et al., (1988) Science 242: 423-426. 8. Arakawa et al., (1996) J. Biochem 120: 657-662. 9. Chaudray et al., (1989) Nature 339: 394-397. 10. Jones et al., Nature 321: 522-525 (1986). 11. Reichmann et al., Nature 332: 323-329 (1988). 12. Presta et al., Curr. Op. Struct. Biol. 2: 593-596 (1992). 13. Galiana et al., J. Neurosci. Res. (1990) 26: 269-277.

20060612

20100420

20070322

97245.0

G01N33567

KOLKER, DANIEL E

METHOD OF ISOLATING CYTOTOXIC HETEROCOMPLEX ASSOCIATED WITH MULTIPLE SCLEROSIS

UNDISCOUNTED

ACCEPTED

G01N

ACCEPTED

Methods for acquiring and processing seismic data from quasi-simultaneously activated translating energy sources

A method for obtaining seismic data is disclosed. A constellation of seismic energy sources is translated along a survey path. The seismic energy sources include a reference energy source and a satellite energy source. The reference energy source is activated and the satellite energy source is activated at a time delay relative to the activation of the reference energy source. This is repeated at each of the spaced apart activation locations along the survey path to generate a series of superposed wavefields. The time delay is varied between each of the spaced apart activation locations. Seismic data processing comprises sorting the traces into a common-geometry domain and replicating the traces into multiple datasets associated with each particular energy source. Each trace is time adjusted in each replicated dataset in the common-geometry domain using the time delays associated with each particular source. This result in signals generated from that particular energy source being generally coherent while rendering signals from the other energy source is generally incoherent. The coherent and incoherent signals are then filtered to attenuate incoherent signals.

1. A method for obtaining seismic data comprising the steps of: (a) translating a constellation of seismic energy sources along a survey path, the seismic energy sources including a reference energy source and at least one satellite energy source; (b) activating the reference energy source and the at least one satellite energy source at a time delay relative to the activation of the reference energy source once each at spaced apart activation locations along the survey path to generate a series of superposed wavefields which propagate through a subsurface and are reflected from and refracted through material heterogeneities in the subsurface, the time delay being varied between the spaced apart activation locations; and (c) recording seismic data including seismic traces generated by the series of superposed wavefields utilizing spaced apart receivers. 2. The method of claim 1 further comprising: processing the seismic data using the time delays to separate signals generated from the respective energy sources. 3. The method of claim 2 wherein: the step of recording seismic data includes recording amplitudes of the superposed wavefields, the location of the receivers, the locations of the energy sources, and the time delays between the activations of the reference energy source and the at least one satellite energy source. 4. The method of claim 2 wherein: processing the seismic data further includes sorting into a common-geometry domain and replicating the seismic traces of data into multiple datasets associated with each particular energy source; time adjusting each trace in each replicated dataset in the common-geometry domain using the time delays associated with each particular source to make signals generated from that particular energy source generally coherent while rendering signals from the other energy sources generally incoherent. 5. The method of claim 4 wherein: the common-geometry domain is one of common-midpoint, common-offset, common-receiver and common-azimuth. 6. The method of claim 4 further comprising: attenuating the incoherent signals from the datasets of coherent signal and incoherent signal associated with the respective energy sources to produce enhanced data sets associated with the respective energy sources. 7. The method of claim 6 wherein: the attenuation step includes using at least one of Radon filtering, FX filtering, dynamic noise attenuation, stacking, and migration. 8. The method of claim 6 wherein: the step of attenuation includes using dynamic noise attenuation wherein the relative amplitudes of the coherent signals from each of the respective energy sources are preserved. 9. The method of claim 1 wherein: the at least one satellite energy source includes a plurality of energy sources, and time delays are variable between each of the plurality of energy sources in the constellation at each of the activation locations. 10. The method of claim 1 wherein: the time delay includes a constant portion tc which remains constant for any particular source for the duration of the seismic survey and a variable portion tv, which varies for each source and for each activation location. 11. The method of claim 10 wherein: the constant portion tc is different for each satellite source. 12. The method of claim 1 wherein: the receivers are disposed generally in a linear alignment along a predetermined length. 13. The method of claim 12 wherein: an elongate streamer includes a cable and the receivers and the streamer is towed by a marine vessel. 14. The method of claim 13 wherein: the reference energy source and the at least one satellite energy source is generally collinear with the streamer. 15. The method of claim 13 wherein: at least one of the energy sources is located laterally outboard from the linear alignment of receivers a distance of at least one-tenth of the length of the receiver cable. 16. The method of claim 13 wherein: the energy source located farthest upstream from the streamer is located at least one half the length of streamer upstream from the streamer. 17. The method of claim 13 wherein: the energy source located farthest downstream from the streamer is located at least one half the length of streamer downstream from the streamer. 18. The method of claim 1 wherein: the receivers are fixed relative to the earth. 19. The method of claim 1 wherein: an elongated cable of receivers resides inside a well bore. 20. The method of claim 1 wherein: the variable time delays range from plus to minus one-half the time interval between successive activation locations.

TECHNICAL FIELD The present invention relates generally to seismic exploration, and more particularly, to acquiring and processing seismic data generated from generally simultaneously activated seismic energy sources. BACKGROUND OF THE INVENTION In the hydrocarbon exploration industry, remote sensing of underground geological formations using seismic waves provides information on the location, shape, and rock and fluid properties of potential hydrocarbon reservoirs. The standard technique comprises the activation of a source of acoustic energy which radiates seismic waves into the earth. These seismic waves reflect from and refract through subsurface geologic layers (acoustic illumination or insonification). The recording of these seismic waves by many different receivers (pressure or motion sensors) are ideally situated so as to optimize the ratio of information obtained to cost. This basic sourcing/insonification/recording procedure is repeated many times at slightly different locations over a subsurface region of interest. However, the resolution required of the seismic data for a detailed interpretation and adequate risk reduction can be suboptimal given the cost constraints inherent in seismic acquisition. Methods have been taught using generally simultaneously fired energy sources in an effort to obtain more information for a given cost. Edington, U.S. Pat. No. 4,953,657 teaches a method of time delay source coding. In this method “a series of shots is made at each shotpoint with a determinable time delay between the activation of each source for each shot”. The “series of shots” refers to occupying each shotpoint location for several consecutive shots. This methodology may be acceptable for seismic acquisition on land where seismic sources can easily remain fixed at one shot location for an indefinite time. However, the method is not well suited for marine recording in which a seismic receiver cable is being towed behind a boat. A certain minimum velocity is necessary to preserve the approximately linear trajectory of the cable. De Kok et. al, U.S. Pat. No. 6,545,944, teaches a method for acquiring and processing seismic data from several simultaneously activated sources. In particular, the method requires that several independently controllable “source elements” be activated in a fixed sequence, at successive neighboring locations. This activation sequence unavoidably smears the energy from a single effective source across several neighboring shot locations, necessitating an interpolation step and the introduction of unwanted interpolation noise. Further, the success of building an effective source by spatial sequencing of source sub-elements appears to depend sensitively on source timing precision and sea-state. Beasley et al., U.S. Pat. No. 5,924,049 also teaches a method of acquiring and processing seismic data using several separate sources. In the preferred embodiment, it teaches that the sources can be activated sequentially with a constant inter-source time delay (up to 15 and 20 seconds). During the processing stage, the method requires anywhere from 2% to 33% of data overlap between panels of data from different sources. Further, it relies on conflicting dips to discriminate energy coming from different source directions, which requires a specific spatial relationship among the sources and the recording cable, and thus is not well suited to simultaneous signals arriving from approximately the same quadrant. In a subsidiary embodiment, the several sources can be activated exactly concurrently, in which case the sources are then arranged to emit signature-encoded wavefields. The decoding and signal separation associated with this type of concurrent signature encoding is usually unsatisfactory. Furthermore, the sources need to be activated at both the leading and trailing ends of the spaced-apart receivers, which is inflexible. The present invention contrasts with the aforementioned inventions and addresses their shortcomings by teaching a novel way of acquiring and processing seismic data obtained from two or more quasi-simultaneously activated sources. SUMMARY OF THE INVENTION This invention teaches a method for the acquisition of marine or land seismic data using quasi-simultaneously activated translating seismic sources whose radiated seismic energy is superposed and recorded into a common set of receivers. Also taught is the subsequent data processing required to separate these data into several independent records associated with each individual source. Quasi-simultaneous acquisition and its associated processing as described herein enable high quality seismic data to be acquired for greater operational efficiency, as compared to a conventional seismic survey. A method for obtaining seismic data is taught. A constellation of seismic energy sources is translated along a survey path. The seismic energy sources include a reference energy source and at least one satellite energy source. A number of configurations for the arrangement of the seismic sources and the locations of seismic receivers are disclosed. The reference energy source is activated and the at least one satellite energy source is activated at a time delay relative to the activation of the reference energy source. This activation of sources occurs once each at spaced apart activation locations along the survey path to generate a series of superposed wavefields which propagate through a subsurface and are reflected from and refracted through material heterogeneities in the subsurface. The time delay is varied between the spaced apart activation locations. Seismic data is recorded including seismic traces generated by the series of superposed wavefields utilizing spaced apart receivers. The seismic data is then processed using the time delays to separate signals generated from the respective energy sources. More specifically, the processing of the seismic data further includes sorting into a common-geometry domain and replicating the seismic traces of data into multiple datasets associated with each particular energy source. Each trace is time adjusted in each replicated dataset in the common-geometry domain using the time delays associated with each particular source. This results in signals generated from that particular energy source being generally coherent while rendering signals from the other energy sources generally incoherent. The coherent and incoherent signals are then filtered to attenuate incoherent signals using a variety of filtering techniques. It is an object of the present invention to provide a method for acquisition of seismic signals generated “quasi-simultaneously” from several moving separated sources activated with a small time delay, and their subsequent accurate separation during data processing into independent data sets exclusively associated with each individual source. This can greatly improve operational efficiency without compromising data resolution. BRIEF DESCRIPTION OF THE DRAWINGS The following drawings illustrate the characteristic acquisition and processing features of the invention, and are not intended as limitations of these methods. FIG. 1 is a plan view of the acquisition of seismic data using the invention with two quasi-simultaneous sources; FIG. 2 is a profile view of the acquisition of seismic data corresponding to FIG. 1; FIG. 3 illustrates the activation time delays being composed of a constant part and a variable part; FIG. 4 is a common-shot gather showing the coherent superposed signals from the reference and satellite sources; FIG. 5 is a common-midpoint gather showing the coherent signals from the reference source and the incoherent noise from the satellite source; FIG. 6 compares migrated results from both conventional (one-source) acquisition and multiple quasi-simultaneously activated sources; and FIG. 7 is a flowchart summarizing the acquisition, trace-sorting, and noise attenuation segments of this invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS FOR THE INVENTION This invention teaches a method for the acquisition of seismic data using quasi-simultaneous sources, as well as the processing of the superposed signals in order to separate the energy due to each source from the energy due to every other source in the constellation. For the purposes of this invention, the term “constellation” shall mean the set of spaced apart seismic sources bearing any relative spatial relationship among themselves, and able to move as a whole from one location to another as part of a seismic survey. Quasi-simultaneous acquisition and its associated processing as described herein enable high quality seismic data to be acquired at a much greater operational efficiency as compared to a conventional seismic survey. The term “quasi-simultaneous” shall mean that the activation-time differences among the several sources in a constellation are not zero (thus the prefix “quasi”), but yet small enough (typically less than several seconds) so as not to interfere with the previous or succeeding shots of the seismic survey, viz., less than the recording (or “listening”) time of a shot record (thus the term “simultaneous”: operationally simultaneous). Acquisition, trace sorting and time correction, and noise attenuation filtering are described in turn. Acquisition The first step is to acquire seismic data generated by quasi-simultaneous sources. Referring to FIG. 1, in the most preferred embodiment, the acquisition involves three-dimensional marine seismic surveying employing a seismic vessel 10 towing a reference source 11 and several trailing streamers 12 which contain seismic receivers, along with at least one other spaced apart satellite source 14, which is itself towed by a spaced apart vessel 13. The term “reference source” shall mean the source which is fired at seismic recording time zero. It can be the source nearest the recording cable (if source and cable are being towed by the same vessel in marine recording), or for example it can be the source in the constellation which is activated first. In all cases, the satellite source time delays are with respect to the reference source. For identification purposes, the constellation's location can be identified with that of the reference source. The term “satellite source” shall refer to any one of the energy sources other than the reference source. The term “time delay”, abbreviated “Td” shall mean a positive or negative time interval with respect to the reference source and recording time 0, and which is the sum of a positive or negative constant part (here abbreviated by “Tc”) and a positive or negative variable part (here abbreviated by “Tv”). Thus Td=Tc+Tv. For the reference source, Td=0. Alternatively, vessel 13 and source 14 could be located (not shown) collinearly with and downstream from the streamer. These configurations in which the reference and satellite sources are collinear with the set of receivers provide extra offsets as compared to a conventional single-source operation. Preferably, the separation distance between the leading edge of the streamers 12 and the upstream source 14 may be about the length of the streamers 12. Likewise the separation distance between the trailing edge of the streamers 12 and the downstream source 14 (not shown) may be about the length of the streamers 12. Those skilled in the art will appreciate that the acquisition may also be accomplished, by way of example and not limitation, with a source 19 towed by a vessel 18 near the tail end of the receiver cable and between two of the several streamers 12, or with a source 16 towed by a vessel 15 perpendicularly displaced from the direction of the receiver cable, with a source towed by a boat trailing the tail end of the receiver cable by a fixed amount, or even with a second independent source 17 towed behind vessel 10. The configuration in which the satellite source is perpendicularly displaced from the streamer of receivers provides extra azimuths as compared to a single-source operation. Further, those skilled in the art will appreciate that cables of receivers can be towed behind more than one vessel, or that the seismic receivers need not be towed behind a marine vessel but can be fixed to the earth as in land recording, ocean-bottom recording, and marine vertical-cable recording, among others. FIG. 2 is a profile view of the collinear acquisition geometry of FIG. 1. The reference source 11 (with indicated earth coordinates S1) is situated on the recording surface 20 (generally the surface of the Earth) and generates seismic energy 22 which travels down to a geologic reflector 21 and is reflected back toward the receiver cable 12 (one of whose receivers has the indicated earth coordinates R). Meanwhile, the satellite source 14 (with indicated earth coordinates S2) is activated quasi-simultaneously and it also generates seismic energy 23 which reflects back into the receiver cable, where it superposes with the signal from the reference source 11 and where both are recorded. FIG. 4 shows a common-shot gather illustrating the superposition of energy from two quasi-simultaneous sources. A receiver cable 43 records seismic energy along a recording time axis 42. The reference source energy 40 and satellite source energy 41 are interfering and superposed on each trace of the common-shot gather. Given a current location of the constellation within the seismic survey, its Ns sources are activated quasi-simultaneously. The term “Ns” shall refer to the 3 number of spaced apart sources populating the constellation. FIG. 3 illustrates the quasi-simultaneous timing scheme for the case of Ns=4. The constellation of sources is quasi-simultaneously activated at times 30 determined by the interval of time required for the constellation to translate between successive shot locations, which is generally the translation distance divided by the constellation velocity. Most preferably, a Global Positioning System is used to activate the reference activation source at predetermined intervals, for example meters. The quasi-simultaneous source activation-time delay Td 33 (with respect to the reference source) is different for each source within the constellation, and is a sum of two parts. The first component is a predetermined positive or negative constant Tc 31 for a given source in the constellation but can be different for different sources. Its optimum value is dictated by the operational need to capture all of the desired signal from that source into the seismic receivers during the current recording time window, and so depends on the specific acquisition geometry. It can be different for each source in the constellation, but is constant over the course (duration) of the survey (as long as the constellation geometry does not change). In the case of a satellite source collinear with the seismic streamer as in FIG. 1, this time might be, for example, several seconds in advance of (negative number) the near-streamer reference source activation time. The second component is a predetermined variable time delay Tv 32 which is different for each source in the constellation, and also changes with each succeeding location of the constellation within the seismic survey. In the preferred embodiment this variable component is a predetermined positive or negative random value whose value ranges from plus to minus ten times the source waveform's dominant period, although greater times are also possible. This random time dithering introduces a source-specific time-delay encoding (not signature encoding) among the several sources within the constellation, whose resultant wavefields are all superposed in the recording cable. Although not necessary, it may be beneficial to prevent successive random values of Td to be too close to one another. This can be avoided by requiring that successive values of Td be differentiated by a predetermined minimum positive or negative value. This can be accomplished simply by generating a replacement random value that is satisfactory. This overcomes the potential problem of “runs” of the same value in a random sequence, which when applied to the source time delays might create short patches of coherence where none is desired. Although Tc and Tv are both predetermined, it is only their sum Td that is required in processing, and due to possible slight variation in actual source activation times, Td must be accurately measured and recorded during acquisition. The entire seismic survey then consists of quasi-simultaneously activating the entire constellation once at each geographic location in the survey (at resultant times 30), and then moving the constellation a predetermined amount to a new location, and repeating the quasi-simultaneous source activation procedure. Common-Geometry Trace Sorting and Trace Time-Correction Trace sorting will now be described. After acquisition, each trace contains superposed seismic signals (reflections, refractions, etc.) from each of the Ns sources. The first stage in separating the signals from the constellation's several sources is to spatially reorganize the seismic traces from the common shot gathers into a suitable domain in which the signal from each successive source in the constellation can be selectively made coherent and all others made incoherent. As illustrated in FIG. 2, each trace includes a trace header 24 which contains, among other information, earth coordinates of the receiver and the Ns sources, as well as the time delays Td for each of the Ns−1 satellite sources. The common-shot gathers are resorted Ns times, once for each source in the constellation. Each resorting follows the conventional procedure in which each given trace is placed into a particular common-geometry gather of traces, depending on the source and receiver coordinates and the type of common-geometry desired. For example, common midpoint sorting dictates that the algebraic average of the source and receiver coordinates be a constant. Constant offset sorting dictates that the distance from source to receiver be a constant. Because the trace header contains the coordinates from Ns sources (two in the case of FIG. 2), the current trace is replicated and associated with Ns different midpoints or Ns different offsets, etc., one associated with each of the Ns sources. For each of the Ns sources with which the trace is in turn identified, the time delay associated with that trace and source (and which is recorded in header 24) is applied in reverse to the trace timing. Thus, subtracting the time delay Td from the trace time allows the signals in the seismic trace from that source to align with similar signals on other traces within the particular constant-geometry gather, and coherent signals from that source are formed. In the preferred embodiment the traces are resorted into Ns common-midpoint domains, each common-midpoint domain associated with a particular source of the constellation. As a visual aid, FIG. 5 shows a common-midpoint gather from the same dataset as FIG. 4, and contains data ordered along an offset axis 53 and a time axis 52. Those skilled in the art will appreciate that other resorting may also be realized, by way of example and not limitation, by resorting the traces into common-offset domains (useful for some kinds of prestack depth migration), common-receiver domains (useful for recording and migration involving acquisition via vertical marine cable, vertical seismic profile in a well, or ocean-bottom cable), common-azimuth domains (useful for illumination within subsurface shadow zones), or indeed any other common-geometry domain in which subsequent data processing will occur. In each case, resorting the traces independently associates each common-geometry domain with a particular one of the Ns sources in the constellation. In this resorted and time-corrected domain, each source's signal in turn becomes coherent and the signal from all other Ns−1 sources is made incoherent and appears as random noise. In this way the signal from each one of the Ns sources is made to “crystallize” into coherence at the expense of the other Ns−1 sources, producing Ns different datasets, one for each source of the constellation. This is illustrated in FIG. 5, in which the seismic signal 50 from the reference source has been made coherent, while the seismic signal from the satellite source has been turned into incoherent random noise which is scattered throughout the common-midpoint gather. Noise-Attenuation Filtering The next step is filtering out the unwanted noise from each of the resorted datasets. There are several approaches, depending on the particular common-geometry domain and whether the data are migrated or not. In the preferred embodiment, random noise suppression is applied to common-midpoint gathers in which coherent signal events tend to assume a hyperbolic trajectory while random noise does not follow any particular trajectory. The coherent signal events are localized in Radon space whereas the random noise is not localized in Radon space. Muting out unwanted noise events in Radon space followed by an inverse mapping to conventional time-offset space attenuates the random noise. The remaining signal can be used directly, but also can itself be time shifted back into decoherence, at which point it can be subtracted from the complementary gathers associated with the other sources prior to their Radon filtering. Those skilled in the art will appreciate that random noise attenuation may also be accomplished, by way of example and not limitation, by other techniques such as stacking, F-X filtering, and also by Dynamic Noise Attenuation: This method is taught in a patent application entitled “Method for Signal-to-Noise Ratio Enhancement of Seismic Data Using Frequency Dependent True Relative Amplitude Noise Attenuation” to Herkenhoff et. al., U.S. Ser. No. 10/442,392. The DNA Method is an inverse noise weighting algorithm, which can often be a powerful noise attenuation technique and can be used in conjunction with other techniques in any common-geometry domain. The disclosure of this patent application is hereby incorporated by reference in its entirety. The particular importance of this specific step lies in its ability to largely preserve the relative amplitudes of the coherent signals in a gather in the presence of random noise, thus minimizing the effect of amplitude bias. Because attenuation of random noise often amounts to a localized summing over signal trajectories to achieve so-called “root-n” noise reduction, different signal domains require different summing trajectories. Further, because even an approximate velocity model is useful to define signal trajectories as part of the migration summation process, random noise attenuation may be accomplished by taking advantage of the signal/noise separation powers inherent in seismic imaging. Given a velocity model, migration sums events over a very large aperture (an areal aperture in the case of three-dimensional migration), greatly attenuating random noise. In FIG. 6, the results of migrating with a known earth velocity are shown for both a conventional single-source acquisition (left panel) and the two-source quasi-simultaneous acquisition (some gathers from which are shown in FIGS. 4 and 5). Evidently for this dataset migration summing has effectively attenuated the random noise permeating the two-source input gathers from FIG. 5. More importantly, when applied in the common-offset domain, migration produces noise-attenuated common-offset volumes that preserve the prestack AVO information. It is this property that makes the common-offset embodiment particularly attractive. Note that velocity analysis (needed for the migration), which measures semblance, will work even on CMP gathers in which the random noise has not been attenuated. Alternatively, migration of quasi-simultaneous source data even with a suboptimal velocity function, followed by filtering, followed by demigration using the same velocity function can also attenuate random noise. All of the above techniques are equally preferred. Finally, one skilled in the art can appreciate that noise attenuation can also be realized by a concatenation of multiple processing steps such as those described above. The foregoing segments detailed by this invention are summarized in flowchart form in FIG. 7. At each successive location of the constellation within the seismic survey, a master source timer 70 communicates the appropriate time delay 71 (Td) to each of the Ns−1 satellite sources 72. (The reference source, by definition above, has a total time delay of zero.) The sources are thus activated quasi-simultaneously, their energy enters and interacts with the earth layers 73, and the reflected and scattered waves are recorded by a common set of spaced apart receivers 74. The time delays Td associated with each source are also recorded in 74. After acquisition, each trace contains seismic events (reflections, refractions, etc.) from each of the Ns sources. The seismic data are resorted into Ns common-geometry datasets 75 as explained in the reference to FIG. 2 above (such as common-midpoint or common-offset, two particularly good and preferred domains). Then the traces in each of the Ns−1 satellite source datasets have applied to them the negative time delay 76 associated with that trace and that satellite source. Lastly, Ns noise-attenuation filtering operations 77 can be applied, because in each of the Ns data volumes the energy from only one source appears coherent, while the energy from all other sources appears as incoherent noise. While in the foregoing specification this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to alteration and that certain other details described herein can vary considerably without departing from the basic principles of the invention.

<SOH> BACKGROUND OF THE INVENTION <EOH>In the hydrocarbon exploration industry, remote sensing of underground geological formations using seismic waves provides information on the location, shape, and rock and fluid properties of potential hydrocarbon reservoirs. The standard technique comprises the activation of a source of acoustic energy which radiates seismic waves into the earth. These seismic waves reflect from and refract through subsurface geologic layers (acoustic illumination or insonification). The recording of these seismic waves by many different receivers (pressure or motion sensors) are ideally situated so as to optimize the ratio of information obtained to cost. This basic sourcing/insonification/recording procedure is repeated many times at slightly different locations over a subsurface region of interest. However, the resolution required of the seismic data for a detailed interpretation and adequate risk reduction can be suboptimal given the cost constraints inherent in seismic acquisition. Methods have been taught using generally simultaneously fired energy sources in an effort to obtain more information for a given cost. Edington, U.S. Pat. No. 4,953,657 teaches a method of time delay source coding. In this method “a series of shots is made at each shotpoint with a determinable time delay between the activation of each source for each shot”. The “series of shots” refers to occupying each shotpoint location for several consecutive shots. This methodology may be acceptable for seismic acquisition on land where seismic sources can easily remain fixed at one shot location for an indefinite time. However, the method is not well suited for marine recording in which a seismic receiver cable is being towed behind a boat. A certain minimum velocity is necessary to preserve the approximately linear trajectory of the cable. De Kok et. al, U.S. Pat. No. 6,545,944, teaches a method for acquiring and processing seismic data from several simultaneously activated sources. In particular, the method requires that several independently controllable “source elements” be activated in a fixed sequence, at successive neighboring locations. This activation sequence unavoidably smears the energy from a single effective source across several neighboring shot locations, necessitating an interpolation step and the introduction of unwanted interpolation noise. Further, the success of building an effective source by spatial sequencing of source sub-elements appears to depend sensitively on source timing precision and sea-state. Beasley et al., U.S. Pat. No. 5,924,049 also teaches a method of acquiring and processing seismic data using several separate sources. In the preferred embodiment, it teaches that the sources can be activated sequentially with a constant inter-source time delay (up to 15 and 20 seconds). During the processing stage, the method requires anywhere from 2% to 33% of data overlap between panels of data from different sources. Further, it relies on conflicting dips to discriminate energy coming from different source directions, which requires a specific spatial relationship among the sources and the recording cable, and thus is not well suited to simultaneous signals arriving from approximately the same quadrant. In a subsidiary embodiment, the several sources can be activated exactly concurrently, in which case the sources are then arranged to emit signature-encoded wavefields. The decoding and signal separation associated with this type of concurrent signature encoding is usually unsatisfactory. Furthermore, the sources need to be activated at both the leading and trailing ends of the spaced-apart receivers, which is inflexible. The present invention contrasts with the aforementioned inventions and addresses their shortcomings by teaching a novel way of acquiring and processing seismic data obtained from two or more quasi-simultaneously activated sources.

<SOH> SUMMARY OF THE INVENTION <EOH>This invention teaches a method for the acquisition of marine or land seismic data using quasi-simultaneously activated translating seismic sources whose radiated seismic energy is superposed and recorded into a common set of receivers. Also taught is the subsequent data processing required to separate these data into several independent records associated with each individual source. Quasi-simultaneous acquisition and its associated processing as described herein enable high quality seismic data to be acquired for greater operational efficiency, as compared to a conventional seismic survey. A method for obtaining seismic data is taught. A constellation of seismic energy sources is translated along a survey path. The seismic energy sources include a reference energy source and at least one satellite energy source. A number of configurations for the arrangement of the seismic sources and the locations of seismic receivers are disclosed. The reference energy source is activated and the at least one satellite energy source is activated at a time delay relative to the activation of the reference energy source. This activation of sources occurs once each at spaced apart activation locations along the survey path to generate a series of superposed wavefields which propagate through a subsurface and are reflected from and refracted through material heterogeneities in the subsurface. The time delay is varied between the spaced apart activation locations. Seismic data is recorded including seismic traces generated by the series of superposed wavefields utilizing spaced apart receivers. The seismic data is then processed using the time delays to separate signals generated from the respective energy sources. More specifically, the processing of the seismic data further includes sorting into a common-geometry domain and replicating the seismic traces of data into multiple datasets associated with each particular energy source. Each trace is time adjusted in each replicated dataset in the common-geometry domain using the time delays associated with each particular source. This results in signals generated from that particular energy source being generally coherent while rendering signals from the other energy sources generally incoherent. The coherent and incoherent signals are then filtered to attenuate incoherent signals using a variety of filtering techniques. It is an object of the present invention to provide a method for acquisition of seismic signals generated “quasi-simultaneously” from several moving separated sources activated with a small time delay, and their subsequent accurate separation during data processing into independent data sets exclusively associated with each individual source. This can greatly improve operational efficiency without compromising data resolution.

20070220

20100316

20071129

78071.0

G01V100

HUGHES, SCOTT A

METHODS FOR ACQUIRING AND PROCESSING SEISMIC DATA FROM QUASI-SIMULTANEOUSLY ACTIVATED TRANSLATING ENERGY SOURCES

UNDISCOUNTED

ACCEPTED

G01V

ACCEPTED

Resonance security tag with and method of producing such a tag

A resonance security tag (1) comprises a dielectric foil material (2) provided with conductive material layer patterns (3-7) on both sides. The conductive material layer patterns are formed to provide an inductor (3) and a capacitor (4, 6) positioned inside the inductor (3), and mutually connected to form a resonance circuit. By cutting (9) the capacitor (4, 6) free of the dielectric foil material (2) and folding the capacitor (4, 6) away from the position inside the inductor (3), this part is left free for the penetration of magnetic flux through the inductor (3), whereby the detection level is improved and a possibility of reducing the size of the resonance security tag is provided.

1-5. (canceled) 6. Resonance security tag comprising a dielectric foil material provided with a conductive material layer pattern on a first side and a second side of said dielectric foil material, said conductive material layer pattern on the first side of the dielectric foil material being formed to provide an inductor, a first capacitor plate being connected to a first end of the inductor and positioned inside the inductor, and a first connection element connected to an opposite second end of the inductor, the conductive material layer pattern on the second side of the dielectric foil material being formed to provide a second capacitor plate confronting the first capacitor plate and a second connection element, formed to provide a shielding plate, connected to the second capacitor plate and confronting the first connection element, the first connection element and the second connection element being electrically connected, and the dielectric foil material being cut along part of a circumference of the first capacitor plate and the second capacitor plate to provide a cut-free capacitor which is folded away from a position inside the inductor, thus leaving such part free for penetration of magnetic flux through the inductor, wherein the cut-free capacitor is folded to the second side of the dielectric foil material to provide a folded-over capacitor overlaying the shielding plate. 7. Resonance security tag in accordance with claim 6, wherein the shielding plate has a form and size corresponding to form and size of the folded-over capacitor. 8. Resonance security tag in accordance with claim 6, wherein each conductive material layer pattern is formed in such a way that the tag can be positioned on or inside a CD or DVD with a hole from the folded-over capacitor positioned around a central hole in the CD or DVD. 9. Resonance security tag in accordance with claim 7, wherein each conductive material layer pattern is formed in such a way that the tag can be positioned on or inside a CD or DVD with a hole from the folded-over capacitor positioned around a central hole in the CD or DVD. 10. Method of producing a resonance security tag in accordance with claim 6, said method comprising steps of providing the dielectric foil material with the conductive material layer pattern on the first side and the second side thereof, each said conductive material layer pattern being formed to provide the inductor and the first capacitor plate and the second capacitor plate forming a resonance circuit with the first capacitor plate and the second capacitor plate positioned inside the inductor, and further comprising a step of cutting the dielectric foil material along part of a circumference of the first capacitor plate and the second capacitor plate to provide a cut-free capacitor and folding the cut-free capacitor away from a position inside the inductor, thus leaving such part free for penetration of magnetic flux through the inductor, wherein the folding is performed to fold the cut-free capacitor to that side of the tag opposite that side on which the conductive material layer pattern is formed to provide the inductor. 11. Method in accordance with claim 10, wherein the folding is performed by producing a preliminary folding using a jet of air or mechanical means to turn up the cut-free capacitor, and followed by passage of the security tag past a folding tool and a roller, whereby the capacitor is completely folded and pressed into intimate contact with a surface of the resonance security tag. 12. Method of producing a resonance security tag in accordance with claim 7, said method comprising steps of providing the dielectric foil material with the conductive material layer pattern on the first side and the second side thereof, each said conductive material layer pattern being formed to provide the inductor and the first capacitor plate and the second capacitor plate forming a resonance circuit with the first capacitor plate and the second capacitor plate positioned inside the inductor, and further comprising a step of cutting the dielectric foil material along part of a circumference of the first capacitor plate and the second capacitor plate to provide a cut-free capacitor and folding the cut-free capacitor away from a position inside the inductor, thus leaving such part free for penetration of magnetic flux through the inductor, wherein the folding is performed to fold the cut-free capacitor to that side of the tag opposite that side on which the conductive material layer pattern is formed to provide the inductor. 13. Method of producing a resonance security tag in accordance with claim 8, said method comprising steps of providing the dielectric foil material with the conductive material layer pattern on the first side and the second side thereof, each said conductive material layer pattern being formed to provide the inductor and the first capacitor plate and the second capacitor plate forming a resonance circuit with the first capacitor plate and the second capacitor plate positioned inside the inductor, and further comprising a step of cutting the dielectric foil material along part of a circumference of the first capacitor plate and the second capacitor plate to provide a cut-free capacitor and folding the cut-free capacitor away from a position inside the inductor, thus leaving such part free for penetration of magnetic flux through the inductor, wherein the folding is performed to fold the cut-free capacitor to that side of the tag opposite that side on which the conductive material layer pattern is formed to provide the inductor. 14. Method of producing a resonance security tag in accordance with claim 9, said method comprising steps of providing the dielectric foil material with the conductive material layer pattern on the first side and the second side thereof, each said conductive material layer pattern being formed to provide the inductor and the first capacitor plate and the second capacitor plate forming a resonance circuit with the first capacitor plate and the second capacitor plate positioned inside the inductor, and further comprising a step of cutting the dielectric foil material along part of a circumference of the first capacitor plate and the second capacitor plate to provide a cut-free capacitor and folding the cut-free capacitor away from a position inside the inductor, thus leaving such part free for penetration of magnetic flux through the inductor, wherein the folding is performed to fold the cut-free capacitor to that side of the tag opposite that side on which the conductive material layer pattern is formed to provide the inductor.

TECHNICAL FIELD The present invention relates to a resonance security tag of the kind set forth in the preamble of claim 1 and a method of producing such a tag. BACKGROUND ART Resonance security tags of this kind are e.g. known to be used in electronic article surveillance systems (EAS systems) in order to detect unauthorised removal of articles from shops, stores or warehouses, and such resonance security tags are produced in large numbers on a dielectric foil material which is provided with conductive material layer patterns on both sides for forming an inductor and a capacitor forming a resonance circuit having a suitable resonance frequency and to be detected by means of suitable equipment positioned at the exit from the premises. A resonance security tag of this kind is e.g. known from EP-0,285,559. From JP 02-310696 it is known to cut the foil material along part of the circumference of the capacitor elements and fold the cut-free capacitor away from inside the inductor in order to leave this part free for the penetration of magnetic flux through the inductor. However, experiments with this type of EAS-tag have shown a considerable variance in resonance frequency leading to reduced detection rates for such tags, and the present inventor has not seen any EAS-tags on the market which are produced in accordance with the method described in JP-02-310696. DISCLOSURE OF THE INVENTION It is the object of the present invention to provide a resonance security tag of the kind referred to above, with which it is possible to improve the detection level, maintain a precise resonance frequency, and at the same time possibly reducing or maintaining the small size of the resonance security tag, and this object is achieved with a resonance security tag of the kind, which according to the present invention also comprises the features set forth in the characterising clause of claim 1. With this arrangement, the central part of the inductor is made free in order to allow penetration of the magnetic flux through the inductor, whereby a higher detection rate is achieved, and the resonance frequency is maintained within narrow limits despite the folding operation due to the folding being performed to the side opposite the inductor pattern and presence of a shielding plate having a form and size corresponding to the form and size of the folded over capacitor plates improving the frequency precision. Furthermore, the present invention relates to a method of producing such a tag. Preferred embodiments of the resonance security tag in accordance with the present invention, the advantages of which will be evident from the following description, are revealed in the subordinate claims. BRIEF DESCRIPTION OF THE DRAWINGS In the following detailed part of the present description, the invention will be explained in more detail with reference to the exemplary embodiments of a resonance security tag according to the invention shown in the drawings, in which FIG. 1 schematically shows a tag positioned between a transmitter and a receiver at the exit from the store or like for detecting the presence of the tag at the exit, FIG. 2 schematically shows an equivalent circuit diagram of the situation shown in FIG. 1 for explaining the parameters for improving the detection level, FIG. 3 shows the conductive material layer pattern on a first side of the dielectric foil material of a resonance security tag in accordance with the present invention, FIG. 4 shows the conductive material layer pattern on both sides of the dielectric foil material of a resonance security tag in accordance with the present invention, FIG. 5 shows schematically in a perspective view a partially folded cut free capacitor of a resonance security tag in accordance with FIGS. 3 and 4, FIG. 6 shows the resonance security tag of FIG. 5 with the capacitor in a completely folded position, FIG. 7 schematically shows suggested instruments for performing the folding of the capacitor, and FIG. 8 shows an alternative embodiment of the resonance security tag specially formed to be positioned on or inside a CD or DVD in accordance with a preferred embodiment of the present invention. DESCRIPTION OF THE PREFERRED EMBODIMENTS Referring to FIGS. 1 and 2, the quality of a resonance security tag is discussed in the following. In FIGS. 1 and 2, the tag 1 is positioned between a transmitter Tx in an electronic article surveillance system (EAS system), and a receiver Rx of said system. The transmitter transmits a radio frequency signal within a specific frequency range and whenever a tag with at resonance frequency within this range is within the range of the transmitter and the receiver, the receiver will be able to detect the resonance frequency of the tag. The detection rate or quality will be dependent on the Q-value of the resonance circuit and the physical size thereof. The formula Q = 1 r ⁢ ⁢ L C ( 1 ) indicates that in order to obtain a high Q-value, it is desired to have a small value of r, a high value of L and a small value of C. A low value of r can be obtained by choosing a conductive material layer in the tag like e.g. silver and a high value of L can be obtained by providing several windings in the inductor and at the same time the capacitor can be chosen with a small capacitance C. In practice, however, this is not how it is done due to the fact that the price of silver is too high and many windings of the inductor coil will demand more material and surface area for the tag, which would increase the price of the tag. Furthermore, if many small windings are chosen in order to save material costs for the conductive material layer, the value of r will increase. If a very small value of C of e.g. 10 pF is chosen, the resonance circuit will be sensitive to external influence such as stray capacities, which would change the resonance frequency. As can be seen from the above, the design of the resonance circuit for an EAS system is a compromise between price and size, among other things. In the market there is a wish for a cheap tag as well as a small tag with a high rate of detection and Q-value. Accordingly, the resonance circuit normally comprises a dielectric foil material 2 of polypropylene or polyethylene provided with an electrically conductive material layer pattern on both sides, said conductive material usually being of aluminium. The electrical equivalent diagram shown in FIG. 2 corresponds in principle to an EAS system and the mutual induction coefficients between the inductors L1, L2 and L3 are M12 and M23, respectively. The loss resistance in the resonance circuit in the tag is represented by r. The input resistance in the measuring circuit is represented by R. The measured voltage Vm represents the signal strength from the resonance security tag. The resonance circuit L2,r,C is positioned between the transmitter coil L1 and the receiver coil L3. The formula for the received signal strength Vm is Vm = ω 0 ⁡ ( M ⁢ ⁢ 12 · M ⁢ ⁢ 23 / L ⁢ ⁢ 1 ) · V ⁢ ⁢ 1 r ( 2 ) where ω0 is equal to 2 π f0 (f0 is the resonance frequency). V1 is the voltage of the signal generator. When the coils L1, L2 and L3 (the cross-sections S1, S3>S2), are arranged as shown, the mutual inductances are M12=K12√{square root over ( )}S2 L2 and M23=K23√{square root over ( )}S2 L2 (3), where K12 and K23 are constants. Using (2) and (3), we have: Vm=K12 K23 (V1/L1) (ω0L2/r)S2=K*Q*S (4) K is a constant and Q is a measure for the quality of the resonance circuit Q = 1 r ⁢ ⁢ L C S is the area surrounded by the magnetic flux. From the above it can be seen that Vm is proportional to Q*S. In order to improve the tag, it is possible to increase Q or S or both. The magnetic flux, which has to pass through the centre of the coil, is partially blocked by the capacitor in this position in a normal tag, referring to FIGS. 3 and 4. In order to increase the magnetic flux through the coil centre, it is desired to make the area of the capacitor as small as possible. As mentioned earlier, a certain minimum size of the capacitor is given, which leads to a restriction of the area in the centre of the coil which is free to allow the magnetic flux through the coil. The present invention removes the capacitor from the centre of the coil, whereby the magnetic flux through the coil centre is increased and thus the detection rate for the EAS system is increased considerably. In FIG. 3 is shown the conductive material layer pattern on the first side of the dielectric foil material 2, which is formed to provide an inductor 3, a first capacitor plate 4 connected to a first end of the inductor 3 and positioned inside the inductor 3, and a first connection element 5 connected to an opposite end of the inductor 3. In FIG. 4 the conductive material layer pattern on the second, opposite side of the dielectric foil material 2 is shown superposed on the pattern of FIG. 3. The conductive material layer pattern on the second side of the dielectric foil material 2 is formed to provide a second capacitor plate 6 confronting the first capacitor plate 4 and a shielding plate 7 connected to the capacitor plate 6 and confronting the first connection element 5. The shielding plate 7 provides a patch of conductive material layer with a form and size corresponding to the form and size of the first and the second capacitor plate 4, 6. As shown schematically in FIG. 5, the capacitor plates 4, 6 have been cut 9 along part of the circumference of the first and second capacitor plates 4, 6 in order to fold the capacitor 4, 6 away from the central position inside the inductor 3. As shown in FIG. 6, the cut-free capacitor 4, 6 is folded completely along the folding line 10 over to overlay the shielding plate 7. Due to the fact that the capacitive coupling between the shielding plate 7 and the windings of the inductor 3 is constant, the folding of the capacitor 4, 6 to overlay the shielding plate 7 will result in a well defined controlled change in resonance frequency. The distance between the folded over capacitor 4, 6 and the shielding plate 7 is precisely fixed. In order to compensate for possible mechanical tolerances in the folding of the capacitor, the shielding plate 7 is preferably provided with dimensions larger than the capacitor plates 4, 6 such that the folded over capacitor plates 4,6 will always be positioned inside the circumference of the shielding plate 7. The electrical contact 8 between the first connection element 5 and the shielding plate 7 is preferably provided by irregular holes through the dielectric foil material 2 in the area of these elements 5, 7 before or after the folding of the capacitor plates 4, 6. The cut 9 along part of the circumference of the first and second capacitor plates 4, 6 can be provided by mechanical means, by laser cutting, by heating the capacitor plates 4, 6, etc. The first part of the folding of the capacitor 4, 6 may be provided by mechanical means or by means of a jet of air, etc. An example of mechanical means for providing the folding of the capacitor 4, 6 is shown in FIG. 7, in which a folding tool 12 is positioned stationary over the foil material 2 and the foil material is moved towards this folding tool which folds the turned up capacitor 4, 6. In order to move the folded capacitor 4, 6 into intimate contact with the shielding plate 7 on the upper side of the tag, a further roller-formed tool 13 is positioned immediately after the folding tool 12 seen in the movement direction of the foil 2. The tag in accordance with the present invention is especially suited to be used as an EAS tag for a CD or DVD due to the fact that the hole in the middle can be positioned over the hole in the CD or DVD and the coil can be positioned so as to surround this hole in a position in which the CD or DVD has no metallic layer and thus allows the radio frequency field to pass through the area where the tag is positioned. This would not have been possible with a conventional tag due to the fact that a tag of this small size would not be detectable in an EAS system when the tag is produced in accordance with the conventional technique. The tag in accordance with the present invention can, as shown in FIG. 8, be positioned centrally in a CD or DVD and may be integrated into the DVD between the layers of the DVD. In this situation the EAS tag cannot be removed without destroying the DVD. The construction in accordance with the present invention has improved the specifications of the resonance circuit to an extent that allows a 10-20% reduction in the size of the resonance circuit. Due to the fact that material costs are the main costs in producing such tags, this reduction in size leads to a corresponding reduction in price for the tags. Above, the invention has been described in connection with preferred embodiments thereof, however, many modifications may be envisaged by a person skilled in the art without departing from the scope of the following claims.

<SOH> BACKGROUND ART <EOH>Resonance security tags of this kind are e.g. known to be used in electronic article surveillance systems (EAS systems) in order to detect unauthorised removal of articles from shops, stores or warehouses, and such resonance security tags are produced in large numbers on a dielectric foil material which is provided with conductive material layer patterns on both sides for forming an inductor and a capacitor forming a resonance circuit having a suitable resonance frequency and to be detected by means of suitable equipment positioned at the exit from the premises. A resonance security tag of this kind is e.g. known from EP-0,285,559. From JP 02-310696 it is known to cut the foil material along part of the circumference of the capacitor elements and fold the cut-free capacitor away from inside the inductor in order to leave this part free for the penetration of magnetic flux through the inductor. However, experiments with this type of EAS-tag have shown a considerable variance in resonance frequency leading to reduced detection rates for such tags, and the present inventor has not seen any EAS-tags on the market which are produced in accordance with the method described in JP-02-310696.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>In the following detailed part of the present description, the invention will be explained in more detail with reference to the exemplary embodiments of a resonance security tag according to the invention shown in the drawings, in which FIG. 1 schematically shows a tag positioned between a transmitter and a receiver at the exit from the store or like for detecting the presence of the tag at the exit, FIG. 2 schematically shows an equivalent circuit diagram of the situation shown in FIG. 1 for explaining the parameters for improving the detection level, FIG. 3 shows the conductive material layer pattern on a first side of the dielectric foil material of a resonance security tag in accordance with the present invention, FIG. 4 shows the conductive material layer pattern on both sides of the dielectric foil material of a resonance security tag in accordance with the present invention, FIG. 5 shows schematically in a perspective view a partially folded cut free capacitor of a resonance security tag in accordance with FIGS. 3 and 4 , FIG. 6 shows the resonance security tag of FIG. 5 with the capacitor in a completely folded position, FIG. 7 schematically shows suggested instruments for performing the folding of the capacitor, and FIG. 8 shows an alternative embodiment of the resonance security tag specially formed to be positioned on or inside a CD or DVD in accordance with a preferred embodiment of the present invention. detailed-description description="Detailed Description" end="lead"?

20060726

20090224

20070531

92594.0

G08B1314

FAN, HONGMIN

RESONANCE SECURITY TAG WITH AND METHOD OF PRODUCING SUCH A TAG

SMALL

ACCEPTED

G08B

ACCEPTED

Automatic steering control apparatus and autopilot

An object of the present invention is to provide an automatic steering control apparatus, including an autopilot, which enables a ship to turn around a desired fixed point as a turning center with a desired turning radius without being affected by an extraneous factor, such as a tidal current or the like. To achieve the object, a center position, a turning radius and a turning direction for turning are initially designated by the operator, a tangent to a turning circle at an intersection of a straight line from the turning center to a position of the ship and the turning circle, and a course of the ship is controlled to approach the tangent.

1. An automatic steering control apparatus which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising: an input device for inputting a desired turning center position; a memory for storing the turning center position input by the input device; and a rudder angle output device for outputting a command rudder angle so that a track of the ship draws an arc around a turning center stored in the memory with a turning radius, the turning radius being a distance from the position of the ship measured by the ship's positioning device to the turning center. 2. An autopilot which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising: an input device for inputting a desired turning center position; a memory for storing the turning center position input by the input device; and a rudder angle adjuster for adjusting a rudder angle so that a track of the ship draws an arc around a turning center stored in the memory with a turning radius, the turning radius being a distance from the position of the ship measured by the ship's positioning device to the turning center. 3. An automatic steering control apparatus which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising: an input device for inputting a desired turning radius and a desired turning center position; a memory for storing the turning radius and the turning center position input by the input device; and a rudder angle output device for outputting a command rudder angle so that a distance from the position of the ship measured by the ship's positioning device to a turning center stored in the memory, approaches the turning radius stored in the memory, wherein the rudder angle output device outputs a command rudder angle so as to adjust a rudder angle so that a track of the ship draws an arc around the turning center with the turning radius from the time when the distance from the position of the ship to the turning center becomes substantially equal to the turning radius. 4. An autopilot which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising: an input device for inputting a desired turning radius and a desired turning center position; a memory for storing the turning radius and the turning center position input by the input device; and a rudder angle adjuster for adjusting a rudder angle so that a distance from the position of the ship measured by the ship's positioning device to a turning center stored in the memory, approaches the turning radius stored in the memory, wherein the rudder angle adjuster adjusts a rudder angle so that a track of the ship draws an arc around the turning center with the turning radius from the time when the distance from the position of the ship to the turning center becomes substantially equal to the turning radius. 5. The autopilot according to claim 2, wherein the input device can input a desired turning direction, the memory stores the turning direction input by the input device, and the rudder angle adjuster adjust a rudder angle so that the ship turns in the turning direction stored in the memory. 6. The automatic steering control apparatus according to claim 3, comprising an interrupt controller for independently changing the turning direction, the turning radius and the turning center position stored in the memory. 7. An autopilot which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising: an input device for inputting a desired turning direction, a desired turning radius, and a desired turning center position; a memory for storing the turning radius and the turning center position input by the input device; and a rudder angle adjuster for obtaining a straight line connecting the position of the ship measured by the ship's positioning device and a turning center stored in the memory for storing the turning center position, obtaining an intersection of the straight line and a turning circle drawn around the turning center stored in the memory with the turning radius stored in the memory, obtaining a tangent to the turning circle at the intersection, calculating a distance difference between the position of the ship and the intersection, and adjusting a rudder angle so that a course direction of the ship approaches the turning direction of the tangent stored in the memory.

CROSS REFERENCE OF RELATED APPLICATION Japanese Patent Application Tokugan No. 2003-418313 is hereby incorporated by reference. TECHNICAL FIELD OF THE INVENTION The present invention relates to an automatic steering control apparatus for ships which outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, and more particularly, to an automatic steering control apparatus, including an autopilot, which enables a ship to turn around a desired turning center position with a desired turning radius. BACKGROUND OF THE INVENTION Conventional autopilots automatically steer a ship carrying the device in a manner which causes a bearing deviation of a current course of the ship from a target course, which is set manually, to be “0”. In this case, when an initial bearing deviation is large, an order rudder angle having a large value is output. Therefore, a limiter is provided so that, when the value is larger than or equal to a predetermined value, a load larger than or equal to a predetermined value is prevented from being applied to actual steering of the ship. An output of the limiter is transferred to an actuator, which in turn outputs a response rudder angle. After the response rudder angle is added with a disturbance factor, the result is transferred to a rudder of a ship body. A motion of a ship is measured as a bearing angle using a bearing sensor. Conventional autopilots perform turning in accordance with a limit value of the limiter when a target course having a large bearing deviation is set. Therefore, after changing a course, stationary deviation and overshoot occur, so that smooth automatic course change cannot be achieved. This causes a significant problem that, when there is a sea area which should be avoided, such as a floating obstruction or the like, a path different from an initially predicted turning path may be actually passed, so that safe course change cannot be achieved. Therefore, in such a sea area, course change needs to be performed by an effort made by a steersman, but not using an autopilot, resulting in an increase in load to the steersman. A conventional autopilot which solves the problem will be described. According to the conventional autopilot, a turning radius and a turning center as well as a target course are preset, as accumulated information, on plane coordinate axes. A rudder angle is adjusted so that the track of a ship carrying the device draws an arc having the turning radius with respect to the turning center. Thereby, automatic course change can be smoothly and stably achieved, and a course after course change can be accurately predicted. In addition, a waste motion during automatic course change is reduced, thereby reducing fuel consumption (see Patent Document 1). Patent Document 1: JP H08-119197A However, since the conventional autopilot does not have means for finding a position of a ship carrying the device, the rudder angle is unavoidably set to be constant when a turning motion is performed. In the case of this method, the ship is drifted by an extraneous factor, such as tidal current, wind, or the like, in a direction of the extraneous factor, so that the turning center is also moved while the ship is turning (see FIG. 1). Therefore, although a turning operation is tried by the conventional autopilot, the ship only continues to turn in a constant direction, and cannot turn around a fixed point. An object of the present invention is to provide an automatic steering control apparatus and an autopilot which have means for turning around a desired turning center position without being affected by extraneous factors, such as tidal current and the like. SUMMARY OF THE INVENTION The present invention provides an automatic steering control apparatus which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning center position, a memory for storing the turning center position input by the input device, and a rudder angle output device for outputting a command rudder angle so that a track of the ship draws an arc around a turning center stored in the memory with a turning radius, the turning radius being a distance from the position of the ship measured by the ship's positioning device to the turning center. The present invention also provides an automatic steering control apparatus which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning radius and a desired turning center position, a memory for storing the turning radius and the turning center position input by the input device, and a rudder angle output device for outputting a command rudder angle so that a distance from the position of the ship measured by the ship's positioning device to a turning center stored in the memory, approaches the turning radius stored in the memory. The rudder angle output device outputs a command rudder angle so as to adjust a rudder angle so that a track of the ship draws an arc around the turning center with the turning radius from the time when the distance from the position of the ship to the turning center becomes substantially equal to the turning radius. The present invention also provides an autopilot which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning center position, a memory for storing the turning center position input by the input device, and a rudder angle adjuster for adjusting a rudder angle so that a track of the ship draws an arc around a turning center stored in the memory with a turning radius, the turning radius being a distance from the position of the ship measured by the ship's positioning device to the turning center. The present invention also provides an autopilot which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning radius and a desired turning center position, a memory for storing the turning radius and the turning center position input by the input device, and a rudder angle adjuster for adjusting a rudder angle so that a distance from the position of the ship measured by the ship's positioning device to a turning center stored in the memory, approaches the turning radius stored in the memory. The rudder angle adjuster adjusts a rudder angle so that a track of the ship draws an arc around the turning center with the turning radius from the time when the distance from the position of the ship to the turning center becomes substantially equal to the turning radius. In the autopilot of the present invention, the input device can input a desired turning direction, the memory stores the turning direction input by the input device, and the rudder angle adjuster adjust a rudder angle so that the ship turns in the turning direction stored in the memory. [The autopilot of the present invention also has an interrupt controller for independently changing the turning direction, the turning radius and the turning center position, all of which are stored in the memory.] The present invention also provides an autopilot which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning direction, a desired turning radius, and a desired turning center position, a memory for storing the turning direction, the turning radius and the turning center position input by the input device, and a rudder angle adjuster for obtaining a straight line connecting the position of the ship measured by the ship's positioning device and a turning center stored in the memory for storing the turning center position, obtaining an intersection of the straight line and a turning circle drawn around the turning center stored in the memory with the turning radius stored in the memory, obtaining a tangent to the turning circle at the intersection, calculating a distance difference between the position of the ship and the intersection, and adjusting a rudder angle so that a course direction of the ship approaches the turning direction stored in the memory, of the tangent. According to the above-described configuration, it is possible to provide an automatic steering control apparatus and an autopilot which comprise means for enabling a ship to turn around a desired turning center position as a center without being affected by an extraneous factor, such as a tidal current or the like. In the case of conventional autopilots, a ship carrying the device only travels in a straight line toward a target bearing. According to the present invention, the ship can accurately turn around a designated turning center position while maintaining a designated turning radius, without being affected by an extraneous factor, such as a tidal current or the like. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram illustrating a problem with turning of conventional autopilots. FIG. 2 is a block diagram illustrating an autopilot according to the present invention. FIG. 3 is a diagram illustrating a coordinate system when a ship carrying the autopilot of the present invention starts a turning motion. FIG. 4 is a diagram illustrating an enlarged view of the ship of FIG. 3. FIG. 5 is a diagram illustrating a situation where a ship carrying the autopilot of the present invention starts a turning motion. FIG. 6 is a flowchart illustrating an operating procedure of the autopilot of the present invention. FIG. 7 is a flowchart illustrating an operating procedure for calculating kp. FIG. 8 is a diagram illustrating changes over time in a correction value calculation coefficient kp and a kp adjusted width Δkp. FIG. 9 is a diagram changes over time in a radius error and a response rudder angle. FIG. 10 is a plot diagram from instruction for a turning motion to a turning state. DETAILED DESCRIPTION OF THE INVENTION A configuration of an autopilot according to the present invention is illustrated in FIG. 2. The user inputs a turning center, a turning radius, and a turning direction via an operation section 23. For example, the operation section 23 is composed of a personal computer and the like, and has a memory section thereinside. The memory section can store the turning center, the turning radius and the turning direction which are input by the user. 26 indicates a rudder machine which comprises a rudder angle adjuster for adjusting a rudder angle based on an instruction from a control section 25. The instruction input to the rudder machine 26 (rudder angle adjuster) is calculated by the control section 25 based on the turning center, the turning radius and the turning direction, and a heading of the ship obtained from a bearing sensor 24. A method for enabling a turning motion of the autopilot of the present invention will be described in detail with reference to FIGS. 3 to 5. FIG. 3 is a diagram illustrating a coordinate system when a ship carrying the autopilot of the present invention starts a turning motion. FIG. 4 is a diagram illustrating an enlarged view of the ship of FIG. 3. FIG. 5 is a diagram illustrating a situation where the ship carrying the autopilot of the present invention starts a turning motion. The ship carrying the autopilot of the present invention is provided with a positioning device for measuring a position of the ship (e.g., a navigation device 22 (FIG. 2), such as a GPS positioning device, etc.), and can measure the position S(x, y) of the ship. The operator sets a turning center O(xo, yo) and a turning radius. Therefore, these values are known values. Thus, a radius error: R_err obtained by subtracting the turning radius from a distance between the position of the ship and the turning center can be easily calculated. A point where a straight line connecting the position of the ship and the turning center and a turning circle intersect is represented by P. A tangent to the turning circle at the point P is calculated, and a tangential bearing: Co_P is calculated, depending on the turning direction. After calculating the tangential bearing Co_P, the radius error: R_err is multiplied by a variable coefficient to calculate a set bearing Co_set. Specifically, when R_err is positive (outside beyond the turning radius), Co_set is obtained by: Co_set=Co—P+kp·R—err (clockwise direction) Co_set=Co—P−kp·R—err (anticlockwise direction) where Co_P is: OP(→)+90° in the case of the clockwise direction, and OP(→)−90° in the case of the anticlockwise direction. The set bearing Co_set thus calculated is assumed to be a controlled course of autopilot. Note that, as described below, kp is a variable coefficient which varies in association with the radius error: R_err which varies over time. The kp is related to the radius error. This value is adjusted by addition or subtraction of Δkp in predetermined time intervals, depending on a required robustness of a control. In an example hereinafter described, if an evaluated value calculated based on the radius error and a bearing deviation is better than an evaluated value obtained during the previous adjustment, 2Δkp (constant value) is subtracted from kp at that time. If the evaluated value calculated based on the radius error and the bearing deviation is worse than the evaluated value obtained during the previous adjustment, Δkp (constant value) is added to kp at that time. By performing this control continuously, a control of robustness required against disturbance can be sequentially performed, thereby making it possible to draw a track close to a perfect circle around a fixed point as a center. In the present invention, only the set bearing (rudder angle) is calculated. Thereafter, the autopilot is used to control the rudder by a PID control which is the same as that which is used when the course is maintained. Note that the PID control is a control technique which is most commonly used among automatic control techniques, and in which a combination of P: Proportional, I: Integral, and D: Differential is used to achieve a fine control, resulting in a smooth control. The autopilot of the present invention has a feedback mechanism in addition to the conventional configuration, and regularly calculates a deviation from the desired turning circle, and performs a control so that the error approaches zero. An operating procedure of the autopilot of the present invention will be hereinafter described (see FIG. 6). Before performing turning, a ship's speed V is obtained using the navigation device, and when the ship's speed V is higher than a preset speed (10 kt in this example), it is determined that the speed is so high that a turning motion cannot be performed, so that a turning operation is not started. After the ship's speed V becomes slower than the preset speed, the operator designates the following. Turning center position (latitude longitude) Turning radius Turning direction (clockwise anticlockwise) These values are stored in the memory section of the operation section. These values can be preset. Also, before or after the input by the operator, the position of the ship is obtained from the navigation device, and the heading of the ship is obtained from the bearing sensor. Based on the designation by the operator, a distance difference between a distance Rnow from the position S of the ship to the turning center O, and a turning radius Rcircle (set by the operator) which is a distance from the intersection P to the turning center O, is obtained as a radius error R_err which is a distance from the position of the ship to the intersection P. Next, a tangent to the turning circle at the intersection P of a straight line which is drawn from the turning center O to the position of the ship S and the turning circle, is calculated. Note that, in this case, depending on the designated turning direction, the bearing Co_P of the tangential direction is obtained by, as described above: OP(→)+90° in the case of the clockwise direction, and OP(→)−90° in the case of the anticlockwise direction. Based on these values, a set direction Co_set is obtained by: Co_set=Co—P+kp·R—err (clockwise direction), and Co_set=Co—P−kp·R—err (anticlockwise direction). A deviation angle DV is obtained from a difference between the set bearing Co_set and the heading Hd of the ship. Thereafter, the deviation angle DV is used as an input for the course maintaining operation (PID control) which is performed as a common process by the autopilot, or as evaluation of the control. Specifically, when the deviation angle is large, there is a large deviation from a target course, so that it can be evaluated that the control is poor, and therefore, the rudder is largely steered in an actual control. In this embodiment, when the deviation angle DV is larger than or equal to a predetermined value, the ship is turned in the “turning” step of FIG. 6. At the same time, the set bearing is recalculated. After this process, a “set bearing output” is performed with respect to the control section of the autopilot. When the deviation angle DV is smaller than or equal to the predetermined value, if the radius error R_err is within a predetermined plus/minus range around the position P of FIG. 5 as a center (in this embodiment, −0.03 nm (nautical mile)<R_err<0.03 nm), the “set bearing output” is enabled, and if the radius error R_err exceeds the range, the turning motion is not immediately started, and the ship is caused to turn and gradually approach a planned turning circle while turning a path larger than the desired turning circle. For example, if the ship is at a distance of miles from the desired turning circle, the ship turns on a circumference of a turning circle, and initially goes straight toward the turning circle, i.e., gives a highest priority to approaching the turning circle. If the heading of the ship is directed to an opposite direction (directed to the left, directed to the center, etc., though a clockwise direction is desired), the ship needs to be initially directed in a bearing which causes the ship to go roughly along the turning circle. Such an operation is performed in an “off-range control process”. In the “off-range control process”, further, recalculation of the set bearing is also performed. Next, the variable coefficient: kp which is multiplied by the radius error: R_err will be described in detail (see FIG. 7). The kp is a variable coefficient which is multiplied by R_err when the set bearing Co_set is calculated (see the expressions above), and as described above, varies over time in association with R_err. The kp is adjusted by addition or subtraction of Δkp in predetermined time intervals, depending on a required robustness of a control. Specifically, the proportional coefficient kp which is multiplied by the radius error R_err, is adjusted based on an evaluated value eval which is calculated from the deviation angle and the radius error, and the previous evaluated value eval_last. A procedure for the adjustment will be described as follows. (S0) An initial evaluated value is calculated in accordance with expression (1): eval=R—errˆ2+0.1*dv—gˆ2 (1) where R_err is the radius error, dv_g is the deviation angle, 0.1 preceding dv_g is a coefficient obtained by experiments (the coefficient is not limited to this value). (S1) A flag is checked. When the flag is not ON, (S2) the adjusted amount Δkp is calculated in accordance with expression (2): Δkp=co—eval*d—eval (2) where an evaluated value difference d_eval is given by expression (3): d—eval=eval−lim—eval (3) where lim_eval and co_eval mean a dead zone of the evaluated value, and a coefficient for calculation of Δkp, respectively. (S3) The adjusted amount Δkp is added to kp. (S4) The flag is set to be ON. (S5) After a predetermined time (determined by the size of the circumference and the ship's speed) elapses, the evaluated value eval obtained by S0 is compared with the previous evaluated value eval_last. (S6) As the result of the comparison, (i) when eval>eval_last (No in S5 of FIG. 7), it means that the evaluation becomes worse, and since the process of (S3) has an adverse influence, a counter operation is performed, i.e., Δkp×2 is subtracted from kp. The resultant kp is smaller by Δkp than kp before the addition in (S3). (ii) When eval<eval_last (Yes in S5 of FIG. 6 [FIG. 7]), it means that the evaluation becomes better, i.e., the process of (S3) has a satisfactory result. Therefore, Δkp is further added. The resultant kp is larger than by 2×Δkp than kp before the addition in (S3). (S7) The flag is set to be OFF. (S8) The value of eval_last is rewritten. By repeatedly performing the control loop of FIG. 7, when a strong control is required, the evaluation tends to be increased by the process of (S6)(i), so that kp increases. When a weak control is enough, the evaluation becomes worse (excessive control) due to the process of (S6)(ii), so that kp decreases. Thereby, kp is gradually adjusted. The value of Δkp ranges from a negative value to a positive value, depending on the value of Δeval. When the value of Δeval is large, the evaluated value significantly changes, and therefore, the adjustment speed is increased by increasing the value of Δkp. Conversely, when the value of Δeval is small, the evaluation is not much changed by the adjustment, and therefore, the value of Δkp is decreased so as to eliminate waste adjustment, thereby making it possible to prevent the value of kp from changing. Note that, as illustrated in FIG. 7, this loop is alternately repeated between the right and left sides thereof. This algorithm calculates and controls only the heading of the ship, but not the speed and others. Thereafter, the same PID control as that when the course is maintained is used to control the rudder. FIGS. 8 to 10 illustrate the results of simulation of the present invention. “R=0.2” means a turning radius of 0.2 nm. “Ship's LL” means that a mode in which the position of the ship is the center of the turning circle at the start, is carried out (there are other modes in which the center is designated using a cursor from a distant place, and a final point is set as the center after determining a route). As an extraneous factor, there is a tidal current of 1.5 kt in a constant direction. In FIG. 9, it can be seen that the radius error fluctuates around zero, having positive values and negative values. In FIG. 10, the center position of a turning motion does not move no matter that there is an extraneous factor which is a tidal current. Although the heading of the ship may be opposite to a designated turning direction, when the heading of the ship is significantly deviated from the tangential bearing (e.g., 40°), the course is initially changed using the tangential bearing as a set bearing (turn to the closer of the right and the left), and after a deviation angle between the tangent and the heading of the ship has become small, a control for correcting the radius is performed. In the above-described example, the operator designates all of the turning center position, the turning radius and the turning direction. The present invention is not limited to the example. For example, the rudder angle may be adjusted until a distance from the position of the ship to the turning center becomes substantially equal to the turning radius, and then, from that time, the rudder angle may be adjusted so that a track of the ship draws an arc having the turning radius with respect to the turning center. The operator may designate only the turning center position and the turning radius, and may not designate the turning direction, and the ship may automatically turn to a direction close to the heading of the ship. Alternatively, when the operator may designate only the turning center position, a distance from the turning center position to the position of the ship may be automatically recognized as the turning radius, and the ship may be controlled to perform a turning motion in a traveling direction of the ship directly from the position of the ship. In the case of conventional autopilots, a ship carrying the device only travels in a straight line toward a target bearing. According to the present invention, the ship can accurately turn around a destination (a designated turning center position) with a designated turning radius. With this function, the autopilot can be applied to wider applications, including, for example: search (the surrounding of a point can be searched in a fish sonar or the like by changing the turning radius); life saving (life saving can be performed around the ship without hitting a subject to be saved, by turning the ship accurately); standby (holding the ship at a fixed point requires a complicated operation which is a combination of adjustment of an engine, operation of a rudder, and the like, but if low-speed turning is performed, such a complicated operation is not required); and in addition, by moving the turning center, a combination of the autopilot and an echo sounder can be used for production of a sea floor map and resource prospecting. INDUSTRIAL APPLICABILITY The present invention relates to an automatic steering control apparatus for ships which outputs a command rudder angle based on a deviation of the heading of the ship from a reference course, and particularly, can be used for an autopilot which enables a ship to turn around a desired turning center position with a desired turning radius.

<SOH> BACKGROUND OF THE INVENTION <EOH>Conventional autopilots automatically steer a ship carrying the device in a manner which causes a bearing deviation of a current course of the ship from a target course, which is set manually, to be “0”. In this case, when an initial bearing deviation is large, an order rudder angle having a large value is output. Therefore, a limiter is provided so that, when the value is larger than or equal to a predetermined value, a load larger than or equal to a predetermined value is prevented from being applied to actual steering of the ship. An output of the limiter is transferred to an actuator, which in turn outputs a response rudder angle. After the response rudder angle is added with a disturbance factor, the result is transferred to a rudder of a ship body. A motion of a ship is measured as a bearing angle using a bearing sensor. Conventional autopilots perform turning in accordance with a limit value of the limiter when a target course having a large bearing deviation is set. Therefore, after changing a course, stationary deviation and overshoot occur, so that smooth automatic course change cannot be achieved. This causes a significant problem that, when there is a sea area which should be avoided, such as a floating obstruction or the like, a path different from an initially predicted turning path may be actually passed, so that safe course change cannot be achieved. Therefore, in such a sea area, course change needs to be performed by an effort made by a steersman, but not using an autopilot, resulting in an increase in load to the steersman. A conventional autopilot which solves the problem will be described. According to the conventional autopilot, a turning radius and a turning center as well as a target course are preset, as accumulated information, on plane coordinate axes. A rudder angle is adjusted so that the track of a ship carrying the device draws an arc having the turning radius with respect to the turning center. Thereby, automatic course change can be smoothly and stably achieved, and a course after course change can be accurately predicted. In addition, a waste motion during automatic course change is reduced, thereby reducing fuel consumption (see Patent Document 1). Patent Document 1: JP H08-119197A However, since the conventional autopilot does not have means for finding a position of a ship carrying the device, the rudder angle is unavoidably set to be constant when a turning motion is performed. In the case of this method, the ship is drifted by an extraneous factor, such as tidal current, wind, or the like, in a direction of the extraneous factor, so that the turning center is also moved while the ship is turning (see FIG. 1 ). Therefore, although a turning operation is tried by the conventional autopilot, the ship only continues to turn in a constant direction, and cannot turn around a fixed point. An object of the present invention is to provide an automatic steering control apparatus and an autopilot which have means for turning around a desired turning center position without being affected by extraneous factors, such as tidal current and the like.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides an automatic steering control apparatus which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning center position, a memory for storing the turning center position input by the input device, and a rudder angle output device for outputting a command rudder angle so that a track of the ship draws an arc around a turning center stored in the memory with a turning radius, the turning radius being a distance from the position of the ship measured by the ship's positioning device to the turning center. The present invention also provides an automatic steering control apparatus which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning radius and a desired turning center position, a memory for storing the turning radius and the turning center position input by the input device, and a rudder angle output device for outputting a command rudder angle so that a distance from the position of the ship measured by the ship's positioning device to a turning center stored in the memory, approaches the turning radius stored in the memory. The rudder angle output device outputs a command rudder angle so as to adjust a rudder angle so that a track of the ship draws an arc around the turning center with the turning radius from the time when the distance from the position of the ship to the turning center becomes substantially equal to the turning radius. The present invention also provides an autopilot which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning center position, a memory for storing the turning center position input by the input device, and a rudder angle adjuster for adjusting a rudder angle so that a track of the ship draws an arc around a turning center stored in the memory with a turning radius, the turning radius being a distance from the position of the ship measured by the ship's positioning device to the turning center. The present invention also provides an autopilot which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning radius and a desired turning center position, a memory for storing the turning radius and the turning center position input by the input device, and a rudder angle adjuster for adjusting a rudder angle so that a distance from the position of the ship measured by the ship's positioning device to a turning center stored in the memory, approaches the turning radius stored in the memory. The rudder angle adjuster adjusts a rudder angle so that a track of the ship draws an arc around the turning center with the turning radius from the time when the distance from the position of the ship to the turning center becomes substantially equal to the turning radius. In the autopilot of the present invention, the input device can input a desired turning direction, the memory stores the turning direction input by the input device, and the rudder angle adjuster adjust a rudder angle so that the ship turns in the turning direction stored in the memory. [The autopilot of the present invention also has an interrupt controller for independently changing the turning direction, the turning radius and the turning center position, all of which are stored in the memory.] The present invention also provides an autopilot which is carried in a ship having a positioning device for measuring a position of the ship, and outputs a command rudder angle based on a deviation of a heading of the ship from a reference course, comprising an input device for inputting a desired turning direction, a desired turning radius, and a desired turning center position, a memory for storing the turning direction, the turning radius and the turning center position input by the input device, and a rudder angle adjuster for obtaining a straight line connecting the position of the ship measured by the ship's positioning device and a turning center stored in the memory for storing the turning center position, obtaining an intersection of the straight line and a turning circle drawn around the turning center stored in the memory with the turning radius stored in the memory, obtaining a tangent to the turning circle at the intersection, calculating a distance difference between the position of the ship and the intersection, and adjusting a rudder angle so that a course direction of the ship approaches the turning direction stored in the memory, of the tangent. According to the above-described configuration, it is possible to provide an automatic steering control apparatus and an autopilot which comprise means for enabling a ship to turn around a desired turning center position as a center without being affected by an extraneous factor, such as a tidal current or the like. In the case of conventional autopilots, a ship carrying the device only travels in a straight line toward a target bearing. According to the present invention, the ship can accurately turn around a designated turning center position while maintaining a designated turning radius, without being affected by an extraneous factor, such as a tidal current or the like.

20060615

20140107

20070712

67248.0

B62D600

BEHNCKE, CHRISTINE M

AUTOMATIC STEERING CONTROL APPARATUS AND AUTOPILOT

UNDISCOUNTED

ACCEPTED

B62D

ACCEPTED

Electronic high-frequency switch and attenuator with said high-frequency switches

In an electronic high-frequency switch, comprising a field-effect transistor as the switching element, the size of the gate voltage may be switched between at least two values (−5.5 V and −8 V), according to the desired linearity or switching speed. The switching device for the gate voltage is preferably coupled to a correction device in which different correcting values for the different gate voltage values corresponding to different correcting values for transmission or reflection by the high frequency switch are stored.

1-4. (canceled) 5. Electronic high frequency switch with a field effect transistor as the switching element, whose switching condition is controlled via the gate voltage fed from a gate voltage source and is controlled by means of a control circuit between a switching on value and switching off value, characterized in that the size of the gate voltage fed from the gate voltage source is selectable by a changeover device depending on the desired linearity or switching speed (for example, −5V or −8V). 6. High frequency switch according to claim 5, characterized in that the changeover device for the gate voltage is coupled to a correction device in which, for the different gate voltage values, corresponding different correction values for additional high frequency properties of the high frequency switch (transmission or reflection) are stored which, depending on the gate voltage chosen, are used for correcting these additional high frequency properties of the high frequency switch. 7. Attenuator with a plurality of electronic high frequency switches according to claim 5 or 6, characterized in that the size of the gate voltage of at least some of the high frequency switches is switchable between at least two values. 8. Attenuator according to claim 7, with a switchable attenuation member connected on the line side, which is controllable with a correction device in which, depending on the frequency of the high frequency signal fed to the attenuator, correction values for compensating for the frequency-dependent junction loss of the electronic high frequency switch are stored, characterized in that in the correction device, different frequency response correction values are stored for the different gate voltage values of the high frequency switches and that the changeover device for the gate voltage is coupled to this correction device such that, depending on the selected size of the gate voltage, the respective associated frequency response correction values for controlling the attenuation member connected on the line side are used.

The invention relates to an electronic high frequency switch with a field-effect transistor as switching element according to the preamble of the main claim. Electronic high frequency switches of this type having, for example, gallium arsenide field effect transistors as switching elements have now become indispensable in modern measuring equipment. They are used both as individual on-off switches or changeover switches or used combined together, for example, in attenuators. Ideally, high frequency switches of this type should be highly linear in order to generate the least possible intermodulation products. It is only by this means that, for example, signal generators having downstream attenuators can be manufactured with good ACLR values. A precondition for a high degree of linearity, however, is that the gate DC voltage used for switching the transistor has a relatively high value. However, the larger the gate switching voltage is, the slower the switching process of the high frequency switch becomes. An electronic attenuator with field effect transistors is disclosed, for example, by DE 100 63 999 A1. It is an object of the invention to provide an electronic high frequency switch and an attenuator with said high frequency switches whose properties with regard to linearity and switching speed can be optimally selected by the user for the respective application in question. This aim is achieved on the basis of an electronic high frequency switch according to the preamble of claim 1 by means of its characterising features. The aim is fulfilled with respect to the attenuator by the features of claim 3. Advantageous further developments, with regard particularly to its application in an attenuator, are given in the subclaims. The high frequency switch according to the invention can be operated by the user at any time with the respective desired optimum properties with regard to linearity and switching speed. With a simple additional changeover switching device, the size of the gate DC voltage for the field effect transistor may be chosen by the user such that the high frequency switch has either a high level of linearity or a high switching speed. High linearity is achieved for a particular GaAs field effect transistor type with, for example, a relatively high gate DC voltage of −8V. If the gate DC voltage is reduced, for example, to −5.5V, the switching time may be accelerated by a factor of at least ten, although the linearity is thereby worsened. By means of the changeover and by changing the gate switching voltage, apart from the linearity and the switching speed, other high frequency properties of the switch are also altered, even if not so drastically as the linearity and the switching speed. It may therefore be advantageous to compensate for these changes in other high frequency properties of the switch that are caused by changing the gate switching voltage, such as transmission or reflection, through corresponding correction values, and this is the subject matter of the subclaims. Changes in transmission, for example, junction loss in an attenuator can be compensated for depending on the frequency, either through suitable intervention in the circuit itself or by suitably influencing the software controlling the switch, changes to the level of reflection through suitable intervention in the circuit, for example, by connecting in additional components such as capacitors or the like synchronously with the switching over of the gate switching voltage. With an attenuator wherein attenuation members are switched on or off in series or bridged by means of a plurality of electronic high frequency switches, it may be advantageous similarly to control only a part of the high frequency switches utilised for linearity or switching speed. For the continuous conducting branch of an attenuator it may, for example, be advantageous to select the high frequency switches provided there optimised for linearity (with a relatively high gate switching voltage), whilst the subsidiary branches lying parallel thereto are optimised with regard to switching speed (with a relatively low gate switching voltage). The gate switching voltage can also be switchable, depending upon the application, between three or more finely stepped values. A continuous change between a maximum and a minimum gate voltage value is also conceivable. The invention will now be described in greater detail using exemplary embodiments illustrated in schematic drawings, in which: FIG. 1 shows the principle of the circuit of an HF switch according to the invention, FIG. 2 shows its use in an attenuator, and FIG. 3 shows the frequency response of the junction loss of this attenuator. FIG. 1 shows an electronic high frequency switch with a field effect transistor T, which, for example, is designed using GaAs technology and whose source-drain path is connected as a switching element between a high frequency source G and a consumer L. The transistor T is switched on and off via its gate voltage U. Depending on the transistor type, for example, with a gate voltage of 0V (in practice usually −0.6V), the transistor is conductive and therefore connects the signal from the high frequency source G to the consumer L. By applying a negative gate voltage U of, for example, −8V to the gate of the transistor, it is blocked and the source G is therefore disconnected from the consumer. According to the invention, the size of the gate switching voltage U may be selected with a changeover switch S and, in the exemplary embodiment shown here, for the transistor type used by way of example, between two separate voltage sources U1 and U2. One switchable voltage source U1, controlled via the switching control A, supplies either 0V for the “On” condition or −8V for the “Off” condition, whereas the second switchable voltage source U2 supplies either 0V for the “On” condition or −5.5V for the “Off” condition. The user of a measuring device into which this high frequency switching transistor T is installed can therefore choose with the changeover switch S whether, for the current measuring procedure, a high degree of linearity (large gate voltage of, for example, −8V) or a high switching speed (small gate voltage of, for example, −5.5V) is required for the high frequency switch. FIG. 2 illustrates the use of an electronic high frequency switch of this type in an attenuator E in which a plurality of high frequency switches of this type are used for parallel and/or series switching of attenuation members between the input and the output of the attenuator. Attenuators of this type are known per se. The gate voltage for the individual switching transistors T is either derived from a common control voltage source U3 or separate gate voltage sources are provided in the attenuator for the individual switching transistors, as is schematically indicated in FIG. 2 with the voltage sources U4. In both cases, these gate voltage sources are switchable, as in FIG. 1, between at least two different values, so that either optimum linearity or optimum switching speed may be selected. The size of the gate switching voltage influences not only the linearity and the switching speed, but also other high frequency properties of the switch, such as the transmission or reflection. According to a further development of the invention, it has therefore proved to be advantageous to couple the changeover device S for the gate voltage to a corresponding correction device K in which correction values for compensating for these other high frequency properties of the high frequency switch are stored and which, depending on the switching position of the changeover device S, are read from the correction device K and used for additional correction of the high frequency switch. With attenuators, it is known, for correction of the frequency-dependent junction loss generated across the high frequency switches that are used, to connect an additional switchable attenuation member D before the actual attenuator, said attenuation member being controllable via a correction device K dependent upon the frequency f set on the generator G. The junction loss generated in the attenuator E by the high frequency switch has, for example, the shape shown in FIG. 3, i.e. as the frequency increases, the junction loss becomes greater. Therefore with the known device, as the frequency increases, the attenuation member D is switched back to smaller values, so that at the output of the attenuator this frequency response is compensated for accordingly. The associated correction values are stored in the correction device K. The attenuation member D could also be an electronically continuously variable attenuation member which itself is part of a regulation loop. The correction value could then be overlaid on the reference voltage. According to the further development of the invention, the changeover device S for the switchable gate switching voltage U3 or U4 is additionally linked to this correction device K and in the correction device K, for each selectable gate switching voltage, corresponding different correction values are stored in frequency-dependent manner so that, for example, on selection of the gate switching voltage as −8V, a flatter response curve is stored as the correction value than for −5.5V, as shown in FIG. 3. In comparable manner, by suitable intervention in the circuit of the high frequency switch or the attenuator, the transmission or reflection properties of the switch may be corrected depending on the respective gate switching voltage selected. In place of an adjustable attenuation member, an adjustable amplifier could also be used for transmission correction. The invention is not restricted to the exemplary embodiment shown. All the features described may be combined with each other as desired.

20060612

20090210

20070419

89718.0

H01P122

POOS, JOHN W

ELECTRONIC HIGH-FREQUENCY SWITCH AND ATTENUATOR WITH SAID HIGH-FREQUENCY SWITCHES

UNDISCOUNTED

ACCEPTED

H01P

ACCEPTED

Task execution system

A task execution system including at least two processors has a task management table registered with an associated relationship between at least a task, a main execution processor for executing the task and an in-charge-of-stoppage processor for executing the task when the main execution processor stops, means for selecting an executable task from among tasks registered in the task management table, means for checking, if a processor other than the processor trying to execute the selected task is registered as the main execution processor for the selected task, a stoppage state of the processor registered as the main execution processor, and means for executing the selected task if the processor registered as the main execution processor remains stopped.

1. A task execution system including at least two processors, comprising: a task management table registered with an associated relationship between at least a task, a main execution processor for executing the task and an in-charge-of-stoppage processor for executing the task when said main execution processor stops; a selecting unit selecting an executable task from among tasks registered in said task management table; a checking unit checking, if a processor other than said processor trying to execute the selected task is registered as said main execution processor for the selected task, a stoppage state of said processor registered as said main execution processor; and an executing unit executing the selected task if said processor registered as said main execution processor remains stopped. 2. A task execution system including at least two processors, comprising: a judging unit judging whether or not a task requested to be registered can be registered as a task of a main execution processor; a judging unit judging whether or not the task requested to be registered can be registered as a task of an in-charge-of-stoppage processor; a registering unit registering, if judged to be registerable as the task of said main execution processor and if judged to be registerable as a task of said in-charge-of-stoppage processor, an associated relationship between the task requested to be registered, said main execution processor and said in-charge-of-stoppage processor; a selecting unit selecting an executable task from among the registered tasks; a checking unit checking, if a processor other than said processor trying to execute the selected task is registered as said main execution processor for the selected task, a stoppage state of said processor registered as said main execution processor; and an executing unit executing the selected task if said processor registered as said main execution processor remains stopped. 3. A task execution method in a task execution system including at least two processors, comprising: selecting an executable task from among tasks registered in a task management table registered with an associated relationship between at least a task, a main execution processor for executing the task and an in-charge-of-stoppage processor for executing the task when said main execution processor stops; checking, if a processor other than said processor trying to execute the selected task is registered as said main execution processor for the selected task, a stoppage state of said processor registered as said main execution processor; and executing the selected task if said processor registered as said main execution processor remains stopped. 4. A program for making an information processing device including at least two processors, function as: a task management table registered with an associated relationship between at least a task, a main execution processor for executing the task and an in-charge-of-stoppage processor for executing the task when said main execution processor stops; a selecting unit selecting an executable task from among tasks registered in said task management table; a checking unit checking, if a processor other than said processor trying to execute the selected task is registered as said main execution processor for the selected task, a stoppage state of said processor registered as said main execution processor; and an executing unit executing the selected task if said processor registered as said main execution processor remains stopped.

TECHNICAL FIELD The present invention relates to a task execution system including at least two pieces of processors. BACKGROUND ARTS There has hitherto been known a system having a function of changing a task to be processed (refer to, e.g., Patent document 1). In a multiprocessor system, however, if a certain processor falls into stoppage due to a fault, etc., it is impossible to assure an operation of the task processed so far by this processor, resulting in a problem that the operation of the whole system cannot be assured. Note that in a system for actualizing a function in such a way that a plurality of tasks cooperate with each other through task-to-task communications, a task processing system (see, e.g., Patent document 2) capable of easily dealing with a change, etc. of a-massage between the tasks, which is caused by addition/deletion, etc. of the task, is given as what is related to the present invention. (Patent document 1) Japanese Patent Laid-Open Publication No.11-203149 (Patent document 2) Japanese Patent Laid-Open Publication No.6-95896 DISCLOSURE OF THE INVENTION It is an object of the present invention to assure, even if a certain processor stops due to a fault, etc. in a multiprocessor system, an operation of a task processed so far by this processor and also assure an operation of the whole system. The present invention, which was devised to accomplish the above object, is a task execution system including at least two processors, comprising a task management table registered with an associated relationship between at least a task, a main execution processor for executing the task and an in-charge-of-stoppage processor for executing the task when the main execution processor stops, means for selecting an executable task from among tasks registered in the task management table, means for checking, if a processor other than the processor trying to execute the selected task is registered as the main execution processor for the selected task, a stoppage state of the processor registered as the main execution processor, and means for executing the selected task if the processor registered as the main execution processor remains stopped. According to the present invention, the task that is to be invariably executed by a certain processor (the main execution processor) is assigned beforehand to other processor (the in-charge-of-stoppage processor), and there is made a task accepting judgment of the task (including the task assigned). Then, the task is executed by the pre-assigned processor when the above processor falls into the stoppage, thereby making it possible to actualize assurance of the operation of the task assigned and to assure the operation necessary for the system. As a result, there can be improved possibility of assuring the operation of the system even when the system is partially stopped. Further, the present invention can be specified as follows. A task execution system including at least two processors, comprises means for judging whether or not a task requested to be registered can be registered as a task of a main execution processor, means for judging whether or not the task requested to be registered can be registered as a task of an in-charge-of-stoppage processor, means for registering, if judged to be registerable as the task of the main execution processor and if judged to be registerable as a task of the in-charge-of-stoppage processor, an associated relationship between the task requested to be registered, the main execution processor and the in-charge-of-stoppage processor, means for selecting an executable task from among the registered tasks, means for checking, if a processor other than the processor trying to execute the selected task is registered as the main execution processor for the selected task, a stoppage state of the processor registered as the main execution processor, and means for executing the selected task if the processor registered as the main execution processor remains stopped. Moreover, the present invention can be specified by way of the invention of a method as below. A task execution method in a task execution system including at least two processors, comprises selecting an executable task from among tasks registered in a task management table registered with an associated relationship between at least a task, a main execution processor for executing the task and an in-charge-of-stoppage processor for executing the task when the main execution processor stops, checking, if a processor other than the processor trying to execute the selected task is registered as the main execution processor for the selected task, a stoppage state of the processor registered as the main execution processor, and executing the selected task if the processor registered as the main execution processor remains stopped. Still further, the present invention can be specified by way of the invention of a program as follows. A program makes an information processing device including at least two processors, function as a task management table registered with an associated relationship between at least a task, a main execution processor for executing the task and an in-charge-of-stoppage processor for executing the task when the main execution processor stops, means for selecting an executable task from among tasks registered in the task management table, means for checking, if a processor other than the processor trying to execute the selected task is registered as the main execution processor for the selected task, a stoppage state of the processor registered as the main execution processor, and means for executing the selected task if the processor registered as the main execution processor remains stopped. Yet further, the present invention can be also specified as a storage medium stored with the above program, which can be read by an information processing device (computer). BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows an outline of an architecture of a task execution system by way of an embodiment of the present invention; FIG. 2 is a flowchart for explaining an operation of the task execution system in the embodiment of the present invention; and FIG. 3 is a flowchart for explaining the operation of the task execution system in the embodiment of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION A task management system will hereinafter be described with reference to the drawings by way of one embodiment of the present invention. (Outline of Architecture of Present System) FIG. 1 is a diagram for explaining an outline of an architecture of a task execution system. (System Environment) The task execution system in the present embodiment is actualized by a general type of information processing device 100 such as a PDA (Personal Digital Assistant), a personal computer and so on. As shown in FIG. 1, the information processing device 100 includes two pieces of processors 110, 120 (of which one processor will hereinafter be referred to as a main execution processor 110 , and the other processor will be termed an in-charge-of-stoppage processor 120 for the explanatory convenience's sake), a storage device 130 such as a hard disk device, etc., a memory 140 and so forth. Further, the information processing device 100 includes, in some cases, an input device (for example, a key set) for inputting various pieces of information and commands, an image display device (e.g., a liquid crystal display) for displaying a result of processing thereof, a voice output device (for instance, a loudspeaker), etc. (none of these devices are illustrated) Note that the two processors 110, 120 are exemplified for the explanatory convenience's sake, however, the present invention is not limited the two processors. For example, the present invention can be similarly applied even when three or more pieces of processors are provided. (Task and Operating System) A task 141, which is generally called a process or a thread, is a generic name of an execution unit of a program. The task 141 may be generated when in a task registration and may also be previously generated (pooled) as done in the preceding application by the present applicant. The task 141 is, for example, a QoS (Quality of Service) task defined as a variable task capable of controlling a required quantity of resources. The operating system (OS) 142 is, for instance, a real time OS having a function (as a scheduler) of scheduling the respective tasks 141 by a DM (Deadline Monotonic) method. Among the executable tasks 141 (corresponding to execution target tasks according to the present invention) at each scheduling timing, the task 141 exhibiting the shortest period of deadline time is set as an active task. Each of the tasks 141 is managed based on a task management table 143. The task management table 143 is illustrated in the lowest part in FIG. 1. The task management table 143 is a table for managing pieces of information about the respective tasks, and is registered with pieces of the information about the tasks 141, such as a task ID 143a, a main execution processor ID 143b, an in-charge-of-stoppage processor ID 143c, a task execution parameter 143d, and so on. The task ID 143a serves to identify each task 141. The main execution processor ID 143b and the in-charge-of-stoppage processor ID 143c serve to identify the respective processors Start timing, execution alignment time, deadline time, etc. are given as the task execution parameter 143d. The start timing is a period of time (period) till next execution start timing since execution start timing of each task 141. When a certain task 141 is executed, it does not happen that this task 141 is executed afresh during this period. The execution assignment time is defined as a resource quantity (which is, for instance, a period of usage time of each processor) assigned to each of the tasks 141. It is to be noted that the resource is not necessarily assigned continuously for a period of assignment time throughout to the task 141 that has been once assigned the resource. A time assignment may be effected separately any number of times. Further, if preempted by a different task 141 having a higher priority than a certain task 141, processing of this task 141 is interrupted. If the alignment time elapses within a certain period of time, nothing affects the system. This period of time is the deadline time. In the present embodiment, the task 141 exhibiting a short period of deadline time is given a higher priority than that of the task 141 showing a long period of deadline time. The task 141 having the short deadline time (i.e., the task 141 given the high priority) is set as an active task. Predetermined programs such as API (Application Program Interface), etc. for providing the schedule function described above and other various functions that will be described later on, are read by the aforementioned information processing device 100 and installed into the operating system 142, thereby actualizing these functions. Note that the operating system 142 and the predetermined programs, etc. are pre-installed into the storage device 120 or the like, and are properly read into the memory 140 and executed as the necessity arises (see FIG. 1). (Operation at Task Registration) Next, an operation of the task management system having the architecture described above will be explained with reference to the drawings. To start with, processes when registering the task will be described. FIG. 2 is an explanatory flowchart of the processes when registering the task. The operating system 142, etc., is read and executed by the information processing device 100, thereby actualizing the following processes. When a task registration request is given from the operating system 142, a predetermined application, etc. (S100), it is judged whether or not the task 141 requested to be registered (which will hereinafter be also called a registration target task) can be registered as a task of the main execution processor 110 (which is identified, if the registration request in S100 contains the main execution processor ID, by this main execution processor ID) (S101) This is, in the case of registering, for example, the registration target task 141 as a task of the main execution processor 110, the judgment as to whether or not the execution can be done while keeping QoS in a way that includes this s registration target task 141, wherein it is judged whether predetermined conditions are met or not. As a result, if the registration target task 141 i s judged not to be the task of the main execution processor 110 (S101: No), this registration target task 141 is not registered, and registration unpermitted notification is given (S102). While on the other hand, if judged to be registerable as the task of the main execution processor 110 (S101: Yes), it is further judged whether or not the task registration request (S100) is for only the main execution processor (S103). This can be, it is considered, judged by knowing whether or not, for example, the task registration request (S100) contains only the main execution processor ID (i.e., whether this request contains also the in-charge-of-stoppage processor ID or not). As a result, if not judged to contain only the main execution processor ID (for example, if judged to contain also the in-charge-of-stoppage processor ID) (S103: No), it is further judged whether or not this registration target task 141 can be registered as a task of the in-charge-of-stoppage processor (S104). This is, for instance, if this registration target task 141 is registered as the task of the in-charge-of-stoppage processor 120 (which is identified, for example, when the registration request in S100 contains the in-charge-of-stoppage processor ID, by this in-charge-of-stoppage processor ID), a judgment as to whether or not the execution can be done while keeping QoS in a way that includes this registration target task 141, wherein it is judged whether the predetermined conditions are met or not. As a result, if not judged to be registerable as the task of the in-charge-of-stoppage processor 120 (S104: No) this registration target task 141 is not registered, and the registration unpermitted notification is given (S102). While on the other hand, if judged to be registerable as the task of the in-charge-of-stoppage processor 120 (S104: Yes), the registration target task 141 is registered in the task management tables of the main execution processor 110 and of the in-charge-of-stoppage processor 120 (S105). Namely, each task management table 143 is registered with the task ID 143a of the registration target task 141, the main processor ID 143b, the in-charge-of-stoppage processor ID 143c and the task execution parameter 143d. While on the other hand, as a result of the judgment in S103, when judging that the registration request is for only the main execution processor (for instance, if judged not to contain the in-charge-of-stoppage processor ID) (S103: Yes) this registration target task 141 is registered in the task management table 143 of the main execution processor (S106) Namely, the task management table 143 of the main execution processor is registered with the task ID 143a of the task 141 requested to be registered, the main processor ID 143b, and the task execution parameter 143d. As discussed above, when registering the task, there are assigned the processor ID (the main execution processor ID) of the processor that mainly executes the task and the processor ID (the in-charge-of-stoppage processor ID) of the processor that executes the task in case of stoppage of the processor that mainly executes the task. Then, when the task registration request is given (S100), at first, the system making an acceptance judgment executes an acceptance process (S101 , S103, S104), and, if executable, the task requested is registered (S105, S106). (Operation at Task Switchover) Next, processes when switching over the task will be explained. FIG. 3 is an explanatory flowchart showing the processes when switching over the task. The operating system 142 (such as the scheduler), etc. is read and executed by the information processing device 100, thereby actualizing-the following processes. When the scheduler is executed (S200), an executable task is selected from among the registered tasks of the self-processor (S201). For instance, when switchover timing based on the task scheduling is reached, a task exhibiting a shorter period of deadline time is selected from among the tasks 141 registered in the task management table 143 of the self-processor. Note that if none of the executable tasks exist (S202: No), the task switchover process is not executed but is terminated. Whereas if the executable task exists (S202: Yes), it is judged whether or not the self-processor is set as the main execution processor for the task (which will hereinafter be also called a selected task) selected in S201 (S203). The task management table 143 of the self-processor is referred to for making this judgment. The task management table 143 is registered with an associated relationship between the task ID 143a and the main execution processor ID 143b (see FIG. 1). It is therefore possible by referring to this task management table 143 to judge whether or not the self-processor is set as the main execution processor for the selected task. As a result, if the self-processor is judged to be set as the main execution processor for the selected task (S203: Yes), the selected task is set as an execution task (S204) Namely, the selected task is executed. While on the other hand, if the self-processor is not judged to be set as the main execution processor for the selected task (for instance, if a processor other than the self-processor is set as the main execution processor) (S203: No), it is further judged whether or not the processor set as the main execution processor for the selected task is stopped (i.e., a stoppage state of the processor set as the main execution processor is checked) and whether or not the self-processor is set as the in-charge-of-stoppage processor for the selected task (S205). The task management table 143 of the self-processor is referred to for making the latter judgment. The task management table 143 is registered with an associated relationship between the task ID 143a and the in-charge-of-stoppage processor ID 143c (see FIG. 1). It is therefore feasible by referring to this task management table 143 to judge whether or not the self-processor is set as the in-charge-of-stoppage processor for the selected task. Incidentally, it is considered as a method for the latter judgment to check the stoppage state by directly querying, about an operation state, the processor set as the main execution processor for the selected task. As a result, when judging that the processor set as the main execution processor for the selected task remains stopped (such as a case of falling into becoming inoperable due to a fault, etc.), and when the self-processor is set as the in-charge-of-stoppage processor for the selected task (S205: Yes) the selected task is set as the execution task (S204). Namely, the selected task is executed. On the other hand, as a result of the judgment in S205, if it is not judged that the processor set as the main execution processor for the selected task remains stopped, or if the self-processor is not set as the in-charge-of-stoppage processor (S205: No), the operation returns to S201, wherein the processes from S201 onward are re-executed. As discussed above, when each of the processors 110 and 120 executes the task, the task is executed based on the management information of the registered tasks. On this occasion, however, if it proves from reading the processor ID that a processor other than the self-processor is set as the main execution processor (S203: No), a stoppage condition of that processor is checked (S205). If stopped (S205: Yes), the task thereof is executed (S204). Thus, the stoppage condition of the processor is checked at the operation timing of each task (S205), and hence it follows that surrogation of executing the task is promptly conducted. Further, the task that is to be invariably executed by the main execution processor 110 is assigned beforehand to the in-charge-of-stoppage processor 120, whereby the task can be executed by the pre-assigned processor 120 when the processor 120 falls into the stoppage. Accordingly, it is possible to improve the possibility of assuring the operation of the system even when the system is partially stopped. The present invention can be embodied in a variety of forms without deviating from the sprit or the principal features thereof. Hence, the embodiment discussed above is nothing but a mere exemplification in every aspect. The present invention should not be limitedly construed by description of the embodiment. INDUSTRIAL APPLICABILITY According to the present invention, the task that is to be invariably executed by a certain processor (the main execution processor) is assigned beforehand to other processor (the in-charge-of-stoppage processor). The task is executed by the pre-assigned processor when the above processor falls into the stoppage, thereby enabling the improvement of the possibility of assuring the operation of the system even when the system is partially stopped (when the main execution processor stops).

<SOH> BACKGROUND ARTS <EOH>There has hitherto been known a system having a function of changing a task to be processed (refer to, e.g., Patent document 1). In a multiprocessor system, however, if a certain processor falls into stoppage due to a fault, etc., it is impossible to assure an operation of the task processed so far by this processor, resulting in a problem that the operation of the whole system cannot be assured. Note that in a system for actualizing a function in such a way that a plurality of tasks cooperate with each other through task-to-task communications, a task processing system (see, e.g., Patent document 2) capable of easily dealing with a change, etc. of a-massage between the tasks, which is caused by addition/deletion, etc. of the task, is given as what is related to the present invention. (Patent document 1) Japanese Patent Laid-Open Publication No.11-203149 (Patent document 2) Japanese Patent Laid-Open Publication No.6-95896

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows an outline of an architecture of a task execution system by way of an embodiment of the present invention; FIG. 2 is a flowchart for explaining an operation of the task execution system in the embodiment of the present invention; and FIG. 3 is a flowchart for explaining the operation of the task execution system in the embodiment of the present invention. detailed-description description="Detailed Description" end="lead"?

20060619

20110301

20070809

93546.0

G06F946

TO, JENNIFER N

SYSTEM AND METHOD FOR EXECUTING SELECTED TASK BASED ON TASK MANAGEMENT TABLE HAVING AT LEAST ONE TASK AND AT LEAST TWO ASSOCIATED PROCESSORS

UNDISCOUNTED

ACCEPTED

G06F

ACCEPTED

Film for packing liquids or the like and method for manufacturing such a film

Film for packaging liquid products or the like, which mainly consists of a first polyolefin layer, a jointing layer and a layer of polychlorotrifluoroethylene (PCTFE), wherein the PCTFE Layer has a thickness of at least 10 micrometer (μm) and whereby the film is obtained by means of extrusion lamination.

1. Film for packaging liquid products, comprising a first polyolefin layer, a jointing layer and a layer of polychlorotrifluoroethylene (PCTFE), wherein the PCTFE layer has a thickness of at least 10 micrometer (μm) and the film being extrusion laminated. 2. Film according to claim 1, wherein the polyolefin layer and the jointing layer are co-extrusion laminated with the PCTFE layer. 3. Film according to claim 1, wherein the PCTFE layer is made of a homopolymer PCTFE. 4. Film according to claim 1, wherein the PCTFE layer has a thickness of at least 20 μm. 5. Film according to claim 1, wherein the joining layer is formed of a co-polymer of a polyolefin and glycidyl methacrylate. 6. Film according to claim 5, wherein the jointing layer is formed of a co-polymer of ethylene and glycidyl methacrylate (EGMA). 7. Method for manufacturing a film according to claim 1, comprising extruding a jointing layer; compressing between a first roller and a second roller the jointing layer and the foil of PCTFE, together with a polyolefin layer so that the PCTFE foil is thus laminated to the jointing layer. 8. Method according to claim 7, wherein the jointing layer, together with a layer of polyolefin, is extruded onto said first roller in order to form a two-layered roil. 9. Method according to claim 7, including extruding the jointing layer between the rollers, and guiding a polyolefin foil over the first roller and guiding a PCTFE foil over the second roller. 10. Method according to claim 7, including providing at least the first roller with a heat regulation. 11. Method according to claim 7, including coating the second roller with rubber. 12. Method according to claim 7, including providing the second roller with a heat regulator.

The present invention concerns a film for packaging liquid products or the like, in particular for packaging pharmaceutical and/or cosmetic products in a liquid, semi-liquid, dissolved, gelatinous, emulsified state or the like. In the pharmaceutical sector as well as in the cosmetics industry, the demands for the material out of which the packaging is made are very high as far as transparency is concerned, chemical and biochemical reactivity, absorption power, permeability, etcetera. These demands are all the higher when a packaging is concerned in which liquids or the like are stored which may contain a large variety of components, such as for example polar components, non-polar components, ions, salts, oils, surface-active components, anti-microbial components, macromolecules and the like. Although, in the above-mentioned sectors, synthetic packagings are already applied for storing solid materials, these packagings do not meet the demands for storing liquid products, due to too much permeability, too much reactivity, too much absorption power or the like. Up to now, the pharmaceutical industry uses mainly glass packagings, as glass is a suitable recipient for storing such products, but a glass packaging also has major shortcomings. Thus, for example, glass ampoules are known in which a dose of a medicine or the like to be injected is stored, whereby the tip of the ampoule can be broken off before use at a narrowing in the neck of the ampoule. These known glass ampoules are disadvantageous in that they are fragile and have to be packaged with care; moreover, breaking off the tip of the ampoule is not simple, and users can hurt themselves on the glass. It should be noted that when breaking off the tip of the ampoule, minuscule glass particles may end up in the content of the ampoule, which is at least undesirable. Another disadvantage of glass ampoules and of glass packagings in general is that they cannot be deformed, as a result of which they are difficult to stack or cannot be stacked at all without losing space. Another disadvantage of glass packagings not being deformable is that, in many cases, a remainder of liquid will stick on the inside of the glass, as a result of which, when administering a precisely determined dose, a small deviation may occur. Another disadvantage of the non-deformable character of glass packagings is that it is difficult to let a product flow out of a glass packaging at a constant flow rate, requiring for example extra pump systems for pharmaceutical products which have to be administered at a continuous flow rate. Further, glass cartridges are known which are applied for storing injectable products. These cartridges are hermetically sealed by means of a rubber cap which is fixed to the glass by means of a lid made of, for example, aluminium. The dose to be injected is hereby administered by means of a piston provided in the cartridge, whereby the content of the cartridge is guided through a small tube provided with a layer of silicone on the inside. Although these cartridges make it possible to administer a well-dosed amount of medicine or the like, its construction is complex and its production is relatively expensive, especially when the different parts of the cartridge have to be sterilized. Moreover, the silicone which is applied in the above-mentioned tube is non-desirable, as silicone may influence the composition of a medicine or the like stored in the cartridge, with possible pernicious consequences for the patient whom the medicine is being administered to. In order to remedy several of the above-mentioned disadvantages, films are already known which can be used for packaging pharmaceutical or cosmetic products in a liquid state or the like, but these different known films all have specific major disadvantages. Thus, films made of PVC (polyvinylchloride) are already known whereby components which are hardly or not soluble in water, absorb what are called non-polar components out of the stored product in the PVC, as a result of which the concentration of these non-polar components in the stored product decreases in time, and the products may thus lose their effective character. Other known films, made for example of PE (polyethylene), PP (polypropene), poly-1-butene (PB) or the like, are in turn permeable to certain oils, such as for example paraffin oil, so that, when such a packaging is used for such oils, the packaging will feel greasy for example after a few days, and which results in an unacceptable loss of oil; also certain surface-active components, such as dodecane, migrate particularly fast through PE films or the like. Also other known films, such as films made of acrylonitrile-methylacrylate co-polymer cannot be used for storing products with a wide range of components, as such films appear to be non-resistive to the large reactivity of for example peroxide derivatives, which are applied in cosmetics because of their bleaching properties, and as such films are not sufficiently impermeable to moisture. Finally, there are also multilayered films. Thus, films are known with an inner layer made of acrylonitrile-methylacrylate (A/MA/B), followed by a jointing layer, with which is bonded a layer of a co-polymer from PCTFE (polychlorotrifluoroethylene). A disadvantage of these known films is that the A/MA/B discolours during the sterilization by means of radiation, as a result of which the content of a packaging on the basis of such a film will not be clearly visible when it is finally used, so that a possible precipitation of for example macromolecules cannot be visually detected when administering the stored product. In another known PCTFE film, the inner layer consists of ethylene acrylic acid (EAA), whereby the EAA is disadvantageous in that it is reactive in relation to certain polar and aliphatic components, which components consequently cannot be stored in such a film without their composition being altered after a while. In another PCTFE film, a film which is 7.5 μm (micrometer) thick made of PCTFE copolymer is used which is limited by a jointing layer on the inner side of the packaging, onto which is provided a PE layer. The disadvantage of this known film is that tests have proven that the PCTFE layer of a PCTFE copolymer lets more water vapour through than a film made of homopolymer PCTFE. Moreover, a PCTFE polymer layer with a thickness of 7.5 μm lets water vapour through relatively quickly, so that the concentration of certain components of the products which are stored in this packaging may increase as the water evaporates through the packaging. By the word homopolymer is hereby meant a polymer which is built up of a chain of identical molecules, in this case chlorotrifluoroehtylene, whereby all the molecules, to the exception of the terminal ones, are covalently connected in an identical manner. The present invention aims a packaging which offers a solution to the above-mentioned and other disadvantages. To this end, the invention concerns a packaging for liquid products or the like, which mainly consists of a first polyolefin layer, a jointing layer and a layer of polychlorotrifluoroethylene (PCTFE), whereby the PCTFE layer has a thickness of at least 10 micrometer (μm) and whereby the film is obtained by means of extrusion lamination or co-extrusion lamination. By the term polyolefin are hereby understood polymers which are mainly built up of carbon atoms and hydrogen atoms, such as for example polyethylene, polypropylene, 1-butene, 4-methyl pentane, etc. The PCTFE layer is preferably made of homopolymer PCTFE. The layer of homopolymer PCTFE preferably also has a thickness of at least 50 μm. An advantage of this film is that, partly thanks to the thickness of the PCTFE layer and the fact that homopolymer PCTFE is being applied, it is relatively impermeable to products in a liquid state or the like, as well as to gaseous products. Another advantage is that the film according to the invention is transparent and does not discolour under the influence of ionizing radiation, which is typically used to sterilize among others packaging materials, which has as a plus that the film, after sterilization by means of radiation, stays optimally transparent, so that the quality of products packaged in the film can always be visually checked. Preferably, the jointing layer also consists of a co-polymer made of a polyolefin and glycidyl methacrylate, such as for example ethylene glycidyl methacrylate co-polymer (EGMA), which offers the advantage that this jointing layer is practically not affected by migrating components of the packaged product, so that the compound of the film layers is not broken. An advantage of the thus obtained film composition is that the used materials, in the sate in which they are in in the film, are chemically practically inert and absorb relatively little or no components at all. An advantage linked to this is that, thanks to the inertness of the packaging film according to the invention and the good sealing which can be obtained with this film, the composition of the packaged products will change only little in time, as a result of which the packaged products will have a longer shelf life. Apart from a film for packaging liquid products or the like, the present invention also aims a method which makes it possible to manufacture such a film. Up to now, no method was known for manufacturing a PCTFE film with a relatively large thickness, as described above. To this end, the invention concerns a method which can be applied for manufacturing a film according to any of the preceding claims, whereby the jointing layer is extruded, characterised in that the jointing layer and the above-mentioned foil of PCTFE, together with a polyolefin layer, are compressed between a first roller and a second roller, whereby the PCTFE foil is thus laminated to the jointing layer. An advantage of this method according to the invention is that, by bonding the jointing layer with the PCTFE foil by means of lamination, any thickness whatsoever of PCTFE foil can be used. Another advantage which is linked to the application of an extrusion lamination is that, when manufacturing the film, the difference in viscosity between the jointing layer, PCTFE and possibly the applied polyolefin does not have to be taken into account, as these substances can be extruded at different moments, so that a larger range of polyolefins can be applied, as well as a larger range of substances which can be applied as jointing layer. In order to better explain the characteristics of the invention, the following preferred embodiment of a film according to the invention for packaging liquid products or the like, as well as some preferred embodiments of the methods according to the invention for manufacturing the above-mentioned film are described as an example only without being limitative in any way, with reference to the accompanying drawings, in which: FIG. 1 schematically represents a film according to the invention seen as a section; FIG. 2 represents a method for manufacturing a film according to the invention; FIG. 3 represents a variant of FIG. 2. FIG. 1 represents a film 1 according to the invention for packaging liquid products or the like, which mainly consists of a first layer 2 and a PCTFE layer 3, in between which is provided a jointing layer 4. The first layer 2, in particular the layer which is designed as contact layer for the content of the packaging, consists of a transparent, colourfast and inert synthetic layer, which in this case consists of a polyolefin such as PE, PP and/or PB. The thickness of the first layer 2 may vary between 5 μm and some 1000 μm, with a preferred thickness of some 20 to 50 μm. The PCTFE layer 3 preferably consists of homopolymer PCTFE and has a thickness of at least 10 μm and preferably at least 50 μm. The jointing layer 4 consists, just as the first layer 2, of a transparent and colourfast synthetic material, for example a co-polymer of ethylene and glycidyl methacrylate having a thickness of 3 to 50 μm or, preferably, a thickness of 3 to 10 μm. Such a film 1 is particularly suitable for packaging pharmaceutical or cosmetic products in a liquid state or the like and which may contain a wide range of components, including for example oils, such as paraffin oil; solutions of macromolecules, such as for example proteins, etc. As PE, PP and/or PB are preferably used as a first layer 2, which synthetic materials can for example be welded under the influence of heat, the packaging can be sealed quickly and in a simple manner. Consequently, the film 1 can be applied as a packaging in the shape of for example little bags or in place of glass ampoules for any of the above-mentioned components. Naturally, it is always possible to coat the film 1 on the outside, in particular on the PCTFE layer 3, with other layers, for example a rigid synthetic layer to reinforce the film 1, or with other functional coatings. It is also possible to manufacture symmetric films, whereby a jointing layer 4 and a polyolefin layer 2 are again provided on the outside, on the PCTFE layer 3, thus creating a film 1 which can be used on either side. It is also possible to provide an extra functional layer on the inside of the film 1, in particular on the polyolefin layer 2, such as for example a layer made of terpolymers of PE or the like, which makes it possible to better weld the film 1 onto itself or which provides another weld strength to the film 1. Further, it should be noted that EGMA co-polymer is not the only jointing layer 4 which can be applied; also other substances or combinations of substances can be applied, either or not depending on the purpose for which the film 1 is designed. Other possible jointing layers consist for example of ethylene-methyl acrylate-glycidyl methacrylate terpolymers; ethylene-acrylate co-polymer; terpolymers of ethylene, ester acryl groups and glycidyl methacrylate; and other ones, also including two-layered or multilayered jointing layers. The above-described film 1 can be manufactured in a simple manner by means of a device 5 and a method, which will be described hereafter. The device 5 for manufacturing a film 1 according to the invention is represented in FIG. 2 and mainly consists of an extrusion device 6 and two rollers 7 and 8 placed opposite to each other, whereby a longitudinal passage 9 is provided between the rollers whose width is somewhat smaller than or equal to the thickness of the film 1 to be manufactured. Both rollers 7 and 8 are preferably provided with a heat regulation and a drive, which are not represented in the figures, whereby the second roller 8 is in this case coated with a flexible material, such as rubber. Further, the device 5 also comprises a feed roller 10 onto which is wound a foil 11 of homopolymer PCTFE. The method for manufacturing the film 1 by means of the above-mentioned device is simple and as follows. PE, PP and/or PB are simultaneously extruded with EGMA in the known manner on the first roller 7, whereby a two-layered foil 12 of PE or the like and EGMA co-polymer is formed. The formed two-layered foil 12 is carried off as a result of a rotation of the first roller 7 in the direction of the passage 9 between the two rollers 7 and 8, which rotate in opposite directions. The PCTFE foil 11 is guided from the drive roller 10 over the second roller 8 and pressed against the EGMA co-polymer side of the two-layered foil 12 between the first roller 7 and the second roller 8, whereby the PCTFE foil 11 and the two-layered foil 12 are laminated, such that the film 1 is created, in which the EGMA co-polymer layer forms the above-mentioned jointing layer 4, and whereby the set temperatures of the first roller 7 and of the second roller 8 play a major part in bonding the two-layered foil 12 with the PCTFE foil 11. According to a variant of this method, which is represented in FIG. 3, the EGMA co-polymer is extruded between a polyolefin foil 13 which is partly unwound over the first roller 7 and the PCTFE foil 11 which is guided over the second roller 8. Between both rollers 7-8, the different foils 11, 13 and the EGMA layer are laminated. The invention is by no means limited to the above-described embodiment given as an example and represented in the accompanying drawings; on the contrary, such a film for packaging liquid products or the like according to the invention and a method which can be applied for manufacturing such a film can be made in all sorts of shapes and dimensions and according to different variants while still remaining within the scope of the invention.

20060619

20101123

20070621

70381.0

B32B2730

ZACHARIA, RAMSEY E

FILM FOR PACKING LIQUIDS OR THE LIKE AND METHOD FOR MANUFACTURING SUCH A FILM

UNDISCOUNTED

ACCEPTED

B32B

ACCEPTED

Semiconductor package with integrated heatsink and electromagnetic shield

The invention provides a mounting for a printed circuit board which mounting is suitable for receiving a semiconductor assembly wherein the mounting comprises: a base support having a semiconductor assembly facing surface, and an opposed printed surface board facing surface; a cover having a semiconductor assembly facing surface, an opposed heat radiating surface; a connecting formation which joins the cover to the base support and provides an electrical and thermal communication between the cover and the base support wherein the connecting formation has a semiconductor assembly facing surface, an outer opposed surface and a thickness between the two surfaces; and a plurality of package connectors extending from the base support each of which package connectors have a printed surface board facing surface; an array of mountings; and a semiconductor package comprising a semiconductor assembly having one or more semiconductor chips, which assembly is mounted on the mounting wherein the package connectors of the mounting are in a spaced relationship with the base support and are linked electrically with the semiconductor assembly and the cover is arranged to be in a spaced parallel relationship with the base support.

1. A mounting for a semiconductor assembly comprising: a first portion for mounting a semiconductor assembly; a second portion; and a connecting portion joining the first and second portions and arranged to allow folding of the second portion over the first portion to form a cover, wherein the mounting comprises a sealing material at least partially encapsulating the mounting and the semiconductor assembly such that at least part of a printed circuit board facing surface of the first portion and/or the heat radiating surface of the second portion are left exposed. 2. (canceled) 3. A mounting according to claim 1 wherein the first portion of the mounting comprises a formation of electrical connectors, which have said printed circuit board facing said surfaces, which are not covered by said sealing material. 4. A mounting according to claim 1, wherein the second portion is arranged to be in a spaced parallel relationship with the first portion. 5. A mounting according to claim 1, wherein the second portion further comprises at least one additional edge portion arranged to extend when the mounting is folded beyond at least one edge of the first portion of the mounting. 6. A mounting according to claim 5 wherein the mounting is in the form of an EMI enhanced package wherein the second portion is provided with four additional edge portions to define four walls to protect the semiconductor assembly. 7. A mounting according to claim 1, wherein the mounting is formed from a single sheet of electrically and thermally conducting material which is preferably copper. 8. A mounting according to claim 1, wherein the connecting portion is provided with folding means to enable the folding of the second portion over the first portion, and the folding means is preferably at least one weakened line, such as a scored line or an etched line in the mounting having a thickness that is less than that of the rest of the mounting, and more preferably the folding means includes two weakened lines, one between the first portion and the connecting portion and one between the second portion and the connecting portion. 9. A mounting according to claim 1, wherein the mounting is provided with a third portion and second folding portion arranged to allow folding of the third portion over the second portion to form said cover, preferably such that the third portion is in a spaced parallel relationship with the first portion and second portion. 10. A mounting according to claim 1, wherein the mounting further comprises a means for mounting surface mount technology (SMT) component which is preferably a passive component, for example a resistor, capacitor, and/or inductor. 11. A mounting according to claim 10 wherein the SMT mounting means comprises one or more recesses in the second portion. 12. A mounting according to claim 1, wherein the cover is patterned or formed to function as a passive component which is preferably an antenna, an inductor, an interdigitated and/or parallel plate capacitor, a microstrip coupler and/or a filter. 13. A mounting according to claim 1, wherein the mounting further comprises means adapted for mounting a sensor semiconductor assembly, preferably the sensor mounting means is adapted for mounting an image sensor semiconductor assembly, biometric sensor semiconductor assembly and/or pressure sensor semiconductor assembly. 14. A mounting according to claim 1, wherein the cover is adapted to provide direct access to the semiconductor assembly, preferably such direct access means comprises an aperture in the cover. 15. A mounting according to claim 14 wherein the mounting is further adapted to mount an optical component in relationship to an image sensor semiconductor chip. 16. A mounting according to claim 14 wherein the direct access means is further defined by having one or more recesses about its perimeter, which recesses preferably face towards, or away from, a mounted semiconductor assembly. 17. A mounting according to claim 14, wherein the direct access means and/or the recesses can be used to locate a further component for use in the semiconductor assembly. 18. A mounting according to claim 1, wherein the mounting further comprises one or more recesses formed within the cover into which mould material can flow to secure the cover. 19. A mounting according to claim 1, which further comprises a means to permit coupling of selected frequencies of electromagnetic radiation through the mounting, preferably the frequency coupling means comprises one or more apertures in the cover of appropriate dimension to permit coupling at a selected frequency. 20. A mounting according to claim 1, wherein the formation of electrical connectors is in a spaced relationship with the base support and are linked electrically with the semiconductor assembly. 21.-22. (canceled) 23. A mounting according to claim 1, wherein the mounting further comprises a heat dissipation means to provide a low thermally resistive path between a mounted semiconductor assembly and the cover of the package. 24. A mounting according to claim 1, wherein the mounting is part of an array of a plurality of mountings. 25.-40. (canceled) 41. A mounting for a semiconductor assembly comprising: a first portion for mounting a semiconductor assembly; a second portion; and a connecting portion joining said first portion and said second portion and arranged to allow folding of said second portion over said first portion to form a cover, wherein said cover is patterned or formed to function as a passive component. 42. A mounting for a semiconductor assembly comprising: a first portion for mounting a semiconductor assembly; a second portion; and a connecting portion joining said first and said second portion and arranged to allow folding of said second portion over said first portion to form a cover, wherein said cover is adapted to provide direct access to the semiconductor assembly.

The present invention relates to semiconductor packages, mounting assemblies therefor and methods of manufacture thereof, and more particularly but not solely to, micro mounting packages that have an integrated heatsink and electromagnetic shield. The objective of any electronics package is to protect sensitive integrated circuits from harsh environments without inhibiting electrical performance. The package is used to electrically and mechanically attach a chip to an intended device. One popular family of electronics package is the Micro Leadframe Packaging (MLP) also known as Quad-Flat-No-Lead (QFN) or Dual-Flat-No-Lead (DFN). MLP is based upon a patterned and etched metal mounting commonly with a central pad, onto which a single or multiple semiconductor chips or dies are mounted, connected with wirebonds to isolated package pins, then encapsulated in a plastic sealing material. The sealing material is applied around the metal of the mounting and the integrated circuit with wirebonds to form a hard, protective plastic body. Further information relative to mounting technology may be found in Chapter 8 of the book Micro Electronics Packaging Handbook, (1989), edited by R. Tummala and E. Rymaszewski, incorporated by reference herein. This book is published by Van Nostrand Reinhold, 115 Fifth Avenue, New York, N.Y. Generally, manufacture is completed using an array of multiple MLP mountings. After encapsulation a mounting is separated from any supporting peripheral mounting structures and neighbouring packages by a punch or a saw. It may be stated generally that there is a desire in the electronics packaging industry to reduce size and cost whilst at the same time as integrating more functionality. One proven route to increase functionality is to include several integrated circuits in the same MLP. Modern assembly techniques allow dies to be stacked or flip mounted (i.e. mounted in an inverted orientation) known as “flip-chip” mounting, ensuring a minimal final package size. There are additional problems to be solved in the electronics packaging industry. One such problem is that many types of integrated circuit produce high levels of unwanted thermal energy, even when in normal operation. These circuits still require integration. Thermal design is also important and a method of dissipating heat to maintain electrical and mechanical stability has been sought. Another such problem is that many electronics products need to operate in an electrically noisy environment. A method of protecting a sensitive integrated circuit within the package from unwanted electrical interference has also been sought. A further such problem is that many electronics products require direct electrical connection to the system ground potential to obtain optimum performance. If this connection is electrically impaired (e.g. by resistive or inductive impairment) many integrated circuits particularly operating at intermediate and high frequencies or with high electrical currents may be adversely affected. A method of providing a low resistance, low inductance path to system ground has been sought. SUMMARY OF THE INVENTION The present invention relates to a semiconductor package, a mounting assembly therefor and a method of manufacture, and more particularly but not limited to, a micro mounting package that has an integrated heatsink and electromagnetic shield. According to a first aspect of the invention there is provided a mounting for a semiconductor assembly including a first portion for mounting at least one semiconductor device, a second portion and a connecting portion joining the first and second portions and arranged to allow folding of the second portion over the semiconductor device. The connecting portion may provide thermal and electrical communication between the first and second portions of the mounting. The first portion of the mounting may comprise a formation of leadframe package connectors. The first portion of the mounting may further comprise a base support for at least one semiconductor device. The second portion may comprise a cover having a semiconductor assembly-facing surface and an opposed heat-radiating surface. The electrical connectors of the mounting are in a spaced relationship with the base support and are linked electrically with the semiconductor assembly. The cover is arranged to be in a spaced parallel relationship with the base support. The cover may further comprise at least one additional edge portion arranged to extend when the mounting is folded beyond at least one edge of the first portion of the mounting. Such an edge portion can be folded to form a sidewall. The mounting is preferably formed from a single sheet of electrically and thermally conducting material, which is preferably a metal, more preferably copper. The mounting may be part of an array of a plurality of mountings. The mounting is preferably provided with folding means to enable it to be bent such that the cover can be arranged to be in a spaced parallel relationship to the first portion. The folding means is preferably a weakened line, such as a scored line or an etched line in the mounting having a thickness that is less than that of the rest of the mounting. Preferably the mounting includes two weakened lines, one between the first portion and the connecting portion and one between the second portion and the connecting portion. The cover of the mounting is arranged to be mechanically and electrically connected to the base support and the base support is normally connected to System Ground potential (GND) on the final product printed circuit board. The particularly advantageous feature of the present invention is the cover which provides three functions (a) a simple heatsink (b) a low resistance, low inductive path to electrical Ground (GND) and (c) to act as a local electromagnetic shield protecting sensitive functions within, or without, from unwanted electromagnetic interference. The semiconductor chip may be electrically connected to a portion of the mounting by wirebonding. Alternatively, the chip may be mounted using flip-chip mounting, such as bump soldering. The new mounting package can be used for single or multiple chip applications. Where multiple chips are integrated it is often beneficial to “flip” smaller (daughter) chips onto a larger (mother) die. The new package facilitates connection to a simple heatsink and electromagnetic shield and System Ground (GND). Through modern assembly techniques the present invention reduces cost and area usage on a printed circuit board whilst improving thermal and electrical performance. The semiconductor assembly is preferably attached to the base support and/or the cover. Where the assembly comprises two or more semiconductor chips, it is preferably attached to the base support and the cover. This enables a daughter semiconductor chip to be connected more directly to system ground. The assembly is preferably electrically attached to the base support and/or cover, more preferably by conductive wire or conductive epoxy or solder material. A semiconductor package incorporating the mounting preferably comprises a sealing material at least partially encapsulating the mounting and the semiconductor assembly. This is in order to protect and support the contents of the package. At least part of the printed circuit board facing surfaces of the package connectors and base support or the heat radiating surface of the cover may not be covered by the sealing material, being left exposed to aid the dissipation of heat. The mounting preferably further comprises heat dissipation means to provide a low thermally resistive path between a mounted semiconductor assembly and the cover of the package. The mounting may be provided with a third portion and second folding portion arranged to allow folding of the third portion over the semiconductor device. The third portion is in a spaced parallel relationship with the base support and second portion. The mounting may further comprise means for mounting surface mount technology (SMT) components. Such components may comprise passive components, for example resistors, capacitors, or inductors. Such means may comprise recesses in the mounting cover to mount SMT components. The cover of the mounting may be patterned to function as a passive component. For example, the top cover may be formed as a serpentine inductor. Other passive components can be integrated. The cover may be patterned as an interdigitated or parallel plate capacitor. The cover may also be patterned to integrate other components such as antenna, microstrip couplers and filters. The mounting preferably further comprises an EMI enhanced package wherein the cover is fabricated with additional fold means to enable the cover to be bent to define walls in relationship with the semiconductor assembly. The mounting may further comprise means adapted for mounting sensor semiconductor chips. The cover of the mounting may be adapted to provide direct access to the semiconductor assembly. Such means may comprise an aperture in the package mounting cover. The mounting may be further adapted to mount optical components in relationship to an image sensor semiconductor chips. The aperture may be further defined by having recesses about its perimeter. The recesses may face towards, or away from, a mounted semiconductor device. The aperture and the recesses can be used to locate further components for use in the semiconductor assembly. The mounting may be further adapted to provide for mounting biometric semiconductor chips. The mounting may be further adapted to provide for mounting pressure sensor semiconductor chips. The mounting according to the invention preferably further comprises one or more recesses formed within the cover into which mould material can flow to secure the cover in the package. The mounting according to the invention preferably further comprises means to permit coupling of selected frequencies of electromagnetic radiation through the leadframe. Such means may comprise apertures in the cover of the mounting of appropriate dimension to permit coupling at a selected frequency. In another aspect of the invention there is provided a method of manufacturing a semiconductor assembly comprising the steps of: preparing a mounting for a semiconductor device; mounting a semiconductor chip on the mounting; electrically connecting the semiconductor chip to the mounting; and folding a portion of the mounting over the semiconductor assembly. The step of preparing the mounting may further comprise forming functional features in the mountings. The features may be formed by, for example, cutting, scribing, stamping or etching. The step of preparing a mounting may further comprise forming fold lines into the mountings. The folded portion may be folded through a total of 180°, for example by being folded through 90° along each of two fold lines. The folded portion can then be in a spaced parallel relationship with the portion the semiconductor chip is mounted on. The method may further comprise folding a further portion of the mounting over the semiconductor assembly. The method may further comprise folding additional portions of the mounting to form, for example, sidewalls in the mounting. The functional features may further include heatsinks. Passive components can also be formed in portions of the mounting. The method may further comprise the step of sealing said mounting. Any suitable sealant could be used for this purpose, for example, a dielectric sealant. The method further comprises forming an aperture in a portion of the mounting. Recesses can be defined about the perimeter of the aperture. The recesses may face towards, or away from, a mounted semiconductor device. The method may further include mounting and aligning components for use in the semiconductor assembly. Such further components include optical components, such as lenses or filters. The components may be mounted on the mounting before it is folded such that folding the mounting brings the component into the desired final position in the assembly. The method may further comprise electrically connecting the semiconductor chip to using wirebonding. The semiconductor chip may be flip-chip mounted. The method further comprises mounting further semiconductor chips on the same mounting. The further chips can be mounted using adjacent or stacked wirebond and/or flip-chip mounting. The mounted chips can be connected to a common mounting and/or each other. The mounting may be one of an array of such mountings. The mounting can be separated from the array by, for example, cutting, punching or sawing. In another aspect of the invention there is provided a method of manufacturing a semiconductor mounting wherein individual mountings are patterned on a sheet of conducting material, wherein the individual mountings are defined with a first portion for mounting at least one semiconductor device, a second portion and a connecting portion joining the first and second portions and arranged to allow folding of the second option over the semiconductor device. The mountings may be patterned by casting, etching or stamping. The sheet may be a suitable metal, for example, copper. The individual mountings may be part of an array of such mountings. The method further includes the step of separating individual mountings from the array. The invention is illustrated with reference to the following Figures of the drawings wherein: FIG. 1 shows a side elevation, cross-sectional view of a known MLP-type semiconductor package; FIG. 2 shows a side elevation, cross-sectional view of an MLP-type semiconductor package according to the invention with a formed upper pad; FIG. 3 shows a top plan view of an MLP-type semiconductor package according to the invention; FIG. 4 shows a bottom plan view of an MLP-type semiconductor package according to the invention; FIG. 5 shows a plan view of a known MLP-type semiconductor mounting; FIG. 6 shows a plan view of an MLP-type semiconductor mounting according to the invention, laid flat and showing formed upper pad prior to bend; FIG. 7 shows a plan view of a manufacturing array of mountings according to the present invention; FIG. 8 shows a plan view of a laid flat MLP-type semiconductor mounting according to the present invention wherein the mounting has no package connectors on the edge adjacent the cover to maximise the area of the connecting formation; FIG. 9 shows a plan view of a laid flat MLP-type semiconductor mounting according to the present invention having a cover which is defined with apertures; FIG. 10 shows a plan view of a laid flat MLP-type semiconductor mounting according to the present invention having four package connectors on the side adjacent the cover; FIG. 11 shows a side elevation, cross-sectional view of a second embodiment of a semiconductor package according to the present invention; FIG. 12 shows a side elevation, cross-sectional view of a third embodiment of a semiconductor package constructed in accordance with the principles of the present invention; FIG. 13 shows a side elevation, cross-sectional view of the construction of a single bend point; FIG. 14 shows how a pair of bend points may be used to construct the connecting formation used in the present invention; FIG. 15 shows a side-elevation, cross-sectional view of the second embodiment of the present invention mounted on a printed circuit board. FIG. 16 shows a side elevation, cross-sectional view of a known flip-chip onto leadframe MLP-type package; FIG. 17 shows a top plan view of a mounting used to make the package of FIG. 16; FIG. 18 shows a side elevation, cross-sectional view of a flip-chip onto leadframe MLP-type package according to the invention with a formed upper pad; FIG. 19 shows a top plan view of a mounting used to make the package of FIG. 18; FIG. 20 shows a side elevation, cross-sectional view of a flip-chip onto leadframe MLP-type package according to the invention with a formed upper pad and base pad; FIG. 21 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with heatsink die enhanced feature; FIG. 22 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with stacked die; FIG. 23 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with integrated surface mounted (SMT) passive components; FIG. 24 shows a top plan view of a mounting used to make the package of FIG. 23; FIG. 25 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with enhanced EMI shielding; FIG. 26 shows a top plan view of a mounting used to make the package of FIG. 25; FIG. 27 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an aperture feature; FIG. 28 shows a top plan view of a mounting used to make the package of FIG. 27; FIG. 29 shows a top plan view of a mounting according to the invention used to make an MLP-type package with a circular aperture feature; FIG. 30 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an aperture feature fitted with a lens, made using the mounting of FIG. 29; FIG. 31 shows a top plan view of a mounting according to the invention used to make an MLP-type package with a double pad feature and aperture feature; FIG. 32 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a double pad feature and aperture feature fitted with a lens, made using the mounting of FIG. 31; FIG. 33 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a double pad feature and aperture feature fitted with a lens; FIG. 34 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with exposed die feature; FIG. 35 shows a side elevation, cross-sectional view of a further embodiment of an MLP-type package according to the invention with exposed die feature; FIG. 36 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with exposed die feature and gel-filled cavity; FIG. 37 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an entirely encapsulated, non-exposed cover pad; FIG. 38 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a partially exposed top metal pad; FIG. 39 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a patterned underside of the top metal pad; FIG. 40 shows a side elevation, cross-sectional view of an MLP-type package according to the invention showing a dielectric fill material dispensed over the die surface; and FIG. 41 shows a mounting for making an MLP-type package according to the invention with electromagnetic coupling apertures; FIG. 42 shows a section through an MLP-type package according to the invention; FIG. 43 shows a section through a further MLP-type package according to the invention; FIG. 44 shows a mounting for making an MLP package according to the invention with a cover pad including the definition of a serpentine inductor with a semiconductor chip shown mounted to the base with wirebonds connecting to the perimeter connectors and to the inductor; FIG. 45 shows a mounting for making a package according to the invention with a top cover pad in addition to a defined serpentine inductor; and FIGS. 46 to 48 show the results of modelling packages according to the invention. Before discussing the embodiments of the present invention, the prior art MLP-type semiconductor package is discussed below in order to provide background information regarding the techniques of construction of MLP-type semiconductor packaging. In reference to FIG. 1, there is shown a side-elevation, cross-sectional view of a known MLP-type semiconductor package 40. The semiconductor package contains a mounting 47 consisting of a base support (also referred to as a paddle or base mounting pad) 42, a plurality of package connectors (also referred to as package pins) 44, a single semiconductor chip 41 connected to the base 42 by bonding layer 48 and a plurality of wires (also referred to as wirebonds) 43 which link the chip 41 to the package connectors 44. The complete assembly is enclosed in a nonconductive sealing material 45. Sealing material 45 may be a thermoplastic or thermoset resin (including an epoxy, phenolic and/or silicone resin). Numerous techniques for secure attachment of a semiconductor chip 41 to the base 42 are in practice, including conductive and/or nonconductive epoxy or solder 48. The top surface of the semiconductor chip 41, usually has, at its periphery, a plurality of connecting pads 46. A plurality of package connectors 44 surround the mounted semiconductor chip 41 and base 42. Wires 43 electrically connect to the semiconductor die connecting pads 46 and the package connectors 44. The package base support 42 and connectors 44 are rectangular in cross-section but may be etched to improve fixing to sealing material 45. The pluralities of package connectors 44 are commonly located at the periphery of the semiconductor package 40. The base support 42 is generally located centrally to the package base. Package connectors 44 and base support 42 are used to connect to a printed circuit board (PCB), not shown. An MLP-type semiconductor package aids dissipation of heat generated from the operation of the semiconductor chip 41 via the lower exposed surface of the base support 42 and the lower and lateral exposed surfaces of the package connectors 44. Some heat is also dissipated from the upper surface, to air surrounding the semiconductor package 40. However the sealing material 45 tends to prevent this by insulating the semiconductor chip 41. Semiconductor chips 41 are designed for many different applications and markets. Often there is an advantage in providing an electromagnetic shield over and in close proximity to the semiconductor chip 41. Such a shield may protect the semiconductor chip from unwanted interference from external radio signals and propagated waves but also protect the external system from signals generated from semiconductor chip 41 under its own operation. The prior art package has no externally exposed top metal pad to aid additional thermal dissipation or to give electromagnetic shielding protection to the semiconductor chip 41 or external system by presenting a shield or barrier to radio signals. The prior art package does not allow direct connection to the rear face of a stacked (flip-chip) mounted daughter die when mounted to the upper surface of the semiconductor die 41 on the base 42. FIGS. 2 to 4 and 6 to 14 illustrate aspects of the invention. In these Figures, like features are indicated by like identification numbers. Referring to FIG. 2, here shown is a side-elevation, cross-sectional view of semiconductor package 50. This is the first embodiment of a semiconductor package according to the present invention. The semiconductor package contains a mounting 57 consisting of a base support 52, a cover 60, connecting formation 59, a plurality of package connectors 54, a single semiconductor chip 51 and a plurality of wires 53. The complete assembly is enclosed in a nonconductive sealing material 55. Sealing material 55 may be a thermoplastic or thermoset resin (including an epoxy, phenolic and/or silicone resin). FIG. 2 shows a semiconductor chip 51 mounted to the base support 52. Numerous techniques of secure attachment are in practice, including conductive and nonconductive epoxies, or solder 58. The top surface of the semiconductor chip 51, usually has, at its periphery, a plurality of connecting pads 56. A plurality of package connectors 54 surround the mounted semiconductor chip 51 and base support 52. Wires 53 electrically connect to the semiconductor die connecting pads 56 and the package connectors 54. The pluralities of package connectors 54 are located at the periphery of the semiconductor package 50. The base support 52 is generally located centrally to the package base. Package connectors 54 and base support 52 are used to connect to a printed circuit board (not shown). The connecting formation 59 connects the base support 52 and cover 60. The connecting formation 59 provides a low resistance, low inductance thermally efficient path from the cover 60 to the base mounting pad 52 and to the external printed circuit board (not shown). The base support 52 and cover 60, the connecting formation 59 and package connectors 54 are secured to a mounting foil via mounting supporting structures or tie-bars (not shown). Tie bars and other supporting structures are trimmed off at the package dicing stage of manufacture. The mounting 57 may be etched to provide additional locking strength between the mounting 57 and the sealing material 55. The connecting 30 formation 59 has a weakened fold line in the form of a lateral etch, cut or scribe used at each end of the connecting formation 59 to define bend points 70 for the formation of the cover 60 of the package. The top side of the base support 52 is attached to the semiconductor chip while the bottom side of the base mounting pad 52 is exposed to the outside of the semiconductor package 50. The bottom side of the base support 52 and the upper side of the cover 60 are electroplated with a corrosion-minimizing material such as tin, gold, tin lead, tin bismuth, nickel palladium or other suitable alloy. The bottom side of the base support 52 will be mounted to the printed circuit board (not shown). The topside of the cover 60 is exposed to the outside of the semiconductor package 50 and is generally centrally located in the top surface of the package. The mounting 57 is fabricated from a sheet of electrically and heat conducting material such as copper. Heat generated from the operation of the semiconductor chip 51 is dissipated throughout the semiconductor package and through the bottom of the base mounting pad 52 to the printed circuit board. The exposed cover 60 will aid heat dissipation. Heat will also be dissipated through the plurality of package connectors 54. The plurality of package connectors 54 does not normally touch the base mounting pad 52. Still referring to FIG. 2, semiconductor package 50 has a semiconductor chip 51 attached to the base support 52 via an adhesive or suitable solder material 58. The plurality of package connectors 54 electrically connect to the semiconductor chip 51 through a plurality of wires 53. Each wire 53 has a first end electrically connected to one of the bond pads 56 on the top side of the semiconductor chip 51 and a second end connected to the lower portion of one of the package connectors 54. Wires can be made of any electrically conductive material; gold aluminium or silver are common choices. Sealing material 55 preserves the spatial relationship between the cover 60 and the base support 52, the connecting formation 59, wires 53, mounted semiconductor chip 51, and semiconductor package connectors 54. The sealing material 55 forms a rigid structure to maintain protection and form to the semiconductor package 50 and its component parts. After sealing only the areas of the base support 52 and cover 60, lower and outer edges of the package pins 54 remain exposed allowing connection to a printed circuit board. FIG. 3 shows a top plan view of semiconductor package 50. The cover 60 is located generally to the middle of the semiconductor package 50. At the four edges of the semiconductor package 50 sealing material 55 is shown defining the outer edge. The sealing material 55 ensures an interlocking structure with the cover 60. Only the upper portion of the cover 60 is exposed. FIG. 4 shows a bottom plan view of the semiconductor package 50. As shown the base support 52 is located, generally, to the middle of the semiconductor package 50, surrounded on four sides by a plurality of package connectors 54. At the four edges of the semiconductor package 50, sealing material 55 defines the outer edge. The sealing material 55 ensures an interlocking structure with the base support 52 and package connectors 54. Only the lower exposed and plated portion of the package connectors 54 and base support 52 are visible. FIG. 5 shows a top plan view of a known MLP-type package 47 for a semiconductor package 40. As shown the base support 42 is located generally to the middle of the semiconductor package 40, surrounded on four sides by a plurality of package connectors 44. FIG. 6 shows a plan view of a mounting 57 for a semiconductor package 50 according to the present invention shown in its basic state prior to bending. Support structures 74 for mounting definition are shown for two pins on the package near to where the connecting formation 59 is defined. Other tie-bars and support structures for mounting manufacture are not shown, however the plurality of package connectors 54 are shown interconnected as the case may be before trimming. Etched or scribed bend points 70 (dotted) are positioned to define the connecting formation 59. A dashed line is shown intersecting each about the plurality of package connectors 54. The dashed line indicates the package outer dimension after dicing. FIG. 7 shows a plan view of an array 77 of multiple individual mountings 57 for semiconductor package 50 to show how an individual mounting 57 may be manufactured from a larger area of metal material. The array 77 can be initially manufactured by a variety of process, for example, casting, etching or stamping. The array layout allows for the simple assembly of a semiconductor package. Using the array shown in FIG. 7 as an example, a semiconductor chip 51 can be mounted on individual MLP mountings 57 as shown. Semiconductor chips can be placed on each mounting using standard techniques, for example, processing the array to fix and solder the components on the mount. The processing can include solder bumping, epoxying and wire connecting. The packages can be further processed, for example using such techniques as solder reflow, injection of dielectric 55 onto the mount, semiconductor-mounting binder curing and so forth. The individual mounts are then folded through 90° along each of the fold lines 70 so that the cover 60 extends over the chip 51, parallel to the base 52 and connectors 54. The sealing material 55 is then injected between the cover and the chip 51. Mountings can be separated from any supporting peripheral mounting structures and neighbouring packages by, for example, a punch or a saw that cuts along the dashed lines of FIG. 6. Since the fold lines 70 are within the dashed lines after folding, the connecting portion 59 remains in place after cleaving. Alternatively, the individual MLPs can be cut and processed individually. FIG. 8 shows a plan view of a variation of the mounting 57 shown in FIG. 6 for a semiconductor package 50. In the mounting shown in FIG. 8, there are no pins on side adjacent the connecting formation 59. Tie-bars and support structures for mounting manufacture are omitted, however the plurality of package connectors 54 for the other three sides are shown interconnected as the case may be before trimming. A semiconductor package using this type of amounting can be assembled using the same techniques described above. FIG. 9 shows a plan view of a variation of the mounting 57 for semiconductor package 50 shown in FIG. 6. The cover 60 forms a plurality of apertures. An example, arbitrary, pattern is shown though an alternative pattern could be used. The apertures can be made in the cover 60 as and when required during the assembly process described above by cutting, etching or punching the desired pattern in the cover. The apertures could be made, for example, while the mounting is in an array of the sort shown in FIG. 7, or afterwards, when it has been separated. FIG. 10 shows a plan view of a variation of the mounting 57 shown in FIG. 6. In this example, there are four pins on the package side where the connecting formation 59 is defined. FIG. 11 shows a side-elevation, cross-sectional view of a second embodiment of a semiconductor package 50 according to the invention. In this embodiment, multiple semiconductor chips are integrated. There is a single mother semiconductor chip 61 and two inverted chips 62, 63 mounted on the mother semiconductor chip 61. The larger mother semiconductor chip 61 may be mounted first to the base support 52. The top surface of the semiconductor chip 61, is specifically designed to have corresponding connection pads 64 upon which to mount a plurality of smaller daughter chips 62, 63. Modern “flip-chip” assembly techniques are used to mount the daughter chips 62, 63 upon the upper surface of the mother semiconductor chip 61. The daughter semiconductor chips 62, 63 are pre-thinned and prefabricated, perhaps at wafer level, with materials to form a plurality of “bumps” to facilitate the flip-chip connection. Singular bumps 66 are positioned at each of the connection pads 65 of the daughter die 62, 63. Popular methods of bumping semiconductor chips are, solder deposition/reflow or gold stud. Alternative attachment materials include anisotropic conducting materials. Under-fill material 67 may be added between the mother and daughter chips to improve reliability and thermal performance of the flip-chip bonds 66. Some types of under-fill material 67 can be applied to the flip-chip stack either before or after the placement is made. The direct connection of electrical, and mechanical path from the daughter chips 62, 63 to the cover 60 will aid thermal and electrical performance. The exposed cover 60 will aid heat dissipation. In this example the mother chip 61 is mounted on the base 52 using the techniques described above. Additional connection pads 64 can be fixed at the desired points on the mother chip 61 and solder bumped chips can be located on the mother chip and reflow soldered. The assembly can be cleaned if necessary to remove any debris from the reflow process. If desired, the space between the daughter chips 62 and the mother chip 61 can be filled using standard underfill techniques and materials. Alternative flip-chip techniques can be employed, such as thermocompression bonding, thermosonic bonding and using conductive adhesives. An alternative substrate material such as flex, pcb, ceramic or glass may also be used in place of the described mother semiconductor chip 61. FIG. 12 shows a side-elevation, cross-sectional view of a third embodiment of a semiconductor package 50. In this embodiment, as in the second embodiment shown in FIG. 11, multiple semiconductor chips are integrated. The plurality of wires 53 in the second embodiment are replaced with through-hole vias 68 in the mother semiconductor chip 61. The mother semiconductor chip 61 is designed with through-hole vias 68 with upper and lower capture pads 75, which facilitate a vertical connection through to the base of the chip 61. The through-hole via 68 and capture pads 75 may be designed to align and allow connection directly with the package connectors 54 and/or base support 52. Multiple through-hole vias 68 may be arrayed to improve electrical connection or thermal relief. Conductive epoxy or solder material 58 is pre-deposited upon the plurality of package connectors 54. This deposition of a conductive layer or solder 58 is made at the same time as the deposition of epoxy or solder material on the base support 52. Upon placement of the mother semiconductor chip 61 a desired electrical connection between the underside of the mother semiconductor chip 61 and package connectors 54 and/or base support 52 is formed. An alternative substrate material such as flex, pcb, ceramic or glass may also be used in place of the described mother semiconductor chip 61. FIG. 13(a) shows a side-elevation, cross-sectional view of a defined bend line 70 in the mounting metal foil. Processes of etching and scribing are used to define a particular cross-section within the mounting metal foil which will provide a repeatable, reliable and robust mechanism for bending of the mounting to form the connecting formation 59 and cover 60. FIG. 13(b) shows a side-elevation, cross-sectional view of the same single defined bend line 70 in the mounting metal foil after being formed to an angle of 90 degrees. FIG. 14(a) shows a side-elevation, cross-sectional view of two defined bend line 70 in the mounting metal foil. The bend points 70 are defined at a distance specific and relating to the desired height of connecting formation 59 and separation from base support 52 and cover 60. Processes of etching and/or scribing are used to define a particular cross-section within the mounting metal foil which will provide a repeatable, reliable and robust mechanism for bending of the mounting to form the connecting formation 59 and cover 60. FIG. 14(b) shows a side-elevation, cross-sectional view of same two defined bend line 70 in the mounting metal foil after each is bent through to an angle of 90 degrees. FIGS. 13(b) and 14(b) show the bend line feature formed by the removal of material from the outer side of the bend. There are advantages to methods of bending with the etched or scribed line 70 on the inner side of the bend. One advantage of this is that it allows greater control over the bending action. This is because the two sides of the etched or scribed line come into contact at a predetermined bending angle and stop the bending at that angle. Angles other than 90 degrees can be used. For example three bends of 60 degrees each could be used. FIG. 15 shows a side-elevation, cross-sectional view of the second embodiment of the present invention, a semiconductor package 50 mounted to a printed circuit board 73. A thermally conductive material 71 is deposited upon the top surface (cover 60) of the package and used to dissipate heat. The thermally conductive material 71 is shown deposited so that it makes contact to a suitable casing or body 72 of the final product. Open arrows depict the general dissipation of heat energy away from the package. Further embodiments of the invention use flip-chip bonding techniques. Before discussing these further embodiments in detail, the prior art flip-chip-onto-leadframe-pin MLP-type semiconductor package is discussed below. FIG. 16 shows a cross-sectional view of a known flip-chip-onto-leadframe-pin MLP package. A top plan view of the same prior art mounting or leadframe for a flip-chip-onto-leadframe-pin QFN package is shown in FIG. 17. With reference to FIG. 16, here the semiconductor die has been “bumped” using standard techniques to provide physical and electrically conductive connection to each of its signal pads. As previously mentioned above, popular methods of implementing the conductive bumps 66 are by gold stud, deposited and reflowed solder or deposited conductive column structures. The die has then been flipped over and mounted directly to the leadframe package pins using recognised methods. The package is moulded and diced using standard processes. With reference to FIG. 17, the mounting 7 is designed with elongated peripheral pins making the desired connection from package edge to underneath the semiconductor die. In this type of “flip-chip-onto-leadframe-pin” MLP package, the base die mounting pad used in wirebonded QFN packages is often removed to allow the inward extension of the peripheral package signal pads under the die. This also improves access for mould material. Although not shown, it is also possible to have a base pad present allowing multiple connections under the chip. Thermal performance is improved through such an array of bumps connecting to this pad. FIGS. 18 to 22 illustrate further aspects of the invention applied particularly to flip-chip mounting in packages. Like numerals refer to like features. With reference to FIG. 18, here is shown a cross-sectional view of an embodiment of a flip-chip-onto leadframe-pin MLP package, according to the invention. A plan view of the mounting design for the embodiment of FIG. 18 is shown in FIG. 19. Referring to FIG. 18, here, as with the prior art, a pre-bumped semiconductor die 41 has been flipped and mounted onto the base mounting pins 44. Here the embodiment improves upon the prior art by providing an additional, exposed top pad heatsink and EMI shield. The top metal pad 60 is formed and attached to the back of the die 41 using standard materials such as solder paste or conductive adhesives. The side view of a half-etched support structure 72 is shown extending and anchoring the top pad and pins. This can be seen more clearly in FIG. 19. Referring to FIG. 19, the mounting design for the embodiment is shown with the top die pad 60 lying flat. The top pad and bend structures 74 are mechanically supported by mounting material structures. FIG. 20 shows a further embodiment of a flip-chip-onto-leadframe-pin package, where a base pad 52 is present thus enabling multiple die connections under the chip 51. Thermal performance is improved through the flip-chip bumps connecting to this pad. FIG. 21 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a heatsink die. This embodiment is intended for use where extra thermal dissipation is required. The embodiment shown in FIG. 21 has an additional “die” 80 of thermally conductive material mounted upon the surface of the semiconductor die 51. A thermally conductive adhesive can be used to fix the thermally conductive material to the surface of the semiconductor chip 51. The thermally conductive material could be a diced piece of metal, such as copper, or a non-electrically conducting elastomeric material. The thermally conductive material may also be placed upon the upper face of the top pad, while flat and prior to leadframe bending. A half-etch recess (not shown) may also be defined to aid alignment of the thermally conductive die. In the example shown, the process for assembling the package is substantially the same as described for other embodiments, but with the additional step of placing the die 80 onto the chip 51 before the cover is folded over. Thermal performance is thereby improved by providing a low thermally resistive path to the top and bottom package boundaries. This method is particularly suitable for medium to large sized die where there is sufficient surface area to safely mount the die of thermally conductive material without disrupting peripheral wirebonds. As previously shown in and discussed for FIG. 11, die may be stacked. FIG. 22 shows a further embodiment of the invention where multiple (four-shown) semiconductor die 51a-d have been stacked using a combination of standard assembly techniques such as flip-chip and wirebond. FIG. 22 shows a cross-section dissecting the package centre. The package provides both a thermally enhanced and EMI screened MLP packaging solution for multiple chips. The top die 51d (flip-chip mounted) has a direct connection the package's top metal pad thus providing an excellent route to dissipate heat away from the die stack. This type of package can be assembled in the same manner as for a single chip package but with the following additional steps. After the first chip 51a has been mounted a variety of techniques can be used to mount the other chips, including thinned die, thinned die attach and spacing methods, and low-profile wire bonding techniques. The additional chips can stacked face up and wire bonded, as for 51b and 51c. The chips can also be flip-chip mounted as detailed above. The chips may be wire bonded onto a common package, as shown here, or wire bonded die-to-die. Edge connectors (not shown) can also be used to connect multiple dies to a common mounting. Vias in the chips could also be used to provide interconnection. The finished leadframe package can itself be stacked. Further aspects of the invention incorporate surface mount technology (SMT) and passive components into the MLP package. FIG. 23 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with integrated SMT passive components, in this example a leadframe based System-in-Package (SiP) solution. As discussed above the MLP package can be equipped with a top metal pad cover 60. Recesses 84, here indicated by a dotted line, can be defined in the cover. The recess can extend the cover to provide a connection to the SMP passive The package is assembled in the manner described above. Discrete components such as surface mount capacitors or resistors are arranged to fit within these recesses. These components may be supportive to the correct function of the semiconductor die. Integrated passive networks can be deployed using, for example, ceramic substrate, GaAs or silicon thin film technology. Such integrated passive networks are often used in filter circuits and other RF applications. The profile of the recesses 84 cut in the top pad can be varied to provide sufficient depth for the passive components to be fixed in place. FIG. 24, for example, shows how a recess 84 has been cut in the package's top metal pad, adapting it to give sufficient clearance to allow the larger support components and secondary die to retain the accepted standard height. The embodiment shown can be further modified to form a simultaneous electrical connection to both the package top pad and a bottom signal pin enhancing thermal performance and EMI protection. Further embodiments of the invention incorporate enhanced EMI features into the MLP package. A cross-sectional and plan view of an EMI enhanced package and its mounting are shown respectively in FIGS. 25 and 26. In these examples, the top metal pad 60 has been enlarged and fabricated with additional fold lines 86 using the same process as that used to define the bend points discussed previously, for example for FIGS. 9 and 10. The fold lines define sidewalls 88. In the embodiment shown in FIGS. 25 and 26, the leadframe top metal pad 60, while still flat, can be shaped by various means, for example a mechanical stamp tool, to form the sides and the base of an up-turned open box. After subassembly, the formed box could, as with the principal embodiment's top metal pad, be bent up and over the mounted die subassembly. The combined box shape and interconnecting vertical structure equipped with the key bend points act as an electrically grounded EMI shield. As shown in FIG. 26, the boxed sidewalls 88 could be designed to maintain clearance or, where contact is required, provide a good electrical connection to the perimeter or centre ground pads of the leadframe base. With reference to FIG. 26, the larger top pad with defined fold lines is shown lying flat. The final package dimension is indicated by dashed lines. Defined bend points are indicated by dotted lines. Perimeter cut-outs or reliefs can be designed to optimise space around sensitive electrical pins. The top metal pad is equipped with sidewalls 88 which are arranged to allow sufficient access for the plastic mould material. The assembly of the enhanced EMI protection package shown in FIGS. 25 and 26 follows the same steps as the other packages described above but with an additional step of bending the cover 60 at bend lines 88 to form the sidewalls 88. FIGS. 27 to 36 illustrate further aspects of the invention featuring an aperture in the MLP package, where it is advantageous to gain access by various means to the surface of the semiconductor chip. In particular, FIGS. 27 to 34 show embodiments for the packaging of image sensor semiconductor chips 91 for use in imaging systems, for example digital camera applications. Such devices require a window 96 in the package allowing light to fall onto the chip surface. Image sensor chips are equipped with arrays of receptors capable of capturing the light and passing this information as an electrical signal to the system. The cover 98 is equipped with an aperture to provide a semi-rigid frame or support for the holding and mounting of the glass and/or lens. The package offers an optimised, cheap and low profile solution overcoming many of the assembly issues reported by image sensor manufacturers. For example, correct alignment of components such as lenses in optical systems is important to quality control. Furthermore, assembly of the different components needed to make such an optical system can be intricate and time consuming, increasing manufacturing costs. FIG. 27 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an aperture feature. In this example, a “die” 100 of transparent material has been fixed upon the surface of the semiconductor chip using standard assembly techniques. Here a half-etch recess 102 has been used to aid glass die alignment and adhesion. The transparent material could be a cut piece of glass, a pre-shaped lens, a combination of both of these. The package body mould material could also be transparent. FIGS. 28 and 29 respectively show a square or round “window” 96 could be defined in the top metal pad. If a square glass die (for example IR filter, Borosilicate, or pre-shaped lens) is used it may be placed upon the upper or lower face of the top pad, while flat, and prior to leadframe bending, thus simplifying the assembly process for this type of device. This type of package construction is particularly suitable for medium-larger sized die where there is sufficient chip area to safely mount the glass die without disrupting peripheral wirebonds. A transparent epoxy of a similar refractive index to the glass is recommended for fixing the glass to the semiconductor and leadframe surfaces. FIG. 30 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an aperture feature fitted with a lens 104. In this example, showing the cross-sectional ellipse of a lens made of transparent material, the lens has been fixed to the outer surface of the top metal pad using standard assembly techniques. A half-etch recess 106 around the aperture has been used to aid lens alignment and adhesion. The space between the lens underside and semiconductor chip surface is filled with a transparent material 108 such as an epoxy. The semiconductor and lens package can be assembled from a mounting with an aperture in the top pad as follows. A semiconductor chip 91 can be placed on a mounting using the standard techniques described before. The individual mounts are then folded through a nominal angle of 90° along each of the fold lines 70 so that the cover 98 extends over the chip 91, parallel to the base 52 and connectors 54. The transparent material, 108 can be injected to fill the void between the chip 91 and aperture 96. Alternatively it can be applied to the chip 91 before folding of the mounting. The sealing material 55 is then injected between the cover and the chip 91. The lens 104 is then fixed to the assembly, using the recess 106 to align the lens correctly to the chip 91. FIG. 31 shows a top plan view of a round “window” 96 can be defined in a double metal pad 110 arrangement. FIGS. 32 and 33 shows how this double pad 110 in the leadframe can be alternatively formed to hold a square glass die 98 and/or pre-shaped (round) lens 102. This general method and form for holding a single square glass die and/or pre-shaped lens may be extended to provide a structure to hold multiple lenses or die. This type of assembly can be used where there is a need for a complex lens/optical system assembly, for example, combining lenses with optical filters. The packages shown in FIGS. 32 and 33 offer an improved method of assembly. As before, beginning from a flat mounting, for example that shown in FIG. 31, the chip is fixed and connected to the mounting and the square die attached to the chip 91. The lens 102 is placed on the double pad 110, on the round aperture 92. The lens can be secured into place using the recess 106 for alignment. The double pad is folded along fold lines 70 as before, bending a first pad over the chip 91 and die 98 as previously described. The portion holding the lens 102 is then bent back over the first pad such that the lens is held between the first and second top pads. The two apertures in the pad are aligned such that the edges of the aperture of the lower top pad form lower edges to align the lens. This procedure allows the lens assembly to be easily assembled and correctly aligned. Furthermore, the open aperture type of MLP package can be deployed in sensor applications, for example for use in biometrics applications. FIGS. 34 and 35 show two such embodiments of the invention for biometrics systems. In FIG. 35 the top metal pad is attached directly to the chip 111 using standard materials and techniques. The top surface 112 of the chip is exposed. In many biometrics applications the top surface 112 of a protective coated semiconductor chip 111 needs to be exposed to allow an interface with the “real world”. An example is a fingerprint identification chip where the user's finger is placed upon the surface of the die. The frame is designed to fully expose the semiconductor die sensor array without causing disruption to the peripheral wirebonds. An alternative sensor embodiment is shown in FIG. 36. This figure shows a side elevation, cross-sectional view of an MLP-type package with exposed die feature and gel-filled cavity 116. This configuration can be used in, for example, pressure sensing applications. In such a pressure sensor the interface gel material 116 acts as a medium to track environmental pressure changes to the surface of the semiconductor chip. The gel material also acts to protect the sensitive die surface. The inventions top metal pad is used to provide a supportive frame and desired opening allowing accurate forming of the gel material 116. The sensor package may be pre or post-moulded using the techniques previously described. The frame and gel window is configured to allow sufficient gel material to access the semiconductor die pressure sensor. In a further embodiment, the cover of a chip package can be tailored to specific applications and needs, as illustrated in FIGS. 37 to 43. For example, FIG. 37 shows the further embodiment where the package is equipped with an internal top metal pad 60 acting as an EMI shield. The top metal pad structure 60 is surrounded by the mould material 55 and no external exposure of the top pad is provided. The mould material defines the outer boundary of the top of the package. FIG. 38 shows a side elevation, cross-sectional view of an MLP-type package with a partially exposed top metal pad EMI shield. In this example the package is equipped with a partially exposed top metal pad 60. The top metal pad 60 provides a combined EMI shield and heat sink, shown here patterned with trenches 112 using the standard leadframe half-etch processes. The pattern formed by the trenches found in its outer surface 112 is designed to allow a controlled mould material ingress, improving manufacturability, and reliability by retaining the cover in place in the package. The patterned surface allows for improved interlocking of the pad 60 and mould material 55. The highest points of the patterned top pad can be arranged to remain exposed after moulding. A partial external exposure of the top pad is therefore provided. The top pad pattern may be designed to still provide sufficient exposed metal for access to the top metal pad. The mould material partially defines the outer boundary of the top of the package. Package reliability is enhanced through the use of the extra anchor points provided at the patterned upper side of the top metal pad. FIG. 39 shows the cross-section of a package with the patterned trenches 126 underside of the top metal pad 60. Reliability of the package structure may be enhanced through the use of a patterned underside of the top metal pad, allowing improved integrity of the mould and frame structure. The pattern could be designed as a combined series of half-etch channels, fully etched holes or full thickness recesses. The design of the pattern can optimised for mould access and flow and to avoid air/gas bubbles. Other materials can also be combined in the MLP assembly. For example, FIG. 40 shows how a glob-top 130 or other suitable dielectric fill material may be dispensed over the active die surface and other subassembly structures (for example, wirebonds), prior to bending the top metal pad. This provides additional structural protection for the chips mounted in the package. The electromagnetic coupling capabilities of the MLP package can also be further enhanced. For example, FIG. 41 shows how apertures or slots 130 are formed within the top metal pad to permit the electromagnetic coupling of waves of a certain frequency (wavelength) through the top metal pad. This structure may be of advantage for the mounting for a radio system's antenna or electromagnetic coupling to other popular microwave components such as filters and waveguides. FIGS. 42 and 43 show how further stack constructions can be used to optimise thermal, electrical and EMI shielding in a multiple die stack. Here two chips 132 are shown mounted conventionally and a third chip 134 is flip-chip mounted and connected to them. The basic design of having a top metal pad is unchanged. In FIG. 42 the base die attach pad has been etched to a partial thickness using the techniques already discussed and FIG. 43 shows how solder spheres may be used to connect a mother die to the peripheral package pads. The EMI shielding discussed above can be adapted to meet the appropriate government regulations and to further meet the operating requirements of the mounted semiconductor assembly, for example to provide immunity from other interfering RF signals or allow operation of RF circuitry within the package. The package and mounting can be adapted to meet appropriate regulations for various and known wireless standards. Furthermore, such RF SiP solutions as discussed above can provide for integrated antenna means in the cover 60. The MLP packaging described above can be further adapted to include useful structures and functions. For example, FIG. 44 shows how the top metal pad 60 can be defined with apertures to provide an inductive element 154. In this example, a semiconductor chip 150 is shown mounted with its wirebonds 152 connecting the chip to peripheral base pins. The top pad structure 60 is etched in a serpentine pattern 154 to form a serpentine inductor. The inductor is formed about the two connecting formations 59 equipped with defined bend points 70, (indicated by dotted lines) and thus sits above the mounted semiconductor once the package has been assembled as described above. The example shown in FIG. 44 shows how the continuous serpentine path of the top metal pad 60 is designed to electrically and physically connect to peripheral or package base pins through two connecting formations 59 equipped with defined bend points. This connecting method provides a robust, reliable and low resistance connection to the inductive element 150 the two connecting formations may also be used to define the final package height. Situating the inductive element in a parallel, upper plain above the semiconductor chip assembly and base/peripheral package pins further reduces the component package area. The package design in the example shown in FIG. 44 also shows how wirebonds, or alternatively flip-chip connections, can be used to electrically connect the semiconductor chip to the peripheral package pins and base pads for connection to the inductive element. When connected to a system neutral RF, for example, Ground or direct current Voltage Supply, the upper plain inductive element has the additional advantage of functioning as an integrated EMI shield and heatsink/heatspreader, as previously described above. It is further possible to combine the inductive element with a further metal pad, as shown in FIG. 45. In this example a second top metal pad 160 may be formed to fit over the semiconductor chip assembly and the inductive element. Electrical and physical isolation between the inductor and shield would be maintained. The separation between bend points in the single connecting formation connecting the top metal pad to the semiconductor ship die attach pad is greater than between those on the connecting formations for the inductor to provide sufficient final package height and to ensure that the cover is spaced from the inductor. This approach to integrating inductive elements into the package can also be used for integrating other passive components such as capacitors, for example interdigitated capacitors. It would also be possible to extend the approach to help integrate other components such as microstrip couplers and filters. FIG. 46 is a table of results of electromagnetic interference simulations for the package design shown in FIG. 2. A series of comparative simulations were conducted on a standard package with no top metal pad and the improved package with the top metal pad 60 acting as a shield. Using recognised methods of emission type EMI simulation, monitor points were distributed at representative positions surrounding the package. The packages shown in the above examples can be demonstrated to provide a local EMI shield. The simulations show improvements in shield effectiveness of approximately 10 dB at application frequencies of up to 10 GHz for the E field, and of approximately 20 dB for the H field. Effective EMI shielding is important for meeting regulations on electromagnetic emissions, especially considering the higher frequencies at which modern electronics equipment operates. It will be appreciated that several design factors, such as the spacing between the cover or top pad and the semiconductor chip, and the overhang of the top pad, can be optimized to improve shielding effectiveness. Further simulated results for larger packages have shown improved results for shield effectiveness up to 40 dB at frequencies of up to 10 GHz. Computer simulations of thermal dissipation in the package show improvements over conventional packages. The structure and immediate environment of the package was simulated using computational fluid dynamics software. The die sizes, materials and constant power dissipations assumed are given in the table of FIG. 47. FIG. 48 is a table of results of thermal simulations for the multiple stacked die in a package as shown in FIG. 11. In this example two daughter die are flip-chip mounted onto a third mother die. In such a package the top metal pad would be attached to the rear top side of the daughter die using conductive epoxy and the mother die would be attached to the package using conductive epoxy. As can be seen from the table, the heat dissipation simulations show improvements in heat dissipation of approximately 21 degrees C., an improvement of 22%, in the daughter chips 62,63 compared to standard packaging configurations. The thermal energy produced by the daughter die is dissipated through the packages internal structure to the printed circuit board. By improving the thermal dissipation qualities of the packaging it is possible to mount more semiconductor chips that consume more power and therefore generate more heat. For example, it would be possible to drive semiconductor chips at higher speeds without failure due to overheating.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to a semiconductor package, a mounting assembly therefor and a method of manufacture, and more particularly but not limited to, a micro mounting package that has an integrated heatsink and electromagnetic shield. According to a first aspect of the invention there is provided a mounting for a semiconductor assembly including a first portion for mounting at least one semiconductor device, a second portion and a connecting portion joining the first and second portions and arranged to allow folding of the second portion over the semiconductor device. The connecting portion may provide thermal and electrical communication between the first and second portions of the mounting. The first portion of the mounting may comprise a formation of leadframe package connectors. The first portion of the mounting may further comprise a base support for at least one semiconductor device. The second portion may comprise a cover having a semiconductor assembly-facing surface and an opposed heat-radiating surface. The electrical connectors of the mounting are in a spaced relationship with the base support and are linked electrically with the semiconductor assembly. The cover is arranged to be in a spaced parallel relationship with the base support. The cover may further comprise at least one additional edge portion arranged to extend when the mounting is folded beyond at least one edge of the first portion of the mounting. Such an edge portion can be folded to form a sidewall. The mounting is preferably formed from a single sheet of electrically and thermally conducting material, which is preferably a metal, more preferably copper. The mounting may be part of an array of a plurality of mountings. The mounting is preferably provided with folding means to enable it to be bent such that the cover can be arranged to be in a spaced parallel relationship to the first portion. The folding means is preferably a weakened line, such as a scored line or an etched line in the mounting having a thickness that is less than that of the rest of the mounting. Preferably the mounting includes two weakened lines, one between the first portion and the connecting portion and one between the second portion and the connecting portion. The cover of the mounting is arranged to be mechanically and electrically connected to the base support and the base support is normally connected to System Ground potential (GND) on the final product printed circuit board. The particularly advantageous feature of the present invention is the cover which provides three functions (a) a simple heatsink (b) a low resistance, low inductive path to electrical Ground (GND) and (c) to act as a local electromagnetic shield protecting sensitive functions within, or without, from unwanted electromagnetic interference. The semiconductor chip may be electrically connected to a portion of the mounting by wirebonding. Alternatively, the chip may be mounted using flip-chip mounting, such as bump soldering. The new mounting package can be used for single or multiple chip applications. Where multiple chips are integrated it is often beneficial to “flip” smaller (daughter) chips onto a larger (mother) die. The new package facilitates connection to a simple heatsink and electromagnetic shield and System Ground (GND). Through modern assembly techniques the present invention reduces cost and area usage on a printed circuit board whilst improving thermal and electrical performance. The semiconductor assembly is preferably attached to the base support and/or the cover. Where the assembly comprises two or more semiconductor chips, it is preferably attached to the base support and the cover. This enables a daughter semiconductor chip to be connected more directly to system ground. The assembly is preferably electrically attached to the base support and/or cover, more preferably by conductive wire or conductive epoxy or solder material. A semiconductor package incorporating the mounting preferably comprises a sealing material at least partially encapsulating the mounting and the semiconductor assembly. This is in order to protect and support the contents of the package. At least part of the printed circuit board facing surfaces of the package connectors and base support or the heat radiating surface of the cover may not be covered by the sealing material, being left exposed to aid the dissipation of heat. The mounting preferably further comprises heat dissipation means to provide a low thermally resistive path between a mounted semiconductor assembly and the cover of the package. The mounting may be provided with a third portion and second folding portion arranged to allow folding of the third portion over the semiconductor device. The third portion is in a spaced parallel relationship with the base support and second portion. The mounting may further comprise means for mounting surface mount technology (SMT) components. Such components may comprise passive components, for example resistors, capacitors, or inductors. Such means may comprise recesses in the mounting cover to mount SMT components. The cover of the mounting may be patterned to function as a passive component. For example, the top cover may be formed as a serpentine inductor. Other passive components can be integrated. The cover may be patterned as an interdigitated or parallel plate capacitor. The cover may also be patterned to integrate other components such as antenna, microstrip couplers and filters. The mounting preferably further comprises an EMI enhanced package wherein the cover is fabricated with additional fold means to enable the cover to be bent to define walls in relationship with the semiconductor assembly. The mounting may further comprise means adapted for mounting sensor semiconductor chips. The cover of the mounting may be adapted to provide direct access to the semiconductor assembly. Such means may comprise an aperture in the package mounting cover. The mounting may be further adapted to mount optical components in relationship to an image sensor semiconductor chips. The aperture may be further defined by having recesses about its perimeter. The recesses may face towards, or away from, a mounted semiconductor device. The aperture and the recesses can be used to locate further components for use in the semiconductor assembly. The mounting may be further adapted to provide for mounting biometric semiconductor chips. The mounting may be further adapted to provide for mounting pressure sensor semiconductor chips. The mounting according to the invention preferably further comprises one or more recesses formed within the cover into which mould material can flow to secure the cover in the package. The mounting according to the invention preferably further comprises means to permit coupling of selected frequencies of electromagnetic radiation through the leadframe. Such means may comprise apertures in the cover of the mounting of appropriate dimension to permit coupling at a selected frequency. In another aspect of the invention there is provided a method of manufacturing a semiconductor assembly comprising the steps of: preparing a mounting for a semiconductor device; mounting a semiconductor chip on the mounting; electrically connecting the semiconductor chip to the mounting; and folding a portion of the mounting over the semiconductor assembly. The step of preparing the mounting may further comprise forming functional features in the mountings. The features may be formed by, for example, cutting, scribing, stamping or etching. The step of preparing a mounting may further comprise forming fold lines into the mountings. The folded portion may be folded through a total of 180°, for example by being folded through 90° along each of two fold lines. The folded portion can then be in a spaced parallel relationship with the portion the semiconductor chip is mounted on. The method may further comprise folding a further portion of the mounting over the semiconductor assembly. The method may further comprise folding additional portions of the mounting to form, for example, sidewalls in the mounting. The functional features may further include heatsinks. Passive components can also be formed in portions of the mounting. The method may further comprise the step of sealing said mounting. Any suitable sealant could be used for this purpose, for example, a dielectric sealant. The method further comprises forming an aperture in a portion of the mounting. Recesses can be defined about the perimeter of the aperture. The recesses may face towards, or away from, a mounted semiconductor device. The method may further include mounting and aligning components for use in the semiconductor assembly. Such further components include optical components, such as lenses or filters. The components may be mounted on the mounting before it is folded such that folding the mounting brings the component into the desired final position in the assembly. The method may further comprise electrically connecting the semiconductor chip to using wirebonding. The semiconductor chip may be flip-chip mounted. The method further comprises mounting further semiconductor chips on the same mounting. The further chips can be mounted using adjacent or stacked wirebond and/or flip-chip mounting. The mounted chips can be connected to a common mounting and/or each other. The mounting may be one of an array of such mountings. The mounting can be separated from the array by, for example, cutting, punching or sawing. In another aspect of the invention there is provided a method of manufacturing a semiconductor mounting wherein individual mountings are patterned on a sheet of conducting material, wherein the individual mountings are defined with a first portion for mounting at least one semiconductor device, a second portion and a connecting portion joining the first and second portions and arranged to allow folding of the second option over the semiconductor device. The mountings may be patterned by casting, etching or stamping. The sheet may be a suitable metal, for example, copper. The individual mountings may be part of an array of such mountings. The method further includes the step of separating individual mountings from the array. The invention is illustrated with reference to the following Figures of the drawings wherein: FIG. 1 shows a side elevation, cross-sectional view of a known MLP-type semiconductor package; FIG. 2 shows a side elevation, cross-sectional view of an MLP-type semiconductor package according to the invention with a formed upper pad; FIG. 3 shows a top plan view of an MLP-type semiconductor package according to the invention; FIG. 4 shows a bottom plan view of an MLP-type semiconductor package according to the invention; FIG. 5 shows a plan view of a known MLP-type semiconductor mounting; FIG. 6 shows a plan view of an MLP-type semiconductor mounting according to the invention, laid flat and showing formed upper pad prior to bend; FIG. 7 shows a plan view of a manufacturing array of mountings according to the present invention; FIG. 8 shows a plan view of a laid flat MLP-type semiconductor mounting according to the present invention wherein the mounting has no package connectors on the edge adjacent the cover to maximise the area of the connecting formation; FIG. 9 shows a plan view of a laid flat MLP-type semiconductor mounting according to the present invention having a cover which is defined with apertures; FIG. 10 shows a plan view of a laid flat MLP-type semiconductor mounting according to the present invention having four package connectors on the side adjacent the cover; FIG. 11 shows a side elevation, cross-sectional view of a second embodiment of a semiconductor package according to the present invention; FIG. 12 shows a side elevation, cross-sectional view of a third embodiment of a semiconductor package constructed in accordance with the principles of the present invention; FIG. 13 shows a side elevation, cross-sectional view of the construction of a single bend point; FIG. 14 shows how a pair of bend points may be used to construct the connecting formation used in the present invention; FIG. 15 shows a side-elevation, cross-sectional view of the second embodiment of the present invention mounted on a printed circuit board. FIG. 16 shows a side elevation, cross-sectional view of a known flip-chip onto leadframe MLP-type package; FIG. 17 shows a top plan view of a mounting used to make the package of FIG. 16 ; FIG. 18 shows a side elevation, cross-sectional view of a flip-chip onto leadframe MLP-type package according to the invention with a formed upper pad; FIG. 19 shows a top plan view of a mounting used to make the package of FIG. 18 ; FIG. 20 shows a side elevation, cross-sectional view of a flip-chip onto leadframe MLP-type package according to the invention with a formed upper pad and base pad; FIG. 21 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with heatsink die enhanced feature; FIG. 22 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with stacked die; FIG. 23 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with integrated surface mounted (SMT) passive components; FIG. 24 shows a top plan view of a mounting used to make the package of FIG. 23 ; FIG. 25 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with enhanced EMI shielding; FIG. 26 shows a top plan view of a mounting used to make the package of FIG. 25 ; FIG. 27 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an aperture feature; FIG. 28 shows a top plan view of a mounting used to make the package of FIG. 27 ; FIG. 29 shows a top plan view of a mounting according to the invention used to make an MLP-type package with a circular aperture feature; FIG. 30 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an aperture feature fitted with a lens, made using the mounting of FIG. 29 ; FIG. 31 shows a top plan view of a mounting according to the invention used to make an MLP-type package with a double pad feature and aperture feature; FIG. 32 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a double pad feature and aperture feature fitted with a lens, made using the mounting of FIG. 31 ; FIG. 33 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a double pad feature and aperture feature fitted with a lens; FIG. 34 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with exposed die feature; FIG. 35 shows a side elevation, cross-sectional view of a further embodiment of an MLP-type package according to the invention with exposed die feature; FIG. 36 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with exposed die feature and gel-filled cavity; FIG. 37 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an entirely encapsulated, non-exposed cover pad; FIG. 38 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a partially exposed top metal pad; FIG. 39 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a patterned underside of the top metal pad; FIG. 40 shows a side elevation, cross-sectional view of an MLP-type package according to the invention showing a dielectric fill material dispensed over the die surface; and FIG. 41 shows a mounting for making an MLP-type package according to the invention with electromagnetic coupling apertures; FIG. 42 shows a section through an MLP-type package according to the invention; FIG. 43 shows a section through a further MLP-type package according to the invention; FIG. 44 shows a mounting for making an MLP package according to the invention with a cover pad including the definition of a serpentine inductor with a semiconductor chip shown mounted to the base with wirebonds connecting to the perimeter connectors and to the inductor; FIG. 45 shows a mounting for making a package according to the invention with a top cover pad in addition to a defined serpentine inductor; and FIGS. 46 to 48 show the results of modelling packages according to the invention. detailed-description description="Detailed Description" end="lead"? Before discussing the embodiments of the present invention, the prior art MLP-type semiconductor package is discussed below in order to provide background information regarding the techniques of construction of MLP-type semiconductor packaging. In reference to FIG. 1 , there is shown a side-elevation, cross-sectional view of a known MLP-type semiconductor package 40 . The semiconductor package contains a mounting 47 consisting of a base support (also referred to as a paddle or base mounting pad) 42 , a plurality of package connectors (also referred to as package pins) 44 , a single semiconductor chip 41 connected to the base 42 by bonding layer 48 and a plurality of wires (also referred to as wirebonds) 43 which link the chip 41 to the package connectors 44 . The complete assembly is enclosed in a nonconductive sealing material 45 . Sealing material 45 may be a thermoplastic or thermoset resin (including an epoxy, phenolic and/or silicone resin). Numerous techniques for secure attachment of a semiconductor chip 41 to the base 42 are in practice, including conductive and/or nonconductive epoxy or solder 48 . The top surface of the semiconductor chip 41 , usually has, at its periphery, a plurality of connecting pads 46 . A plurality of package connectors 44 surround the mounted semiconductor chip 41 and base 42 . Wires 43 electrically connect to the semiconductor die connecting pads 46 and the package connectors 44 . The package base support 42 and connectors 44 are rectangular in cross-section but may be etched to improve fixing to sealing material 45 . The pluralities of package connectors 44 are commonly located at the periphery of the semiconductor package 40 . The base support 42 is generally located centrally to the package base. Package connectors 44 and base support 42 are used to connect to a printed circuit board (PCB), not shown. An MLP-type semiconductor package aids dissipation of heat generated from the operation of the semiconductor chip 41 via the lower exposed surface of the base support 42 and the lower and lateral exposed surfaces of the package connectors 44 . Some heat is also dissipated from the upper surface, to air surrounding the semiconductor package 40 . However the sealing material 45 tends to prevent this by insulating the semiconductor chip 41 . Semiconductor chips 41 are designed for many different applications and markets. Often there is an advantage in providing an electromagnetic shield over and in close proximity to the semiconductor chip 41 . Such a shield may protect the semiconductor chip from unwanted interference from external radio signals and propagated waves but also protect the external system from signals generated from semiconductor chip 41 under its own operation. The prior art package has no externally exposed top metal pad to aid additional thermal dissipation or to give electromagnetic shielding protection to the semiconductor chip 41 or external system by presenting a shield or barrier to radio signals. The prior art package does not allow direct connection to the rear face of a stacked (flip-chip) mounted daughter die when mounted to the upper surface of the semiconductor die 41 on the base 42 . FIGS. 2 to 4 and 6 to 14 illustrate aspects of the invention. In these Figures, like features are indicated by like identification numbers. Referring to FIG. 2 , here shown is a side-elevation, cross-sectional view of semiconductor package 50 . This is the first embodiment of a semiconductor package according to the present invention. The semiconductor package contains a mounting 57 consisting of a base support 52 , a cover 60 , connecting formation 59 , a plurality of package connectors 54 , a single semiconductor chip 51 and a plurality of wires 53 . The complete assembly is enclosed in a nonconductive sealing material 55 . Sealing material 55 may be a thermoplastic or thermoset resin (including an epoxy, phenolic and/or silicone resin). FIG. 2 shows a semiconductor chip 51 mounted to the base support 52 . Numerous techniques of secure attachment are in practice, including conductive and nonconductive epoxies, or solder 58 . The top surface of the semiconductor chip 51 , usually has, at its periphery, a plurality of connecting pads 56 . A plurality of package connectors 54 surround the mounted semiconductor chip 51 and base support 52 . Wires 53 electrically connect to the semiconductor die connecting pads 56 and the package connectors 54 . The pluralities of package connectors 54 are located at the periphery of the semiconductor package 50 . The base support 52 is generally located centrally to the package base. Package connectors 54 and base support 52 are used to connect to a printed circuit board (not shown). The connecting formation 59 connects the base support 52 and cover 60 . The connecting formation 59 provides a low resistance, low inductance thermally efficient path from the cover 60 to the base mounting pad 52 and to the external printed circuit board (not shown). The base support 52 and cover 60 , the connecting formation 59 and package connectors 54 are secured to a mounting foil via mounting supporting structures or tie-bars (not shown). Tie bars and other supporting structures are trimmed off at the package dicing stage of manufacture. The mounting 57 may be etched to provide additional locking strength between the mounting 57 and the sealing material 55 . The connecting 30 formation 59 has a weakened fold line in the form of a lateral etch, cut or scribe used at each end of the connecting formation 59 to define bend points 70 for the formation of the cover 60 of the package. The top side of the base support 52 is attached to the semiconductor chip while the bottom side of the base mounting pad 52 is exposed to the outside of the semiconductor package 50 . The bottom side of the base support 52 and the upper side of the cover 60 are electroplated with a corrosion-minimizing material such as tin, gold, tin lead, tin bismuth, nickel palladium or other suitable alloy. The bottom side of the base support 52 will be mounted to the printed circuit board (not shown). The topside of the cover 60 is exposed to the outside of the semiconductor package 50 and is generally centrally located in the top surface of the package. The mounting 57 is fabricated from a sheet of electrically and heat conducting material such as copper. Heat generated from the operation of the semiconductor chip 51 is dissipated throughout the semiconductor package and through the bottom of the base mounting pad 52 to the printed circuit board. The exposed cover 60 will aid heat dissipation. Heat will also be dissipated through the plurality of package connectors 54 . The plurality of package connectors 54 does not normally touch the base mounting pad 52 . Still referring to FIG. 2 , semiconductor package 50 has a semiconductor chip 51 attached to the base support 52 via an adhesive or suitable solder material 58 . The plurality of package connectors 54 electrically connect to the semiconductor chip 51 through a plurality of wires 53 . Each wire 53 has a first end electrically connected to one of the bond pads 56 on the top side of the semiconductor chip 51 and a second end connected to the lower portion of one of the package connectors 54 . Wires can be made of any electrically conductive material; gold aluminium or silver are common choices. Sealing material 55 preserves the spatial relationship between the cover 60 and the base support 52 , the connecting formation 59 , wires 53 , mounted semiconductor chip 51 , and semiconductor package connectors 54 . The sealing material 55 forms a rigid structure to maintain protection and form to the semiconductor package 50 and its component parts. After sealing only the areas of the base support 52 and cover 60 , lower and outer edges of the package pins 54 remain exposed allowing connection to a printed circuit board. FIG. 3 shows a top plan view of semiconductor package 50 . The cover 60 is located generally to the middle of the semiconductor package 50 . At the four edges of the semiconductor package 50 sealing material 55 is shown defining the outer edge. The sealing material 55 ensures an interlocking structure with the cover 60 . Only the upper portion of the cover 60 is exposed. FIG. 4 shows a bottom plan view of the semiconductor package 50 . As shown the base support 52 is located, generally, to the middle of the semiconductor package 50 , surrounded on four sides by a plurality of package connectors 54 . At the four edges of the semiconductor package 50 , sealing material 55 defines the outer edge. The sealing material 55 ensures an interlocking structure with the base support 52 and package connectors 54 . Only the lower exposed and plated portion of the package connectors 54 and base support 52 are visible. FIG. 5 shows a top plan view of a known MLP-type package 47 for a semiconductor package 40 . As shown the base support 42 is located generally to the middle of the semiconductor package 40 , surrounded on four sides by a plurality of package connectors 44 . FIG. 6 shows a plan view of a mounting 57 for a semiconductor package 50 according to the present invention shown in its basic state prior to bending. Support structures 74 for mounting definition are shown for two pins on the package near to where the connecting formation 59 is defined. Other tie-bars and support structures for mounting manufacture are not shown, however the plurality of package connectors 54 are shown interconnected as the case may be before trimming. Etched or scribed bend points 70 (dotted) are positioned to define the connecting formation 59 . A dashed line is shown intersecting each about the plurality of package connectors 54 . The dashed line indicates the package outer dimension after dicing. FIG. 7 shows a plan view of an array 77 of multiple individual mountings 57 for semiconductor package 50 to show how an individual mounting 57 may be manufactured from a larger area of metal material. The array 77 can be initially manufactured by a variety of process, for example, casting, etching or stamping. The array layout allows for the simple assembly of a semiconductor package. Using the array shown in FIG. 7 as an example, a semiconductor chip 51 can be mounted on individual MLP mountings 57 as shown. Semiconductor chips can be placed on each mounting using standard techniques, for example, processing the array to fix and solder the components on the mount. The processing can include solder bumping, epoxying and wire connecting. The packages can be further processed, for example using such techniques as solder reflow, injection of dielectric 55 onto the mount, semiconductor-mounting binder curing and so forth. The individual mounts are then folded through 90° along each of the fold lines 70 so that the cover 60 extends over the chip 51 , parallel to the base 52 and connectors 54 . The sealing material 55 is then injected between the cover and the chip 51 . Mountings can be separated from any supporting peripheral mounting structures and neighbouring packages by, for example, a punch or a saw that cuts along the dashed lines of FIG. 6 . Since the fold lines 70 are within the dashed lines after folding, the connecting portion 59 remains in place after cleaving. Alternatively, the individual MLPs can be cut and processed individually. FIG. 8 shows a plan view of a variation of the mounting 57 shown in FIG. 6 for a semiconductor package 50 . In the mounting shown in FIG. 8 , there are no pins on side adjacent the connecting formation 59 . Tie-bars and support structures for mounting manufacture are omitted, however the plurality of package connectors 54 for the other three sides are shown interconnected as the case may be before trimming. A semiconductor package using this type of amounting can be assembled using the same techniques described above. FIG. 9 shows a plan view of a variation of the mounting 57 for semiconductor package 50 shown in FIG. 6 . The cover 60 forms a plurality of apertures. An example, arbitrary, pattern is shown though an alternative pattern could be used. The apertures can be made in the cover 60 as and when required during the assembly process described above by cutting, etching or punching the desired pattern in the cover. The apertures could be made, for example, while the mounting is in an array of the sort shown in FIG. 7 , or afterwards, when it has been separated. FIG. 10 shows a plan view of a variation of the mounting 57 shown in FIG. 6 . In this example, there are four pins on the package side where the connecting formation 59 is defined. FIG. 11 shows a side-elevation, cross-sectional view of a second embodiment of a semiconductor package 50 according to the invention. In this embodiment, multiple semiconductor chips are integrated. There is a single mother semiconductor chip 61 and two inverted chips 62 , 63 mounted on the mother semiconductor chip 61 . The larger mother semiconductor chip 61 may be mounted first to the base support 52 . The top surface of the semiconductor chip 61 , is specifically designed to have corresponding connection pads 64 upon which to mount a plurality of smaller daughter chips 62 , 63 . Modern “flip-chip” assembly techniques are used to mount the daughter chips 62 , 63 upon the upper surface of the mother semiconductor chip 61 . The daughter semiconductor chips 62 , 63 are pre-thinned and prefabricated, perhaps at wafer level, with materials to form a plurality of “bumps” to facilitate the flip-chip connection. Singular bumps 66 are positioned at each of the connection pads 65 of the daughter die 62 , 63 . Popular methods of bumping semiconductor chips are, solder deposition/reflow or gold stud. Alternative attachment materials include anisotropic conducting materials. Under-fill material 67 may be added between the mother and daughter chips to improve reliability and thermal performance of the flip-chip bonds 66 . Some types of under-fill material 67 can be applied to the flip-chip stack either before or after the placement is made. The direct connection of electrical, and mechanical path from the daughter chips 62 , 63 to the cover 60 will aid thermal and electrical performance. The exposed cover 60 will aid heat dissipation. In this example the mother chip 61 is mounted on the base 52 using the techniques described above. Additional connection pads 64 can be fixed at the desired points on the mother chip 61 and solder bumped chips can be located on the mother chip and reflow soldered. The assembly can be cleaned if necessary to remove any debris from the reflow process. If desired, the space between the daughter chips 62 and the mother chip 61 can be filled using standard underfill techniques and materials. Alternative flip-chip techniques can be employed, such as thermocompression bonding, thermosonic bonding and using conductive adhesives. An alternative substrate material such as flex, pcb, ceramic or glass may also be used in place of the described mother semiconductor chip 61 . FIG. 12 shows a side-elevation, cross-sectional view of a third embodiment of a semiconductor package 50 . In this embodiment, as in the second embodiment shown in FIG. 11 , multiple semiconductor chips are integrated. The plurality of wires 53 in the second embodiment are replaced with through-hole vias 68 in the mother semiconductor chip 61 . The mother semiconductor chip 61 is designed with through-hole vias 68 with upper and lower capture pads 75 , which facilitate a vertical connection through to the base of the chip 61 . The through-hole via 68 and capture pads 75 may be designed to align and allow connection directly with the package connectors 54 and/or base support 52 . Multiple through-hole vias 68 may be arrayed to improve electrical connection or thermal relief. Conductive epoxy or solder material 58 is pre-deposited upon the plurality of package connectors 54 . This deposition of a conductive layer or solder 58 is made at the same time as the deposition of epoxy or solder material on the base support 52 . Upon placement of the mother semiconductor chip 61 a desired electrical connection between the underside of the mother semiconductor chip 61 and package connectors 54 and/or base support 52 is formed. An alternative substrate material such as flex, pcb, ceramic or glass may also be used in place of the described mother semiconductor chip 61 . FIG. 13 ( a ) shows a side-elevation, cross-sectional view of a defined bend line 70 in the mounting metal foil. Processes of etching and scribing are used to define a particular cross-section within the mounting metal foil which will provide a repeatable, reliable and robust mechanism for bending of the mounting to form the connecting formation 59 and cover 60 . FIG. 13 ( b ) shows a side-elevation, cross-sectional view of the same single defined bend line 70 in the mounting metal foil after being formed to an angle of 90 degrees. FIG. 14 ( a ) shows a side-elevation, cross-sectional view of two defined bend line 70 in the mounting metal foil. The bend points 70 are defined at a distance specific and relating to the desired height of connecting formation 59 and separation from base support 52 and cover 60 . Processes of etching and/or scribing are used to define a particular cross-section within the mounting metal foil which will provide a repeatable, reliable and robust mechanism for bending of the mounting to form the connecting formation 59 and cover 60 . FIG. 14 ( b ) shows a side-elevation, cross-sectional view of same two defined bend line 70 in the mounting metal foil after each is bent through to an angle of 90 degrees. FIGS. 13 ( b ) and 14 ( b ) show the bend line feature formed by the removal of material from the outer side of the bend. There are advantages to methods of bending with the etched or scribed line 70 on the inner side of the bend. One advantage of this is that it allows greater control over the bending action. This is because the two sides of the etched or scribed line come into contact at a predetermined bending angle and stop the bending at that angle. Angles other than 90 degrees can be used. For example three bends of 60 degrees each could be used. FIG. 15 shows a side-elevation, cross-sectional view of the second embodiment of the present invention, a semiconductor package 50 mounted to a printed circuit board 73 . A thermally conductive material 71 is deposited upon the top surface (cover 60 ) of the package and used to dissipate heat. The thermally conductive material 71 is shown deposited so that it makes contact to a suitable casing or body 72 of the final product. Open arrows depict the general dissipation of heat energy away from the package. Further embodiments of the invention use flip-chip bonding techniques. Before discussing these further embodiments in detail, the prior art flip-chip-onto-leadframe-pin MLP-type semiconductor package is discussed below. FIG. 16 shows a cross-sectional view of a known flip-chip-onto-leadframe-pin MLP package. A top plan view of the same prior art mounting or leadframe for a flip-chip-onto-leadframe-pin QFN package is shown in FIG. 17 . With reference to FIG. 16 , here the semiconductor die has been “bumped” using standard techniques to provide physical and electrically conductive connection to each of its signal pads. As previously mentioned above, popular methods of implementing the conductive bumps 66 are by gold stud, deposited and reflowed solder or deposited conductive column structures. The die has then been flipped over and mounted directly to the leadframe package pins using recognised methods. The package is moulded and diced using standard processes. With reference to FIG. 17 , the mounting 7 is designed with elongated peripheral pins making the desired connection from package edge to underneath the semiconductor die. In this type of “flip-chip-onto-leadframe-pin” MLP package, the base die mounting pad used in wirebonded QFN packages is often removed to allow the inward extension of the peripheral package signal pads under the die. This also improves access for mould material. Although not shown, it is also possible to have a base pad present allowing multiple connections under the chip. Thermal performance is improved through such an array of bumps connecting to this pad. FIGS. 18 to 22 illustrate further aspects of the invention applied particularly to flip-chip mounting in packages. Like numerals refer to like features. With reference to FIG. 18 , here is shown a cross-sectional view of an embodiment of a flip-chip-onto leadframe-pin MLP package, according to the invention. A plan view of the mounting design for the embodiment of FIG. 18 is shown in FIG. 19 . Referring to FIG. 18 , here, as with the prior art, a pre-bumped semiconductor die 41 has been flipped and mounted onto the base mounting pins 44 . Here the embodiment improves upon the prior art by providing an additional, exposed top pad heatsink and EMI shield. The top metal pad 60 is formed and attached to the back of the die 41 using standard materials such as solder paste or conductive adhesives. The side view of a half-etched support structure 72 is shown extending and anchoring the top pad and pins. This can be seen more clearly in FIG. 19 . Referring to FIG. 19 , the mounting design for the embodiment is shown with the top die pad 60 lying flat. The top pad and bend structures 74 are mechanically supported by mounting material structures. FIG. 20 shows a further embodiment of a flip-chip-onto-leadframe-pin package, where a base pad 52 is present thus enabling multiple die connections under the chip 51 . Thermal performance is improved through the flip-chip bumps connecting to this pad. FIG. 21 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with a heatsink die. This embodiment is intended for use where extra thermal dissipation is required. The embodiment shown in FIG. 21 has an additional “die” 80 of thermally conductive material mounted upon the surface of the semiconductor die 51 . A thermally conductive adhesive can be used to fix the thermally conductive material to the surface of the semiconductor chip 51 . The thermally conductive material could be a diced piece of metal, such as copper, or a non-electrically conducting elastomeric material. The thermally conductive material may also be placed upon the upper face of the top pad, while flat and prior to leadframe bending. A half-etch recess (not shown) may also be defined to aid alignment of the thermally conductive die. In the example shown, the process for assembling the package is substantially the same as described for other embodiments, but with the additional step of placing the die 80 onto the chip 51 before the cover is folded over. Thermal performance is thereby improved by providing a low thermally resistive path to the top and bottom package boundaries. This method is particularly suitable for medium to large sized die where there is sufficient surface area to safely mount the die of thermally conductive material without disrupting peripheral wirebonds. As previously shown in and discussed for FIG. 11 , die may be stacked. FIG. 22 shows a further embodiment of the invention where multiple (four-shown) semiconductor die 51 a - d have been stacked using a combination of standard assembly techniques such as flip-chip and wirebond. FIG. 22 shows a cross-section dissecting the package centre. The package provides both a thermally enhanced and EMI screened MLP packaging solution for multiple chips. The top die 51 d (flip-chip mounted) has a direct connection the package's top metal pad thus providing an excellent route to dissipate heat away from the die stack. This type of package can be assembled in the same manner as for a single chip package but with the following additional steps. After the first chip 51 a has been mounted a variety of techniques can be used to mount the other chips, including thinned die, thinned die attach and spacing methods, and low-profile wire bonding techniques. The additional chips can stacked face up and wire bonded, as for 51 b and 51 c . The chips can also be flip-chip mounted as detailed above. The chips may be wire bonded onto a common package, as shown here, or wire bonded die-to-die. Edge connectors (not shown) can also be used to connect multiple dies to a common mounting. Vias in the chips could also be used to provide interconnection. The finished leadframe package can itself be stacked. Further aspects of the invention incorporate surface mount technology (SMT) and passive components into the MLP package. FIG. 23 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with integrated SMT passive components, in this example a leadframe based System-in-Package (SiP) solution. As discussed above the MLP package can be equipped with a top metal pad cover 60 . Recesses 84 , here indicated by a dotted line, can be defined in the cover. The recess can extend the cover to provide a connection to the SMP passive The package is assembled in the manner described above. Discrete components such as surface mount capacitors or resistors are arranged to fit within these recesses. These components may be supportive to the correct function of the semiconductor die. Integrated passive networks can be deployed using, for example, ceramic substrate, GaAs or silicon thin film technology. Such integrated passive networks are often used in filter circuits and other RF applications. The profile of the recesses 84 cut in the top pad can be varied to provide sufficient depth for the passive components to be fixed in place. FIG. 24 , for example, shows how a recess 84 has been cut in the package's top metal pad, adapting it to give sufficient clearance to allow the larger support components and secondary die to retain the accepted standard height. The embodiment shown can be further modified to form a simultaneous electrical connection to both the package top pad and a bottom signal pin enhancing thermal performance and EMI protection. Further embodiments of the invention incorporate enhanced EMI features into the MLP package. A cross-sectional and plan view of an EMI enhanced package and its mounting are shown respectively in FIGS. 25 and 26 . In these examples, the top metal pad 60 has been enlarged and fabricated with additional fold lines 86 using the same process as that used to define the bend points discussed previously, for example for FIGS. 9 and 10 . The fold lines define sidewalls 88 . In the embodiment shown in FIGS. 25 and 26 , the leadframe top metal pad 60 , while still flat, can be shaped by various means, for example a mechanical stamp tool, to form the sides and the base of an up-turned open box. After subassembly, the formed box could, as with the principal embodiment's top metal pad, be bent up and over the mounted die subassembly. The combined box shape and interconnecting vertical structure equipped with the key bend points act as an electrically grounded EMI shield. As shown in FIG. 26 , the boxed sidewalls 88 could be designed to maintain clearance or, where contact is required, provide a good electrical connection to the perimeter or centre ground pads of the leadframe base. With reference to FIG. 26 , the larger top pad with defined fold lines is shown lying flat. The final package dimension is indicated by dashed lines. Defined bend points are indicated by dotted lines. Perimeter cut-outs or reliefs can be designed to optimise space around sensitive electrical pins. The top metal pad is equipped with sidewalls 88 which are arranged to allow sufficient access for the plastic mould material. The assembly of the enhanced EMI protection package shown in FIGS. 25 and 26 follows the same steps as the other packages described above but with an additional step of bending the cover 60 at bend lines 88 to form the sidewalls 88 . FIGS. 27 to 36 illustrate further aspects of the invention featuring an aperture in the MLP package, where it is advantageous to gain access by various means to the surface of the semiconductor chip. In particular, FIGS. 27 to 34 show embodiments for the packaging of image sensor semiconductor chips 91 for use in imaging systems, for example digital camera applications. Such devices require a window 96 in the package allowing light to fall onto the chip surface. Image sensor chips are equipped with arrays of receptors capable of capturing the light and passing this information as an electrical signal to the system. The cover 98 is equipped with an aperture to provide a semi-rigid frame or support for the holding and mounting of the glass and/or lens. The package offers an optimised, cheap and low profile solution overcoming many of the assembly issues reported by image sensor manufacturers. For example, correct alignment of components such as lenses in optical systems is important to quality control. Furthermore, assembly of the different components needed to make such an optical system can be intricate and time consuming, increasing manufacturing costs. FIG. 27 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an aperture feature. In this example, a “die” 100 of transparent material has been fixed upon the surface of the semiconductor chip using standard assembly techniques. Here a half-etch recess 102 has been used to aid glass die alignment and adhesion. The transparent material could be a cut piece of glass, a pre-shaped lens, a combination of both of these. The package body mould material could also be transparent. FIGS. 28 and 29 respectively show a square or round “window” 96 could be defined in the top metal pad. If a square glass die (for example IR filter, Borosilicate, or pre-shaped lens) is used it may be placed upon the upper or lower face of the top pad, while flat, and prior to leadframe bending, thus simplifying the assembly process for this type of device. This type of package construction is particularly suitable for medium-larger sized die where there is sufficient chip area to safely mount the glass die without disrupting peripheral wirebonds. A transparent epoxy of a similar refractive index to the glass is recommended for fixing the glass to the semiconductor and leadframe surfaces. FIG. 30 shows a side elevation, cross-sectional view of an MLP-type package according to the invention with an aperture feature fitted with a lens 104 . In this example, showing the cross-sectional ellipse of a lens made of transparent material, the lens has been fixed to the outer surface of the top metal pad using standard assembly techniques. A half-etch recess 106 around the aperture has been used to aid lens alignment and adhesion. The space between the lens underside and semiconductor chip surface is filled with a transparent material 108 such as an epoxy. The semiconductor and lens package can be assembled from a mounting with an aperture in the top pad as follows. A semiconductor chip 91 can be placed on a mounting using the standard techniques described before. The individual mounts are then folded through a nominal angle of 90° along each of the fold lines 70 so that the cover 98 extends over the chip 91 , parallel to the base 52 and connectors 54 . The transparent material, 108 can be injected to fill the void between the chip 91 and aperture 96 . Alternatively it can be applied to the chip 91 before folding of the mounting. The sealing material 55 is then injected between the cover and the chip 91 . The lens 104 is then fixed to the assembly, using the recess 106 to align the lens correctly to the chip 91 . FIG. 31 shows a top plan view of a round “window” 96 can be defined in a double metal pad 110 arrangement. FIGS. 32 and 33 shows how this double pad 110 in the leadframe can be alternatively formed to hold a square glass die 98 and/or pre-shaped (round) lens 102 . This general method and form for holding a single square glass die and/or pre-shaped lens may be extended to provide a structure to hold multiple lenses or die. This type of assembly can be used where there is a need for a complex lens/optical system assembly, for example, combining lenses with optical filters. The packages shown in FIGS. 32 and 33 offer an improved method of assembly. As before, beginning from a flat mounting, for example that shown in FIG. 31 , the chip is fixed and connected to the mounting and the square die attached to the chip 91 . The lens 102 is placed on the double pad 110 , on the round aperture 92 . The lens can be secured into place using the recess 106 for alignment. The double pad is folded along fold lines 70 as before, bending a first pad over the chip 91 and die 98 as previously described. The portion holding the lens 102 is then bent back over the first pad such that the lens is held between the first and second top pads. The two apertures in the pad are aligned such that the edges of the aperture of the lower top pad form lower edges to align the lens. This procedure allows the lens assembly to be easily assembled and correctly aligned. Furthermore, the open aperture type of MLP package can be deployed in sensor applications, for example for use in biometrics applications. FIGS. 34 and 35 show two such embodiments of the invention for biometrics systems. In FIG. 35 the top metal pad is attached directly to the chip 111 using standard materials and techniques. The top surface 112 of the chip is exposed. In many biometrics applications the top surface 112 of a protective coated semiconductor chip 111 needs to be exposed to allow an interface with the “real world”. An example is a fingerprint identification chip where the user's finger is placed upon the surface of the die. The frame is designed to fully expose the semiconductor die sensor array without causing disruption to the peripheral wirebonds. An alternative sensor embodiment is shown in FIG. 36 . This figure shows a side elevation, cross-sectional view of an MLP-type package with exposed die feature and gel-filled cavity 116 . This configuration can be used in, for example, pressure sensing applications. In such a pressure sensor the interface gel material 116 acts as a medium to track environmental pressure changes to the surface of the semiconductor chip. The gel material also acts to protect the sensitive die surface. The inventions top metal pad is used to provide a supportive frame and desired opening allowing accurate forming of the gel material 116 . The sensor package may be pre or post-moulded using the techniques previously described. The frame and gel window is configured to allow sufficient gel material to access the semiconductor die pressure sensor. In a further embodiment, the cover of a chip package can be tailored to specific applications and needs, as illustrated in FIGS. 37 to 43 . For example, FIG. 37 shows the further embodiment where the package is equipped with an internal top metal pad 60 acting as an EMI shield. The top metal pad structure 60 is surrounded by the mould material 55 and no external exposure of the top pad is provided. The mould material defines the outer boundary of the top of the package. FIG. 38 shows a side elevation, cross-sectional view of an MLP-type package with a partially exposed top metal pad EMI shield. In this example the package is equipped with a partially exposed top metal pad 60 . The top metal pad 60 provides a combined EMI shield and heat sink, shown here patterned with trenches 112 using the standard leadframe half-etch processes. The pattern formed by the trenches found in its outer surface 112 is designed to allow a controlled mould material ingress, improving manufacturability, and reliability by retaining the cover in place in the package. The patterned surface allows for improved interlocking of the pad 60 and mould material 55 . The highest points of the patterned top pad can be arranged to remain exposed after moulding. A partial external exposure of the top pad is therefore provided. The top pad pattern may be designed to still provide sufficient exposed metal for access to the top metal pad. The mould material partially defines the outer boundary of the top of the package. Package reliability is enhanced through the use of the extra anchor points provided at the patterned upper side of the top metal pad. FIG. 39 shows the cross-section of a package with the patterned trenches 126 underside of the top metal pad 60 . Reliability of the package structure may be enhanced through the use of a patterned underside of the top metal pad, allowing improved integrity of the mould and frame structure. The pattern could be designed as a combined series of half-etch channels, fully etched holes or full thickness recesses. The design of the pattern can optimised for mould access and flow and to avoid air/gas bubbles. Other materials can also be combined in the MLP assembly. For example, FIG. 40 shows how a glob-top 130 or other suitable dielectric fill material may be dispensed over the active die surface and other subassembly structures (for example, wirebonds), prior to bending the top metal pad. This provides additional structural protection for the chips mounted in the package. The electromagnetic coupling capabilities of the MLP package can also be further enhanced. For example, FIG. 41 shows how apertures or slots 130 are formed within the top metal pad to permit the electromagnetic coupling of waves of a certain frequency (wavelength) through the top metal pad. This structure may be of advantage for the mounting for a radio system's antenna or electromagnetic coupling to other popular microwave components such as filters and waveguides. FIGS. 42 and 43 show how further stack constructions can be used to optimise thermal, electrical and EMI shielding in a multiple die stack. Here two chips 132 are shown mounted conventionally and a third chip 134 is flip-chip mounted and connected to them. The basic design of having a top metal pad is unchanged. In FIG. 42 the base die attach pad has been etched to a partial thickness using the techniques already discussed and FIG. 43 shows how solder spheres may be used to connect a mother die to the peripheral package pads. The EMI shielding discussed above can be adapted to meet the appropriate government regulations and to further meet the operating requirements of the mounted semiconductor assembly, for example to provide immunity from other interfering RF signals or allow operation of RF circuitry within the package. The package and mounting can be adapted to meet appropriate regulations for various and known wireless standards. Furthermore, such RF SiP solutions as discussed above can provide for integrated antenna means in the cover 60 . The MLP packaging described above can be further adapted to include useful structures and functions. For example, FIG. 44 shows how the top metal pad 60 can be defined with apertures to provide an inductive element 154 . In this example, a semiconductor chip 150 is shown mounted with its wirebonds 152 connecting the chip to peripheral base pins. The top pad structure 60 is etched in a serpentine pattern 154 to form a serpentine inductor. The inductor is formed about the two connecting formations 59 equipped with defined bend points 70 , (indicated by dotted lines) and thus sits above the mounted semiconductor once the package has been assembled as described above. The example shown in FIG. 44 shows how the continuous serpentine path of the top metal pad 60 is designed to electrically and physically connect to peripheral or package base pins through two connecting formations 59 equipped with defined bend points. This connecting method provides a robust, reliable and low resistance connection to the inductive element 150 the two connecting formations may also be used to define the final package height. Situating the inductive element in a parallel, upper plain above the semiconductor chip assembly and base/peripheral package pins further reduces the component package area. The package design in the example shown in FIG. 44 also shows how wirebonds, or alternatively flip-chip connections, can be used to electrically connect the semiconductor chip to the peripheral package pins and base pads for connection to the inductive element. When connected to a system neutral RF, for example, Ground or direct current Voltage Supply, the upper plain inductive element has the additional advantage of functioning as an integrated EMI shield and heatsink/heatspreader, as previously described above. It is further possible to combine the inductive element with a further metal pad, as shown in FIG. 45 . In this example a second top metal pad 160 may be formed to fit over the semiconductor chip assembly and the inductive element. Electrical and physical isolation between the inductor and shield would be maintained. The separation between bend points in the single connecting formation connecting the top metal pad to the semiconductor ship die attach pad is greater than between those on the connecting formations for the inductor to provide sufficient final package height and to ensure that the cover is spaced from the inductor. This approach to integrating inductive elements into the package can also be used for integrating other passive components such as capacitors, for example interdigitated capacitors. It would also be possible to extend the approach to help integrate other components such as microstrip couplers and filters. FIG. 46 is a table of results of electromagnetic interference simulations for the package design shown in FIG. 2 . A series of comparative simulations were conducted on a standard package with no top metal pad and the improved package with the top metal pad 60 acting as a shield. Using recognised methods of emission type EMI simulation, monitor points were distributed at representative positions surrounding the package. The packages shown in the above examples can be demonstrated to provide a local EMI shield. The simulations show improvements in shield effectiveness of approximately 10 dB at application frequencies of up to 10 GHz for the E field, and of approximately 20 dB for the H field. Effective EMI shielding is important for meeting regulations on electromagnetic emissions, especially considering the higher frequencies at which modern electronics equipment operates. It will be appreciated that several design factors, such as the spacing between the cover or top pad and the semiconductor chip, and the overhang of the top pad, can be optimized to improve shielding effectiveness. Further simulated results for larger packages have shown improved results for shield effectiveness up to 40 dB at frequencies of up to 10 GHz. Computer simulations of thermal dissipation in the package show improvements over conventional packages. The structure and immediate environment of the package was simulated using computational fluid dynamics software. The die sizes, materials and constant power dissipations assumed are given in the table of FIG. 47 . FIG. 48 is a table of results of thermal simulations for the multiple stacked die in a package as shown in FIG. 11 . In this example two daughter die are flip-chip mounted onto a third mother die. In such a package the top metal pad would be attached to the rear top side of the daughter die using conductive epoxy and the mother die would be attached to the package using conductive epoxy. As can be seen from the table, the heat dissipation simulations show improvements in heat dissipation of approximately 21 degrees C., an improvement of 22%, in the daughter chips 62 , 63 compared to standard packaging configurations. The thermal energy produced by the daughter die is dissipated through the packages internal structure to the printed circuit board. By improving the thermal dissipation qualities of the packaging it is possible to mount more semiconductor chips that consume more power and therefore generate more heat. For example, it would be possible to drive semiconductor chips at higher speeds without failure due to overheating. detailed-description description="Detailed Description" end="tail"?

20060616

20110201

20070719

95587.0

H01L2302

TRAN, THIEN F

SEMICONDUCTOR PACKAGE WITH INTEGRATED HEATSINK AND ELECTROMAGNETIC SHIELD

SMALL

ACCEPTED

H01L

ACCEPTED

Methods and Apparatus for Multi-Carrier Communications with Variable Channel Bandwidth

Methods and apparatus for multi-carrier communication with variable channel bandwidth are disclosed, where the time frame structure and the OFDM symbol structure are invariant and the frequency-domain signal structure is flexible. In one embodiment, a mobile station, upon entering a geographic area, uses a core-band to initiate communication and obtain essential information and subsequently switches to full operating bandwidth of the area for the remainder of the communication. If the mobile station operates in a wide range of bandwidths, the mobile station divides the full range into sub-ranges and adjusts its sampling frequency and its FFT size in each sub-range.

1. In a variable bandwidth wireless communication system capable of communicating under multiple different communication schemes that each have a different bandwidth, a process of generating an information bearing signal for wireless transmission, the process comprising: utilizing a specified number of subcarriers to construct a channel with a particular bandwidth; utilizing subchannels that include groups of subcarriers; providing a fixed time-domain signal structure, including symbol length; maintaining a substantially constant ratio between a sampling frequency and a size of FFT (Fast Fourier Transform) and IFFT (Inverse Fast Fourier Transform) or a fixed spacing between adjacent subcarriers; adding or subtracting some of the subcarriers or subchannels to scale the channel and achieve a required bandwidth; and wherein a core-band, substantially centered at an operating center frequency of the different communication schemes, is utilized for radio control and operation signaling, where the core-band is substantially not wider than a smallest possible operating channel bandwidth of the system. 2. The process of claim 1, wherein the wireless signal is: transmitted by a mobile station in a multi-cell, multi-base-station environment; a multi-carrier code division multiple access (MC-CDMA) or an orthogonal frequency division multiple access (OFDMA); and utilized with downlink, uplink, or both, where a duplexing technique is either Time Division Duplexing (TDD) or Frequency Division Duplexing (FDD). 3. The process of claim 1, wherein the wireless signal has a primary preamble sufficient for basic radio operation, and wherein: the primary preamble is a direct sequence in the time domain with a frequency content confined within the core-band or is an OFDM symbol corresponding to a particular frequency pattern within the core-band; and properties of the primary preamble comprise: a large correlation peak with respect to sidelobes, in case of an autocorrelation; a small cross-correlation coefficient with respect to power of other primary preambles, in case of a cross-correlation with other primary preambles; and a small peak-to-average ratio; and wherein a large number of primary preamble sequences exhibit such properties. 4. The process of claim 3, wherein an auxiliary preamble, occupying the side-band, is combined with the primary preamble to form a full-bandwidth preamble in either the time domain or the frequency domain, wherein the side-band is the difference between the core-band and an operating bandwidth, and wherein: the auxiliary preamble is either a direct sequence in the time domain with a frequency response confined within the side-band, or is an OFDM symbol corresponding to a particular frequency pattern within the side-band; the full-bandwidth preamble allows a base station to broadcast the full-bandwidth preamble and a mobile station to use the primary preamble of the full-bandwidth preamble to access the base station; and properties of the full-bandwidth preamble sequence comprise: a large correlation peak with respect to sidelobes, in case of an autocorrelation; a large ratio between the correlation peak and sidelobes, in case of a correlation with the primary preamble of the full-bandwidth preamble. a small cross-correlation coefficient with respect to power of other full-bandwidth preamble sequences, in case of cross-correlation with other full-bandwidth preambles a small cross-correlation coefficient with respect to the power of the full-bandwidth preamble, in case of cross-correlation with a primary preamble different from the primary preamble of the full-bandwidth preamble; a small peak-to-average ratio; and wherein a large number of full-bandwidth preamble sequences exhibit such properties. 5. The process of claim 1, wherein for a wide range of system bandwidths the bandwidth range is divided into smaller ranges, where the lowest range of bandwidth is a fundamental range and other ranges are higher ranges, and wherein in a higher range: the sampling frequency is a multiple of the sampling frequency of the fundamental range and the corresponding FFT length is multiplied by a substantially same factor as the sampling frequency is multiplied by, to maintain time duration of the OFDM symbol structure; the FFT length is maintained and the OFDM symbol duration is shortened accordingly; or the FFT length is increased and the OFDM symbol duration is shortened accordingly; and wherein the width of the core-band is less than or equal to a smallest bandwidth in the fundamental range. 6. In a variable bandwidth communication network of base stations and mobile stations, wherein a signal utilizes subchannels that include groups of subcarriers, a method of adjusting a mobile station bandwidth to an operating bandwidth of a base station, the method comprising: maintaining a fixed time-domain signal structure; maintaining a substantially constant ratio between a sampling frequency and a size of FFT (Fast Fourier Transform); adjusting a number of subcarriers or subchannels to scale a channel and attain a desired bandwidth; utilizing a core-band, substantially centered at an operating center frequency, for radio control and operation signaling, wherein the core-band is not wider than a smallest possible operating channel bandwidth of the network; and a configuration wherein the mobile station, upon entering an area, scans spectral bands of different center frequencies and upon detecting a signal in a spectral band of a center frequency: determines the operating channel bandwidth by a center-frequency-to-bandwidth-mapping; or decodes the bandwidth information provided to the mobile station via downlink signaling. 7. The method of claim 6, wherein the center-frequency-to-bandwidth-mapping employs a table look-up and the information provided to the mobile station via downlink signaling is in a broadcasting channel or preamble and is transmitted within the core-band. 8. The method of claim 6, wherein the signal is a multi-carrier code division multiple access (MC-CDMA) or an orthogonal frequency division multiple access (OFDMA), and the signal is utilized with downlink, uplink, or both, where a duplexing technique is either Time Division Duplexing (TDD) or Frequency Division Duplexing (FDD). 9. The method of claim 6, wherein the signal has: a primary preamble, sufficient for basic radio operation, which is a direct sequence in the time domain with a frequency content confined within the core-band or is an OFDM symbol corresponding to a particular frequency pattern within the core-band; and an auxiliary preamble which occupies side-bands and is combined with the primary preamble to form a full-bandwidth preamble, and wherein the auxiliary preamble is either a direct sequence in the time domain with a frequency response confined within side-bands or is an OFDM symbol corresponding to a particular frequency pattern within side-bands, where the side-bands are the difference between the core-band and the operating bandwidth. 10. The method of claim 6, wherein for a wide range of operating bandwidths the bandwidth range is divided into smaller ranges, where the lowest range of bandwidth is a fundamental range and other ranges are higher ranges, and wherein in a higher range: the sampling frequency is a multiple of the sampling frequency of the fundamental range and the corresponding FFT size is multiplied by a substantially same factor as the sampling frequency has been multiplied by, to maintain time duration of the OFDM symbol structure; the FFT size is maintained and the OFDM symbol duration is shortened accordingly; or the FFT size is increased and the OFDM symbol duration is shortened accordingly; and wherein the width of the core-band is less than or equal to a smallest bandwidth in the fundamental range. 11. In a variable bandwidth communication network wherein a communication signal utilizes subchannels that are composed of groups of subcarriers, a mobile transceiver with an adaptable bandwidth, the transceiver comprising: an analog-to-digital converter for signal sampling; a Fast Fourier Transform and Inverse Fast Fourier Transform processor (FFT/IFFT), wherein a substantially constant ratio is maintained between a sampling frequency and a size of the FFT/IFFT; a scanner for scanning spectral bands of specified center frequencies, upon entering an area, to find a signal and to determine an operating channel bandwidth; a facility for sustaining a core-band for pertinent communications, wherein the core-band is not wider than smallest possible operating channel bandwidth of the network; and a facility for adding to the subcarriers to widen the channel bandwidth for remainder of the communication. 12. The transceiver of claim 11, wherein the center-frequency-to-bandwidth-mapping employs a table look-up and the information provided to the mobile transceiver as downlink information is in a broadcasting channel or preamble. 13. The transceiver of claim 11, wherein the signal is a multi-carrier code division multiple access (MC-CDMA) or an orthogonal frequency division multiple access (OFDMA), and the signal is utilized with downlink, uplink, or both, where a duplexing technique is either Time Division Duplexing (TDD) or Frequency Division Duplexing (FDD). 14. The transceiver of claim 11, wherein for a wide range of operating bandwidths the bandwidth range is divided into smaller ranges, where the lowest range of bandwidth is a fundamental range and other ranges are higher ranges, and wherein in a higher range: the sampling frequency is a multiple of the sampling frequency of the fundamental range and the corresponding FFT/IFFT size is multiplied by a substantially same factor as the sampling frequency is multiplied by, to maintain time duration of the OFDM symbol structure; the FFT/IFFT size is maintained and the OFDM symbol duration is shortened accordingly; or the FFT/IFFT size is increased and the OFDM symbol duration is shortened accordingly; and wherein the width of the core-band is less than or equal to a smallest bandwidth in the fundamental range. 15. The transceiver of claim 11, wherein the transceiver is a mobile station and the communication network is a wireless network of base stations and mobile stations. 16. The transceiver of claim 11, wherein the signal has: an essential preamble, sufficient for basic radio operation, which is a direct sequence in the time domain with a frequency content confined within the core-band or is an OFDM symbol corresponding to a particular frequency pattern within the core-band; and an auxiliary preamble which occupies side-bands and is combined with the essential preamble to form a full-bandwidth preamble, and wherein the auxiliary preamble is either a direct sequence in the time domain with a frequency response confined within side-bands or is an OFDM symbol corresponding to a particular frequency pattern within side-bands, where the side-bands are the difference between the core-band and the operating bandwidth. 17. The transceiver of claim 11, wherein the transceiver uses the core-band during an initial communication stage and the operating bandwidth during normal operation, and wherein upon entering into an area, the mobile transceiver starts with the core-band and switches to the operating bandwidth for additional data and radio control subchannels. 18. An apparatus for use in a communication system, the apparatus comprising: a mobile station with an FFT (Fast Fourier Transform) facility configured to: divide a wide range of operating bandwidths into smaller bandwidth ranges, wherein a width of a predetermined band for basic system information communication is less than or substantially equal to the smallest operating bandwidth of any of the bandwidth range, and wherein in a bandwidth range: a sampling frequency is a multiple of a sampling frequency of the lowest bandwidth range and the FFT is sized corresponding to the sampling frequency, to maintain time duration of an OFDM symbol structure; the FFT size is maintained and the OFDM symbol duration is shortened accordingly; or the FFT size is increased and the OFDM symbol duration is shortened accordingly; scan spectral bands, when entering an area, to determine the operating bandwidth upon detecting a signal in a spectral band; and switch to the operating bandwidth by adding subcarriers to transmitting signals, wherein a specified number of subcarriers form a channel with a particular bandwidth. 19. The system of claim 18, wherein determining the operating bandwidth is by table look-up or down-link signaling. 20. In a variable bandwidth communication network of base stations and mobile stations, wherein a signal utilizes subchannels that include groups of subcarriers, a means for adjusting a mobile station bandwidth to an operating bandwidth of a base station, the means comprising: means for maintaining a fixed time-domain signal structure; means for maintaining a substantially constant ratio between a sampling frequency and a size of FFT (Fast Fourier Transform); means for adjusting the number of subcarriers or subchannels to scale the channel and attain a desired bandwidth; means for utilizing a core-band, substantially centered at an operating center frequency, for essential communications, wherein the core-band is not wider than smallest possible operating channel bandwidth of the network; and means for scanning spectral bands of different center frequencies, detecting a signal in a spectral band of a center frequency, and determining the operating channel bandwidth of an area. 21. In an adaptive variable bandwidth wireless communication system capable of communicating under multiple different communication schemes that each have a different bandwidth, a signal for wireless transmission, the signal comprising: subcarriers, wherein a specified number of subcarriers constitute a channel with a particular bandwidth; a fixed time-domain signal structure; a core-band utilized for radio control and operation signaling, where the core-band is substantially not wider than a smallest possible operating channel bandwidth of the system; and a configuration wherein: a substantially constant ratio between a sampling frequency and a size of FFT (Fast Fourier Transform) and IFFT (Inverse Fast Fourier Transform) of the signal or a fixed spacing between adjacent subcarriers is maintained; and at least some of the subcarriers are added or subtracted to scale the channel and achieve a required bandwidth.

CROSS-REFERENCE TO RELATED APPLICATION(S) This application claims the benefit of U.S. Provisional Patent Application No. 60/567,233, filed on May 1, 2004. This application also relates to PCT Application No. PCT/US2005/001939 filed Jan. 20, 2005, which claims the benefit of U.S. Provisional Application No. 60/540,032 filed Jan. 29, 2004; PCT Application No. PCT/US2005/004601 filed Feb. 14, 2005, which claims the benefit of U.S. Provisional Application No. 60/544,521 filed Feb. 13, 2004; PCT Application No. PCT/US2005/003889 filed Feb. 7, 2005, which claims the benefit of U.S. Provisional Application No. 60/542,317 filed Feb. 7, 2004; and PCT Application No. PCT/US2005/008169 filed Mar. 9, 2005, which claims the benefit of U.S. Provisional Application No. 60/551,589 filed Mar. 9, 2004. BACKGROUND While it is ideal for a broadband wireless communication device to be able to roam from one part of the world to another, wireless communication spectra are heavily regulated and controlled by individual countries or regional authorities. It also seems inevitable that each country or region will have its own different spectral band for broadband wireless communications. Furthermore, even within a country or region, a wireless operator may own and operate on a broadband spectrum that is different in frequency and bandwidth from other operators. The existing and future bandwidth variety presents a unique challenge in designing a broadband wireless communication system and demands flexibility and adaptability. Multi-carrier communication systems are designed with a certain degree of flexibility. In a multi-carrier communication system such as multi-carrier code division multiple access (MC-CDMA) and orthogonal frequency division multiple access (OFDMA), information is multiplexed on subcarriers that are mutually orthogonal in the frequency domain. Design flexibility is a result of the ability to manipulate parameters such as the number of subcarriers and the sampling frequency. For example, by using a different sampling frequency, a DVB-T (Digital Video Broadcasting-Terrestrial) device is capable of receiving signals broadcasted from a DVB-T station that is operating on a 6-, 7-, or 8-MHz bandwidth. However, the change in the time-domain structure brings about a series of system problems. A varying sampling rate alters the symbol length, frame structure, guard time, prefix, and other time-domain properties, which adversely affects the system behavior and performance. For example, the MAC layer and even the layers above have to keep track of all the time-domain parameters in order to perform other network functions such as handoff, and thereby the complexity of the system will exponentially increase. In addition, the change in symbol length causes control and signaling problems and the change in the frame structure may cause unacceptable jitters in some applications such as voice over IP. A practical and feasible solution for multi-carrier communication with variable channel bandwidth is desirable. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic presentation of a radio resource divided into small units in both the frequency and time domains: subchannels and time slots. FIG. 2 illustrates a relationship between sampling frequency, channel bandwidth, and usable subcarriers. FIG. 3 shows a basic structure of a multi-carrier signal in the frequency domain, made up of subcarriers. FIG. 4 shows a basic structure of a multi-carrier signal in the time domain, generally made up of time frames, time slots, and OFDM symbols. FIG. 5 shows a cellular wireless network comprised of a plurality of cells, wherein in each of the cells coverage is provided by a base station (BS). FIG. 6 illustrates a variable channel bandwidth being realized by adjusting a number of usable subcarriers, whose spacing is set constant. FIG. 7 depicts a time-domain windowing function applied to OFDM symbols to shape the OFDM spectrum to conform to a given spectral mask. FIG. 8 depicts a preamble designed to occupy either an entire operating bandwidth or a core-band. FIG. 9 shows an entire range (e.g., from 5 Mhz to 40 MHz) of bandwidth variation being divided into smaller groups or trunks (e.g., 5-10 MHz, 10-20 MHz, 20-40 MHz, in sizes), wherein each trunk is handled in one particular range. FIG. 10 illustrates a multi-cell, multi-user cellular system comprising multiple base stations and mobile stations. DETAILED DESCRIPTION The multi-carrier system mentioned here can be of any format such as OFDM, or Multi-Carrier Code Division Multiple Access (MC-CDMA). The presented methods can also be applied to downlink, uplink, or both, where the duplexing technique is either Time Division Duplexing (TDD) or Frequency Division Duplexing (FDD). The following description provides specific details for a thorough understanding of the various embodiments and for the enablement of one skilled in the art. However, one skilled in the art will understand that the invention may be practiced without such details. In some instances, well-known structures and functions have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. The terminology used in the description presented below is intended to be interpreted in its broadest reasonable manner, even though it is being used in conjunction with a detailed description of certain specific embodiments of the invention. Certain terms may even be emphasized below; however, any terminology intended to be interpreted in any restricted manner will be overtly and specifically defined as such in this Detailed Description section. Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise,” “comprising,” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to.” Words using the singular or plural number in this Detailed Description section also include the plural or singular number respectively. Additionally, the words “herein,” “above,” “below” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of this application. When the claims use the word “or” in reference to a list of two or more items, that word covers all of the following interpretations of the word: any of the items in the list, all of the items in the list and any combination of the items in the list. Multi-Carrier Communication System The physical media resource (e.g., radio or cable) in a multi-carrier communication system can be divided in both the frequency and time domains. This canonical division provides a high flexibility and fine granularity for resource sharing. FIG. 1 presents a radio resource divided into small units in both the frequency and time domains—subchannels and time slots. The subchannels are formed by subcarriers. The basic structure of a multi-carrier signal in the frequency domain is made up of subcarriers. For a given bandwidth of a spectral band or channel (Bch) the number of usable subcarriers is finite and limited, whose value depends on a size of an FFT (Fast Fourier Transform) employed, a sampling frequency (fs), and an effective bandwidth (Beff). FIG. 2 illustrates a schematic relationship between the sampling frequency, the channel bandwidth, and the usable subcarriers. As shown, the Beff is a percentage of Bch. A basic structure of a multi-carrier signal in the frequency domain is made up of subcarriers and, illustrated in FIG. 3, which shows three types of subcarriers as follow: 1. Data subcarriers, which carry information data; 2. Pilot subcarriers, whose phases and amplitudes are predetermined and made known to all receivers, and which are used for assisting system functions such as estimation of system parameters; and 3. Silent subcarriers, which have no energy and are used as guard bands and DC carriers. The data subcarriers can be arranged into groups called subchannels to support scalability and multiple-access. Each subchannel may be set at a different power level. The subcarriers forming one subchannel may or may not be adjacent to each other. Each user may use some or all of the subchannels. A subchannel formed by the contiguous subcarriers is called a congregated or clustered subchannel. A congregated subchannel may have a different power level from others. FIG. 4 illustrates the basic structure of a multi-carrier signal in the time domain which is generally made up of time frames, time slots, and OFDM symbols. A frame consists of a number of time slots, whereas each time slot is comprised of one or more OFDM symbols. The OFDM time domain waveform is generated by applying the inverse-fast-Fourier-transform (IFFT) to the OFDM signals in the frequency domain. A copy of the last portion of the time waveform, known as the cyclic prefix (CP), is inserted at the beginning of the waveform itself to form an OFDM symbol. The downlink transmission in each frame begins with a downlink preamble, which can be the first or more of the OFDM symbols in the first downlink (DL) slot. The DL preamble is used at a base station to broadcast radio network information such as synchronization and cell identification. Similarly, uplink transmission can begin with an uplink preamble, which can be the first or more of the OFDM symbols in the first uplink (UL) slot. The UL preamble is used by mobile stations to carry out the functions such as initial ranging during power up and handoff, periodic ranging and bandwidth request, channel sounding to assist downlink scheduling or advanced antenna technologies, and other radio functions. Cellular Wireless Networks In a cellular wireless network, the geographical region to be serviced by the network is normally divided into smaller areas called cells. In each cell the coverage is provided by a base station. This type of structure is normally referred to as the cellular structure. FIG. 5 depicts a cellular wireless network comprised of a plurality of cells. In each of these cells the coverage is provided by a base station (BS). A base station is connected to the backbone of the network via a dedicated link and also provides radio links to the mobile stations within its coverage. Within each coverage area, there are located mobile stations to be used as an interface between the users and the network. A base station also serves as a focal point to distribute information to and collect information from its mobile stations by radio signals. If a cell is divided into sectors, from system engineering point of view each sector can be considered as a cell. In this context, the terms “cell” and “sector” are interchangeable. Variable Bandwidth OFDMA In accordance with aspects of certain embodiments of the invention, a variable bandwidth system is provided, while the time-domain signal structure (such as the OFDM symbol length and frame duration) is fixed regardless of the bandwidths. This is achieved by keeping the ratio constant between the sampling frequency and the length of FFT/IFFT. Equivalently, the spacing between adjacent subcarriers is fixed. In some embodiments, the variable channel bandwidth is realized by adjusting the number of usable subcarriers. In the frequency domain, the entire channel is aggregated by subchannels. (The structure of a subchannel is designed in a certain way to meet the requirements of FEC (Forward Error Correction) coding and, therefore, should be maintained unchanged.) However, the number of subchannels can be adjusted to scale the channel in accordance with the given bandwidth. In such realization, a specific number of subchannels, and hence the number of usable subcarriers, constitute a channel of certain bandwidth. For example, FIG. 6 illustrates the signal structure in the frequency domain for a communication system with parameters specified in Table 1 below. The numbers of usable subcarriers are determined based on the assumption that the effective bandwidth Beff is 90% of the channel bandwidth Bch. The variable channel bandwidth is realized by adjusting the number of usable subcarriers, whose spacing is set constant. The width of a core-band is less than the smallest channel bandwidth in which the system is to operate. TABLE 1 Sample System Parameters Sampling freq. 11.52 MHz FFT size 1024 points Subcarrier spacing 11.25 kHz Channel bandwidth 10 MHz 8 MHz 6 MHz 5 MHz # of usable subcarriers 800 640 480 400 In this realization, using the invariant OFDM symbol structure allows the use of same design parameters for signal manipulation in the time-domain for a variable bandwidth. For example, in an embodiment depicted in FIG. 7, a particular windowing design shapes the spectrum to conform to a given spectral mask and is independent of the operating bandwidth. Radio Operation via Core-Band To facilitate the user terminals to operate in a variable bandwidth (VB) environment, specific signaling and control methods are required. Radio control and operation signaling is realized through the use of a core-band (CB). A core-band, substantially centered at the operating center frequency, is defined as a frequency segment that is not greater than the smallest operating channel bandwidth among all the possible spectral bands that the receiver is designed to operate with. For example, for a system that is intended to work at 5-, 6-, 8-, and 10-Mhz, the width of the CB can be 4 MHz, as shown in FIG. 6. The rest of the bandwidth is called sideband (SB). In one embodiment relevant or essential radio control signals such as preambles, ranging signals, bandwidth request, and/or bandwidth allocation are transmitted within the CB. In addition to the essential control channels, a set of data channels and their related dedicated control channels are placed within the CB to maintain basic radio operation. Such a basic operation, for example, constitutes the primary state of operation. When entering into the network, a mobile station starts with the primary state and transits to the normal full-bandwidth operation to include the sidebands for additional data and radio control channels. In another embodiment, a preamble, called an essential, or primary preamble (EP), is designed to only occupy the CB, as depicted in FIG. 8. The EP alone is sufficient for the basic radio operation. The EP can be either a direct sequence in the time domain with its frequency response confined within the CB, or an OFDM symbol corresponding to a particular pattern in the frequency domain within the CB. In either case, an EP sequence may possess some or all of the following properties: 1. Its autocorrelation exhibits a relatively large ratio between the correlation peak and sidelobe levels. 2. Its cross-correlation coefficient with another EP sequence is significantly small with respect to the power of the EP sequences. 3. Its peak-to-average ratio is relatively small. 4. The number of EP sequences that exhibit the above three properties is relatively large. In yet another embodiment, a preamble, called an auxiliary preamble (AP), which occupies the SB, is combined with the EP to form a full-bandwidth preamble (FP) (e.g., appended in the frequency domain or superimposed in the time domain). An FP sequence may possess some or all of the following properties: 1. Its autocorrelation exhibits a relatively large ratio between the correlation peak and sidelobe levels. 2. Its cross-correlation coefficient with another FP sequences is significantly small with respect to the power of the FP sequences. 3. Its peak-to-average ratio is relatively small. 4. The number of FP sequences that exhibits the above three properties is relatively large. In still another embodiment, the formation of an FP by adding an AP allows a base station to broadcast the FP, and a mobile station to use its corresponding EP, to access this base station. An FP sequence may also possess some or all of the following properties: 1. Its correlation with its own EP exhibits a relatively large ratio between the correlation peak and sidelobe levels. 2. Its cross-correlation coefficient with any EP sequence other than its own is significantly small with respect to its power. 3. The number of FP sequences that exhibit the above two properties is relatively large. Automatic Bandwidth Recognition The VB-OFDMA receiver is capable of automatically recognizing the operating bandwidth when it enters in an operating environment or service area of a particular frequency and channel bandwidth. The bandwidth information can be disseminated in a variety of forms to enable Automatic Bandwidth Recognition (ABR). In one embodiment, a mobile station, when entering in an environment or an area that supports the VB operation or services, will scan the spectral bands of different center frequencies. If it detects the presence of a signal in a spectral band of a particular center frequency by using envelope detection, received signal strength indicator (RSSI), or by other detection methods, it can determine the operating channel bandwidth by bandwidth-center frequency association such as table lookup. For example, a table such as Table 2 is stored in the receiver. Based on the center frequency that it has detected, the mobile station looks up the value of the channel bandwidth from the table. TABLE 2 Sample Center Frequency and Corresponding Bandwidth Center frequency Channel Bandwidth 2.31 GHz 10 MHz 2.56 GHz 6 MHz 2.9 G 8 MHz In another embodiment, the system provides the bandwidth information via downlink signaling, such as using a broadcasting channel or a preamble. When entering into a VB network, the mobile stations will scan the spectral bands of different center frequencies in which the receiver is designed to operate and decode the bandwidth information contained in the broadcasting channel or preamble. Multi-Mode (Multi-Range) VB-OFDMA In accordance with the principles of this invention, multi-modes are devised for a VB-OFDMA system to handle an exceptionally wide range of variation in channel bandwidth. The entire range of bandwidth variation is divided into smaller parts—not necessarily in equal size—each of which will be dealt with as a separate mode or range. FIG. 9 illustrates the entire range (e.g., from 5 MHz to 40 MHz) of bandwidth variation being divided into smaller parts (e.g., 5-10 MHz, 10-20 MHz, 20-40 MHz, in sizes). Each part is handled in one particular mode. The mode for the lowest range of bandwidth is labeled as “fundamental mode” and other modes are called “higher modes” (Mode 1, Mode 2, etc.). The sampling frequency of a higher mode is higher than the sampling frequency of the fundamental mode. In one embodiment the sampling frequency of a higher mode is a multiple of the sampling frequency of the fundamental mode. In this embodiment, in the higher modes, the FFT size can be multiplied in accordance with the sampling frequency, thereby maintaining the time duration of the OFDM symbol structure. For example, the parameters for the case of a multi-mode design are given in Table 3. Alternatively, a higher mode can be realized by maintaining the FFT size and shortening the OFDM symbol duration accordingly. For example, for Mode 1 in Table 3, the FFT size can be maintained at 1024, whereas the sampling frequency is doubled and the symbol length is a half of that for the fundamental range. Yet another higher-mode realization is to both increase the FFT size and shorten the symbol duration accordingly. For example, for Mode 2 (20 MHz to 40 MHz in bandwidth), both the FFT size and the sampling frequency can be doubled as those of the fundamental range, whereas the symbol length is halved as that of the fundamental range. The width of the CB in a multi-mode VB-OFDMA system may not be greater than the smallest bandwidth in the fundamental mode. TABLE 3 Sample System Parameters Mode 1 Fundamental-Mode Sampling freq. 23.04 MHz 11.52 MHz FFT size 2048 points 1024 points Subcarrier spacing 11.25 kHz Channel bandwidth (MHz) 20 18 15 12 10 8 6 5 # of usable subcarriers 1600 1440 1200 960 800 680 480 400 FIG. 10 illustrates a multi-cell, multi-user cellular system comprising multiple base stations and mobile stations. The system of FIG. 10 is an example of an environment in which the attributes of the invention can be utilized. While specific circuitry may be employed to implement the above embodiments, aspects of the invention can be implemented in a suitable computing environment. Although not required, aspects of the invention may be implemented as computer-executable instructions, such as routines executed by a general-purpose computer, e.g., a server computer, wireless device or personal computer. Those skilled in the relevant art will appreciate that aspects of the invention can be practiced with other communications, data processing, or computer system configurations, including: Internet appliances, hand-held devices (including personal digital assistants (PDAs)), wearable computers, all manner of cellular or mobile phones, multi-processor systems, microprocessor-based or programmable consumer electronics, set-top boxes, network PCs, mini-computers, mainframe computers, and the like. Indeed, the term “computer” refers to any of the above devices and systems, as well as any data processor. Aspects of the invention can be embodied in a special purpose computer or data processor that is specifically programmed, configured, or constructed to perform one or more of the processes explained in detail herein. Aspects of the invention can also be practiced in distributed computing environments where tasks or modules are performed by remote processing devices, which are linked through a communications network, such as a Local Area Network (LAN), Wide Area Network (WAN), or the Internet. In a distributed computing environment, program modules may be located in both local and remote memory storage devices. Aspects of the invention may be stored or distributed on computer-readable media, including magnetically or optically readable computer discs, hard-wired or preprogrammed chips (e.g., EEPROM semiconductor chips), nanotechnology memory, biological memory, or other data storage media. Indeed, computer implemented instructions, data structures, screen displays, and other data under aspects of the invention may be distributed over the Internet or over other networks (including wireless networks), on a propagated signal on a propagation medium (e.g., an electromagnetic wave(s), a sound wave, etc.) over a period of time, or they may be provided on any analog or digital network (packet switched, circuit switched, or other scheme). Those skilled in the relevant art will recognize that portions of the invention reside on a server computer, while corresponding portions reside on a client computer such as a mobile or portable device, and thus, while certain hardware platforms are described herein, aspects of the invention are equally applicable to nodes on a network. The above detailed description of the embodiments of the invention is not intended to be exhaustive or to limit the invention to the precise form disclosed above. While specific embodiments of, and examples for, the invention are described above for illustrative purposes, various equivalent modifications are possible within the scope of the invention, as those skilled in the relevant art will recognize. For example, while processes are presented in a given order, alternative embodiments may perform routines having steps in a different order, and some processes may be deleted, moved, added, subdivided, combined, and/or modified. Each of these processes may be implemented in a variety of different ways. The teachings provided herein can be applied to other systems, not necessarily the system described herein. The elements and acts of the various embodiments described above can be combined to provide further embodiments. All of the above patents and applications and other references, including any that may be listed in accompanying filing papers, are incorporated herein by reference. Aspects of the invention can be modified, if necessary, to employ the systems, functions, and concepts of the various references described above to provide yet further embodiments of the invention. Particular terminology used when describing certain features or aspects of the invention should not be taken to imply that the terminology is being redefined herein to be restricted to any specific characteristics, features, or aspects of the invention with which that terminology is associated. In general, the terms used in the following claims should not be construed to limit the invention to the specific embodiments disclosed in the specification, unless the above Detailed Description section explicitly defines such terms. Accordingly, the actual scope of the invention encompasses not only the disclosed embodiments, but also all equivalent ways of practicing or implementing the invention. The above detailed description of the embodiments of the invention is not intended to be exhaustive or to limit the invention to the precise form disclosed above or to the particular field of usage mentioned in this disclosure. While specific embodiments of, and examples for, the invention are described above for illustrative purposes, various equivalent modifications are possible within the scope of the invention, as those skilled in the relevant art will recognize. Also, the teachings of the invention provided herein can be applied to other systems, not necessarily the system described above. The elements and acts of the various embodiments described above can be combined to provide further embodiments. All of the above patents and applications and other references, including any that may be listed in accompanying filing papers, and the PCT Application entitled “Methods and Apparatus for Communication with Time-Division Duplexing,” filed Apr. 29, 2005, assigned to Waltical Solutions, (Attorney Docket No. 42938-8011) are incorporated herein by reference. Aspects of the invention can be modified, if necessary, to employ the systems, functions, and concepts of the various references described above to provide yet further embodiments of the invention. Changes can be made to the invention in light of the above “Detailed Description.” While the above description details certain embodiments of the invention and describes the best mode contemplated, no matter how detailed the above appears in text, the invention can be practiced in many ways. Therefore, implementation details may vary considerably while still being encompassed by the invention disclosed herein. As noted above, particular terminology used when describing certain features or aspects of the invention should not be taken to imply that the terminology is being redefined herein to be restricted to any specific characteristics, features, or aspects of the invention with which that terminology is associated. In general, the terms used in the following claims should not be construed to limit the invention to the specific embodiments disclosed in the specification, unless the above Detailed Description section explicitly defines such terms. Accordingly, the actual scope of the invention encompasses not only the disclosed embodiments, but also all equivalent ways of practicing or implementing the invention under the claims. While certain aspects of the invention are presented below in certain claim forms, the inventors contemplate the various aspects of the invention in any number of claim forms. Accordingly, the inventors reserve the right to add additional claims after filing the application to pursue such additional claim forms for other aspects of the invention.

<SOH> BACKGROUND <EOH>While it is ideal for a broadband wireless communication device to be able to roam from one part of the world to another, wireless communication spectra are heavily regulated and controlled by individual countries or regional authorities. It also seems inevitable that each country or region will have its own different spectral band for broadband wireless communications. Furthermore, even within a country or region, a wireless operator may own and operate on a broadband spectrum that is different in frequency and bandwidth from other operators. The existing and future bandwidth variety presents a unique challenge in designing a broadband wireless communication system and demands flexibility and adaptability. Multi-carrier communication systems are designed with a certain degree of flexibility. In a multi-carrier communication system such as multi-carrier code division multiple access (MC-CDMA) and orthogonal frequency division multiple access (OFDMA), information is multiplexed on subcarriers that are mutually orthogonal in the frequency domain. Design flexibility is a result of the ability to manipulate parameters such as the number of subcarriers and the sampling frequency. For example, by using a different sampling frequency, a DVB-T (Digital Video Broadcasting-Terrestrial) device is capable of receiving signals broadcasted from a DVB-T station that is operating on a 6-, 7-, or 8-MHz bandwidth. However, the change in the time-domain structure brings about a series of system problems. A varying sampling rate alters the symbol length, frame structure, guard time, prefix, and other time-domain properties, which adversely affects the system behavior and performance. For example, the MAC layer and even the layers above have to keep track of all the time-domain parameters in order to perform other network functions such as handoff, and thereby the complexity of the system will exponentially increase. In addition, the change in symbol length causes control and signaling problems and the change in the frame structure may cause unacceptable jitters in some applications such as voice over IP. A practical and feasible solution for multi-carrier communication with variable channel bandwidth is desirable.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a schematic presentation of a radio resource divided into small units in both the frequency and time domains: subchannels and time slots. FIG. 2 illustrates a relationship between sampling frequency, channel bandwidth, and usable subcarriers. FIG. 3 shows a basic structure of a multi-carrier signal in the frequency domain, made up of subcarriers. FIG. 4 shows a basic structure of a multi-carrier signal in the time domain, generally made up of time frames, time slots, and OFDM symbols. FIG. 5 shows a cellular wireless network comprised of a plurality of cells, wherein in each of the cells coverage is provided by a base station (BS). FIG. 6 illustrates a variable channel bandwidth being realized by adjusting a number of usable subcarriers, whose spacing is set constant. FIG. 7 depicts a time-domain windowing function applied to OFDM symbols to shape the OFDM spectrum to conform to a given spectral mask. FIG. 8 depicts a preamble designed to occupy either an entire operating bandwidth or a core-band. FIG. 9 shows an entire range (e.g., from 5 Mhz to 40 MHz) of bandwidth variation being divided into smaller groups or trunks (e.g., 5-10 MHz, 10-20 MHz, 20-40 MHz, in sizes), wherein each trunk is handled in one particular range. FIG. 10 illustrates a multi-cell, multi-user cellular system comprising multiple base stations and mobile stations. detailed-description description="Detailed Description" end="lead"?

20070605

20100831

20071018

67449.0

H04J1100

SEKUL, MARIA LYNN

METHODS AND APPARATUS FOR MULTI-CARRIER COMMUNICATIONS WITH VARIABLE CHANNEL BANDWIDTH

UNDISCOUNTED

ACCEPTED

H04J

ACCEPTED

Methods for Fabrication Isolated Micro-and Nano-Structures Using Soft or Imprint Lithography

The presently disclosed subject matter describes the use of fluorinated elastomer-based materials, in particular perfluoropolyether (PFPE)-based materials, in high-resolution soft or imprint lithographic applications, such as micro- and nanoscale replica molding, and the first nano-contact molding of organic materials to generate high fidelity features using an elastomeric mold. Accordingly, the presently disclosed subject matter describes a method for producing free-standing, isolated nanostructures of any shape using soft or imprint lithography techniques.

1. A method for forming one or more particles, the method comprising: (a) providing a patterned template and a substrate, wherein the patterned template comprises a patterned template surface having a plurality of recessed areas formed therein; (b) disposing a volume of liquid material in or on at least one of: (i) the patterned template surface; and (ii) the plurality of recessed areas; and (c) forming one or more particles by one of: (i) contacting the patterned template surface with the substrate and treating the liquid material; and (ii) treating the liquid material. 2. The method of claim 1, wherein the patterned template comprises a solvent resistant, low surface energy polymeric material. 3. The method of claim 1, wherein the patterned template comprises a solvent resistant elastomeric material. 4. The method of claim 1, wherein at least one of the patterned template and substrate comprises a material selected from the group consisting of a perfluoropolyether material, a fluoroolefin material, an acrylate material, a silicone material, a styrenic material, a fluorinated thermoplastic elastomer (TPE), a triazine fluoropolymer, a perfluorocyclobutyl material, a fluorinated epoxy resin, and a fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction. 5. The method of claim 4, wherein the perfluoropolyether material comprises a backbone structure selected from the group consisting of: wherein X is present or absent, and when present comprises an endcapping group. 6. The method of claim 4, wherein the fluoroolefin material is selected from the group consisting of: wherein CSM comprises a cure site monomer. 7. The method of claim 4, wherein the fluoroolefin material is made from monomers which comprise tetrafluoroethylene, vinylidene fluoride or hexafluoropropylene. 2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole, a functional fluoroolefin, functional acrylic monomer, a functional methacrylic monomer. 8. The method of claim 4, wherein the silicone material comprises a fluoroalkyl functionalized polydimethylsiloxane (PDMS) having the following structure: wherein: R is selected from the group consisting of an acrylate, a methacrylate, and a vinyl group; and Rf comprises a fluoroalkyl chain. 9. The method of claim 4, wherein the styrenic material comprises a fluorinated styrene monomer selected from the group consisting of: wherein Rf comprises a fluoroalkyl chain. 10. The method of claim 4, wherein the acrylate material comprises a fluorinated acrylate or a fluorinated methacrylate having the following structure: wherein: R is selected from the group consisting of H, alkyl, substituted alkyl, aryl, and substituted aryl; and Rf comprises a fluoroalkyl chain. 11. The method of claim 4, wherein the triazine fluoropolymer comprises a fluorinated monomer. 12. The method of claim 4, wherein the fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction comprises a functionalized olefin. 13. The method of claim 12, wherein the functionalized olefin comprises a functionalized cyclic olefin. 14. The method of claim 1, wherein at least one of the patterned template and the substrate has a surface energy lower than 18 mN/m. 15. The method of claim 1, wherein at least one of the patterned template and the substrate has a surface energy lower than 15 mN/m. 16. The method of claim 1, wherein the substrate is selected from the group consisting of a polymer material, an inorganic material, a silicon material, a quartz material, a glass material, and surface treated variants thereof. 17. The method of claim 1, wherein the substrate comprises a patterned area. 18. The method of claim 1, wherein the plurality of recessed areas comprises a plurality of cavities. 19. The method of claim 18, wherein the plurality of cavities comprise a plurality of structural features. 20. The method of claim 19, wherein the plurality of structural features has a dimension ranging from about 10 microns to about 1 nanometer in size. 21. The method of claim 19, wherein the plurality of structural features has a dimension ranging from about 10 microns to about 1 micron in size. 22. The method of claim 19, wherein the plurality of structural features has a dimension ranging from about 1 micron to about 100 nm in size. 23. The method of claim 19, wherein the plurality of structural features has a dimension ranging from about 100 nm to about 1 nm in size. 24. The method of claim 1, wherein the one or more particles are essentially free of a scum layer. 25. The method of claim 1, wherein the patterned template comprises a patterned template formed by a replica molding process. 26. The method of claim 25, wherein the replica molding process comprises: (a) providing a master template; (b) contacting a liquid material with the master template; and (c) curing the liquid material to form a patterned template. 27. The method of claim 26, wherein the master template is selected from the group consisting of: (a) a template formed from a lithography process; (b) a naturally occurring template; and (c) combinations thereof. 28. The method of claim 27, wherein the natural template is selected from one of a biological structure and a self-assembled structure. 29. The method of claim 28, wherein the one of a biological structure and a self-assembled structure is selected from the group consisting of a naturally occurring crystal, a protein, an enzyme, a virus, a micelle, and a tissue surface. 30. The method of claim 1, comprising modifying the patterned template surface by a surface modification step. 31. The method of claim 30, wherein the surface modification step is selected from the group consisting of a plasma treatment, a chemical treatment, and an adsorption process. 32. The method of claim 31, wherein the adsorption process comprises adsorbing molecules selected from the group consisting of a polyelectrolyte, a poly(vinylalcohol), an alkylhalosilane, and a ligand. 33. The method of claim 1, comprising positioning the patterned template and the substrate in a spaced relationship to each other such that the patterned template surface and the substrate face each other in a predetermined alignment. 34. The method of claim 1, wherein the liquid material is selected from the group consisting of a polymer, a solution, a monomer, a plurality of monomers, a polymerization initiator, a polymerization catalyst, an inorganic precursor, a metal precursor, a pharmaceutical agent, a tag, a magnetic material, a paramagnetic material, a superparamagnetic material, a ligand, a cell penetrating peptide, a porogen, a surfactant, a plurality of immiscible liquids, a solvent, and a charged species. 35. The method of claim 34, wherein the pharmaceutical agent is selected from the group consisting of a drug, a peptide, RNAi, and DNA. 36. The method of claim 34, wherein the tag is selected from the group consisting of a fluorescence tag, a radiolabeled tag, and a contrast agent. 37. The method of claim 34, wherein the ligand comprises a cell targeting peptide. 38. The method of claim 1, wherein the liquid material comprises a non-wetting agent. 39. The method of claim 1, wherein the disposing of the volume of liquid material is regulated by a spreading process. 40. The method of claim 39, wherein the spreading process comprises: (a) disposing a first volume of liquid material on the patterned template to form a layer of liquid material on the patterned template; and (b) drawing an implement across the layer of liquid material to: (i) remove a second volume of liquid material from the layer of liquid material on the patterned template; and (ii) leave a third volume of liquid material on the patterned template. 41. The method of claim 1, wherein the contacting of the patterned template surface with the substrate displaces essentially all of the disposed liquid material from between the patterned template surface and the substrate. 42. The method of claim 1, wherein the treating of the liquid material comprises a process selected from the group consisting of a thermal process, a photochemical process, and a chemical process. 43. The method of claim 1, further comprising: (a) reducing the volume of the liquid material disposed in the plurality of recessed areas by one of: (i) applying a contact pressure to the patterned template surface; and (ii) allowing a second volume of the liquid to evaporate or permeate through the template; (b) removing the contact pressure applied to the patterned template surface; (c) introducing gas within the recessed areas of the patterned template surface; (d) treating the liquid material to form one or more particles within the recessed areas of the patterned template surface; and (e) releasing the one or more particles. 44. The method of claim 43, wherein the releasing of the one or more particles is performed by one of: (a) applying the patterned template to a substrate, wherein the substrate has an affinity for the one or more particles; (b) deforming the patterned template such that the one or more particles is released from the patterned template; (c) swelling the patterned template with a first solvent to extrude the one or more particles; and (d) washing the patterned template with a second solvent, wherein the second solvent has an affinity for the one or more particles. 45. The method of claim 1, comprising harvesting or collecting the particles. 46. The method of claim 45, wherein the harvesting or collecting of the particles comprises a process selected from the group consisting of scraping with a medical scalpel, a brushing process, a dissolution process, an ultrasound process, a megasonics process, an electrostatic process, and a magnetic process. 47. The method of claim 1, wherein the method comprises a batch process. 48. The method of claim 47, wherein the batch process is selected from one of a semi-batch process and a continuous batch process. 49. A particle or plurality of particles formed by the method of claim 1. 50. The plurality of particles of claim 49, wherein the plurality of particles comprises a plurality of monodisperse particles. 51. The particle or plurality of particles of claim 49, wherein the particle or plurality of particles is selected from the group consisting of a semiconductor device, a crystal, a drug delivery vector, a gene delivery vector, a disease detecting device, a disease locating device, a photovoltaic device, a solar cell device, a porogen, a cosmetic, an electret, an additive, a catalyst, a sensor, a detoxifying agent, an abrasive, a micro-electro-mechanical system (MEMS), a cellular scaffold, a taggart, a pharmaceutical agent, and a biomarker. 52. The particle or plurality of particles of claim 49, wherein the particle or plurality of particles comprise a freestanding structure. 53. The method of claim 1, comprising forming a multi-dimensional structure, the method comprising: (a) providing a particle of claim 49; (b) providing a second patterned template; (c) disposing a second liquid material in the second patterned template; (d) contacting the second patterned template with the particle of step (a); and (e) treating the second liquid material to form a multi-dimensional structure. 54. The method of claim 1, comprising forming an interconnected structure. 55. The method of claim 54, wherein the interconnected structure comprises a plurality of shape and size specific holes. 56. The method of claim 55, wherein the interconnected structure comprises a membrane. 57. A method for delivering a therapeutic agent to a target, the method comprising: (a) providing a particle of claim 49; (b) admixing the therapeutic agent with the particle; and (c) delivering the particle comprising the therapeutic agent to the target. 58. The method of claim 57, wherein the therapeutic agent is selected from one of a drug and genetic material. 59. The method of claim 58, wherein the genetic material is selected from the group consisting of a non-viral gene vector, DNA, RNA, RNAi, and a viral particle. 60. The method of claim 59, wherein the particle comprises a biodegradable polymer. 61. The method of claim 60, wherein the biodegradable polymer is selected from the group consisting of a polyester, a polyanhydride, a polyamide, a phosphorous-based polymer, a poly(cyanoacrylate), a polyurethane, a polyorthoester, a polydihydropyran, and a polyacetal. 62. The method of claim 61, wherein the polyester is selected from the group consisting of polylactic acid, polyglycolic acid, poly(hydroxybutyrate), poly(ε-caprolactone), poly(β-malic acid), and poly(dioxanones). 63. The method of claim 61, wherein the polyanhydride is selected from the group consisting of poly(sebacic acid), poly(adipic acid), and poly(terpthalic acid). 64. The method of claim 61, wherein the polyamide is selected from the group consisting of poly(imino carbonates) and polyaminoacids. 65. The method of claim 61, wherein the phosphorous-based polymer is selected from the group consisting of a polyphosphate, a polyphosphonate, and a polyphosphazene. 66. The method of claim 60, wherein the biodegradable polymer further comprises a polymer that is responsive to a stimulus. 67. The method of claim 66, wherein the stimulus is selected from the group consisting of pH, radiation, ionic strength, temperature, an alternating magnetic field, and an alternating electric field. 68. The method of claim 67, wherein the stimulus comprises an alternating magnetic field. 69. The method of claim 57, comprising exposing the particle to an alternating magnetic field once the particle is delivered to the target. 70. The method of claim 69, wherein the exposing of the particle to an alternating magnetic field causes the particle to produce heat through one of a hypothermia process and a thermo ablation process. 71. The method of claim 70, wherein the heat produced by the particle induces one of a phase change in the polymer component of the particle and a hyperthermic treatment of the target. 72. The method of claim 71, wherein the phase change in the polymer component of the particle comprises a change from a solid phase to a liquid phase. 73. The method of claim 72, wherein the phase change from a solid phase to a liquid phase causes the therapeutic agent to be released from the particle. 74. The method of claim 73, wherein the release of the therapeutic agent from the particle comprises a controlled release. 75. The method of claim 57, wherein the target is selected from the group consisting of a cell-targeting peptide, a cell-penetrating peptide, an integrin receptor peptide (GRGDSP), a melanocyte stimulating hormone, a vasoactive intestional peptide, an anti-Her2 mouse antibody, and a vitamin. 76. A method for forming a pattern on a substrate, the method comprising: (a) providing patterned template and a substrate, wherein the patterned template comprises a patterned template surface having a plurality of recessed areas formed therein; (b) disposing a volume of liquid material in or on at least one of: (i) the patterned template surface; and (ii) the plurality of recessed areas; (c) contacting the patterned template surface with the substrate; and (d) treating the liquid material to form a pattern on the substrate. 77. The method of claim 76, wherein the patterned template comprises a solvent resistant elastomeric material. 78. The method of claim 76, wherein at least one of the patterned template and substrate comprises a material selected from the group consisting of a perfluoropolyether material, a fluoroolefin material, an acrylate material, a silicone material, a styrenic material, a fluorinated thermoplastic elastomer (TPE), a triazine fluoropolymer, a perfluorocyclobutyl material, a fluorinated epoxy resin, and a fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction. 79. The method of claim 78, wherein the perfluoropolyether material comprises a backbone structure selected from the group consisting of: wherein X is present or absent, and when present comprises an endcapping group. 80. The method of claim 78, wherein the fluoroolefin material is selected from the group consisting of: wherein CSM comprises a cure site monomer. 81. The method of claim 78 wherein the fluoroolefin material is made from monomers which comprise tetrafluoroethylene, vinylidene fluoride or hexafluoropropylene. 2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole, a functional fluoroolefin, functional acrylic monomer, a functional methacrylic monomer. 82. The method of claim 78, wherein the silicone material comprises a fluoroalkyl functionalized polydimethylsiloxane (PDMS) having the following structure: wherein: R is selected from the group consisting of an acrylate, a methacrylate, and a vinyl group; and Rf comprises a fluoroalkyl chain. 83. The method of claim 78, wherein the styrenic material comprises a fluorinated styrene monomer selected from the group consisting of: wherein Rf comprises a fluoroalkyl chain. 84. The method of claim 78, wherein the acrylate material comprises a fluorinated acrylate or a fluorinated methacrylate having the following structure: wherein: R is selected from the group consisting of H, alkyl, substituted alkyl, aryl, and substituted aryl; and Rf comprises a fluoroalkyl chain. 85. The method of claim 78, wherein the triazine fluoropolymer comprises a fluorinated monomer. 86. The method of claim 78, wherein the fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction comprises a functionalized olefin. 87. The method of claim 86, wherein the functionalized olefin comprises a functionalized cyclic olefin. 88. The method of claim 76, wherein at least one of the patterned template and the substrate has a surface energy lower than 18 mN/m. 89. The method of claim 76, wherein at least one of the patterned template and the substrate has a surface energy lower than 15 mN/m. 90. The method of claim 76, wherein the substrate is selected from the group consisting of a polymer material, an inorganic material, a silicon material, a quartz material, a glass material, and surface treated variants thereof. 91. The method of claim 76, wherein the substrate is selected from one of an electronic device in the process of being manufactured and a photonic device in the process of being manufactured. 92. The method of claim 76, wherein the substrate comprises a patterned area. 93. The method of claim 76, wherein the plurality of recessed areas comprises a plurality of cavities. 94. The method of claim 93, wherein the plurality of cavities comprise a plurality of structural features. 95. The method of claim 94, wherein the plurality of structural features has a dimension ranging from about 10 microns to about 1 nanometer in size. 96. The method of claim 94, wherein the plurality of structural features has a dimension ranging from about 10 microns to about 1 micron in size. 97. The method of claim 94, wherein the plurality of structural features has a dimension ranging from about 1 micron to about 100 nm in size. 98. The method of claim 94, wherein the plurality of structural features has a dimension ranging from about 100 nm to about 1 nm in size. 99. The method of claim 76, wherein the liquid material is selected from the group consisting of a polymer, a solution, a monomer, a plurality of monomers, a polymerization initiator, a polymerization catalyst, an inorganic precursor, a metal precursor, a pharmaceutical agent, a tag, a magnetic material, a paramagnetic material, a superparamagnetic material, a ligand, a cell penetrating peptide, a porogen, a surfactant, a plurality of immiscible liquids, a solvent, and a charged species. 100. The method of claim 99, wherein the pharmaceutical agent is selected from the group consisting of a drug, a peptide, RNAi, and DNA. 101. The method of claim 99, wherein the tag is selected from the group consisting of a fluorescence tag, a radiolabeled tag, and a contrast agent. 102. The method of claim 99, wherein the ligand comprises a cell targeting peptide. 103. The method of claim 76, wherein the liquid material is selected from one of a resist polymer and a low-k dielectric 104. The method of claim 76, wherein the liquid material comprises a non-wetting agent. 105. The method of claim 76, wherein the disposing of the volume of liquid material is regulated by a spreading process. 106. The method of claim 105, wherein the spreading process comprises: (a) disposing a first volume of liquid material on the patterned template to form a layer of liquid material on the patterned template; and (b) drawing an implement across the layer of liquid material to: (i) remove a second volume of liquid material from the layer of liquid material on the patterned template; and (ii) leave a third volume of liquid material on the patterned template. 107. The method of claim 76, wherein the contacting of the first template surface with the substrate eliminates essentially all of the disposed volume of liquid material. 108. The method of claim 76, wherein the treating of the liquid material comprises a process selected from the group consisting of a thermal process, a photochemical process, and a chemical process. 109. The method of claim 76, comprising a batch process. 110. The method of claim 109, wherein the batch process is selected from one of a semi-batch process and a continuous batch process. 111. A patterned substrate formed by the method of claim 76. 112. An apparatus for forming one or more particles, the apparatus comprising: (a) a patterned template and a substrate, wherein the patterned template comprises a patterned template surface having a plurality of recessed areas formed therein; (b) a reservoir for disposing a volume of liquid material in or on at least one of: (i) the patterned template surface; and (ii) the plurality of recessed areas; and (c) a controller for forming one or more particles by one of: (i) contacting the patterned template surface with the substrate and treating the liquid material; and (ii) treating the liquid material. 113. The apparatus of claim 112, further comprising an inspecting device for one of inspecting, measuring, and both inspecting and measuring one or more characteristics or the one or more particles. 114. An apparatus for forming a pattern on a substrate, the apparatus comprising: (a) a patterned template and a substrate, wherein the patterned template comprises a patterned template surface having a plurality of recessed areas formed therein; (b) a reservoir for disposing a volume of liquid material in or on at least one of: (i) the patterned template surface; and (ii) the plurality of recessed areas; (c) a controller for forming the pattern on the substrate by: (i) contacting the patterned template surface with the substrate; and (ii) treating the liquid material. 115. The apparatus of claim 114, further comprising an inspecting device for one of inspecting, measuring, and both inspecting and measuring one or more characteristics of the pattern on the substrate. 116. A method of forming a pattern on a surface, the method comprising selectively exposing the surface of an article to an agent by: (a) shielding a first portion of the surface of the article with a masking system, wherein the masking system comprises a elastomeric mask in conformal contact with the surface of the article; and (b) applying an agent to be patterned within the masking system to a second portion of the surface of the article, while preventing application of the agent to the first portion shielded by the masking system. 117. The method of claim 116, wherein the elastomeric mask comprises a plurality of channels. 118. The method of claim 117, wherein each of the channels has a cross-sectional dimension of less than about 1 millimeter. 119. The method of claim 117, wherein each of the channels has a cross-sectional dimension of less than about 1 micron. 120. The method of claim 116, wherein the agent swells the elastomeric mask less than about 25%. 121. The method of claim 116, wherein the agent comprises an organic electroluminescent material or a precursor thereof. 122. The method of claim 121, further comprising: (a) allowing the organic electroluminescent material to form from the agent at the second portion of the surface, and (b) establishing electrical communication between the organic electroluminescent material and an electrical circuit. 123. The method of claim 116, wherein the agent comprises the product of a deposition process, wherein the deposition process is selected from the group consisting of a chemical vapor deposition process, a gas phase deposition process, an electron-beam deposition process, an electron-beam evaporation process, an electron-beam sputtering process, and an electrochemical deposition process. 124. The method of claim 116, wherein the agent comprises a product of electroless deposition. 125. The method of claim 116, wherein the agent is applied from a fluid precursor. 126. The method of claim 125, wherein the fluid precursor is selected from the group consisting of a solution of an inorganic compound, a suspension of an inorganic compound, a suspension of particles in a fluid carrier, and a chemically active agent in a fluid carrier. 127. The method of claim 116, wherein the inorganic compound hardens on the second portion of the article surface. 128. The method of claim 126, further comprising allowing the fluid carrier to dissipate thereby depositing the particles at the first region of the article surface. 129. The method of claim 126, further comprising allowing the fluid carrier to dissipate thereby depositing the chemically active agent at the first region of the article surface. 130. The method of claim 126, wherein the chemically active agent comprises a polymer precursor. 131. The method of claim 130, further comprising forming a polymeric article from the polymer precursor. 132. The method of claim 126, wherein the chemically active agent comprises an agent capable of promoting deposition of a material. 133. The method of claim 126, wherein the chemically active agent comprises an etchant. 134. The method of claim 116, further comprising allowing the second portion of the surface of the article to be etched. 135. The method of claim 116, further comprising removing the elastomeric mask of the masking system from the first portion of the article surface while leaving the agent adhered to the second portion of the article surface.

CROSS REFERENCE TO RELATED APPLICATIONS This application is based on and claims priority to U.S. Provisional Patent Application Ser. No. 60/531,531, filed Dec. 19, 2003, U.S. Provisional Patent Application Ser. No. 60/583,170, filed Jun. 25, 2004, U.S. Provisional Patent Application Ser. No. 60/604,970, filed Aug. 27, 2004, each of which is incorporated herein by reference in its entirety. GOVERNMENT INTEREST This invention was made with U.S. Government support from the Office of Naval Research Grant No. N00014210185 and the Science and Technology Center program of the National Science Foundation under Agreement No. CHE-9876674. The U.S. Government has certain rights in the invention. TECHNICAL FIELD Methods for preparing micro- and/or nanoscale particles using soft or imprint lithography. A method for delivering a therapeutic agent to a target. Methods for forming a micro- or nano-scale pattern on a substrate using soft or imprint lithography. Abbreviations ° C. degrees Celsius cm=centimeter DBTDA=dibutyltin diacetate DMA=dimethylacrylate DMPA=2,2-dimethoxy-2-phenylacetophenone EIM=2-isocyanatoethyl methacrylate FEP=fluorinated ethylene propylene Freon 113=1,1,2-trichlorotrifluoroethane g=grams h=hours Hz=hertz IL=imprint lithography kg=kilograms kHz=kilohertz kPa=kilopascal MCP=microcontact printing MEMS=micro-electro-mechanical system MHz=megahertz MIMIC=micro-molding in capillaries mL=milliliters mm=millimeters mmol=millimoles mN=milli-Newton m.p.=melting point mW=milliwatts NCM=nano-contact molding NIL=nanoimprint lithography nm=nanometers PDMS=polydimethylsiloxane PEG=poly(ethylene glycol) PFPE=perfluoropolyether PLA=poly(lactic acid) PP=polypropylene Ppy=poly(pyrrole) psi=pounds per square inch PVDF=poly(vinylidene fluoride) PTFE=polytetrafluoroethylene SAMIM=solvent-assisted micro-molding SEM=scanning electron microscopy S-FIL=“step and flash” imprint lithography Si=silicon TMPTA=trimethylopropane triacrylate μm=micrometers UV=ultraviolet W=watts ZDOL=poly(tetrafluoroethylene oxide-co-difluoromethylene oxide)α,ω diol BACKGROUND The availability of viable nanofabrication processes is a key factor to realizing the potential of nanotechnologies. In particular, the availability of viable nanofabrication processes is important to the fields of photonics, electronics, and proteomics. Traditional imprint lithographic (IL) techniques are an alternative to photolithography for manufacturing integrated circuits, micro- and nano-fluidic devices, and other devices with micrometer and/or nanometer sized features. There is a need in the art, however, for new materials to advance IL techniques. See Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575; Xia, Y., et al., Chem. Rev., 1999, 99, 1823-1848; Resnick, D. J., et al., Semiconductor International, 2002, June, 71-78; Choi, K. M., et al., J. Am. Chem. Soc., 2003, 125, 4060-4061; McClelland, G. M., et al., Appl. Phys. Lett., 2002, 81, 1483; Chou, S. Y., et al., J. Vac. Sci. Technol. B, 1996, 14, 4129; Otto, M., et al., Microelectron. Eng., 2001, 57, 361; and Bailey, T., et al., J. Vac. Sci. Technol., B, 2000, 18, 3571. Imprint lithography comprises at least two areas: (1) soft lithographic techniques, see Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575, such as solvent-assisted micro-molding (SAMIM); micro-molding in capillaries (MIMIC); and microcontact printing (MCP); and (2) rigid imprint lithographic techniques, such as nano-contact molding (NCM), see McClelland, G. M., et al., Appl. Phys. Lett., 2002, 81, 1483; Otto, M., et al., Microelectron. Eng., 2001, 57, 361; “step and flash” imprint lithographic (S-FIL), see Bailey, T., et al., J. Vac. Sci. Technol., B, 2000, 18, 3571; and nanoimprint lithography (NIL), see Chou, S. Y., et al., J. Vac. Sci. Technol. B, 1996, 14, 4129. Polydimethylsiloxane (PDMS) based networks have been the material of choice for much of the work in soft lithography. See Quake, S. R., et al., Science, 2000, 290, 1536; Y. N. Xia and G. M. Whitesides, Angew. Chem. Int. Ed. Engl. 1998, 37, 551; and Y. N. Xia, et al., Chem. Rev. 1999, 99, 1823. The use of soft, elastomeric materials, such as PDMS, offers several advantages for lithographic techniques. For example, PDMS is highly transparent to ultraviolet (UV) radiation and has a very low Young's modulus (approximately 750 kPa), which gives it the flexibility required for conformal contact, even over surface irregularities, without the potential for cracking. In contrast, cracking can occur with molds made from brittle, high-modulus materials, such as etched silicon and glass. See Bietsch, A., et al., J. Appl. Phys., 2000, 88, 4310-4318. Further, flexibility in a mold facilitates the easy release of the mold from masters and replicates without cracking and allows the mold to endure multiple imprinting steps without damaging fragile features. Additionally, many soft, elastomeric materials are gas permeable, a property that can be used to advantage in soft lithography applications. Although PDMS offers some advantages in soft lithography applications, several properties inherent to PDMS severely limit its capabilities in soft lithography. First, PDMS-based elastomers swell when exposed to most organic soluble compounds. See Lee, J. N., et al., Anal. Chem., 2003, 75, 6544-6554. Although this property is beneficial in microcontact printing (MCP) applications because it allows the mold to adsorb organic inks, see Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575, swelling resistance is critically important in the majority of other soft lithographic techniques, especially for SAMIM and MIMIC, and for IL techniques in which a mold is brought into contact with a small amount of curable organic monomer or resin. Otherwise, the fidelity of the features on the mold is lost and an unsolvable adhesion problem ensues due to infiltration of the curable liquid into the mold. Such problems commonly occur with PDMS-based molds because most organic liquids swell PDMS. Organic materials, however, are the materials most desirable to mold. Additionally, acidic or basic aqueous solutions react with PDMS, causing breakage of the polymer chain. Secondly, the surface energy of PDMS (approximately 25 mN/m) is not low enough for soft lithography procedures that require high fidelity. For this reason, the patterned surface of PDMS-based molds is often fluorinated using a plasma treatment followed by vapor deposition of a fluoroalkyl trichlorosilane. See Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575. These fluorine-treated silicones swell, however, when exposed to organic solvents. Third, the most commonly-used commercially available form of the material used in PDMS molds, e.g., Sylgard 1840 (Dow Corning Corporation, Midland, Mich., United States of America) has a modulus that is too low (approximately 1.5 MPa) for many applications. The low modulus of these commonly used PDMS materials results in sagging and bending of features and, as such, is not well suited for processes that require precise pattern placement and alignment. Although researchers have attempted to address this last problem, see Odom, T. W., et al., J. Am. Chem. Soc., 2002, 124, 12112-12113; Odom, T. W. et al., Langmuir, 2002, 18, 5314-5320; Schmid, H., et al., Macromolecules, 2000, 33, 3042-3049; Csucs, G., et al., Langmuir, 2003, 19, 6104-6109; Trimbach, D., et al., Langmuir, 2003, 19, 10957-10961, the materials chosen still exhibit poor solvent resistance and require fluorination steps to allow for the release of the mold. Rigid materials, such as quartz glass and silicon, also have been used in imprint lithography. See Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575; Resnick, D. J., et al., Semiconductor International, 2002, June, 71-78; McClelland, G. M., et al., Appl. Phys. Lett., 2002, 81, 1483; Chou, S. Y., et al., J. Vac. Sci. Technol. B, 1996, 14, 4129; Otto, M., et al., Microelectron. Eng., 2001, 57, 361; and Bailey, T., et al., J. Vac. Sci. Technol., B, 2000, 18, 3571; Chou, S. Y., et al., Science, 1996, 272, 85-87; Von Werne, T. A., et al., J. Am. Chem. Soc., 2003, 125, 3831-3838; Resnick, D. J., et al., J. Vac. Sci. Technol. B, 2003, 21, 2624-2631. These materials are superior to PDMS in modulus and swelling resistance, but lack flexibility. Such lack of flexibility inhibits conformal contact with the substrate and causes defects in the mask and/or replicate during separation. Another drawback of rigid materials is the necessity to use a costly and difficult to fabricate hard mold, which is typically made by using conventional photolithography or electron beam (e-beam) lithography. See Chou, S. Y., et al., J. Vac. Sci. Technol. B, 1996, 14, 4129. More recently, the need to repeatedly use expensive quartz glass or silicon molds in NCM processes has been eliminated by using an acrylate-based mold generated from casting a photopolymerizable monomer mixture against a silicon master. See McClelland, G. M., et al., Appl. Phys. Lett., 2002, 81, 1483, and Jung, G. Y., et al., Nanoletters, 2004, ASAP. This approach also can be limited by swelling of the mold in organic solvents. Despite such advances, other disadvantages of fabricating molds from rigid materials include the necessity to use fluorination steps to lower the surface energy of the mold, see Resnick, D. J., et al., Semiconductor International, 2002, June, 71-78, and the inherent problem of releasing a rigid mold from a rigid substrate without breaking or damaging the mold or the substrate. See Resnick, D. J., et al., Semiconductor International, 2002, June, 71-78; Bietsch, A., J. Appl. Phys., 2000, 88, 4310-4318. Khang, D. Y., et al., Langmuir, 2004, 20, 2445-2448, have reported the use of rigid molds composed of thermoformed Teflon AF® (DuPont, Wilmington, Del., United States of America) to address the surface energy problem. Fabrication of these molds, however, requires high temperatures and pressures in a melt press, a process that could be damaging to the delicate features on a silicon wafer master. Additionally, these molds still exhibit the intrinsic drawbacks of other rigid materials as outlined hereinabove. Further, a clear and important limitation of fabricating structures on semiconductor devices using molds or templates made from hard materials is the usual formation of a residual or “scum” layer that forms when a rigid template is brought into contact with a substrate. Even with elevated applied forces, it is very difficult to completely displace liquids during this process due to the wetting behavior of the liquid being molded, which results in the formation of a scum layer. Thus, there is a need in the art for a method of fabricating a pattern or a structure on a substrate, such as a semiconductor device, which does not result in the formation of a scum layer. The fabrication of solvent resistant, microfluidic devices with features on the order of hundreds of microns from photocurable perfluoropolyether (PFPE) has been reported. See Rolland, J. P., et al., J. Am. Chem. Soc., 2004, 126, 2322-2323. PFPE-based materials are liquids at room temperature and can be photochemically cross-linked to yield tough, durable elastomers. Further, PFPE-based materials are highly fluorinated and resist swelling by organic solvents, such as methylene chloride, tetrahydrofuran, toluene, hexanes, and acetonitrile among others, which are desirable for use in microchemistry platforms based on elastomeric microfluidic devices. There is a need in the art, however, to apply PFPE-based materials to the fabrication of nanoscale devices for related reasons. Further, there is a need in the art for improved methods for forming a pattern on a substrate, such as method employing a patterned mask. See U.S. Pat. No. 4,735,890 to Nakane et al.; U.S. Pat. No. 5,147,763 to Kamitakahara et al.; U.S. Pat. No. 5,259,926 to Kuwabara et al.; and International PCT Publication No. WO 99/54786 to Jackson et al., each of which is incorporated herein by reference in their entirety. There also is a need in the art for an improved method for forming isolated structures that can be considered “engineered” structures, including but not limited to particles, shapes, and parts. Using traditional IL methods, the scum layer that almost always forms between structures acts to connect or link structures together, thereby making it difficult, if not impossible to fabricate and/or harvest isolated structures. There also is a need in the art for an improved method for forming micro- and nanoscale charged particles, in particular polymer electrets. The term “polymer electrets” refers to dielectrics with stored charge, either on the surface or in the bulk, and dielectrics with oriented dipoles, frozen-in, ferrielectric, or ferroelectric. On the macro scale, such materials are used, for example, for electronic packaging and charge electret devices, such as microphones and the like. See Kressman, R., et al., Space-Charge Electrets, Vol. 2, Laplacian Press, 1999; and Harrison, J. S., et al., Piezoelectic Polymers, NASA/CR-2001-211422, ICASE Report No. 2001-43. Poly(vinylidene fluoride) (PVDF) is one example of a polymer electret material. In addition to PVDF, charge electret materials, such as polypropylene (PP), Teflon-fluorinated ethylene propylene (FEP), and polytetrafluoroethylene (PTFE), also are considered polymer electrets. Further, there is a need in the art for improved methods for delivering therapeutic agents, such as drugs, non-viral gene vectors, DNA, RNA, RNAi, and viral particles, to a target. See Biomedical Polymers, Shalaby, S. W., ed., Harner/Gardner Publications, Inc., Cincinnati, Ohio, 1994; Polymeric Biomaterials, Dumitrin, S., ed., Marcel Dekkar, Inc., New York, N.Y., 1994; Park, K., et al., Biodegradable Hydrogels for Drug Delivery, Technomic Publishing Company, Inc., Lancaster, Pa., 1993; Gumargalieva, et al., Biodegradation and Biodeterioration of Polymers: Kinetic Aspects, Nova Science Publishers, Inc., Commack, New York, 1998; Controlled Drug Delivery, American Chemical Society Symposium Series 752, Park, K., and Mrsny, R. J., eds., Washington, D.C., 2000; Cellular Drug Delivery: Principles and Practices, Lu, D. R., and Oie, S., eds., Humana Press, Totowa, N.J., 2004; and Bioreversible Carriers in Drug Design: Theory and Applications, Roche, E. B., ed., Pergamon Press, New York, N.Y., 1987. For a description of representative therapeutic agents for use in such delivery methods, see U.S. Pat. No. 6,159,443 to Hallahan, which is incorporated herein by reference in its entirety. In sum, there exists a need in the art to identify new materials for use in imprint lithographic techniques. More particularly, there is a need in the art for methods for the fabrication of structures at the tens of micron level down to sub-100 nm feature sizes. SUMMARY In some embodiments, the presently disclosed subject matter describes a method for forming one or more particles, the method comprising: (a) providing a patterned template and a substrate, wherein the patterned template comprises a patterned template surface having a plurality of recessed areas formed therein; (b) disposing a volume of liquid material in or on at least one of: (i) the patterned template surface; and (ii) the plurality of recessed areas; and (c) forming one or more particles by one of: (i) contacting the patterned template surface with the substrate and treating the liquid material; and (ii) treating the liquid material. In some embodiments of the method for forming one or more particles, the patterned template comprises a solvent resistant, low surface energy polymeric material derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template. In some embodiments, the patterned template comprises a solvent resistant elastomeric material. In some embodiments, at least one of the patterned template and substrate comprises a material selected from the group consisting of a perfluoropolyether material, a fluoroolefin material, an acrylate material, a silicone material, a styrenic material, a fluorinated thermoplastic elastomer (TPE), a triazine fluoropolymer, a perfluorocyclobutyl material, a fluorinated epoxy resin, and a fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction. In some embodiments, the presently disclosed subject matter comprises a method for delivering a therapeutic agent to a target, the method comprising: (a) providing a particle formed by the method described hereinabove; (b) admixing the therapeutic agent with the particle; and (c) delivering the particle comprising the therapeutic agent to the target. In some embodiments of the method for delivering a therapeutic agent to a target, the therapeutic agent is selected from one of a drug and genetic material. In some embodiments, the genetic material is selected from the group consisting of a non-viral gene vector, DNA, RNA, RNAi, and a viral particle. In some embodiments, the particle comprises a biodegradable polymer, wherein the biodegradable polymer is selected from the group consisting of a polyester, a polyanhydride, a polyamide, a phosphorous-based polymer, a poly(cyanoacrylate), a polyurethane, a polyorthoester, a polydihydropyran, and a polyacetal. In some embodiments, the presently disclosed subject matter describes a method for forming a pattern on a substrate, the method comprising: (a) providing a patterned template and a substrate, wherein the patterned template comprises a patterned template surface having a plurality of recessed areas formed therein; (b) disposing a volume of liquid material in or on at least one of: (i) the patterned template surface; and (ii) the plurality of recessed areas; (c) contacting the patterned template surface with the substrate; and (d) treating the liquid material to form a pattern on the substrate. In some embodiments of the method for forming a pattern on a substrate, the patterned template comprises a solvent resistant, low surface energy polymeric material derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template. In some embodiments, the patterned template comprises a solvent resistant elastomeric material. In some embodiments, at least one of the patterned template and substrate comprises a material selected from the group consisting of a perfluoropolyether material, a fluoroolefin material, an acrylate material, a silicone material, a styrenic material, a fluorinated thermoplastic elastomer (TPE), a triazine fluoropolymer, a perfluorocyclobutyl material, a fluorinated epoxy resin, and a fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction. Accordingly, it is an object of the present invention to provide a novel method of making micro-, nano-, and sub-nanostructures. This and other objects are achieved in whole or in part by the presently disclosed subject matter. An object of the presently disclosed subject matter having been stated hereinabove, other aspects and objects will become evident as the description proceeds when taken in connection with the accompanying Drawings and Examples as best described herein below. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A-1D are a schematic representation of an embodiment of the presently disclosed method for preparing a patterned template. FIGS. 2A-2E are a schematic representation of the presently disclosed method for forming one or more micro- and/or nanoscale particles. FIGS. 3A-3F are a schematic representation of the presently disclosed method for preparing one or more spherical particles. FIGS. 4A-4D are a schematic representation of the presently disclosed method for fabricating charged polymeric particles. FIG. 4A represents the electrostatic charging of the molded particle during polymerization or crystallization; FIG. 4B represents a charged nano-disc; FIG. 4C represents typical random juxtapositioning of uncharged nano-discs; and FIG. 4D represents the spontaneous aggregation of charged nano-discs into chain-like structures. FIGS. 5A-5D are a schematic illustration of multilayer particles that can be formed using the presently disclosed soft lithography method. FIGS. 6A-6C are schematic representation of a the presently disclosed method for making three-dimensional nanostructures using a soft lithography technique. FIGS. 7A-7F are a schematic representation of an embodiment of the presently disclosed method for preparing a multi-dimensional complex structure. FIGS. 8A-8E are a schematic representation of the presently disclosed imprint lithography process resulting in a “scum layer.” FIGS. 9A-9E are a schematic representation of the presently disclosed imprint lithography method, which eliminates the “scum layer” by using a functionalized, non-wetting patterned template and a non-wetting substrate. FIGS. 10A-10E are a schematic representation of the presently disclosed solvent-assisted micro-molding (SAMIM) method for forming a pattern on a substrate. FIG. 11 is a scanning electron micrograph of a silicon master comprising 3-μm arrow-shaped patterns. FIG. 12 is a scanning electron micrograph of a silicon master comprising 500 nm conical patterns that are <50 nm at the tip. FIG. 13 is a scanning electron micrograph of a silicon master comprising 200 nm trapezoidal patterns. FIG. 14 is a scanning electron micrograph of 200-nm isolated trapezoidal particles of poly(ethylene glycol) (PEG) diacrylate. FIG. 15 is a scanning electron micrograph of 500-nm isolated conical particles of PEG diacrylate. FIG. 16 is a scanning electron micrograph of 3-μm isolated arrow-shaped particles of PEG diacrylate. FIG. 17 is a scanning electron micrograph of 200-nm×750-nm×250-nm rectangular shaped particles of PEG diacrylate. FIG. 18 is a scanning electron micrograph of 200-nm isolated trapezoidal particles of trimethylopropane triacrylate (TMPTA). FIG. 19 is a scanning electron micrograph of 500-nm isolated conical particles of TMPTA. FIG. 20 is a scanning electron micrograph of 500-nm isolated conical particles of TMPTA, which have been printed using an embodiment of the presently described non-wetting imprint lithography method and harvested mechanically using a doctor blade. FIG. 21 is a scanning electron micrograph of 200-nm isolated trapezoidal particles of poly(lactic acid) (PLA). FIG. 22 is a scanning electron micrograph of 200-nm isolated trapezoidal particles of poly(lactic acid) (PLA), which have been printed using an embodiment of the presently described non-wetting imprint lithography method and harvested mechanically using a doctor blade. FIG. 23 is a scanning electron micrograph of 3-μm isolated arrow-shaped particles of PLA. FIG. 24 is a scanning electron micrograph of 500-nm isolated conical-shaped particles of PLA. FIG. 25 is a scanning electron micrograph of 200-nm isolated trapezoidal particles of poly(pyrrole) (Ppy). FIG. 26 is a scanning electron micrograph of 3-μm arrow-shaped Ppy particles. FIG. 27 is a scanning electron micrograph of 500-nm conical shaped Ppy particles. FIGS. 28A-28C are fluorescence confocal micrographs of 200-nm isolated trapezoidal particles of PEG diacrylate that contain fluorescently tagged DNA. FIG. 28A is a fluorescent confocal micrograph of 200 nm trapezoidal PEG nanoparticles which contain 24-mer DNA strands that are tagged with CY-3. FIG. 28B is optical micrograph of the 200-nm isolated trapezoidal particles of PEG diacrylate that contain fluorescently tagged DNA. FIG. 28C is the overlay of the images provided in FIGS. 28A and 28B, showing that every particle contains DNA. FIG. 29 is a scanning electron micrograph of fabrication of 200-nm PEG-diacrylate nanoparticles using “double stamping.” FIG. 30 is an atomic force micrograph image of 140-nm lines of TMPTA separated by distance of 70 nm that were fabricated using a PFPE mold. FIGS. 31A and 31B are a scanning electron micrograph of mold fabrication from electron-beam lithographically generated masters. FIG. 31A is a scanning electron micrograph of silicon/silicon oxide masters of 3 micron arrows. FIG. 31B is a scanning electron micrograph of silicon/silicon oxide masters of 200-nm×800-nm bars. FIGS. 32A and 32B are an optical micrographic image of mold fabrication from photoresist masters. FIG. 32A is a SU-8 master. FIG. 32B is a PFPE-DMA mold templated from a photolithographic master. FIGS. 33A and 33B are an atomic force micrograph of mold fabrication from Tobacco Mosaic Virus templates. FIG. 33A is a master. FIG. 33B is a PFPE-DMA mold templated from a virus master. FIGS. 34A and 34B are an atomic force micrograph of mold fabrication from block copolymer micelle masters. FIG. 34A is a polystyrene-polyisoprene block copolymer micelle. FIG. 34B is a PFPE-DMA mold templated from a micelle master. FIGS. 35A and 35B are an atomic force micrograph of mold fabrication from brush polymer masters. FIG. 35A is a brush polymer master. FIG. 35B is a PFPE-DMA mold templated from a brush polymer master. DETAILED DESCRIPTION The presently disclosed subject matter will now be described more fully hereinafter with reference to the accompanying Examples, in which representative embodiments are shown. The presently disclosed subject matter can, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the embodiments to those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently described subject matter belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Throughout the specification and claims, a given chemical formula or name shall encompass all optical and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist. I. Materials The presently disclosed subject matter broadly describes solvent resistant, low surface energy polymeric materials, derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template for use in high-resolution soft or imprint lithographic applications, such as micro- and nanoscale replica molding. In some embodiments, the patterned temp late comprises a solvent resistant, elastomer-based material, such as but not limited to a fluorinated elastomer-based materials. Further, the presently disclosed subject matter describes the first nano-contact molding of organic materials to generate high fidelity features using an elastomeric mold. Accordingly, the presently disclosed subject matter describes a method for producing free-standing, isolated micro- and nanostructures of any shape using soft or imprint lithography techniques. Representative micro- and nanostructures include but are not limited to micro- and nanoparticles, and micro- and nano-patterned substrates. The nanostructures described by the presently disclosed subject matter can be used in several applications, including, but not limited to, semiconductor manufacturing, such as molding etch barriers without scum layers for the fabrication of semiconductor devices; crystals; materials for displays; photovoltaics; a solar cell device; optoelectronic devices; routers; gratings; radio frequency identification (RFID) devices; catalysts; fillers and additives; detoxifying agents; etch barriers; atomic force microscope (AFM) tips; parts for nano-machines; the delivery of a therapeutic agent, such as a drug or genetic material; cosmetics; chemical mechanical planarization (CMP) particles; and porous particles and shapes of any kind that will enable the nanotechnology industry. Representative solvent resistant elastomer-based materials include but are not limited to fluorinated elastomer-based materials. As used herein, the term “solvent resistant” refers to a material, such as an elastomeric material that neither swells nor dissolves in common hydrocarbon-based organic solvents or acidic or basic aqueous solutions. Representative fluorinated elastomer-based materials include but are not limited to perfluoropolyether (PFPE)-based materials. A photocurable liquid PFPE exhibits desirable properties for soft lithography. A representative scheme for the synthesis and photocuring of functional PFPEs is provided in Scheme 1. Additional schemes for the synthesis of functional perfluoropolyethers are provided in Examples 7.1 through 7.6. This PFPE material has a low surface energy (for example, about 12 mN/m); is non-toxic, UV transparent, and highly gas permeable; and cures into a tough, durable, highly fluorinated elastomer with excellent release properties and resistance to swelling. The properties of these materials can be tuned over a wide range through the judicious choice of additives, fillers, reactive co-monomers, and functionalization agents. Such properties that are desirable to modify, include, but are not limited to, modulus, tear strength, surface energy, permeability, functionality, mode of cure, solubility and swelling characteristics, and the like. The non-swelling nature and easy release properties of the presently disclosed PFPE materials allows for nanostructures to be fabricated from any material. Further, the presently disclosed subject matter can be expanded to large scale rollers or conveyor belt technology or rapid stamping that allow for the fabrication of nanostructures on an industrial scale. In some embodiments, the patterned template comprises a solvent resistant, low surface energy polymeric material derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template. In some embodiments, the patterned template comprises a solvent resistant elastomeric material. In some embodiments, at least one of the patterned template and substrate comprises a material selected from the group consisting of a perfluoropolyether material, a fluoroolefin material, an acrylate material, a silicone material, a styrenic material, a fluorinated thermoplastic elastomer (TPE), a triazine fluoropolymer, a perfluorocyclobutyl material, a fluorinated epoxy resin, and a fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction. In some embodiments, the perfluoropolyether material comprises a backbone structure selected from the group consisting of: wherein X is present or absent, and when present comprises an endcapping group. In some embodiments, the fluoroolefin material is selected from the group consisting of: wherein CSM comprises a cure site monomer. In some embodiments, the fluoroolefin material is made from monomers which comprise tetrafluoroethylene, vinylidene fluoride or hexafluoropropylene. 2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole, a functional fluoroolefin, functional acrylic monomer, a functional methacrylic monomer. In some embodiments, the silicone material comprises a fluoroalkyl functionalized polydimethylsiloxane (PDMS) having the following structure: wherein: R is selected from the group consisting of an acrylate, a methacrylate, and a vinyl group; and Rf comprises a fluoroalkyl chain. In some embodiments, the styrenic material comprises a fluorinated styrene monomer selected from the group consisting of: wherein Rf comprises a fluoroalkyl chain. In some embodiments, the acrylate material comprises a fluorinated acrylate or a fluorinated methacrylate having the following structure: wherein: R is selected from the group consisting of H, alkyl, substituted alkyl, aryl, and substituted aryl; and Rf comprises a fluoroalkyl chain. In some embodiments, the triazine fluoropolymer comprises a fluorinated monomer. In some embodiments, the fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction comprises a functionalized olefin. In some embodiments, the functionalized olefin comprises a functionalized cyclic olefin. In some embodiments, at least one of the patterned template and the substrate has a surface energy lower than 18 mN/m. In some embodiments, at least one of the patterned template and the substrate has a surface energy lower than 15 mN/m. From a property point of view, the exact properties of these molding materials can be adjusted by adjusting the composition of the ingredients used to make the materials. In particular the modulus can be adjusted from low (approximately 1 MPa) to multiple GPa. II. Formation of Isolated Micro- and/or Nanoparticles In some embodiments, the presently disclosed subject matter provides a method for making isolated micro- and/or nanoparticles. In some embodiments, the process comprises initially forming a patterned substrate. Turning now to FIG. 1A, a patterned master 100 is provided. Patterned master 100 comprises a plurality of non-recessed surface areas 102 and a plurality of recesses 104. In some embodiments, patterned master 100 comprises an etched substrate, such as a silicon wafer, which is etched in the desired pattern to form patterned master 100. Referring now to FIG. 1B, a liquid material 106, for example, a liquid fluoropolymer composition, such as a PFPE-based precursor, is then poured onto patterned master 100. Liquid material 106 is treated by treating process Tr, for example exposure to UV light, thereby forming a treated liquid material 108 in the desired pattern. Referring now to FIGS. 1C and 1D, a force Fr is applied to treated liquid material 108 to remove it from patterned master 100. As shown in FIGS. 1C and 1D, treated liquid material 108 comprises a plurality of recesses 110, which are mirror images of the plurality of non-recessed surface areas 102 of patterned master 100. Continuing with FIGS. 1C and 1D, treated liquid material 108 comprises a plurality of first patterned surface areas 112, which are mirror images of the plurality of recesses 104 of patterned master 100. Treated liquid material 108 can now be used as a patterned template for soft lithography and imprint lithography applications. Accordingly, treated liquid material 108 can be used as a patterned template for the formation of isolated micro- and nanoparticles. For the purposes of FIGS. 1A-1D, 2A-2E, and 3A-3F, the numbering scheme for like structures is retained throughout. Referring now to FIG. 2A, in some embodiments, a substrate 200, for example, a silicon wafer, is treated or is coated with a non-wetting material 202. In some embodiments, non-wetting material 202 comprises an elastomer (such a solvent resistant elastomer, including but not limited to a PFPE elastomer) that can be further exposed to UV light and cured to form a thin, non-wetting layer on the surface of substrate 200. Substrate 200 also can be made non-wetting by treating substrate 200 with non-wetting agent 202, for example a small molecule, such as an alkyl- or fluoroalkyl-silane, or other surface treatment. Continuing with FIG. 2A, a droplet 204 of a curable resin, a monomer, or a solution in which the desired particles will be formed is then placed on the coated substrate 200. Referring now to FIG. 2A and FIG. 2B, patterned template 108 (as shown in FIG. 1D) is then contacted with droplet 204 so that droplet 204 fills the plurality of recessed areas 110 of patterned template 108. Referring now to FIGS. 2C and 2D, a force Fa is applied to patterned template 108. While not wishing to be bound by any particular theory, once force Fa is applied, the affinity of patterned template 108 for non-wetting coating or surface treatment 202 on substrate 200 in combination with the non-wetting behavior of patterned template 108 and surface treated or coated substrate 200 causes droplet 204 to be excluded from all areas except for recessed areas 110. Further, in embodiments essentially free of non-wetting or low wetting material 202 with which to sandwich droplet 204, a “scum” layer that interconnects the objects being stamped forms. Continuing with FIGS. 2C and 2D, the material filling recessed areas 110, e.g., a resin, monomer, solvent, and combinations thereof, is then treated by a treating process Tr, e.g., photocured through patterned template 108 or thermally cured while under pressure, to form a plurality of micro- and/or nanoparticles 206. In some embodiments, a material, including but not limited to a polymer, an organic compound, or an inorganic compound, can be dissolved in a solvent, patterned using patterned template 108, and the solvent can be released. Continuing with FIGS. 2C and 2D, once the material filling recessed areas 110 is treated, patterned template 108 is removed from substrate 200. Micro- and/or nanoparticles 206 are confined to recessed areas 110 of patterned template 108. In some embodiments, micro- and/or nanoparticles 206 can be retained on substrate 200 in defined regions once patterned template 108 is removed. This embodiment can be used in the manufacture of semiconductor devices where essentially scum-layer free features could be used as etch barriers or as conductive, semiconductive, or dielectric layers directly, mitigating or reducing the need to use traditional and expensive photolithographic processes. Referring now to FIGS. 2D and 2E, micro- and/or nanoparticles 206 can be removed from patterned template 108 to provide freestanding particles by a variety of methods, which include but are not limited to: (1) applying patterned template 108 to a surface that has an affinity for the particles 206; (2) deforming patterned template 108, or using other mechanical methods, including sonication, in such a manner that the particles 206 are naturally released from patterned template 108; (3) swelling patterned template 108 reversibly with supercritical carbon dioxide or another solvent that will extrude the particles 206; and (4) washing patterned template 108 with a solvent that has an affinity for the particles 206 and will wash them out of patterned template 108. In some embodiments, the method comprises a batch process. In some embodiments, the batch process is selected from one of a semi-batch process and a continuous batch process. Referring now to FIG. 2F, an embodiment of the presently disclosed subject matter wherein particles 206 are produced in a continuous process is schematically presented. An apparatus 199 is provided for carrying out the process. Indeed, while FIG. 2F schematically presents a continuous process for particles, apparatus 199 can be adapted for batch processes, and for providing a pattern on a substrate continuously or in batch, in accordance with the presently disclosed subject matter and based on a review of the presently disclosed subject matter by one of ordinary skill in the art. Continuing, then, with FIG. 2F, droplet 204 of liquid material is applied to substrate 200′ via reservoir 203. Substrate 202′ can be coated or not coated with a non-wetting agent. Substrate 200′ and pattern template 108′ are placed in a spaced relationship with respect to each other and are also operably disposed with respect to each other to provide for the conveyance of droplet 204 between patterned template 108′ and substrate 200′. Conveyance is facilitated through the provision of pulleys 208, which are in operative communication with controller 201. By way of representative non-limiting examples, controller 201 can comprise a computing system, appropriate software, a power source, a radiation source, and/or other suitable devices for controlling the functions of apparatus 199. Thus, controller 201 provides for power for and other control of the operation of pulleys 208 to provide for the conveyance of droplet 204 between patterned template 108′ and substrate 200′. Particles 206 are formed and treated between substrate 200′ and patterned template 108′ by a treating process TR, which is also controlled by controller 201. Particles 206 are collected in an inspecting device 210, which is also controlled by controller 201. Inspecting device 210 provides for one of inspecting, measuring, and both inspecting and measuring one or more characteristics of particles 206. Representative examples of inspecting devices 210 are disclosed elsewhere herein. Thus, in some embodiments, the method for forming one or more particles comprises: (a) providing a patterned template and a substrate, wherein the patterned template comprises a first patterned template surface having a plurality of recessed areas formed therein; (b) disposing a volume of liquid material in or on at least one of: (i) the first patterned template surface; and (ii) the plurality of recessed areas; and (c) forming one or more particles by one of: (i) contacting the patterned template surface with the substrate and treating the liquid material; and (ii) treating the liquid material. In some embodiments of the method for forming one or more particles, the patterned template comprises a solvent resistant, low surface energy polymeric material derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template. In some embodiments, the patterned template comprises a solvent resistant elastomeric material. In some embodiments, at least one of the patterned template and substrate comprises a material selected from the group consisting of a perfluoropolyether material, a fluoroolefin material, an acrylate material, a silicone material, a styrenic material, a fluorinated thermoplastic elastomer (TPE), a triazine fluoropolymer, a perfluorocyclobutyl material, a fluorinated epoxy resin, and a fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction. In some embodiments, the perfluoropolyether material comprises a backbone structure selected from the group consisting of: wherein X is present or absent, and when present comprises an endcapping group. In some embodiments, the fluoroolefin material is selected from the group consisting of: wherein CSM comprises a cure site monomer. In some embodiments, the fluoroolefin material is made from monomers which comprise tetrafluoroethylene, vinylidene fluoride or hexafluoropropylene. 2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole, a functional fluoroolefin, functional acrylic monomer, a functional methacrylic mono mer. In some embodiments, the silicone material comprises a fluoroalkyl functionalized polydimethylsiloxane (PDMS) having the following structure: wherein: R is selected from the group consisting of an acrylate, a methacrylate, and a vinyl group; and Rf comprises a fluoroalkyl chain. In some embodiments, the styrenic material comprises a fluorinated styrene monomer selected from the group consisting of: wherein Rf comprises a fluoroalkyl chain. In some embodiments, the acrylate material comprises a fluorinated acrylate or a fluorinated methacrylate having the following structure: wherein: R is selected from the group consisting of H, alkyl, substituted alkyl, aryl, and substituted aryl; and Rf comprises a fluoroalkyl chain. In some embodiments, the triazine fluoropolymer comprises a fluorinated monomer. In some embodiments, the fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction comprises a functionalized olefin. In some embodiments, the functionalized olefin comprises a functionalized cyclic olefin. In some embodiments, at least one of the patterned template and the substrate has a surface energy lower than 18 mN/m. In some embodiments, at least one of the patterned template and the substrate has a surface energy lower than 15 mN/m. In some embodiments, the substrate is selected from the group consisting of a polymer material, an inorganic material, a silicon material, a quartz material, a glass material, and surface treated variants thereof. In some embodiments, the substrate comprises a patterned area. In some embodiments, the plurality of recessed areas comprises a plurality of cavities. In some embodiments, the plurality of cavities comprises a plurality of structural features. In some embodiments, the plurality of structural features has a dimension ranging from about 10 microns to about 1 nanometer in size. In some embodiments, the plurality of structural features has a dimension ranging from about 10 microns to about 1 micron in size. In some embodiments, the plurality of structural features has a dimension ranging from about 1 micron to about 100 nm in size. In some embodiments, the plurality of structural features has a dimension ranging from about 100 nm to about 1 nm in size. In some embodiments, the patterned template comprises a patterned template formed by a replica molding process. In some embodiments, the replica molding process comprises: providing a master template; contacting a liquid material with the master template; and curing the liquid material to form a patterned template. In some embodiments, the master template is selected from the group consisting of: a template formed from a lithography process; a naturally occurring template; and combinations thereof. In some embodiments, the natural template is selected from one of a biological structure and a self-assembled structure. In some embodiments, the one of a biological structure and a self-assembled structure is selected from the group consisting of a naturally occurring crystal, an enzyme, a virus, a protein, a micelle, and a tissue surface. In some embodiments, the method comprises modifying the patterned template surface by a surface modification step. In some embodiments, the surface modification step is selected from the group consisting of a plasma treatment, a chemical treatment, and an adsorption process. In some embodiments, the adsorption process comprises adsorbing molecules selected from the group consisting of a polyelectrolyte, a poly(vinylalcohol), an alkylhalosilane, and a ligand. In some embodiments, the method comprises positioning the patterned template and the substrate in a spaced relationship to each other such that the patterned template surface and the substrate face each other in a predetermined alignment. In some embodiments, the liquid material is selected from the group consisting of a polymer, a solution, a monomer, a plurality of monomers, a polymerization initiator, a polymerization catalyst, an inorganic precursor, a metal precursor, a pharmaceutical agent, a tag, a magnetic material, a paramagnetic material, a ligand, a cell penetrating peptide, a porogen, a surfactant, a plurality of immiscible liquids, a solvent, a charged species, and combinations thereof. In some embodiments, the pharmaceutical agent is selected from the group consisting of a drug, a peptide, RNAi, and DNA. In some embodiments, the tag is selected from the group consisting of a fluorescence tag, a radiolabeled tag, and a contrast agent. In some embodiments, the ligand comprises a cell targeting peptide. In some embodiments, the liquid material comprises a non-wetting agent. In some embodiments, the liquid material comprises one phase. In some embodiments, the liquid material comprises a plurality of phases. In some embodiments, the liquid material is selected from the group consisting of multiple liquids, multiple immiscible liquids, surfactants, dispersions, emulsions, micro-emulsions, micelles, particulates, colloids, porogens, active ingredients, and combinations thereof. In some embodiments, the disposing of the volume of liquid material on one of the patterned template and the substrate is regulated by a spreading process. In some embodiments, the spreading process comprises: (a) disposing a first volume of liquid material on one of the patterned template and the substrate to form a layer of liquid material thereon; and (b) drawing an implement across the layer of liquid material to: (i) remove a second volume of liquid material from the layer of liquid material on the one of the patterned template and the substrate; and (ii) leave a third volume of liquid material on the one of the patterned template and the substrate. In some embodiments, an article is contacted with the layer of liquid material and a force is applied to the article to thereby remove the liquid material from the one of the patterned material and the substrate. In some embodiments, the article is selected from the group consisting of a roller and a “squeegee” blade. In some embodiments, the liquid material is removed by some other mechanical means. In some embodiments, the contacting of the patterned template surface with the substrate forces essentially all of the disposed liquid material from between the patterned template surface and the substrate. In some embodiments, the treating of the liquid material comprises a process selected from the group consisting of a thermal process, a photochemical process, and a chemical process. In some embodiments as described in detail herein below, the method further comprises: (a) reducing the volume of the liquid material disposed in the plurality of recessed areas by one of: (i) applying a contact pressure to the patterned template surface; and (ii) allowing a second volume of the liquid to evaporate or permeate through the template; (b) removing the contact pressure applied to the patterned template surface; (c) introducing gas within the recessed areas of the patterned template surface; (d) treating the liquid material to form one or more particles within the recessed areas of the patterned template surface; and (e) releasing the one or more particles. In some embodiments, the releasing of the one or more particles is performed by one of: (a) applying the patterned template to a substrate, wherein the substrate has an affinity for the one or more particles; (b) deforming the patterned template such that the one or more particles is released from the patterned template; (c) swelling the patterned template with a first solvent to extrude the one or more particles; (d) washing the patterned template with a second solvent, wherein the second solvent has an affinity for the one or more particles; and (e) applying a mechanical force to the one or more particles. In some embodiments, the mechanical force is applied by contacting one of a Doctor blade and a brush with the one or more particles. In some embodiments, the mechanical force is applied by ultrasonics, megasonics, electrostatics, or magnetics means. In some embodiments, the method comprises harvesting or collecting the particles. In some embodiments, the harvesting or collecting of the particles comprises a process selected from the group consisting of scraping with a doctor blade, a brushing process, a dissolution process, an ultrasound process, a megasonics process, an electrostatic process, and a magnetic process. In some embodiments, the presently disclosed subject matter describes a particle or plurality of particles formed by the methods described herein. In some embodiments, the plurality of particles comprises a plurality of monodisperse particles. In some embodiments, the particle or plurality of particles is selected from the group consisting of a semiconductor device, a crystal, a drug delivery vector, a gene delivery vector, a disease detecting device, a disease locating device, a photovoltaic device, a porogen, a cosmetic, an electret, an additive, a catalyst, a sensor, a detoxifying agent, an abrasive, such as a CMP, a micro-electro-mechanical system (MEMS), a cellular scaffold, a taggart, a pharmaceutical agent, and a biomarker. In some embodiments, the particle or plurality of particles comprise a freestanding structure. Further, in some embodiments, the presently disclosed subject matter describes a method of fabricating isolated liquid objects, the method comprising (a) contacting a liquid material with the surface of a first low surface energy material; (b) contacting the surface of a second low surface energy material with the liquid, wherein at least one of the surfaces of either the first or second low surface energy material is patterned; (c) sealing the surfaces of the first and the second low surface energy materials together; and (d) separating the two low surface energy materials to produce a replica pattern comprising liquid droplets. In some embodiments, the liquid material comprises poly(ethylene glycol)-diacrylate. In some embodiments, the low surface energy material comprises perfluoropolyether-diacrylate. In some embodiments, a chemical process is used to seal the surfaces of the first and the second low surface energy materials. In some embodiments, a physical process is used to seal the surfaces of the first and the second low surface energy materials. In some embodiments, one of the surfaces of the low surface energy material is patterned. In some embodiments, one of the surfaces of the low surface energy material is not patterned. In some embodiments, the method further comprises using the replica pattern composed of liquid droplets to fabricate other objects. In some embodiments, the replica pattern of liquid droplets is formed on the surface of the low surface energy material that is not patterned. In some embodiments, the liquid droplets undergo direct or partial solidification. In some embodiments, the liquid droplets undergo a chemical transformation. In some embodiments, the solidification of the liquid droplets or the chemical transformation of the liquid droplets produce freestanding objects. In some embodiments, the freestanding objects are harvested. In some embodiments, the freestanding objects are bonded in place. In some embodiments, the freestanding objects are directly solidified, partially solidified, or chemically transformed. In some embodiments, the liquid droplets are directly solidified, partially solidified, or chemically transformed on or in the patterned template to produce objects embedded in the recesses of the patterned template. In some embodiments, the embedded objects are harvested. In some embodiments, the embedded objects are bonded in place. In some embodiments, the embedded objects are used in other fabrication processes. In some embodiments, the replica pattern of liquid droplets is transferred to other surfaces. In some embodiments, the transfer takes place before the solidification or chemical transformation process. In some embodiments, the transfer takes place after the solidification or chemical transformation process. In some embodiments, the surface to which the replica pattern of liquid droplets is transferred is selected from the group consisting of a non-low surface energy surface, a low surface energy surface, a functionalized surface, and a sacrificial surface. In some embodiments, the method produces a pattern on a surface that is essentially free of one or more scum layers. In some embodiments, the method is used to fabricate semiconductors and other electronic and photonic devices or arrays. In some embodiments, the method is used to create freestanding objects. In some embodiments, the method is used to create three-dimensional objects using multiple patterning steps. In some embodiments, the isolated or patterned object comprises materials selected from the group consisting of organic, inorganic, polymeric, and biological materials. In some embodiments, a surface adhesive agent is used to anchor the isolated structures on a surface. In some embodiments, the liquid droplet arrays or solid arrays on patterned or non-patterned surfaces are used as regiospecific delivery devices or reaction vessels for additional chemical processing steps. In some embodiments, the additional chemical processing steps are selected from the group consisting of printing of organic, inorganic, polymeric, biological, and catalytic systems onto surfaces; synthesis of organic, inorganic, polymeric, biological materials; and other applications in which localized delivery of materials to surfaces is desired. Applications of the presently disclosed subject matter include, but are not limited to, micro and nanoscale patterning or printing of materials. In some embodiments, the materials to be patterned or printed are selected from the group consisting of surface-binding molecules, inorganic compounds, organic compounds, polymers, biological molecules, nanoparticles, viruses, biological arrays, and the like. In some embodiments, the applications of the presently disclosed subject matter include, but are not limited to, the synthesis of polymer brushes, catalyst patterning for CVD carbon nanotube growth, cell scaffold fabrication, the application of patterned sacrificial layers, such as etch resists, and the combinatorial fabrication of organic, inorganic, polymeric, and biological arrays. In some embodiments, non-wetting imprint lithography, and related techniques, are combined with methods to control the location and orientation of chemical components within an individual object. In some embodiments, such methods improve the performance of an object by rationally structuring the object so that it is optimized for a particular application. In some embodiments, the method comprises incorporating biological targeting agents into particles for drug delivery, vaccination, and other applications. In some embodiments, the method comprises designing the particles to include a specific biological recognition motif. In some embodiments, the biological recognition motif comprises biotin/avidin and/or other proteins. In some embodiments, the method comprises tailoring the chemical composition of these materials and controlling the reaction conditions, whereby it is then possible to organize the biorecognition motifs so that the efficacy of the particle is optimized. In some embodiments, the particles are designed and synthesized so that recognition elements are located on the surface of the particle in such a way to be accessible to cellular binding sites, wherein the core of the particle is preserved to contain bioactive agents, such as therapeutic molecules. In some embodiments, a non-wetting imprint lithography method is used to fabricate the objects, wherein the objects are optimized for a particular application by incorporating functional motifs, such as biorecognition agents, into the object composition. In some embodiments, the method further comprises controlling the microscale and nanoscale structure of the object by using methods selected from the group consisting of self-assembly, stepwise fabrication procedures, reaction conditions, chemical composition, crosslinking, branching, hydrogen bonding, ionic interactions, covalent interactions, and the like. In some embodiments, the method further comprises controlling the microscale and nanoscale structure of the object by incorporating chemically organized precursors into the object. In some embodiments, the chemically organized precursors are selected from the group consisting of block copolymers and core-shell structures. In sum, the presently disclosed subject matter describes a non-wetting imprint lithography technique that is scalable and offers a simple, direct route to such particles without the use of self-assembled, difficult to fabricate block copolymers and other systems. III. Formation of Rounded Particles Through “Liquid Reduction” Referring now to FIGS. 3A through 3F, the presently disclosed subject matter provides a “liquid reduction” process for forming particles that have shapes that are not conformal to the shape of the template, including but not limited to spherical micro- and nanoparticles. For example, a “cube-shaped” template can allow for sphereical particles to be made, whereas a “Block arrow-shaped” template can allow for “lolli-pop” shaped particles or objects to be made wherein the introduction of a gas allows surface tension forces to reshape the resident liquid prior to treating it. While not wishing to be bound by any particular theory, the non-wetting characteristics that can be provided in some embodiments of the presently disclosed patterned template and/or treated or coated substrate allows for the generation of rounded, e.g., spherical, particles. Referring now to FIG. 3A, droplet 302 of a liquid material is disposed on substrate 300, which in some embodiments is coated or treated with a non-wetting material 304. A patterned template 108, which comprises a plurality of recessed areas 110 and patterned surface areas 112, also is provided. Referring now to FIG. 3B, patterned template 108 is contacted with droplet 302. The liquid material comprising droplet 302 then enters recessed areas 110 of patterned template 108. In some embodiments, a residual, or “scum,” layer RL of the liquid material comprising droplet 302 remains between the patterned template 108 and substrate 300. Referring now to FIG. 3C, a first force Fa1 is applied to patterned template 108. A contact point CP is formed between the patterned template 108 and the substrate and displacing residual layer RL. Particles 306 are formed in the recessed areas 110 of patterned template 108. Referring now to FIG. 3D, a second force Fa2, wherein the force applied by Fa2 is greater than the force applied by Fa1, is then applied to patterned template 108, thereby forming smaller liquid particles 308 inside recessed areas 112 and forcing a portion of the liquid material comprising droplet 302 out of recessed areas 112. Referring now to FIG. 3E, the second force Fa2 is released, thereby returning the contact pressure to the original contact pressure applied by first force Fa1. In some embodiments, patterned template 108 comprises a gas permeable material, which allows a portion of space with recessed areas 112 to be filled with a gas, such as nitrogen, thereby forming a plurality of liquid spherical droplets 310. Once this liquid reduction is achieved, the plurality of liquid spherical droplets 310 are treated by a treating process Tr. Referring now to FIG. 3F, treated liquid spherical droplets 310 are released from patterned template 108 to provide a plurality of freestanding spherical particles 312. IV. Formation of Polymeric Nano- to Micro-Electrets Referring now to FIGS. 4A and 4B, in some embodiments, the presently disclosed subject matter describes a method for preparing polymeric nano- to micro-electrets by applying an electric field during the polymerization and/or crystallization step during molding (FIG. 4A) to yield a charged polymeric particle (FIG. 4B). In some embodiments, the charged polymeric particles spontaneously aggregate into chain-like structures (FIG. 4D) instead of the random configurations shown in FIG. 4C. In some embodiments, the charged polymeric particle comprises a polymeric electret. In some embodiments, the polymeric electret comprises a polymeric nano-electret. In some embodiments, the charged polymeric particles aggregate into chain-like structures. In some embodiments, the charged polymeric particles comprise an additive for an electro-rheological device. In some embodiments, the electro-rheological device is selected from the group consisting of clutches and active dampening devices. In some embodiments, the charged polymeric particles comprise nano-piezoelectric devices. In some embodiments, the nano-piezoelectric devices are selected from the group consisting of actuators, switches, and mechanical sensors. V. Formation of Multilayer Structures In some embodiments, the presently disclosed subject matter provides a method for forming multilayer structures, including multilayer particles. In some embodiments, the multilayer structures, including multilayer particles, comprise nanoscale multilayer structures. In some embodiments, multilayer structures are formed by depositing multiple thin layers of immisible liquids and/or solutions onto a substrate and forming particles as described by any of the methods hereinabove. The immiscibility of the liquid can be based on any physical characteristic, including but not limited to density, polarity, and volatility. Examples of possible morphologies of the presently disclosed subject matter are illustrated in FIGS. 5A-5C and include, but are not limited to, multi-phase sandwich structures, core-shell particles, and internal emulsions, microemulsions and/or nano-sized emulsions. Referring now to FIG. 5A, a multi-phase sandwich structure 500 of the presently disclosed subject matter is shown, which by way of example, comprises a first liquid material 502 and a second liquid material 504. Referring now to FIG. 5B, a core-shell particle 506 of the presently disclosed subject matter is shown, which by way of example, comprises a first liquid material 502 and a second liquid material 504. Referring now to FIG. 5C, an internal emulsion particle 508 of the presently disclosed subject matter is shown, which by way of example, comprises a first liquid material 502 and a second liquid material 504. More particularly, in some embodiments, the method comprises disposing a plurality of immiscible liquids between the patterned template and substrate to form a multilayer structure, e.g., a multilayer nanostructure. In some embodiments, the multilayer structure comprises a multilayer particle. In some embodiments, the multilayer structure comprises a structure selected from the group consisting of multi-phase sandwich structures, core-shell particles, internal emulsions, microemulsions, and nanosized emulsions. VI. Fabrication of Complex Multi-Dimensional Structures In some embodiments, the currently disclosed subject matter provides a process for fabricating complex, multi-dimensional structures. In some embodiments, complex multi-dimensional structures can be formed by performing the steps illustrated in FIGS. 2A-2E. In some embodiments, the method comprises imprinting onto a patterned template that is aligned with a second patterned template (instead of imprinting onto a smooth substrate) to generate isolated multi-dimensional structures that are cured and released as described herein. A schematic illustration of an embodiment of a process for forming complex multi-dimensional structures and examples of such structures are provided in FIGS. 6A-6C. Referring now to FIG. 6A, a first patterned template 600 is provided. First patterned template 600 comprises a plurality of recessed areas 602 and a plurality of non-recessed surfaces 604. Also provided is a second patterned template 606. Second patterned template 606 comprises a plurality of recessed areas 608 and a plurality of non-recessed surfaces 610. As shown in FIG. 6A, first patterned template 600 and second patterned template 606 are aligned in a predetermined spaced relationship. A droplet of liquid material 612 is disposed between first patterned template 600 and second patterned template 606. Referring now to FIG. 6B, patterned template 600 is contacted with patterned template 606. A force Fa is applied to patterned template 600 causing the liquid material comprising droplet 612 to migrate to the plurality of recessed areas 602 and 608. The liquid material comprising droplet 612 is then treated by treating process Tr to form a patterned, treated liquid material 614. Referring now to FIG. 6C, the patterned, treated liquid material 614 of FIG. 6B is released by any of the releasing methods described herein to provide a plurality of multi-dimensional patterned structures 616. In some embodiments, patterned structure 616 comprises a nanoscale-patterned structure. In some embodiments, patterned structure 616 comprises a multi-dimensional structure. In some embodiments, the multi-dimensional structure comprises a nanoscale multi-dimensional structure. In some embodiments, the multi-dimensional structure comprises a plurality of structural features. In some embodiments, the structural features comprise a plurality of heights. In some embodiments, a microelectronic device comprising patterned structure 616 is provided. Indeed, patterned structure 616 can be any structure imaginable, including “dual damscene” structures for microelectronics. In some embodiments, the microelectronic device is selected from the group consisting of integrated circuits, semiconductor particles, quantum dots, and dual damascene structures. In some embodiments, the microelectronic device exhibits certain physical properties selected from the group consisting of etch resistance, low dielectric constant, high dielectric constant, conducting, semiconducting, insulating, porosity, and non-porosity. In some embodiments, the presently disclosed subject matter discloses a method of preparing a multidimensional, complex structure. Referring now to FIGS. 7A-7F, in some embodiments, a first patterned template 700 is provided. First patterned template 700 comprises a plurality of non-recessed surface areas 702 and a plurality of recessed surface areas 704. Continuing particularly with FIG. 7A, also provided is a substrate 706. In some embodiments, substrate 706 is coated with a non-wetting agent 708. A droplet of a first liquid material 710 is disposed on substrate 706. Referring now to FIGS. 7B and 7C, first patterned template 700 is contacted with substrate 706. A force Fa is applied to first patterned template 700 such that the droplet of the first liquid material 710 is forced into recesses 704. The liquid material comprising the droplet of first liquid material 710 is treated by a first treating process Tr1 to form a treated first liquid material within the plurality of recesses 704. In some embodiments, first treating process Tr1 comprises a partial curing process causing the treated first liquid material to adhere to substrate 706. Referring particularly to FIG. 7C, first patterned template 700 is removed to provide a plurality of structural features 712 on substrate 706. Referring now to FIGS. 7D-7F, a second patterned template 714 is provided. Second patterned substrate 714 comprises a plurality of recesses 716, which are filled with a second liquid material 718. The filling of recesses 716 can be accomplished in a manner similar to that described in FIGS. 7A and 7B with respect to recesses 704. Referring particularly to FIG. 7E, second patterned template 714 is contacted with structural features 712. Second liquid material 718 is treated with a second treating process Tr2 such that the second liquid material 718 adheres to the plurality of structural feature 712, thereby forming a multidimensional structure 720. Referring particularly to FIG. 7F, second patterned template 714 and substrate 706 are removed, providing a plurality of free standing multidimensional structures 722. In some embodiments, the process schematically presented in FIGS. 7A-7F can be carried out multiple times as desired to form intricate nanostructures. Accordingly, in some embodiments, a method for forming multidimensional structures is provided, the method comprising: (a) providing a particle prepared by the process described in Figure **; (b) providing a second patterned template; (c) disposing a second liquid material in the second patterned template; (d) contacting the second patterned template with the particle of step (a); and (e) treating the second liquid material to form a multidimensional structure. VII. Imprint Lithography Referring now to FIGS. 8A-8D, a method for forming a pattern on a substrate is illustrated. In the embodiment illustrated in FIG. 8, an imprint lithography technique is used to form a pattern on a substrate. Referring now to FIG. 8A, a patterned template 810 is provided. In some embodiments, patterned template 810 comprises a solvent resistant, low surface energy polymeric material, derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template as defined hereinabove. Patterned template 810 further comprises a first patterned template surface 812 and a second template surface 814. The first patterned template surface 812 further comprises a plurality of recesses 816. The patterned template derived from a solvent resistant, low surface energy polymeric material could be mounted on another material to facilitate alignment of the patterned template or to facilitate continuous processing such as a conveyor belt. This might be particularly useful in the fabrication of precisely placed structures on a surface, such as in the fabrication of a complex devices or a semiconductor, electronic or photonic devices. Referring again to FIG. 8A, a substrate 820 is provided. Substrate 820 comprises a substrate surface 822. In some embodiments, substrate 820 is selected from the group consisting of a polymer material, an inorganic material, a silicon material, a quartz material, a glass material, and surface treated variants thereof. In some embodiments, at least one of patterned template 810 and substrate 820 has a surface energy lower than 18 mN/m. In some embodiments, at least one of patterned template 810 and substrate 820 has a surface energy lower than 15 mN/m. In some embodiments, as illustrated in FIG. 8A, patterned template 810 and substrate 820 are positioned in a spaced relationship to each other such that first patterned template surface 812 faces substrate surface 822 and a gap 830 is created between first patterned template surface 812 and substrate surface 822. This is an example of a predetermined relationship. Referring now to FIG. 8B, a volume of liquid material 840 is disposed in the gap 830 between first patterned template surface 82 and substrate surface 822. In some embodiments, the volume of liquid material 840 is disposed directed on a non-wetting agent (not shown), which is disposed on first patterned template surface 812. Referring now to FIG. 8C, in some embodiments, first patterned template 812 is contacted with the volume of liquid material 840. A force Fa is applied to second template surface 814 thereby forcing the volume of liquid material 840 into the plurality of recesses 816. In some embodiments, as illustrated in FIG. 8C, a portion of the volume of liquid material 840 remains between first patterned template surface 812 and substrate surface 820 after force Fa is applied. Referring again to FIG. 8C, in some embodiments, the volume of liquid material 840 is treated by a treating process T while force Fa is being applied to form a treated liquid material 842. In some embodiments, treating process Tr comprises a process selected from the group consisting of a thermal process, a photochemical process, and a chemical process. Referring now to FIG. 8D, a force Fr is applied to patterned template 810 to remove patterned template 810 from treated liquid material 842 to reveal a pattern 850 on substrate 820 as shown in FIG. 8E. In some embodiments, a residual, or “scum,” layer 852 of treated liquid material 842 remains on substrate 820. More particularly, the method for forming a pattern on a substrate comprises: (a) providing patterned template and a substrate, wherein the patterned template comprises a patterned template surface having a plurality of recessed areas formed therein; (b) disposing a volume of liquid material in or on at least one of: (i) the patterned template surface; and (ii) the plurality of recessed areas; (c) contacting the patterned template surface with the substrate; and (d) treating the liquid material to form a pattern on the substrate. In some embodiments, the patterned template comprises a solvent resistant, low surface energy polymeric material derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template. In some embodiments, the patterned template comprises a solvent resistant elastomeric material. In some embodiments, at least one of the patterned template and substrate comprises a material selected from the group consisting of a perfluoropolyether material, a fluoroolefin material, an acrylate material, a silicone material, a styrenic material, a fluorinated thermoplastic elastomer (TPE), a triazine fluoropolymer, a perfluorocyclobutyl material, a fluorinated epoxy resin, and a fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction. In some embodiments, the perfluoropolyether material comprises a backbone structure selected from the group consisting of: wherein X is present or absent, and when present comprises an endcapping group. In some embodiments, the fluoroolefin material is selected from the group consisting of: wherein CSM comprises a cure site monomer. In some embodiments, the fluoroolefin material is made from monomers, which comprise tetrafluoroethylene, vinylidene fluoride or hexafluoropropylene. 2,2-bis(trifluoromethyl)-4,5-difluoro-1,3-dioxole, a functional fluoroolefin, functional acrylic monomer, a functional methacrylic monomer. In some embodiments, the silicone material comprises a fluoroalkyl functionalized polydimethylsiloxane (PDMS) having the following structure: wherein: R is selected from the group consisting of an acrylate, a methacrylate, and a vinyl group; and Rf comprises a fluoroalkyl chain. In some embodiments, the styrenic material comprises a fluorinated styrene monomer selected from the group consisting of: wherein Rf comprises a fluoroalkyl chain. In some embodiments, the acrylate material comprises a fluorinated acrylate or a fluorinated methacrylate having the following structure: wherein: R is selected from the group consisting of H, alkyl, substituted alkyl, aryl, and substituted aryl; and Rf comprises a fluoroalkyl chain. In some embodiments, the triazine fluoropolymer comprises a fluorinated monomer. In some embodiments, the fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction comprises a functionalized olefin. In some embodiments, the functionalized olefin comprises a functionalized cyclic olefin. In some embodiments, at least one of the patterned template and the substrate has a surface energy lower than 18 mN/m. In some embodiments, at least one of the patterned template and the substrate has a surface energy lower than 15 mN/m. In some embodiments, the substrate is selected from the group consisting of a polymer material, an inorganic material, a silicon material, a quartz material, a glass material, and surface treated variants thereof. In some embodiments, the substrate is selected from one of an electronic device in the process of being manufactured and a photonic device in the process of being manufactured. In some embodiments, the substrate comprises a patterned area. In some embodiments, the plurality of recessed areas comprises a plurality of cavities. In some embodiments, the plurality of cavities comprise a plurality of structural features. In some embodiments, the plurality of structural features has a dimension ranging from about 10 microns to about 1 nanometer in size. In some embodiments, the plurality of structural features has a dimension ranging from about 10 microns to about 1 micron in size. In some embodiments, the plurality of structural features has a dimension ranging from about 1 micron to about 100 nm in size. In some embodiments, the plurality of structural features has a dimension ranging from about 100 nm to about 1 nm in size. In some embodiments, the liquid material is selected from the group consisting of a polymer, a solution, a monomer, a plurality of monomers, a polymerization initiator, a polymerization catalyst, an inorganic precursor, a metal precursor, a pharmaceutical agent, a tag, a magnetic material, a paramagnetic material, a superparamagnetic material, a ligand, a cell penetrating peptide, a porogen, a surfactant, a plurality of immiscible liquids, a solvent, and a charged species. In some embodiments, the pharmaceutical agent is selected from the group consisting of a drug, a peptide, RNAi, and DNA. In some embodiments, the tag is selected from the group consisting of a fluorescence tag, a radiolabeled tag, and a contrast agent. In some embodiments, the ligand comprises a cell targeting peptide. Represesentative superparamagnetic or paramagnetic materials include but are not limited to Fe2O3, Fe3O4, FePt, Co, MnFe2O4, CoFe2O4, CuFe2O4, NiFe2O4 and ZnS doped with Mn for magneto-optical applications, CdSe for optical applications, and borates for boron neutron capture treatment. In some embodiments, the liquid material is selected from one of a resist polymer and a low-k dielectric. In some embodiments, the liquid material comprises a non-wetting agent. In some embodiments, the disposing of the volume of liquid material is regulated by a spreading process. In some embodiments, the spreading process comprises: (a) disposing a first volume of liquid material on the patterned template to form a layer of liquid material on the patterned template; and (b) drawing an implement across the layer of liquid material to: (i) remove a second volume of liquid material from the layer of liquid material on the patterned template; and (ii) leave a third volume of liquid material on the patterned template. In some embodiments, the contacting of the first template surface with the substrate eliminates essentially all of the disposed volume of liquid material. In some embodiments, the treating of the liquid material comprises a process selected from the group consisting of a thermal process, a photochemical process, and a chemical process. In some embodiments, the method comprises a batch process. In some embodiments, the batch process is selected from one of a semi-batch process and a continuous batch process. In some embodiments, the presently disclosed subject matter describes a patterned substrate formed by the presently disclosed methods. VIII. Imprint Lithography Free of a Residual “Scum Layer” A characteristic of imprint lithography that has restrained its full potential is the formation of a “scum layer” once the liquid material, e.g., a resin, is patterned. The “scum layer” comprises residual liquid material that remains between the stamp and the substrate. In some embodiments, the presently disclosed subject matter provides a process for generating patterns essentially free of a scum layer. Referring now to FIGS. 9A-9D, in some embodiments, a method for forming a pattern on a substrate is provided, wherein the pattern is essentially free of a scum layer. Referring now to FIG. 9A, a patterned template 910 is provided. Patterned template 910 further comprises a first patterned template surface 912 and a second template surface 914. The first patterned template surface 912 further comprises a plurality of recesses 916. In some embodiments, a non-wetting agent 960 is disposed on the first patterned template surface 912. Referring again to FIG. 9A, a substrate 920 is provided Substrate 920 comprises a substrate surface 922. In some embodiments, a non-wetting agent 960 is disposed on substrate surface 920. In some embodiments, as illustrated in FIG. 9A, patterned template 910 and substrate 920 are positioned in a spaced relationship to each other such that first patterned template surface 912 faces substrate surface 922 and a gap 930 is created between first patterned template surface 912 and substrate surface 922. Referring now to FIG. 9B, a volume of liquid material 940 is disposed in the gap 930 between first patterned template surface 912 and substrate surface 922. In some embodiments, the volume of liquid material 940 is disposed directly on first patterned template surface 912. In some embodiments, the volume of liquid material 940 is disposed directly on non-wetting agent 960, which is disposed on first patterned template surface 912. In some embodiments, the volume of liquid material 940 is disposed directly on substrate surface 920. In some embodiments, the volume of liquid material 940 is disposed directly on non-wetting agent 960, which is disposed on substrate surface 920. Referring now to FIG. 9C, in some embodiments, first patterned template 912 is contacted with the volume of liquid material 940. A force Fa is applied to second template surface 914 thereby forcing the volume of liquid material 940 into the plurality of recesses 916. In contrast with the embodiment illustrated in FIG. 9, a portion of the volume of liquid material 940 is forced out of gap 930 by force Fo when force Fa is applied. Referring again to FIG. 9C, in some embodiments, the volume of liquid material 940 is treated by a treating process T while force Fa is being applied to form a treated liquid material 942. Referring now to FIG. 9D, a force Fr is applied to patterned template 910 to remove patterned template 910 from treated liquid material 942 to reveal a pattern 950 on substrate 920 as shown in FIG. 9E. In this embodiment, substrate 920 is essentially free of a residual, or “scum,” layer of treated liquid material 942. In some embodiments, at least one of the template surface and substrate comprises a functionalized surface element. In some embodiments, the functionalized surface element is functionalized with a non-wetting material. In some embodiments, the non-wetting material comprises functional groups that bind to the liquid material. In some embodiments, the non-wetting material is selected from the group consisting of a trichloro silane, a trialkoxy silane, a trichloro silane comprising non-wetting and reactive functional groups, a trialkoxy silane comprising non-wetting and reactive functional groups, and mixtures thereof. In some embodiments, the point of contact between the two surface elements is free of liquid material. In some embodiments, the point of contact between the two surface elements comprises residual liquid material. In some embodiments, the height of the residual liquid material is less than 30% of the height of the structure. In some embodiments, the height of the residual liquid material is less than 20% of the height of the structure. In some embodiments, the height of the residual liquid material is less than 10% of the height of the structure. In some embodiments, the height of the residual liquid material is less than 5% of the height of the structure. In some embodiments, the volume of liquid material is less than the volume of the patterned template. In some embodiments, substantially all of the volume of liquid material is confined to the patterned template of at least one of the surface elements. In some embodiments, having the point of contact between the two surface elements free of liquid material retards slippage between the two surface elements. IX. Solvent-Assisted Micro-Molding (SAMIM) In some embodiments, the presently disclosed subject matter describes a solvent-assisted micro-molding (SAMIM) method for forming a pattern on a substrate. Referring now to FIG. 10A, a patterned template 1010 is provided. Patterned template 1010 further comprises a first patterned template surface 1012 and a second template surface 1014. The first patterned template surface 1012 further comprises a plurality of recesses 1016. Referring again to FIG. 10A, a substrate 1020 is provided. Substrate 1020 comprises a substrate surface 1022. In some embodiments, a polymeric material 1070 is disposed on substrate surface 1022. In some embodiments, polymeric material 1070 comprises a resist polymer. Referring again to FIG. 10A, patterned template 1010 and substrate 1020 are positioned in a spaced relationship to each other such that first patterned template surface 1012 faces substrate surface 1022 and a gap 1030 is created between first patterned template surface 1012 and substrate surface 1022. As shown in FIG. 10A, a solvent S is disposed within gap 1030, such that solvent S contacts polymeric material 1070 forming a swollen polymeric material 1072. Referring now to FIGS. 10B and 10C, first patterned template 1012 is contacted with swollen polymeric material 1072. A force Fa is applied to second template surface 1014 thereby forcing a portion of swollen polymeric material 1072 into the plurality of recesses 1016 and leaving a portion of swollen polymeric material 1072 between first patterned template surface 1012 and substrate surface 1020. The swollen polymeric material 1072 is then treated by a treating process Tr while under pressure. Referring now to FIG. 10D, a force Fr is applied to patterned template 1010 to remove patterned template 1010 from treated swollen polymeric material 1072 to reveal a polymeric pattern 1074 on substrate 1020 as shown in FIG. 10E. X. Removing the Patterned Structure from the Patterned Template and/or Substrate In some embodiments, the patterned structure (e.g., a patterned micro- or nanostructure) is removed from at least one of the patterned template and/or the substrate. This can be accomplished by a number of approaches, including but not limited to applying the surface element containing the patterned structure to a surface that has an affinity for the patterned structure; deforming the surface element containing the patterned structure such that the patterned structure is released from the surface element; swelling the surface element containing the patterned structure with a first solvent to extrude the patterned structure; and washing the surface element containing the patterned structure with a second solvent that has an affinity for the patterned structure. In some embodiments, the first solvent comprises supercritical fluid carbon dioxide. In some embodiments, the first solvent comprises water. In some embodiments, the first solvent comprises an aqueous solution comprising water and a detergent. In embodiments, the deforming the surface element is performed by applying a mechanical force to the surface element. In some embodiments, the method of removing the patterned structure further comprises a sonication method. XI. Method of Fabricating Molecules and for Delivering a Therapeutic Agent to a Target In some embodiments, the presently disclosed subject matter describes methods and processes, and products by processes, for fabricating “molecules,” for use in drug discovery and drug therapies. In some embodiments, the method or process for fabricating a molecule comprises a combinatorial method or process. In some embodiments, the method for fabricating molecules comprises a non-wetting imprint lithography method. XI.A Method of Fabricating Molecules In some embodiments, the non-wetting imprint lithography method further comprises a surface derived from or comprising a solvent resistant, low surface energy polymeric material derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template. In some embodiments, the surface comprises a solvent resistant elastomeric material. In some embodiments, the non-wetting imprint lithography method is used to generate isolated structures. In some embodiments, the isolated structures comprise isolated micro-structures. In some embodiments, the isolated structures comprise isolated nano-structures. In some embodiments, the isolated structures comprise a biodegradable material. In some embodiments, the isolated structures comprise a hydrophilic material. In some embodiments, the isolated structures comprise a hydrophobic material. In some embodiments, the isolated structures comprise a particular shape. In some embodiments, the isolated structures further comprise “cargo.” In some embodiments, the non-wetting imprint lithography method further comprises adding molecular modules, fragments, or domains to the solution to be molded. In some embodiments, the molecular modules, fragments, or domains impart functionality to the isolated structures. In some embodiments, the functionality imparted to the isolated structure comprises a therapeutic functionality. In some embodiments, a therapeutic agent, such as a drug, is incorporated into the isolated structure. In some embodiments, the physiologically active drug is tethered to a linker to facilitate its incorporation into the isolated structure. In some embodiments, the domain of an enzyme or a catalyst is added to the isolated structure. In some embodiments, a ligand or an oligopeptide is added to the isolated structure. In some embodiments, the oligopeptide is functional. In some embodiments, the functional oligopeptide comprises a cell targeting peptide. In some embodiments, the functional oligopeptide comprises a cell penetrating peptide. In some embodiments an antibody or functional fragment thereof is added to the isolated structure. In some embodiments, a binder is added to the isolated structure. In some embodiments, the isolated structure comprising the binder is used to fabricate identical structures. In some embodiments, the isolated structure comprising the binder is used to fabricate structures of a varying structure. In some embodiments, the structures of a varying structure are used to explore the efficacy of a molecule as a therapeutic agent. In some embodiments, the shape of the isolated structure mimics a biological agent. In some embodiments, the method further comprises a method for drug discovery. XIB. Method of Delivering a Therapeutic Agent to a Target In some embodiments, a method of delivering a therapeutic agent to a target is disclosed, the method comprising: providing a particle produced as described herein; admixing the therapeutic agent with the particle; and delivering the particle comprising the therapeutic agent to the target. In some embodiments, the therapeutic agent comprises a drug. In some embodiments, the therapeutic agent comprises genetic material. In some embodiments, the genetic material is selected from the group consisting of a non-viral gene vector, DNA, RNA, RNAi, and a viral particle. In some embodiments, the particle has a diameter of less than 100 microns. In some embodiments, the particle has a diameter of less than 10 microns. In some embodiments, the particle has a diameter of less than 1 micron. In some embodiments, the particle has a diameter of less than 100 nm. In some embodiments, the particle has a diameter of less than 10 nm. In some embodiments, the particle comprises a biodegradable polymer. In some embodiments, the biodegradable polymer is selected from the group consisting of a polyester, a polyanhydride, a polyamide, a phosphorous-based polymer, a poly(cyanoacrylate), a polyurethane, a polyorthoester, a polydihydropyran, and a polyacetal. In some embodiments, the polyester is selected from the group consisting of polylactic acid, polyglycolic acid, poly(hydroxybutyrate), poly(ε-caprolactone), poly(β-malic acid), and poly(dioxanones). In some embodiments, the polyanhydride is selected from the group consisting of poly(sebacic acid), poly(adipic acid), and poly(terpthalic acid). In some embodiments, the polyamide is selected from the group consisting of poly(imino carbonates) and polyaminoacids. In some embodiments, the phosphorous-based polymer is selected from the group consisting of polyphosphates, polyphosphonates, and polyphosphazenes. In some embodiments, the polymer is responsive to stimuli, such as pH, radiation, ionic strength, temperature, and alternating magnetic or electric fields. Responses to such stimuli can include swelling and/or heating, which can facilitate release of its cargo, or degradation. In some embodiments, the presently disclosed subject matter describes magneto containing particles for applications in hyperthermia therapy, cancer and gene therapy, drug delivery, magnetic resonance imaging contrast agents, vaccine adjuvants, memory devices, and spintronics. Without being bound to any one particular theory, the magneto containing particles, e.g., a magnetic nanoparticle, produce heat by the process of hyperthermia (between 41 and 46° C.) or thermo ablation (greater than 46° C.), i.e., the controlled heating of the nanoparticles upon exposure to an AC-magnetic field. The heat is used to (i) induce a phase change in the polymer component (for example melt and release an encapsulated material) and/or (ii) hyperthermia treatment of specific cells and/or (iii) increase the effectiveness of the encapsulated material. The triggering mechanism of the magnetic nanoparticles via electromagnetic heating enhance the (iv) degradation rate of the particulate; (v) can induce swelling; and/or (vi) induce dissolution/phase change that can lead to a greater surface area, which can be beneficial when treating a variety of diseases. In some embodiments, the presently disclosed subject matter describes an alternative therapeutic agent delivery method, which utilizes “non-wetting” imprint lithography to fabricate monodisperse magnetic nanoparticles for use in a drug delivery system. Such particles can be used for: (1) hyperthermia treatment of cancer cells; (2) MRI contrast agents; (3) guided delivery of the particle; and (4) triggered degradation of the drug delivery vector. In some embodiments, the therapeutic agent delivery system comprises a biocompatible material and a magnetic nanoparticle. In some embodiments, the biocompatible material has a melting point below 100° C. In some embodiments, the biocompatible material is selected from the group consisting of, but not limited to, a polylactide, a polyglycolide, a hydroxypropylcellulose, and a wax. In some embodiments, once the magnetic nanoparticle is delivered to the target or is in close proximity to the target, the magnetic nanoparticle is exposed to an AC-magnetic field. The exposure to the AC-magnetic field causes the magnetic nanoparticle to undergo a controlled heating. Without being bound to any one particular theory, the controlled heating is a result of a thermo ablation process. In some embodiments, the heat is used to induce a phase change in the polymer component of the nanoparticle. In some embodiments, the phase change comprises a melting process. In some embodiments, the phase change results in the release of an encapsulated material. In some embodiments, the release of an encapsulated material comprises a controlled release. In some embodiments, the controlled release of the encapsulated material results in a concentrated dosing of the therapeutic agent. In some embodiments, the heating results in the hyperthermic treatment of the target, e.g., specific cells. In some embodiments, the heating results in an increase in the effectiveness of the encapsulated material. In some embodiments, the triggering mechanism of the magnetic nanoparticles induced by the electromagnetic heating enhances the degradation rate of the particle and can induce swelling and/or a dissolution/phase change that can lead to a greater surface area which can be beneficial when treating a variety of diseases. In some embodiments, additional components, including drugs, such as an anticancer agent, e.g., nitrogen mustard, cisplatin, and doxorubicin; targeting ligands, such as cell-targeting peptides, cell-penetrating peptides, integrin receptor peptide (GRGDSP), melanocyte stimulating hormone, vasoactive intestional peptide, anti-Her2 mouse antibodies, and a variety of vitamins; viruses, polysaccharides, cyclodextrins, proteins, liposomes, optical nanoparticles, such as CdSe for optical applications, and borate nanoparticles to aid in boron neutron capture therapy (BNCT) targets. The presently described magnetic containing materials also lend themselves to other applications. The magneto-particles can be assembled into well-defined arrays driven by their shape, functionalization of the surface and/or exposure to a magnetic field for investigations of and not limited to magnetic assay devices, memory devices, spintronic applications, and separations of solutions. Thus, the presently disclosed subject matter provides a method for delivering a therapeutic agent to a target, the method comprising: (a) providing a particle prepared by the presently disclosed methods; (b) admixing the therapeutic agent with the particle; and (c) delivering the particle comprising the therapeutic agent to the target. In some embodiments, the therapeutic agent is selected from one of a drug and genetic material. In some embodiments, the genetic material is selected from the group consisting of a non-viral gene vector, DNA, RNA, RNAi, and a viral particle. In some embodiments, the particle comprises a biodegradable polymer. In some embodiments, the biodegradable polymer is selected from the group consisting of a polyester, a polyanhydride, a polyamide, a phosphorous-based polymer, a poly(cyanoacrylate), a polyurethane, a polyorthoester, a polydihydropyran, and a polyacetal. In some embodiments, the polyester is selected from the group consisting of polylactic acid, polyglycolic acid, poly(hydroxybutyrate), poly(ε-caprolactone), poly(β-malic acid), and poly(dioxanones). In some embodiments, the polyanhydride is selected from the group consisting of poly(sebacic acid), poly(adipic acid), and poly(terpthalic acid). In some embodiments, the polyamide is selected from the group consisting of poly(imino carbonates) and polyaminoacids. In some embodiments, the phosphorous-based polymer is selected from the group consisting of a polyphosphate, a polyphosphonate, and a polyphosphazene. In some embodiments, the biodegradable polymer further comprises a polymer that is responsive to a stimulus. In some embodiments, the stimulus is selected from the group consisting of pH, radiation, ionic strength, temperature, an alternating magnetic field, and an alternating electric field. In some embodiments, the stimulus comprises an alternating magnetic field. In some embodiments, the method comprises exposing the particle to an alternating magnetic field once the particle is delivered to the target. In some embodiments, the exposing of the particle to an alternating magnetic field causes the particle to produce heat through one of a hypothermia process and a thermo ablation process. In some embodiments, the heat produced by the particle induces one of a phase change in the polymer component of the particle and a hyperthermic treatment of the target. In some embodiments, the phase change in the polymer component of the particle comprises a change from a solid phase to a liquid phase. In some embodiments, the phase change from a solid phase to a liquid phase causes the therapeutic agent to be released from the particle. In some embodiments, the release of the therapeutic agent from the particle comprises a controlled release. In some embodiments, the target is selected from the group consisting of a cell-targeting peptide, a cell-penetrating peptide, an integrin receptor peptide (GRGDSP), a melanocyte stimulating hormone, a vasoactive intestional peptide, an anti-Her2 mouse antibody, and a vitamin. With respect to the methods of the presently disclosed subject matter, any animal subject can be treated. The term “subject” as used herein refers to any vertebrate species. The methods of the presently claimed subject matter are particularly useful in the diagnosis of warm-blooded vertebrates. Thus, the presently claimed subject matter concerns mammals. In some embodiments provided is the diagnosis and/or treatment of mammals such as humans, as well as those mammals of importance due to being endangered (such as Siberian tigers), of economical importance (animals raised on farms for consumption by humans) and/or social importance (animals kept as pets or in zoos) to humans, for instance, carnivores other than humans (such as cats and dogs), swine (pigs, hogs, and wild boars), ruminants (such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), and horses. Also provided is the diagnosis and/or treatment of livestock, including, but not limited to domesticated swine (pigs and hogs), ruminants, horses, poultry, and the like. The following references are incorporated herein by reference in their entirety. Published International PCT Application No. WO2004081666 to DeSimone et al.; U.S. Pat. No. 6,528,080 to Dunn et al.; U.S. Pat. No. 6,592,579 to Arndt et al., Published International PCT Application No. WO0066192 to Jordan; Hilger, I. et al., Radiology 570-575 (2001); Mornet, S. et al., J. Mat. Chem., 2161-2175 (2004); Berry, C. C. et al., J. Phys. D: Applied Physics 36, R198-R206 (2003); Babincova, M. et al., Bioelectrochemistry 55, 17-19 (2002); Wolf, S. A. et al., Science 16, 1488-1495 (2001); and Sun, S. et al., Science 287, 1989-1992 (2000); U.S. Pat. No. 6,159,443 to Hallahan; and Published PCT Application No. WO 03/066066 to Hallahan et al. XII. Method of Patterning Natural and Synthetic Structures In some embodiments, the presently disclosed subject matter describes methods and processes, and products by processes, for generating surfaces and molds from natural structures, single molecules, or self-assembled structures. Accordingly, in some embodiments, the presently disclosed subject matter describes a method of patterning a natural structure, single molecule, and/or a self-assembled structure. In some embodiments, the method further comprises replicating the natural structure, single molecule, and/or a self-assembled structure. In some embodiments, the method further comprises replicating the functionality of the natural structure, single molecule, and/or a self-assembled structure. More particularly, in some embodiments, the method further comprises taking the impression or mold of a natural structure, single molecule, and/or a self-assembled structure. In some embodiments, the impression or mold is taken with a low surface energy polymeric precursor. In some embodiments, the low surface energy polymeric precursor comprises a perfluoropolyether (PFPE) functionally terminated diacrylate. In some embodiments, the natural structure, single molecule, and/or self-assembled structure is selected from the group consisting of enzymes, viruses, antibodies, micelles, and tissue surfaces. In some embodiments, the impression or mold is used to replicate the features of the natural structure, single molecule, and/or a self-assembled structure into an isolated object or a surface. In some embodiments, a non-wetting imprint lithography method is used to impart the features into a molded part or surface. In some embodiments, the molded part or surface produced by this process can be used in many applications, including, but not limited to, drug delivery, medical devices, coatings, catalysts, or mimics of the natural structures from which they are derived. In some embodiments, the natural structure comprises biological tissue. In some embodiments, the biological tissue comprises tissue from a bodily organ, such as a heart. In some embodiments, the biological tissue comprises vessels and bone. In some embodiments, the biological tissue comprises tendon or cartilage. For example, in some embodiments, the presently disclosed subject matter can be used to pattern surfaces for tendon and cartilage repair. Such repair typically requires the use of collagen tissue, which comes from cadavers and must be machined for use as replacements. Most of these replacements fail because one cannot lay down the primary pattern that is required for replacement. The soft lithographic methods described herein alleviate this problem. In some embodiments, the presently disclosed subject matter can be applied to tissue regeneration using stem cells. Almost all stem cell approaches known in the art require molecular patterns for the cells to seed and then grow, thereby taking the shape of an organ, such as a liver, a kidney, or the like. In some embodiments, the molecular scaffold is cast and used as crystals to seed an organ in a form of transplant therapy. In some embodiments, the stem cell and nano-substrate is seeded into a dying tissue, e.g., liver tissue, to promote growth and tissue regeneration. In some embodiments, the material to be replicated in the mold comprises a material that is similar to or the same as the material that was originally molded. In some embodiments, the material to be replicated in the mold comprises a material that is different from and/or has different properties than the material that was originally molded. This approach could play an important role in addressing the organ transplant shortage. In some embodiments, the presently disclosed subject matter is used to take the impression of one of an enzyme, a bacterium, and a virus. In some embodiments, the enzyme, bacterium, or virus is then replicated into a discrete object or onto a surface that has the shape reminiscent of that particular enzyme, bacterium, or virus replicated into it. In some embodiments, the mold itself is replicated on a surface, wherein the surface-attached replicated mold acts as a receptor site for an enzyme, bacterium, or virus particle. In some embodiments, the replicated mold is useful as a catalyst, a diagnostic sensor, a therapeutic agent, a vaccine, and the like. In some embodiments, the surface-attached replicated mold is used to facilitate the discovery of new therapeutic agents. In some embodiments, the macromolecular, e.g., enzyme, bacterial, or viral, molded “mimics” serve as non-self-replicating entities that have the same surface topography as the original macromolecule, bacterium, or virus. In some embodiments, the molded mimics are used to create biological responses, e.g., an allergic response, to their presence, thereby creating antibodies or activating receptors. In some embodiments, the molded mimics function as a vaccine. In some embodiments, the efficacy of the biologically-active shape of the molded mimics is enhanced by a surface modification technique. XII. Method of Modifying the Surface of an Imprint Lithography Mold to Impart Surface Characteristics to Molded Products In some embodiments, the presently disclosed subject matter describes a method of modifying the surface of an imprint lithography mold. In some embodiments, the method further comprises imparting surface characteristics to a molded product. In some embodiments, the molded product comprises an isolated molded product. In some embodiments, the isolate molded product is formed using a non-wetting imprint lithography technique. In some embodiments, the molded product comprises a contact lens, a medical device, and the like. More particularly, the surface of a solvent resistant, low surface energy polymeric material, or more particularly a PFPE mold is modified by a surface modification step, wherein the surface modification step is selected from the group consisting of plasma treatment, chemical treatment, and the adsorption of molecules. In some embodiments, the molecules adsorbed during the surface modification step are selected from the group consisting of polyelectrolytes, poly(vinylalcohol), alkylhalosilanes, and ligands. In some embodiments, the structures, particles, or objects obtained from the surface-treated molds can be modified by the surface treatments in the mold. In some embodiments, the modification comprises the pre-orientation of molecules or moieties with the molecules comprising the molded products. In some embodiments, the pre-orientation of the molecules or moieties imparts certain properties to the molded products, including catalytic, wettable, adhesive, non-stick, interactive, or not interactive, when the molded product is placed in another environment. In some embodiments, such properties are used to facilitate interactions with biological tissue or to prevent interaction with biological tissues. Applications of the presently disclosed subject matter include sensors, arrays, medical implants, medical diagnostics, disease detection, and separation media. XIV. Methods for Selectively Exposing the Surface of an Article to an Agent Also disclosed herein is a method for selectively exposing the surface of an article to an agent. In some embodiments the method comprises: (a) shielding a first portion of the surface of the article with a masking system, wherein the masking system comprises a elastomeric mask in conformal contact with the surface of the article; and (b) applying an agent to be patterned within the masking system to a second portion of the surface of the article, while preventing application of the agent to the first portion shielded by the masking system. In some embodiments, the elastomeric mask comprises a plurality of channels. In some embodiments, each of the channels has a cross-sectional dimension of less than about 1 millimeter. In some embodiments, each of the channels has a cross-sectional dimension of less than about 1 micron. In some embodiments, each of the channels has a cross-sectional dimension of less than about 100 nm. In some embodiments, each of the channels has a cross-sectional dimension of about 1 nm. In some embodiments, the agent swells the elastomeric mask less than 25%. In some embodiments, the agent comprises an organic electroluminescent material or a precursor thereof. In some embodiments, the method further comprising allowing the organic electroluminescent material to form from the agent at the second portion of the surface, and establishing electrical communication between the organic electroluminescent material and an electrical circuit. In some embodiments, the agent comprises a liquid or is carried in a liquid. In some embodiments, the agent comprises the product of chemical vapor deposition. In some embodiments, the agent comprises a product of deposition from a gas phase. In some embodiments, the agent comprises a product of e-beam deposition, evaporation, or sputtering. In some embodiments, the agent comprises a product of electrochemical deposition. In some embodiments, the agent comprises a product of electroless deposition. In some embodiments, the agent is applied from a fluid precursor. In some embodiments, comprises a solution or suspension of an inorganic compound. In some embodiments, the inorganic compound hardens on the second portion of the article surface. In some embodiments, the fluid precursor comprises a suspension of particles in a fluid carrier. In some embodiments, the method further comprises allowing the fluid carrier to dissipate thereby depositing the particles at the first region of the article surface. In some embodiments, the fluid precursor comprises a chemically active agent in a fluid carrier. In some embodiments, the method further comprises allowing the fluid carrier to dissipate thereby depositing the chemically active agent at the first region of the article surface. In some embodiments, the chemically active agent comprises a polymer precursor. In some embodiments, the method further comprises forming a polymeric article from the polymer precursor. In some embodiments, the chemically active agent comprises an agent capable of promoting deposition of a material. In some embodiments, the chemically active agent comprises an etchant. In some embodiments, the method further comprises allowing the second portion of the surface of the article to be etched. In some embodiments, the method further comprises removing the elastomeric mask of the masking system from the first portion of the article surface while leaving the agent adhered to the second portion of the article surface. XV. Methods for Forming Engineered Membranes The presently disclosed subject matter also describes a method for forming an engineered membrane. In some embodiments, a patterned non-wetting template is formed by contacting a first liquid material, such as a PFPE material, with a patterned substrate and treating the first liquid material, for example, by curing through exposure to UV light to form a patterned non-wetting template. The patterned substrate comprises a plurality of recesses or cavities configured in a specific shape such that the patterned non-wetting template comprises a plurality of extruding features. The patterned non-wetting template is contacted with a second liquid material, for example, a photocurable resin. A force is then applied to the patterned non-wetting template to displace an excess amount of second liquid material or “scum layer.” The second liquid material is then treated, for example, by curing through exposure to UV light to form an interconnected structure comprising a plurality of shape and size specific holes. The interconnected structure is then removed from the non-wetting template. In some embodiments, the interconnected structure is used as a membrane for separations XVI. Methods for Inspecting Processes and Products by Processes It will be important to inspect the objects/structures/particles described herein for accuracy of shape, placement and utility. Such inspection can allow for corrective actions to be taken or for defects to be removed or mitigated. The range of approaches and monitoring devices useful for such inspections include: air gages, which use pneumatic pressure and flow to measure or sort dimensional attributes; balancing machines and systems, which dynamically measure and/or correct machine or component balance; biological microscopes, which typically are used to study organisms and their vital processes; bore and ID gages, which are designed for internal diameter dimensional measurement or assessment; boroscopes, which are inspection tools with rigid or flexible optical tubes for interior inspection of holes, bores, cavities, and the like; calipers, which typically use a precise slide movement for inside, outside, depth or step measurements, some of which are used for comparing or transferring dimensions; CMM probes, which are transducers that convert physical measurements into electrical signals, using various measuring systems within the probe structure; color and appearance instruments, which, for example, typically are used to measure the properties of paints and coatings including color, gloss, haze and transparency; color sensors, which register items by contrast, true color, or translucent index, and are based on one of the color models, most commonly the RGB model (red, green, blue); coordinate measuring machines, which are mechanical systems designed to move a measuring probe to determine the coordinates of points on a work piece surface; depth gages, which are used to measure of the depth of holes, cavities or other component features; digital/video microscopes, which use digital technology to display the magnified image; digital readouts, which are specialized displays for position and dimension readings from inspection gages and linear scales, or rotary encoders on machine tools; dimensional gages and instruments, which provide quantitative measurements of a product's or component's dimensional and form attributes such as wall thickness, depth, height, length, I.D., O.D., taper or bore; dimensional and profile scanners, which gather two-dimensional or three-dimensional information about an object and are available in a wide variety of configurations and technologies; electron microscopes, which use a focused beam of electrons instead of light to “image” the specimen and gain information as to its structure and composition; fiberscopes, which are inspection tools with flexible optical tubes for interior inspection of holes, bores, and cavities; fixed gages, which are designed to access a specific attribute based on comparative gaging, and include Angle Gages, Ball Gages, Center Gages, Drill Size Gages, Feeler Gages, Fillet Gages, Gear Tooth Gages, Gage or Shim Stock, Pipe Gages, Radius Gages, Screw or Thread Pitch Gages, Taper Gages, Tube Gages, U.S. Standard Gages (Sheet/Plate), Weld Gages and Wire Gages; specialty/form gages, which are used to inspect parameters such as roundness, angularity, squareness, straightness, flatness, runout, taper and concentricity; gage blocks, which are manufactured to precise gagemaker tolerance grades for calibrating, checking, and setting fixed and comparative gages; height gages, which are used for measuring the height of components or product features; indicators and comparators, which measure where the linear movement of a precision spindle or probe is amplified; inspection and gaging accessories, such as layout and marking tolls, including hand tools, supplies and accessories for dimensional measurement, marking, layout or other machine shop applications such as scribes, transfer punches, dividers, and layout fluid; interferometers, which are used to measure distance in terms of wavelength and to determine wavelengths of particular light sources; laser micrometers, which measure extremely small distances using laser technology; levels, which are mechanical or electronic tools that measure the inclination of a surface relative to the earth's surface; machine alignment equipment, which is used to align rotating or moving parts and machine components; magnifiers, which are inspection instruments that are used to magnify a product or part detail via a lens system; master and setting gages, which provide dimensional standards for calibrating other gages; measuring microscopes, which are used by toolmakers for measuring the properties of tools, and often are used for dimensional measurement with lower magnifying powers to allow for brighter, sharper images combined with a wide field of view; metallurgical microscopes, which are used for metallurgical inspection; micrometers, which are instruments for precision dimensional gaging consisting of a ground spindle and anvil mounted in a C-shaped steel frame. Noncontact laser micrometers are also available; microscopes (all types), which are instruments that are capable of producing a magnified image of a small object; optical/light microscopes, which use the visible or near-visible portion of the electromagnetic spectrum; optical comparators, which are instruments that project a magnified image or profile of a part onto a screen for comparison to a standard overlay profile or scale; plug/pin gages, which are used for a “go/no-go” assessment of hole and slot dimensions or locations compared to specified tolerances; protractors and angle gages, which measure the angle between two surfaces of a part or assembly; ring gages, which are used for “go/no-go” assessment compared to the specified dimensional tolerances or attributes of pins, shafts, or threaded studs; rules and scales, which are flat, graduated scales used for length measurement, and which for OEM applications, digital or electronic linear scales are often used; snap gages, which are used in production settings where specific diametrical or thickness measurements must be repeated frequently with precision and accuracy; specialty microscopes, which are used for specialized applications including metallurgy, gemology, or use specialized techniques like acoustics or microwaves to perform their function; squares, which are used to indicate if two surfaces of a part or assembly are perpendicular; styli, probes, and cantilevers, which are slender rod-shaped stems and contact tips or points used to probe surfaces in conjunction with profilometers, SPMs, CMMs, gages and dimensional scanners; surface profilometers, which measure surface profiles, roughness, waviness and other finish parameters by scanning a mechanical stylus across the sample or through noncontact methods; thread gages, which are dimensional instruments for measuring thread size, pitch or other parameters; and videoscopes, which are inspection tools that capture images from inside holes, bores or cavities. EXAMPLES The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. Example 1 Representative Procedure for Synthesis and Curing Photocurable Perfluoropolyethers In some embodiments, the synthesis and curing of PFPE materials of the presently disclosed subject matter is performed by using the method described by Rolland J. P., et al., J. Am. Chem. Soc., 2004, 126, 2322-2323. Briefly, this method involves the methacrylate-functionalization of a commercially available PFPE diol (Mn=3800 g/mol) with isocyanatoethyl methacrylate. Subsequent photocuring of the material is accomplished through blending with 1 wt % of 2,2-dimethoxy-2-phenylacetophenone and exposure to UV radiation (λ=365 nm). More particularly, in a typical preparation of perfluoropolyether dimethacrylate (PFPE DMA), poly(tetrafluoroethylene oxide-co-difluoromethylene oxide)α,ω diol (ZDOL, average Mn ca. 3,800 g/mol, 95%, Aldrich Chemical Company, Milwaukee, Wis., United States of America) (5.7227 g, 1.5 mmol) was added to a dry 50 mL round bottom flask and purged with argon for 15 minutes. 2-isocyanatoethyl methacrylate (EIM, 99%, Aldrich) (0.43 mL, 3.0 mmol) was then added via syringe along with 1,1,2-trichlorotrifluoroethane (Freon 113 99%, Aldrich) (2 mL), and dibutyltin diacetate (DBTDA, 99%, Aldrich) (50 μL). The solution was immersed in an oil bath and allowed to stir at 50° C. for 24 h. The solution was then passed through a chromatographic column (alumina, Freon 113, 2×5 cm). Evaporation of the solvent yielded a clear, colorless, viscous oil, which was further purified by passage through a 0.22-μm polyethersulfone filter. In a representative curing procedure for PFPE DMA, 1 wt % of 2,2-dimethoxy-2-phenyl acetophenone (DMPA, 99% Aldrich), (0.05 g, 2.0 mmol) was added to PFPE DMA (5 g, 1.2 mmol) along with 2 mL Freon 113 until a clear solution was formed. After removal of the solvent, the cloudy viscous oil was passed through a 0.22-μm polyethersulfone filter to remove any DMPA that did not disperse into the PFPE DMA. The filtered PFPE DMA was then irradiated with a UV source (Electro-Lite Corporation, Danbury, Conn., United States of America, UV curing chamber model no. 81432-ELC-500, λ=365 nm) while under a nitrogen purge for 10 min. This resulted in a clear, slightly yellow, rubbery material. Example 2 Representative Fabrication of a PFPE DMA Device In some embodiments, a PFPE DMA device, such as a stamp, was fabricated according to the method described by Rolland, J. P., et al., J. Am. Chem. Soc., 2004, 126, 2322-2323. Briefly, the PFPE DMA containing a photoinitiator, such as DMPA, was spin coated (800 rpm) to a thickness of 20 μm onto a Si wafer containing the desired photoresist pattern. This coated wafer was then placed into the UV curing chamber and irradiated for 6 seconds. Separately, a thick layer (about 5 mm) of the material was produced by pouring the PFPE DMA containing photoinitiator into a mold surrounding the Si wafer containing the desired photoresist pattern. This wafer was irradiated with UV light for one minute. Following this, the thick layer was removed. The thick layer was then placed on top of the thin layer such that the patterns in the two layers were precisely aligned, and then the entire device was irradiated for 10 minutes. Once complete, the entire device was peeled from the Si wafer with both layers adhered together. Example 3 Fabrication of Isolated Particles using Non-Wetting Imprint Lithography 3.1 Fabrication of 200-nm Trapezoidal PEG Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (See FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of PEG diacrylate is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) (see FIG. 14). 3.2 Fabrication of 500-nm Conical PEG Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 500-nm conical shapes (see FIG. 12). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of PEG diacrylate is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) (see FIG. 15). 3.3 Fabrication of 3-μm Arrow-Shaped PEG Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 3-μm arrow shapes (see FIG. 11). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of PEG diacrylate is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) (see FIG. 16). 3.4 Fabrication of 200-nm×750-nm×250-nm Rectangular PEG Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm×750-nm×250-nm rectangular shapes. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of PEG diacrylate is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) (see FIG. 17). 3.5 Fabrication of 200-nm Trapezoidal Trimethylopropane Triacrylate (TMPTA) Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, TMPTA is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid: 30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of TMPTA is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess TMPTA. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) (see FIG. 18). 3.6 Fabrication of 500-nm Conical Trimethylopropane Triacrylate (TMPTA) Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 500-nm conical shapes (see FIG. 12). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, TMPTA is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of TMPTA is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess TMPTA. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) (see FIG. 19). Further, FIG. 20 shows a scanning electron micrograph of 500-nm isolated conical particles of TMPTA, which have been printed using an embodiment of the presently described non-wetting imprint lithography method and harvested mechanically using a doctor blade. The ability to harvest particles in such a way offers conclusive evidence for the absence of a “scum layer.” 3.7 Fabrication of 3-μm Arrow-Shaped TMPTA Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 3-μm arrow shapes (see FIG. 11). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, TMPTA is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of TMPTA is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess TMPTA. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM). 3.8 Fabrication of 200-nm Trapezoidal Poly(Lactic Acid) (PLA) Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, one gram of (3S)-cis-3,6-dimethyl-1,4-dioxane-2,5-dione (LA) is heated above its melting temperature (92° C.) to 110° C. and approximately 20 μL of stannous octoate catalyst/initiator is added to the liquid monomer. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of molten LA containing catalyst is then placed on the treated silicon wafer preheated to 110° C. and the patterned PFPE mold is placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess monomer. The entire apparatus is then placed in an oven at 110° C. for 15 hours. Particles are observed after cooling to room temperature and separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) (see FIG. 21). Further, FIG. 22 is a scanning electron micrograph of 200-nm isolated trapezoidal particles of poly(lactic acid) (PLA), which have been printed using an embodiment of the presently described non-wetting imprint lithography method and harvested mechanically using a doctor blade. The ability to harvest particles in such a way offers conclusive evidence for the absence of a “scum layer.” 3.9 Fabrication of 3-μm Arrow-Shaped (PLA) Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 3-μm arrow shapes (see FIG. 11). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, one gram of (3S)-cis-3,6-dimethyl-1,4-dioxane-2,5-dione (LA) is heated above its melting temperature (92° C.) to 110° C. and ˜20 μL of stannous octoate catalyst/initiator is added to the liquid monomer. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of molten LA containing catalyst is then placed on the treated silicon wafer preheated to 110° C. and the patterned PFPE mold is placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess monomer. The entire apparatus is then placed in an oven at 110° C. for 15 hours. Particles are observed after cooling to room temperature and separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) (see FIG. 23). 3.10 Fabrication of 500-nm Conical Shaped (PLA) Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 500-nm conical shapes (see FIG. 12). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, one gram of (3S)-cis-3,6-dimethyl-1,4-dioxane-2,5-dione (LA) is heated above its melting temperature (92° C.) to 110° C. and ˜20 μL of stannous octoate catalyst/initiator is added to the liquid monomer. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of molten LA containing catalyst is then placed on the treated silicon wafer preheated to 110° C. and the patterned PFPE mold is placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess monomer. The entire apparatus is then placed in an oven at 110° C. for 15 hours. Particles are observed after cooling to room temperature and separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) (see FIG. 24). 3.11 Fabrication of 200-nm Trapezoidal Poly(Pyrrole) (Ppy) Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) deposition in a desiccator for 20 minutes. Separately, 50 μL of a 1:1 v:v solution of tetrahydrofuran:pyrrole is added to 50 μL of 70% perchloric acid (aq). A clear, homogenous, brown solution quickly forms and develops into black, solid, polypyrrole in 15 minutes. A drop of this clear, brown solution (prior to complete polymerization) is placed onto a treated silicon wafer and into a stamping apparatus and a pressure is applied to remove excess solution. The apparatus is then placed into a vacuum oven for 15 h to remove the THF and water. Particles are observed using scanning electron microscopy (SEM) (see FIG. 25) after release of the vacuum and separation of the PFPE mold and the treated silicon wafer. 3.12 Fabrication of 3-μm Arrow-Shaped (Ppy) Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 3-μm arrow shapes (see FIG. 11). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Separately, 50 μL of a 1:1 v:v solution of tetrahydrofuran:pyrrole is added to 50 μL of 70% perchloric acid (aq). A clear, homogenous, brown solution quickly forms and develops into black, solid, polypyrrole in 15 minutes. A drop of this clear, brown solution (prior to complete polymerization) is placed onto a treated silicon wafer and into a stamping apparatus and a pressure is applied to remove excess solution. The apparatus is then placed into a vacuum oven for 15 h to remove the THF and water. Particles are observed using scanning electron microscopy (SEM) (see FIG. 26) after release of the vacuum and separation of the PFPE mold and the treated silicon wafer. 3.13 Fabrication of 500-nm Conical (Ppy) Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 500-nm conical shapes (see FIG. 12). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Separately, 50 μL of a 1:1 v:v solution of tetrahydrofuran:pyrrole is added to 50 μL of 70% perchloric acid (aq). A clear, homogenous, brown solution quickly forms and develops into black, solid, polypyrrole in 15 minutes. A drop of this clear, brown solution (prior to complete polymerization) is placed onto a treated silicon wafer and into a stamping apparatus and a pressure is applied to remove excess solution. The apparatus is then placed into a vacuum oven for 15 h to remove the THF and water. Particles are observed using scanning electron microscopy (SEM) (see FIG. 27) after release of the vacuum and separation of the PFPE mold and the treated silicon wafer. 3.14 Encapsulation of Fluorescently Tagged DNA Inside 200-nm Trapezoidal PEG Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. 20 μL of water and 20 μL of PEG diacrylate monomer are added to 8 nanomoles of 24 bp DNA oligonucleotide that has been tagged with a fluorescent dye, CY-3. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of the PEG diacrylate solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate solution. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Particles are observed after separation of the PFPE mold and the treated silicon wafer using confocal fluorescence microscopy (see FIG. 28). Further, FIG. 28A shows a fluorescent confocal micrograph of 200 nm trapezoidal PEG nanoparticles which contain 24-mer DNA strands that are tagged with CY-3. FIG. 28B is optical micrograph of the 200-nm isolated trapezoidal particles of PEG diacrylate that contain fluorescently tagged DNA. FIG. 28C is the overlay of the images provided in FIGS. 28A and 28B, showing that every particle contains DNA. 3.15 Encapsulation of Magnetite Nanoparticles Inside 500-nm Conical PEG Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 500-nm conical shapes (see FIG. 12). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Separately, citrate capped magnetite nanoparticles were synthesized by reaction of ferric chloride (40 mL of a 1 M aqueous solution) and ferrous chloride (10 mL of a 2 M aqueous hydrochloric acid solution) which is added to ammonia (500 mL of a 0.7 M aqueous solution). The resulting precipitate is collected by centrifugation and then stirred in 2 M perchloric acid. The final solids are collected by centrifugation. 0.290 g of these perchlorate-stabilized nanoparticles are suspended in 50 mL of water and heated to 90° C. while stirring. Next, 0.106 g of sodium citrate is added. The solution is stirred at 90° C. for 30 min to yield an aqueous solution of citrate-stabilized iron oxide nanoparticles. 50 μL of this solution is added to 50 μL of a PEG diacrylate solution in a microtube. This microtube is vortexed for ten seconds. Following this, 50 μL of this PEG diacrylate/particle solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate/particle solution. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Nanoparticle-containing PEG-diacrylate particles are observed after separation of the PFPE mold and the treated silicon wafer using optical microscopy. 3.16 Fabrication of Isolated Particles on Glass Surfaces Using “Double Stamping” A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. A flat, non-wetting surface is generated by photocuring a film of PFPE-DMA onto a glass slide, according to the procedure outlined for generating a patterned PFPE-DMA mold. 5 μL of the PEG-diacrylate/photoinitiator solution is pressed between the PFPE-DMA mold and the flat PFPE-DMA surface, and pressure is applied to squeeze out excess PEG-diacrylate monomer. The PFPE-DMA mold is then removed from the flat PFPE-DMA surface and pressed against a clean glass microscope slide and photocured using UV radiation (λ=365 nm) for 10 minutes while under a nitrogen purge. Particles are observed after cooling to room temperature and separation of the PFPE mold and the glass microscope slide, using scanning electron microscopy (SEM) (see FIG. 29). Example 3.17 Encapsulation of Viruses in PEG-Diacrylate Nanoparticles A patterned perfluoropolyether (PFPE) mold is generated by pouring PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 it % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Fluorescently-labeled or unlabeled Adenovirus or Adeno-Associated Virus suspensions are added to this PEG-diacrylate monomer solution and mixed thoroughly. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of the PEG diacrylate/virus solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate solution. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Virus-containing particles are observed after separation of the PFPE mold and the treated silicon wafer using transmission electron microscopy or, in the case of fluorescently-labeled viruses, confocal fluorescence microscopy. Example 3.18 Encapsulation of Proteins in PEG-Diacrylate Nanoparticles A patterned perfluoropolyether (PFPE) mold is generated by pouring PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Fluorescently-labeled or unlabeled protein solutions are added to this PEG-diacrylate monomer solution and mixed thoroughly. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of the PEG diacrylate/virus solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate solution. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Protein-containing particles are observed after separation of the PFPE mold and the treated silicon wafer using traditional assay methods or, in the case of fluorescently-labeled proteins, confocal fluorescence microscopy. Example 3.19 Fabrication of 200-nm Titania Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, 1 g of Pluronic P123 is dissolved in 12 g of absolute ethanol. This solution was added to a solution of 2.7 mL of concentrated hydrochloric acid and 3.88 mL titanium (IV) ethoxide. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of the sol-gel solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess sol-gel precursor. The entire apparatus is then set aside until the sol-gel precursor has solidified. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM). Example 3.20 Fabrication of 200-nm Silica Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, 2 g of Pluronic P123 is dissolved in 30 g of water and 120 g of 2 M HCl is added while stirring at 35° C. To this solution, add 8.50 g of TEOS with stirring at 35° C. for 20 h. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid: 30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of the sol-gel solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess sol-gel precursor. The entire apparatus is then set aside until the sol-gel precursor has solidified. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM). Example 3.21 Fabrication of 200-nm Europium-Doped Titania Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, 1 g of Pluronic P123 and 0.51 g of EuCl3.6H2O are dissolved in 12 g of absolute ethanol. This solution is added to a solution of 2.7 mL of concentrated hydrochloric acid and 3.88 mL titanium (IV) ethoxide. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of the sol-gel solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess sol-gel precursor. The entire apparatus is then set aside until the sol-gel precursor has solidified. Particles are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM). Example 3.22 Encapsulation of CdSe Nanoparticles Inside 200-nm PEG Particles A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 200-nm trapezoidal shapes (see FIG. 13). A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Separately, 0.5 g of sodium citrate and 2 mL of 0.04 M cadmium perchlorate are dissolved in 45 mL of water, and the pH is adjusted to of the solution to 9 with 0.1 M NaOH. The solution is bubbled with nitrogen for 15 minutes. 2 mL of 1 M N,N-dimethylselenourea is added to the solution and heated in a microwave oven for 60 seconds. 50 μL of this solution is added to 50 μL of a PEG diacrylate solution in a microtube. This microtube is vortexed for ten seconds. 50 μL of this PEG diacrylate/CdSe particle solution is placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate solution. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. PEG-diacrylate particles with encapsulated CdSe nanoparticles are observed after separation of the PFPE mold and the treated silicon wafer using TEM or fluorescence microscopy. Example 3.23 Synthetic Replication of Adenovirus Particles Using Non-Wetting Imprint Lithography A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated by dispersing adenovirus particles on a silicon wafer. This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master. Separately, TMPTA is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of TMPTA is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess TMPTA. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Synthetic virus replicates are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) or transmission electron microscopy (TEM). Example 3.24 Synthetic Replication of Earthworm Hemoglobin Protein Using Non-Wetting Imprint Lithography A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated by dispersing earthworm hemoglobin protein on a silicon wafer. This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master. Separately, TMPTA is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of TMPTA is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess TMPTA. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Synthetic protein replicates are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM) or transmission electron microscopy (TEM). Example 3.25 Combinatorial Engineering of 100-nm Nanoparticle Therapeutics A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 100-nm cubic shapes. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Other therapeutic agents (i.e., small molecule drugs, proteins, polysaccharides, DNA, etc.), tissue targeting agents (cell penetrating peptides and ligands, hormones, antibodies, etc.), therapeutic release/transfection agents (other controlled-release monomer formulations, cationic lipids, etc.), and miscibility enhancing agents (cosolvents, charged monomers, etc.) are added to the polymer precursor solution in a combinatorial manner. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of the combinatorially-generated particle precursor solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess solution. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. The PFPE-DMA mold is then separated from the treated wafer, and particles are harvested and the therapeutic efficacy of each combinatorially generated nanoparticle is established. By repeating this methodology with different particle formulations, many combinations of therapeutic agents, tissue targeting agents, release agents, and other important compounds can be rapidly screened to determine the optimal combination for a desired therapeutic application. Example 3.26 Fabrication of a Shape-Specific PEG Membrane A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 3-μm cylindrical holes that are 5 μm deep. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, a poly(ethylene glycol) (PEG) diacrylate (n=9) is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) with trichloro(1H,1H,2H,2H-perfluorooctyl)silane via vapor deposition in a desiccator for 20 minutes. Following this, 50 μL of PEG diacrylate is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess PEG-diacrylate. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. An interconnected membrane is observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM). The membrane is released from the surface by soaking in water and allowing it to lift off the surface. Example 4 Molding of Features for Semiconductor Applications 4.1 Fabrication of 140-nm Lines Separated by 70 nm in TMPTA A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl Example 4 Molding of features for semiconductor applications 4.1 Fabrication of 140-nm Lines Separated by 70 nm in TMPTA A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 140-nm lines separated by 70 nm. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, TMPTA is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) and treating the wafer with an adhesion promoter, (trimethoxysilyl propyl methacryalte). Following this, 50 μL of TMPTA is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to ensure a conformal contact. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Features are observed after separation of the PFPE mold and the treated silicon wafer using atomic force microscopy (AFM) (see FIG. 30). Example 4.1 Molding of a Polystyrene Solution A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 140-nm lines separated by 70 nm. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, polystyrene is dissolved in 1 to 99 wt % of toluene. Flat, uniform, surfaces are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) and treating the wafer with an adhesion promoter. Following this, 50 μL of polystyrene solution is then placed on the treated silicon wafer and the patterned PFPE mold is placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to ensure a conformal contact. The entire apparatus is then subjected to vacuum for a period of time to remove the solvent. Features are observed after separation of the PFPE mold and the treated silicon wafer using atomic force microscopy (AFM) and scanning electron microscopy (SEM). Example 4.2 Molding of Isolated Features on Microelectronics-Compatible Surfaces Using “Double Stamping” A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 140-nm lines separated by 70 nm. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, TMPTA is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. A flat, non-wetting surface is generated by photocuring a film of PFPE-DMA onto a glass slide, according to the procedure outlined for generating a patterned PFPE-DMA mold. 50 μL of the TMPTA/photoinitiator solution is pressed between the PFPE-DMA mold and the flat PFPE-DMA surface, and pressure is applied to squeeze out excess TMPTA monomer. The PFPE-DMA mold is then removed from the flat PFPE-DMA surface and pressed against a clean, flat silicon/silicon oxide wafer and photocured using UV radiation (λ=365 nm) for 10 minutes while under a nitrogen purge. Isolated, poly(TMPTA) features are observed after separation of the PFPE mold and the silicon/silicon oxide wafer, using scanning electron microscopy (SEM). Example 4.3 Fabrication of 200-nm Titania Structures for Microelectronics A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 140-nm lines separated by 70 nm. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, 1 g of Pluronic P123 is dissolved in 12 g of absolute ethanol. This solution was added to a solution of 2.7 mL of concentrated hydrochloric acid and 3.88 mL titanium (IV) ethoxide. Flat, uniform, surfaces are generated by treating a silicon/silicon oxide wafer with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) and drying. Following this, 50 μL of the sol-gel solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess sol-gel precursor. The entire apparatus is then set aside until the sol-gel precursor has solidified. Oxide structures are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM). Example 4.4 Fabrication of 200-nm Silica Structures for Microelectronics A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 140-nm lines separated by 70 nm. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, 2 g of Pluronic P123 is dissolved in 30 g of water and 120 g of 2 M HCl is added while stirring at 35° C. To this solution, add 8.50 g of TEOS with stirring at 35° C. for 20 h. Flat, uniform, surfaces are generated by treating a silicon/silicon oxide wafer with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) and drying. Following this, 50 μL of the sol-gel solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess sol-gel precursor. The entire apparatus is then set aside until the sol gel precursor has solidified. Oxide structures are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM). Example 4.5 Fabrication of 200-nm Europium-Doped Titania Structures for Microelectronics A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 140-nm lines separated by 70 nm. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, 1 g of Pluronic P123 and 0.51 g of EuCl3.6H2O are dissolved in 12 g of absolute ethanol. This solution was added to a solution of 2.7 mL of concentrated hydrochloric acid and 3.88 mL titanium (IV) ethoxide. Flat, uniform, surfaces are generated by treating a silicon/silicon oxide wafer with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) and drying. Following this, 50 μL of the sol-gel solution is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to push out excess sol-gel precursor. The entire apparatus is then set aside until the sol-gel precursor has solidified. Oxide structures are observed after separation of the PFPE mold and the treated silicon wafer using scanning electron microscopy (SEM). Example 4.6 Fabrication of Isolated “Scum Free” Features for Microelectronics A patterned perfluoropolyether (PFPE) mold is generated by pouring a PFPE-dimethacrylate (PFPE-DMA) containing 1-hydroxycyclohexyl phenyl ketone over a silicon substrate patterned with 140-nm lines separated by 70 nm. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the silicon master. Separately, TMPTA is blended with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. Flat, uniform, non-wetting surfaces capable of adhering to the resist material are generated by treating a silicon wafer cleaned with “piranha” solution (1:1 concentrated sulfuric acid:30% hydrogen peroxide (aq) solution) and treating the wafer with a mixture of an adhesion promoter, (trimethoxysilyl propyl methacryalte) and a non-wetting silane agent (1H,1H,2H,2H-perfluorooctyl trimethoxysilane). The mixture can range from 100% of the adhesion promoter to 100% of the non-wetting silane. Following this, 50 μL of TMPTA is then placed on the treated silicon wafer and the patterned PFPE mold placed on top of it. The substrate is then placed in a molding apparatus and a small pressure is applied to ensure a conformal contact and to push out excess TMPTA. The entire apparatus is then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Features are observed after separation of the PFPE mold and the treated silicon wafer using atomic force microscopy (AFM) and scanning electron microscopy (SEM). Example 5 Molding of Natural and Engineered Templates 5.1. Fabrication of a Perfluoropolyether-Dimethacrylate (PFPE-DMA) Mold from a Template Generated Using Electron-Beam Lithography A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated using electron beam lithography by spin coating a bilayer resist of 200,000 MW PMMA and 900,000 MW PMMA onto a silicon wafer with 500-nm thermal oxide, and exposing this resist layer to an electron beam that is translating in a pre-programmed pattern. The resist is developed in 3:1 isopropanol:methyl isobutyl ketone solution to remove exposed regions of the resist. A corresponding metal pattern is formed on the silicon oxide surface by evaporating 5 nm Cr and 15 nm Au onto the resist covered surface and lifting off the residual PMMA/Cr/Au film in refluxing acetone. This pattern is transferred to the underlying silicon oxide surface by reactive ion etching with CF4/O2 plasma and removal of the Cr/Au film in aqua regia. (FIG. 31). This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master. This mold can be used for the fabrication of particles using non-wetting imprint lithography as specified in Particle Fabrication Examples 3.3 and 3.4. 5.2 Fabrication of a Perfluoropolyether-Dimethacrylate (PFPE-DMA) Mold from a Template Generated Using Photolithography. A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated using photolithography by spin coating a film of SU-8 photoresist onto a silicon wafer. This resist is baked on a hotplate at 95° C. and exposed through a pre-patterned photomask. The wafer is baked again at 95° C. and developed using a commercial developer solution to remove unexposed SU-8 resist. The resulting patterned surface is fully cured at 175° C. This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master, and can be imaged by optical microscopy to reveal the patterned PFPE-DMA mold (see FIG. 32). 5.3 Fabrication of a Perfluoropolyether-Dimethacrylate (PFPE-DMA) Mold from a Template Generated from Dispersed Tobacco Mosaic Virus Particles A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated by dispersing tobacco mosaic virus (TMV) particles on a silicon wafer (FIG. 33a). This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master. The morphology of the mold can then be confirmed using Atomic Force Microscopy (FIG. 33b). 5.4. Fabrication of a Perfluoropolyether-Dimethacrylate (PFPE-DMA) Mold from a Template Generated from Block-Copolymer Micelles A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated by dispersing polystyrene-polyisoprene block copolymer micelles on a freshly-cleaved mica surface. This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master. The morphology of the mold can then be confirmed using Atomic Force Microscopy (see FIG. 34). 5.5 Fabrication of a Perfluoropolyether-Dimethacrylate (PFPE-DMA) Mold from a Template Generated from Brush Polymers. A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated by dispersing poly(butyl acrylate) brush polymers on a freshly-cleaved mica surface. This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master. The morphology of the mold can then be confirmed using Atomic Force Microscopy (FIG. 35). Example 5.6 Fabrication of a Perfluoropolyether-Dimethacrylate (PFPE-DMA) Mold from a Template Generated from Earthworm Hemoglobin Protein A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated by dispersing earthworm hemoglobin proteins on a freshly-cleaved mica surface. This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master. The morphology of the mold can then be confirmed using Atomic Force Microscopy. Example 5.7 Fabrication of a Perfluoropolyether-Dimethacrylate (PFPE-DMA) Mold from a Template Generated from Patterned DNA Nanostructures A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated by dispersing DNA nanostructures on a freshly-cleaved mica surface. This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master. The morphology of the mold can then be confirmed using Atomic Force Microscopy. Example 5.8 Fabrication of a Perfluoropolyether-Dimethacrylate (PFPE-DMA) Mold from a Template Generated from Carbon Nanotubes A template, or “master,” for perfluoropolyether-dimethacrylate (PFPE-DMA) mold fabrication is generated by dispersing or growing carbon nanotubes on a silicon oxide wafer. This master can be used to template a patterned mold by pouring PFPE-DMA containing 1-hydroxycyclohexyl phenyl ketone over the patterned area of the master. A poly(dimethylsiloxane) mold is used to confine the liquid PFPE-DMA to the desired area. The apparatus is then subjected to UV light (λ=365 nm) for 10 minutes while under a nitrogen purge. The fully cured PFPE-DMA mold is then released from the master. The morphology of the mold can then be confirmed using Atomic Force Microscopy. Example 6 Method of Making Monodisperse Nanostructures Having a Plurality of Shapes and Sizes In some embodiments, the presently disclosed subject matter describes a novel “top down” soft lithographic technique; non-wetting imprint lithography (NoWIL) which allows completely isolated nanostructures to be generated by taking advantage of the inherent low surface energy and swelling resistance of cured PFPE-based materials. The presently described subject matter provides a novel “top down” soft lithographic technique; non-wetting imprint lithography (NoWIL) which allows completely isolated nanostructures to be generated by taking advantage of the inherent low surface energy and swelling resistance of cured PFPE-based materials. Without being bound to any one particular theory, a key aspect of NoWIL is that both the elastomeric mold and the surface underneath the drop of monomer or resin are non-wetting to this droplet. If the droplet wets this surface, a thin scum layer will inevitably be present even if high pressures are exerted upon the mold. When both the elastomeric mold and the surface are non-wetting (i.e. a PFPE mold and fluorinated surface) the liquid is confined only to the features of the mold and the scum layer is eliminated as a seal forms between the elastomeric mold and the surface under a slight pressure. Thus, the presently disclosed subject matter provides for the first time a simple, general, soft lithographic method to produce nanoparticles of nearly any material, size, and shape that are limited only by the original master used to generate the mold. Using NoWIL, nanoparticles composed of 3 different polymers were generated from a variety of engineered silicon masters. Representative patterns include, but are not limited to, 3-μm arrows (see FIG. 11), conical shapes that are 500 nm at the base and converge to <50 nm at the tip (see FIG. 12), and 200-nm trapezoidal structures (see FIG. 13). Definitive proof that all particles were indeed “scum-free” was demonstrated by the ability to mechanically harvest these particles by simply pushing a doctor's blade across the surface. See FIGS. 20 and 22. Polyethylene glycol (PEG) is a material of interest for drug delivery applications because it is readily available, non-toxic, and biocompatible. The use of PEG nanoparticles generated by inverse microemulsions to, be used as gene delivery vectors has previously been reported. K. McAllister et al., Journal of the American Chemical Society 124, 15198-15207 (Dec. 25, 2002). In the presently disclosed subject matter, NoWIL was performed using a commercially available PEG-diacrylate and blending it with 1 wt % of a photoinitiator, 1-hydroxycyclohexyl phenyl ketone. PFPE molds were generated from a variety of patterned silicon substrates using a dimethacrylate functionalized PFPE oligomer (PFPE DMA) as described previously. See J. P. Rolland, E. C. Hagberg, G. M. Denison, K. R. Carter, J. M. DeSimone, Angewandte Chemie-International Edition 43, 5796-5799 (2004). Flat, uniform, non-wetting surfaces were generated by using a silicon wafer treated with a fluoroalkyl trichlorosilane or by drawing a doctor's blade across a small drop of PFPE-DMA on a glass substrate and photocuring. A small drop of PEG diacrylate was then placed on the non-wetting surface and the patterned PFPE mold placed on top of it. The substrate was then placed in a molding apparatus and a small pressure was applied to push out the excess PEG-diacrylate. The entire apparatus was then subjected to UV light (λ=365 nm) for ten minutes while under a nitrogen purge. Particles were observed after separation of the PFPE mold and flat, non-wetting substrate using optical microscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM). Poly(lactic acid) (PLA) and derivatives thereof, such as poly(lactide-co-glycolide) (PLGA), have had a considerable impact on the drug delivery and medical device communities because it is biodegradable. See K. E. Uhrich, S. M. Cannizzaro, R. S. Langer, K. M. Shakesheff, Chemical Reviews 99, 3181-3198 (November, 1999); A. C. Albertsson, I. K. Varma, Biomacromolecules 4, 1466-1486 (November-December, 2003). As with PEG-based systems, progress has been made toward the fabrication of PLGA particles through various dispersion techniques that result in size distributions and are strictly limited to spherical shapes. See C. Cui, S. P. Schwendeman, Langmuir 34, 8426 (2001). The presently disclosed subject matter demonstrates the use of NoWIL to generate discrete PLA particles with total control over shape and size distribution. For example, in one embodiment, one gram of (3S)-cis-3,6-dimethyl-1,4-dioxane-2,5-dione was heated above its melting temperature to 110° C. and ˜20 μL of stannous octoate catalyst/initiator was added to the liquid monomer. A drop of the PLA monomer solution was then placed into a preheated molding apparatus which contained a non-wetting flat substrate and mold. A small pressure was applied as previously described to push out excess PLA monomer. The apparatus was allowed to heat at 110° C. for 15 h until the polymerization was complete. The PFPE-DMA mold and the flat, non-wetting substrate were then separated to reveal the PLA particles. To further demonstrate the versatility of NoWIL, particles composed of a conducting polymer polypyrrole (PPy) were generated. PPy particles have been formed using dispersion methods, see M. R. Simmons, P. A. Chaloner, S. P. Armes, Langmuir 11, 4222 (1995), as well as “lost-wax” techniques, see P. Jiang, J. F. Bertone, V. L. Colvin, Science 291, 453 (2001). The presently disclosed subject matter demonstrate for the first time, complete control over shape and size distribution of PPy particles. Pyrrole is known to polymerize instantaneously when in contact with oxidants such as perchloric acid. Dravid et al. has shown that this polymerization can be retarded by the addition of tetrahydrofuran (THF) to the pyrrole. See M. Su, M. Aslam, L. Fu, N. Q. Wu, V. P. Dravid, Applied Physics Letters 84, 4200-4202 (May 24, 2004). The presently disclosed subject matter takes advantage of this property in the formation of PPy particles by NoWIL. For example, 50 μL of a 1:1 v/v solution of THF:pyrrole was added to 50 μL of 70% perchloric acid. A drop of this clear, brown solution (prior to complete polymerization) into the molding apparatus and applied pressure to remove excess solution. The apparatus was then placed into the vacuum oven overnight to remove the THF and water. PPy particles were fabricated with good fidelity using the same masters as previously described. Importantly, the materials properties and polymerization mechanisms of PLA, PEG, and PPy are completely different. For example, while PLA is a high-modulus, semicrystalline polymer formed using a metal-catalyzed ring opening polymerization at high temperature, PEG is a malleable, waxy solid that is photocured free radically, and PPy is a conducting polymer polymerized using harsh oxidants. The fact that NoWIL can be used to fabricate particles from these diverse classes of polymeric materials that require very different reaction conditions underscores its generality and importance. In addition to its ability to precisely control the size and shape of particles, NoWIL offers tremendous opportunities for the facile encapsulation of agents into nanoparticles. As described in Example 3-14, NoWIL can be used to encapsulate a 24-mer DNA strand fluorescently tagged with CY-3 inside the previously described 200 nm trapezoidal PEG particles. This was accomplished by simply adding the DNA to the monomer/water solution and molding them as described. We were able to confirm the encapsulation by observing the particles using confocal fluorescence microscopy (see FIG. 28). The presently described approach offers a distinct advantage over other encapsulation methods in that no surfactants, condensation agents, and the like are required. Furthermore, the fabrication of monodisperse, 200 nm particles containing DNA represents a breakthrough step towards artificial viruses. Accordingly, a host of biologically important agents, such as gene fragments, pharmaceuticals, oligonucleotides, and viruses, can be encapsulated by this method. The method also is amenable to non-biologically oriented agents, such as metal nanoparticles, crystals, or catalysts. Further, the simplicity of this system allows for straightforward adjustment of particle properties, such as crosslink density, charge, and composition by the addition of other comonomers, and combinatorial generation of particle formulations that can be tailored for specific applications. Accordingly, NoWIL is a highly versatile method for the production of isolated, discrete nanostructures of nearly any size and shape. The shapes presented herein were engineered non-arbitrary shapes. NoWIL can easily be used to mold and replicate non-engineered shapes found in nature, such as viruses, crystals, proteins, and the like. Furthermore, the technique can generate particles from a wide variety of organic and inorganic materials containing nearly any cargo. The method is simplistically elegant in that it does not involve complex surfactants or reaction conditions to generate nanoparticles. Finally, the process can be amplified to an industrial scale by using existing soft lithography roller technology, see Y. N. Xia, D. Qin, G. M. Whitesides, Advanced Materials 8, 1015-1017 (December, 1996), or silk screen printing methods. Example 7 Synthesis of Functional Perfluoropolyethers Example 7.1 Synthesis of Krytox® (DuPont, Wilmington, Del., United States of America) Diol to be Used as a Functional PFPE Example 7.2 Synthesis of Krytox® (DuPont, Wilmington, Del., United States of America) Diol to be Used as a Functional PFPE Example 7.3 Synthesis of Krytox® (DuPont, Wilmington, Del., United States of America) Diol to be Used as a Functional PFPE Example 7.4 Example of Krytox® (DuPont, Wilmington, Del., United States of America) Diol to be Used as a Functional PFPE Example 7.5 Synthesis of a Multi-Arm PFPE Precursor wherein, X includes, but is not limited to an isocyanate, an acid chloride, an epoxy, and a halogen; R includes, but is not limited to an acrylate, a methacrylate, a styrene, an epoxy, and an amine; and the circle represents any multifunctional molecule, such a cyclic compound. PFPE can be any perfluoropolyether material as described herein, including, but not limited to a perfluoropolyether material comprising a backbone structure as follows: Example 7.6 Synthesis of a Hyperbranched PFPE Precursor wherein, PFPE can be any perfluoropolyether material as described herein, including, but not limited to a perfluoropolyether material comprising a backbone structure as follows: It will be understood that various details of the presently disclosed subject matter can be changed without departing from the scope of the presently disclosed subject matter. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.

<SOH> BACKGROUND <EOH>The availability of viable nanofabrication processes is a key factor to realizing the potential of nanotechnologies. In particular, the availability of viable nanofabrication processes is important to the fields of photonics, electronics, and proteomics. Traditional imprint lithographic (IL) techniques are an alternative to photolithography for manufacturing integrated circuits, micro- and nano-fluidic devices, and other devices with micrometer and/or nanometer sized features. There is a need in the art, however, for new materials to advance IL techniques. See Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575; Xia, Y., et al., Chem. Rev., 1999, 99, 1823-1848; Resnick, D. J., et al., Semiconductor International, 2002, June, 71-78; Choi, K. M., et al., J. Am. Chem. Soc., 2003, 125, 4060-4061; McClelland, G. M., et al., Appl. Phys. Lett., 2002, 81, 1483; Chou, S. Y., et al., J. Vac. Sci. Technol. B, 1996, 14, 4129; Otto, M., et al., Microelectron. Eng., 2001, 57, 361; and Bailey, T., et al., J. Vac. Sci. Technol., B, 2000, 18, 3571. Imprint lithography comprises at least two areas: (1) soft lithographic techniques, see Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575, such as solvent-assisted micro-molding (SAMIM); micro-molding in capillaries (MIMIC); and microcontact printing (MCP); and (2) rigid imprint lithographic techniques, such as nano-contact molding (NCM), see McClelland, G. M., et al., Appl. Phys. Lett., 2002, 81, 1483; Otto, M., et al., Microelectron. Eng., 2001, 57, 361; “step and flash” imprint lithographic (S-FIL), see Bailey, T., et al., J. Vac. Sci. Technol ., B, 2000, 18, 3571; and nanoimprint lithography (NIL), see Chou, S. Y., et al., J. Vac. Sci. Technol. B, 1996, 14, 4129. Polydimethylsiloxane (PDMS) based networks have been the material of choice for much of the work in soft lithography. See Quake, S. R., et al., Science, 2000, 290, 1536; Y. N. Xia and G. M. Whitesides, Angew. Chem. Int. Ed. Engl. 1998, 37, 551; and Y. N. Xia, et al., Chem. Rev. 1999, 99, 1823. The use of soft, elastomeric materials, such as PDMS, offers several advantages for lithographic techniques. For example, PDMS is highly transparent to ultraviolet (UV) radiation and has a very low Young's modulus (approximately 750 kPa), which gives it the flexibility required for conformal contact, even over surface irregularities, without the potential for cracking. In contrast, cracking can occur with molds made from brittle, high-modulus materials, such as etched silicon and glass. See Bietsch, A., et al., J. Appl. Phys., 2000, 88, 4310-4318. Further, flexibility in a mold facilitates the easy release of the mold from masters and replicates without cracking and allows the mold to endure multiple imprinting steps without damaging fragile features. Additionally, many soft, elastomeric materials are gas permeable, a property that can be used to advantage in soft lithography applications. Although PDMS offers some advantages in soft lithography applications, several properties inherent to PDMS severely limit its capabilities in soft lithography. First, PDMS-based elastomers swell when exposed to most organic soluble compounds. See Lee, J. N., et al., Anal. Chem., 2003, 75, 6544-6554. Although this property is beneficial in microcontact printing (MCP) applications because it allows the mold to adsorb organic inks, see Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575, swelling resistance is critically important in the majority of other soft lithographic techniques, especially for SAMIM and MIMIC, and for IL techniques in which a mold is brought into contact with a small amount of curable organic monomer or resin. Otherwise, the fidelity of the features on the mold is lost and an unsolvable adhesion problem ensues due to infiltration of the curable liquid into the mold. Such problems commonly occur with PDMS-based molds because most organic liquids swell PDMS. Organic materials, however, are the materials most desirable to mold. Additionally, acidic or basic aqueous solutions react with PDMS, causing breakage of the polymer chain. Secondly, the surface energy of PDMS (approximately 25 mN/m) is not low enough for soft lithography procedures that require high fidelity. For this reason, the patterned surface of PDMS-based molds is often fluorinated using a plasma treatment followed by vapor deposition of a fluoroalkyl trichlorosilane. See Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575. These fluorine-treated silicones swell, however, when exposed to organic solvents. Third, the most commonly-used commercially available form of the material used in PDMS molds, e.g., Sylgard 1840 (Dow Corning Corporation, Midland, Mich., United States of America) has a modulus that is too low (approximately 1.5 MPa) for many applications. The low modulus of these commonly used PDMS materials results in sagging and bending of features and, as such, is not well suited for processes that require precise pattern placement and alignment. Although researchers have attempted to address this last problem, see Odom, T. W., et al., J. Am. Chem. Soc., 2002, 124, 12112-12113; Odom, T. W. et al., Langmuir, 2002, 18, 5314-5320; Schmid, H., et al., Macromolecules, 2000, 33, 3042-3049; Csucs, G., et al., Langmuir, 2003, 19, 6104-6109; Trimbach, D., et al., Langmuir, 2003, 19, 10957-10961, the materials chosen still exhibit poor solvent resistance and require fluorination steps to allow for the release of the mold. Rigid materials, such as quartz glass and silicon, also have been used in imprint lithography. See Xia, Y., et al., Angew. Chem. Int. Ed., 1998, 37, 550-575; Resnick, D. J., et al., Semiconductor International, 2002, June, 71-78; McClelland, G. M., et al., Appl. Phys. Lett., 2002, 81, 1483; Chou, S. Y., et al., J. Vac. Sci. Technol. B, 1996, 14, 4129; Otto, M., et al., Microelectron. Eng., 2001, 57, 361; and Bailey, T., et al., J. Vac. Sci. Technol ., B, 2000, 18, 3571; Chou, S. Y., et al., Science, 1996, 272, 85-87; Von Werne, T. A., et al., J. Am. Chem. Soc., 2003, 125, 3831-3838; Resnick, D. J., et al., J. Vac. Sci. Technol. B, 2003, 21, 2624-2631. These materials are superior to PDMS in modulus and swelling resistance, but lack flexibility. Such lack of flexibility inhibits conformal contact with the substrate and causes defects in the mask and/or replicate during separation. Another drawback of rigid materials is the necessity to use a costly and difficult to fabricate hard mold, which is typically made by using conventional photolithography or electron beam (e-beam) lithography. See Chou, S. Y., et al., J. Vac. Sci. Technol. B, 1996, 14, 4129. More recently, the need to repeatedly use expensive quartz glass or silicon molds in NCM processes has been eliminated by using an acrylate-based mold generated from casting a photopolymerizable monomer mixture against a silicon master. See McClelland, G. M., et al., Appl. Phys. Lett., 2002, 81, 1483, and Jung, G. Y., et al., Nanoletters, 2004, ASAP. This approach also can be limited by swelling of the mold in organic solvents. Despite such advances, other disadvantages of fabricating molds from rigid materials include the necessity to use fluorination steps to lower the surface energy of the mold, see Resnick, D. J., et al., Semiconductor International, 2002, June, 71-78, and the inherent problem of releasing a rigid mold from a rigid substrate without breaking or damaging the mold or the substrate. See Resnick, D. J., et al., Semiconductor International, 2002, June, 71-78; Bietsch, A., J. Appl. Phys., 2000, 88, 4310-4318. Khang, D. Y., et al., Langmuir, 2004, 20, 2445-2448, have reported the use of rigid molds composed of thermoformed Teflon AF® (DuPont, Wilmington, Del., United States of America) to address the surface energy problem. Fabrication of these molds, however, requires high temperatures and pressures in a melt press, a process that could be damaging to the delicate features on a silicon wafer master. Additionally, these molds still exhibit the intrinsic drawbacks of other rigid materials as outlined hereinabove. Further, a clear and important limitation of fabricating structures on semiconductor devices using molds or templates made from hard materials is the usual formation of a residual or “scum” layer that forms when a rigid template is brought into contact with a substrate. Even with elevated applied forces, it is very difficult to completely displace liquids during this process due to the wetting behavior of the liquid being molded, which results in the formation of a scum layer. Thus, there is a need in the art for a method of fabricating a pattern or a structure on a substrate, such as a semiconductor device, which does not result in the formation of a scum layer. The fabrication of solvent resistant, microfluidic devices with features on the order of hundreds of microns from photocurable perfluoropolyether (PFPE) has been reported. See Rolland, J. P., et al., J. Am. Chem. Soc., 2004, 126, 2322-2323. PFPE-based materials are liquids at room temperature and can be photochemically cross-linked to yield tough, durable elastomers. Further, PFPE-based materials are highly fluorinated and resist swelling by organic solvents, such as methylene chloride, tetrahydrofuran, toluene, hexanes, and acetonitrile among others, which are desirable for use in microchemistry platforms based on elastomeric microfluidic devices. There is a need in the art, however, to apply PFPE-based materials to the fabrication of nanoscale devices for related reasons. Further, there is a need in the art for improved methods for forming a pattern on a substrate, such as method employing a patterned mask. See U.S. Pat. No. 4,735,890 to Nakane et al.; U.S. Pat. No. 5,147,763 to Kamitakahara et al.; U.S. Pat. No. 5,259,926 to Kuwabara et al.; and International PCT Publication No. WO 99/54786 to Jackson et al., each of which is incorporated herein by reference in their entirety. There also is a need in the art for an improved method for forming isolated structures that can be considered “engineered” structures, including but not limited to particles, shapes, and parts. Using traditional IL methods, the scum layer that almost always forms between structures acts to connect or link structures together, thereby making it difficult, if not impossible to fabricate and/or harvest isolated structures. There also is a need in the art for an improved method for forming micro- and nanoscale charged particles, in particular polymer electrets. The term “polymer electrets” refers to dielectrics with stored charge, either on the surface or in the bulk, and dielectrics with oriented dipoles, frozen-in, ferrielectric, or ferroelectric. On the macro scale, such materials are used, for example, for electronic packaging and charge electret devices, such as microphones and the like. See Kressman, R., et al., Space - Charge Electrets , Vol. 2, Laplacian Press, 1999; and Harrison, J. S., et al., Piezoelectic Polymers , NASA/CR-2001-211422, ICASE Report No. 2001-43. Poly(vinylidene fluoride) (PVDF) is one example of a polymer electret material. In addition to PVDF, charge electret materials, such as polypropylene (PP), Teflon-fluorinated ethylene propylene (FEP), and polytetrafluoroethylene (PTFE), also are considered polymer electrets. Further, there is a need in the art for improved methods for delivering therapeutic agents, such as drugs, non-viral gene vectors, DNA, RNA, RNAi, and viral particles, to a target. See Biomedical Polymers , Shalaby, S. W., ed., Harner/Gardner Publications, Inc., Cincinnati, Ohio, 1994; Polymeric Biomaterials , Dumitrin, S., ed., Marcel Dekkar, Inc., New York, N.Y., 1994; Park, K., et al., Biodegradable Hydrogels for Drug Delivery , Technomic Publishing Company, Inc., Lancaster, Pa., 1993; Gumargalieva, et al., Biodegradation and Biodeterioration of Polymers: Kinetic Aspects , Nova Science Publishers, Inc., Commack, New York, 1998 ; Controlled Drug Delivery , American Chemical Society Symposium Series 752, Park, K., and Mrsny, R. J., eds., Washington, D.C., 2000; Cellular Drug Delivery: Principles and Practices , Lu, D. R., and Oie, S., eds., Humana Press, Totowa, N.J., 2004; and Bioreversible Carriers in Drug Design: Theory and Applications , Roche, E. B., ed., Pergamon Press, New York, N.Y., 1987. For a description of representative therapeutic agents for use in such delivery methods, see U.S. Pat. No. 6,159,443 to Hallahan, which is incorporated herein by reference in its entirety. In sum, there exists a need in the art to identify new materials for use in imprint lithographic techniques. More particularly, there is a need in the art for methods for the fabrication of structures at the tens of micron level down to sub-100 nm feature sizes.

<SOH> SUMMARY <EOH>In some embodiments, the presently disclosed subject matter describes a method for forming one or more particles, the method comprising: (a) providing a patterned template and a substrate, wherein the patterned template comprises a patterned template surface having a plurality of recessed areas formed therein; (b) disposing a volume of liquid material in or on at least one of: (i) the patterned template surface; and (ii) the plurality of recessed areas; and (c) forming one or more particles by one of: (i) contacting the patterned template surface with the substrate and treating the liquid material; and (ii) treating the liquid material. In some embodiments of the method for forming one or more particles, the patterned template comprises a solvent resistant, low surface energy polymeric material derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template. In some embodiments, the patterned template comprises a solvent resistant elastomeric material. In some embodiments, at least one of the patterned template and substrate comprises a material selected from the group consisting of a perfluoropolyether material, a fluoroolefin material, an acrylate material, a silicone material, a styrenic material, a fluorinated thermoplastic elastomer (TPE), a triazine fluoropolymer, a perfluorocyclobutyl material, a fluorinated epoxy resin, and a fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction. In some embodiments, the presently disclosed subject matter comprises a method for delivering a therapeutic agent to a target, the method comprising: (a) providing a particle formed by the method described hereinabove; (b) admixing the therapeutic agent with the particle; and (c) delivering the particle comprising the therapeutic agent to the target. In some embodiments of the method for delivering a therapeutic agent to a target, the therapeutic agent is selected from one of a drug and genetic material. In some embodiments, the genetic material is selected from the group consisting of a non-viral gene vector, DNA, RNA, RNAi, and a viral particle. In some embodiments, the particle comprises a biodegradable polymer, wherein the biodegradable polymer is selected from the group consisting of a polyester, a polyanhydride, a polyamide, a phosphorous-based polymer, a poly(cyanoacrylate), a polyurethane, a polyorthoester, a polydihydropyran, and a polyacetal. In some embodiments, the presently disclosed subject matter describes a method for forming a pattern on a substrate, the method comprising: (a) providing a patterned template and a substrate, wherein the patterned template comprises a patterned template surface having a plurality of recessed areas formed therein; (b) disposing a volume of liquid material in or on at least one of: (i) the patterned template surface; and (ii) the plurality of recessed areas; (c) contacting the patterned template surface with the substrate; and (d) treating the liquid material to form a pattern on the substrate. In some embodiments of the method for forming a pattern on a substrate, the patterned template comprises a solvent resistant, low surface energy polymeric material derived from casting low viscosity liquid materials onto a master template and then curing the low viscosity liquid materials to generate a patterned template. In some embodiments, the patterned template comprises a solvent resistant elastomeric material. In some embodiments, at least one of the patterned template and substrate comprises a material selected from the group consisting of a perfluoropolyether material, a fluoroolefin material, an acrylate material, a silicone material, a styrenic material, a fluorinated thermoplastic elastomer (TPE), a triazine fluoropolymer, a perfluorocyclobutyl material, a fluorinated epoxy resin, and a fluorinated monomer or fluorinated oligomer that can be polymerized or crosslinked by a metathesis polymerization reaction. Accordingly, it is an object of the present invention to provide a novel method of making micro-, nano-, and sub-nanostructures. This and other objects are achieved in whole or in part by the presently disclosed subject matter. An object of the presently disclosed subject matter having been stated hereinabove, other aspects and objects will become evident as the description proceeds when taken in connection with the accompanying Drawings and Examples as best described herein below.

20070305

20120911

20090129

58250.0

A61K914

WORSHAM, JESSICA N

METHODS FOR FABRICATING ISOLATED MICRO-AND NANO-STRUCTURES USING SOFT OR IMPRINT LITHOGRAPHY

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Novel stable polymorphic forms of an anticonvulsant

Stable polymorphic forms III, IV and substantially amorphous form of an anticonvulsant, tiagabine hydrochloride.

1. A stable polymorph IV of tiagabine hydrochloride that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at about 13.6, 14.5, 15.4, 16.2, 16.8, 23.0, 24.7, 26.0. 2. A stable polymorph IV of tiagabine hydrochloride that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at 4.46, 5.03, 5.48, 6.46, 7.46, 8.11, 8.35, 9.45, 10.29, 11.41, 11.94, 12.32, 12.91, 13.59, 13.83, 14.52, 14.82, 14.85, 15.36, 15.97, 16.26, 16.83, 17.85, 18.36, 18.59, 18.85, 19.25, 19.45, 20.36, 20.98, 21.59, 22.15, 22.49, 22.99, 23.67, 23.96, 24.75, 25.33, 25.62, 25.97, 26.43, 27.02, 27.48, 27.94, 28.16, 28.88, 29.63, 30.27, 30.87, 31.54, 32.11, 32.52, 32.96, 33.52, 33.89, 34.45, 35.33, 35.59, 36.02, 36.53, 36.77, 37.28, 37.75, 38.24, 39.12. 3. A stable polymorph IV of tiagabine hydrochloride that exhibits unit cell parameters as follows: a=10.788(3)Å α=97.65(2)20 b=11.492(2)Å β=108.92(2)° c=14.799(4)Å γ=101.86(2)20 4. A stable polymorph IV of tiagabine hydrochloride of a particle size with volume mean diameter less than 20 microns. 5. A tiagabine hydrochloride acetonitrile solvate. 6. A crystalline tiagabine hydrochloride acetonitrile solvate. 7. A crystalline tiagabine hydrochloride acetonitrile solvate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at approximately 7.9, 21.5, 22.0, 24.3, 24.9, 26.7, 27.8. 8. An amorphous tiagabine hydrochloride. 9. A process for the preparation of crystalline tiagabine hydrochloride form IV comprising dissolving tiagabine hydrochloride in an organic solvent or a mixture of organic solvent and organic anti-solvent and adding a sufficient amount of organic anti-solvent to the solution to cause crystallization at a selected temperature wherein the selected temperature is such that form IV of tiagabine hydrochloride is crystallized. 10. A process as claimed in claim 9 wherein the organic solvent is dimethylformamide, the organic anti-solvent is toluene, and the selected temperature is 35±10° C. 11. A process as claimed in claim 10 wherein the selected temperature is room temperature followed by cooling to 0 to 10° C. for further crystallization. 12. A process as claimed in claim 9 wherein the tiagabine hydrochloride is dissolved in a mixture of dimethylformamide and toluene and a sufficient amount of toluene is added to cause crystallization at 35±10° C. 13. A process for the preparation of tiagabine hydrochloride form III comprising adding tiagabine hydrochloride to an organic solvent, heating to dissolve and adding sufficient amount of organic anti-solvent to cause crystallization at a selected temperature wherein the selected temperature is such that form III of tiagabine hydrochloride is crystallized. 14. A process as claimed in claim 13 wherein the organic solvent is dimethylformamide, the organic anti-solvent is toluene, wherein the selected temperature is 50 to 55° C. 15. A process as claimed in claim 14 wherein the selected temperature is 50 to 55° C. followed by cooling to 0 to 10° C. for further crystallization. 16. A process for the preparation of crystalline tiagabine hydrochloride form IV comprising crystallizing tiagabine hydrochloride from a solution of tiagabine hydrochloride in an organic solvent or a mixture of organic solvent and organic anti-solvent wherein the solution is seeded with tiagabine hydrochloride form IV seed crystals. 17. A process for the preparation of crystalline tiagabine hydrochloride form III comprising crystallizing tiagabine hydrochloride from a solution of tiagabine hydrochloride in an organic solvent or a mixture of organic solvent and organic anti-solvent wherein the solution is seeded with tiagabine hydrochloride form III seed crystals.

The present invention relates to novel stable polymorphic forms of an anticonvulsant, tiagabine hydrochloride (INN name) used in the treatment of epilepsy. BACKGROUND OF THE INVENTION U.S. Pat. No. 5,010,090 (assigned to Novo Nordisk, referred to hereinafter as '090) discloses tiagabine hydrochloride and the process of its preparation. The process adopted herein is very laborious and expensive as it utilizes column chromatography for purification. Further, the product is crystallised using ethyl acetate, isopropanol, acetone or water yielding product contaminated with high levels of solvent. Use of alternative organic solvents such as acetonitrile, butylacetate, toluene, acetone, dichloromethane etc. also gives product containing various amounts of the used crystallization solvent. The crystallization solvents are unwanted as they affect the stability of pharmaceutical products and are toxic to humans. Further the product manufactured using ethylacetate and other organic solvents often forms clathrates, hence not usable as pharmaceutical material due to high levels of solvent contamination. This patent does not disclose the polymorphic form of tiagabine hydrochloride. U.S. Pat. No. 5,354,760 (assigned to Novo Nordisk, referred to hereinafter as '760) patent provides monohydrate form of tiagabine hydrochlrodie referred to herein as form I. The monohydrate form of tiagabine hydrochloride is stable, non-hygroscopic and is suitable for pharmaceutical formulations as the only residual solvent in the product is water. However, it is reported that the monohydrate crystalline form is less stable at elevated temperature making its use inconvenient during formulation. The '760 patent discloses a process of preparation of form I tiagabine hydrochloride (monohydrate) comprising crystallization of tiagabine hydrochloride form an aqueous solution. U.S. Pat. No. 5,958,951 (assigned to Novo Nordisk, referred to hereinafter as '951) claims anhydrous crystalline form of tiagabine hydrochloride referred to herein as form II. The product obtained was reported to be non-hygroscopic and thermally stable. The process for preparation of form II claimed in '951 was the same as the process disclosed in '760, however the examples differ with respect to the conditions of crystallization for example in the exemplified process of '951 the crystallization from aqueous solution may occur at high temperature of about 52° C. over a period of about 18 hours. Thus, the process for the preparation of anhydrous form is time consuming. OBJECT OF THE INVENTION The object of the present invention is to provide novel stable polymorphic forms III, IV and substantially amorphous form of tiagabine hydrochloride Another object is to provide novel solvate of tiagabine hydrochloride with acetonitrile. Yet another object of the present invention is to provide processes for the preparation of novel polymorphic forms III, IV, novel solvate with acetonitrile and substantially amorphous form of tiagabine hydrochloride. SUMMARY OF THE INVENTION The present invention provides novel stable polymorphic forms of tiagabine hydrochloride, an anticonvulsant. Particularly, the present invention provides novel stable polymorphic forms III and IV of tiagabine hydrochloride. More particularly, the present invention provides stable polymorph IV of tiagabine hydrochloride that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at about 13.6, 14.5, 15.4, 16.2, 16.8, 23.0, 24.7, 26.0 The present invention also provides tiagbine hydrochloride acetonitrile solvate. The present invention also provides amorphous tiagbine hydrochloride. The present invention also provides a process for the preparation of each of the polymorphic forms III and IV of tiagabine hydrochloride and amorphous tiagabine hydrochloride. DETAILED DESCRIPTION OF THE INVENTION When we followed the claimed process of the '951 patent i.e. by dissolving tiagabine hydrochloride in an aqueous hydrochloric acid solution, and precipitating tiagabine hydrochloride from the aqueous hydrochloric acid solution we obtained the anhydrous form II and on analysis found that the cell parameters of the form II were: a=7.775(7)Å α=78.38(9)° b=11.10(1)Å β=75.88(8)° c=14.33(2)Å γ=89.21(9)° Vol=1173.96 Å3 We studied the solubility of tiagabine hydrochloride in various organic solvents and found that tiagabine hydrochloride has limited solubility in various organic solvents compared to that in water. The solubility data is given in Table-1. TABLE 1 SOLUBILITY DATA OF TIAGABINE HYDROCHLORIDE AT ROOM TEMPERATURE S. NO SAMPLE QUANTITY SOLVENT VOLUME OF 1 100 mg Toluene >100 ml 2 100 mg DMF 0.5 ml 3 100 mg Ethylacetate >100 ml 4 100 mg Acetone 24 ml 5 100 mg Methanol 0.2 ml 6 100 mg Ethanol 0.3 ml 7 100 mg IPA 1.3 ml 8 100 mg Acetonitrile >100 ml 9 100 mg Water 0.7 ml Further, whereas the prior art method of crystallization from aqueous solution was item consuming we found that process using crystallization from organic solvents was rapid and resulted in high yields. The stable polymorphic form III of tiagabine hydrochloride exhibits an x-ray diffraction pattern as depicted in FIG. 1. The stable polymorphic form IV of tiagabine hydrochloride exhibits an x-ray diffraction pattern as depicted in FIG. 2. According to one embodiment of the present invention novel stable polymorphic forms of tiagabine hydrochloride may be made available which are stable. Preferably, polymorphic forms III, IV and acetonitrile solvate of tiagabine hydrochloride. The stable polymorph IV of tiagabine hydrochloride exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at approximately 13.6, 14.5, 15.4, 16.2, 16.8, 23.0, 24.7. Preferably, x-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at about 4.46, 5.03, 5.48, 6.46, 7.46, 8.11, 8.35, 9.45, 10.29, 11.41, 11.94, 12.32, 12.91, 13.59, 13.83, 14.52, 14.85, 15.36, 15.97, 16.26, 16.83, 17.85, 18.36, 18.59, 18.85, 19.25, 19.45, 20.36, 20.98, 21.59, 22.15, 22.49, 22.99, 23.67, 23.96, 24.75, 25.33, 25.62, 25.97, 26.43, 27.02, 27.48, 27.94, 28.16, 28.88, 29.63, 30.27, 30.87, 31.54, 32.11, 32.52, 32.96, 33.52, 33.89, 34.45, 35.33, 35.59, 36.02, 36.53, 36.77, 37.28, 37.75, 38.24, 39.12. More preferably, the stable polymorph IV of tiagabine hydrochloride exhibits x-ray powder diffraction pattern as given below: 02θ % Relative Intensity 4.4552 1.19 5.0280 1.57 5.4800 1.40 6.4618 26.01 7.4555 1.14 8.1120 1.05 8.3469 0.55 9.4458 1.10 10.2976 0.07 11.4113 10.74 11.9400 0.48 12.3205 0.54 12.9051 73.52 13.5866 34.36 13.8336 22.44 14.5237 21.87 14.8525 56.45 15.3566 100.00 15.9704 19.58 16.2550 37.61 16.8324 58.66 17.8470 3.19 18.3616 8.99 18.5960 9.64 18.8520 23.20 19.2462 43.35 19.4466 35.71 20.3582 7.12 20.9813 10.55 21.5955 2.40 22.1478 7.55 22.4936 13.01 22.9961 37.54 23.6666 13.88 23.9563 22.03 24.7460 64.16 25.3288 14.29 25.6240 16.37 25.9657 16.05 26.4322 8.81 27.0201 8.24 27.4772 2.36 27.9365 4.32 28.1570 6.49 28.8818 3.13 29.6343 3.57 30.2723 3.56 30.8721 0.87 31.5401 1.93 32.1129 0.31 32.5239 2.94 32.9663 1.20 33.5206 2.07 33.8931 5.86 34.4505 1.63 35.3347 6.23 35.5891 4.77 36.0204 0.29 36.5288 0.90 36.7720 0.81 37.2771 1.76 37.7485 0.72 38.2364 0.52 39.1197 1.45 Stable polymorph IV of tiagabine hydrochloride exhibits unit cell parameters as given below: a=10.788(3)Å α=97.65(2)° b=11.492(2)Å β=108.92(2)° c=14.799(4)Å γ=101.86(2)° Vol=1658.63 Å3 In embodiment of the present invention the stable polymorph IV of tiagabine hydrochloride may be obtained in particle size with volume mean diameter (VMD) less than 20 microns. There is no change in the x-ray diffraction pattern of stable polymorph IV of tiagabine hydrochloride after standing for 6 months under ambient conditions. The process for the preparation of the novel stable polymorphic forms III or IV of tiagabine hydrochloride of the present invention comprises dissolving tiagabine hydrochloride to an organic solvent or a mixture of organic solvent and organic anti-solvent and adding a sufficient amount of organic non-solvent to the solution to cause crystallization at a selected temperature wherein the selected temperature is such that form IV of tiagabine hydrochloride is crystallized. The organic solvent may be water miscible or water immiscible. Water miscible organic solvent may be used alone or in admixture with water. In accordance with another embodiment of the present invention, there is provided a process for the preparation of novel stable polymorphic form III and form IV of tiagabine hydrochloride. A process for the preparation of the novel stable polymorphic form IV of tiagabine hydrochloride comprises dissolving tiagabine hydrochloride in an organic solvent or a mixture of organic solvent and an organic non-solvent and adding a sufficient amount of organic anti-solvent to the solution to cause crystallization at a selected temperature wherein the selected temperature is such that form IV of tiagabine hydrochloride is crystallized preferably the selected temperature may be 35+ or −10° C. The solution may be optionally cooled at 0° to 10° C. for further crystallization. The novel stable polymorphic form IV of tiagabine hydrochloride may also be prepared by crystallizing crystallizing tiagabine hydrochloride from a solution of tiagabine hydrochloride in an organic solvent or a mixture of organic solvent and organic anti-solvent wherein the solution is seeded with tiagabine hydrochloride form IV seed crystals. A process for the preparation the novel stable polymorphic form III of tiagabine hydrochloride comprises adding tiagabine hydrochloride in an organic solvent, heating to dissolve and adding sufficient amount of organic anti-solvent to cause crystallization at a selected temperature wherein the selected temperature is such that form III of tiagabine hydrochloride is crystallized. The novel stable polymorphic form III of tiagabine hydrochloride may also be prepared by crystallizing tiagabine hydrochloride from a solution of tiagabine hydrochloride in an organic solvent or a mixture of organic solvent and organic anti-solvent wherein the solution is seeded with tiagabine hydrochloride form III seed crystals. The organic solvent may be selected from the group consisting of aliphatic or aromatic or cyclic hydrocarbon such as n-pentane, n-hexane, n-octane, cyclohexane, toluene and the like; halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, chlorobenzene; alkanols such as methanol, ethanol, t-butanol, isopropanol, cyclohexanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane; ketones such as acetone, methylethylketone, cyclohexanone; nitriles such as acetonitrile; amides such as dimethylformamide, dimethylacetamide and the like; esters such as ethylacetate, butylacetate; sulfoxides such as dimethylsulfoxide and the like; water and mixtures thereof. The preferred organic solvents used are polar aprotic organic solvents such as dimethylformamide or dimethylsulfoxide. The preferred organic anti-solvent is toluene. The dissolution of tiagabine hydrochloride in solvent(s) may be carried out at ambient or at elevated temperatures. In a preferred embodiment of the invention, the novel stable polymorphic form IV of tiagabine hydrochloride is prepared by dissolving tiagabine hydrochloride in a mixture of dimethylformamide and toluene, followed by adding sufficient quantity of toluene to the resulting solution at room temperature. In another preferred embodiment of the invention, the novel stable polymorphic form III of tiagabine hydrochloride is prepared by adding tiagabine hydrochloride to dimethylformamide, heating to dissolve and adding sufficient amount of toluene to cause crystallization at a temperature ranging from 50 to 55° C. Isolation of the novel polymorphic forms III or IV may be achieved by using techniques such as filtration/centrifugation and drying. Filtration may be carried out in the presence or absence of vacuum. Drying may be carried out at ambient or elevated temperature in the presence or absence of vacuum. The product may be dried using different techniques such as fluid bed drying, tray drying, spray freeze drying and rotatory drying techniques with or without application of vacuum and/or under inert conditions. The new polymorphic forms III and IV of tiagabine hydrochloride are suitable for pharmaceutical formulations. The organic solvent may be selected from the group consisting of aliphatic or aromatic or cyclic hydrocarbon such as n-pentane, n-hexane, n-octane, cyclohexane, toluene and the like; halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, chlorobenzene; alkanols such as methanol, ethanol, t-butanol, isopropanol, cyclohexanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane; ketones such as acetone, methylethylketone, cyclohexanone; nitriles such as acetonitrile; amides such as dimethylformamide, dimethylacetamide and the like; esters such as ethylacetate, butylacetate; sulfoxides such as dimethylsulfoxide and the like; water and mixtures thereof. The dissolution of tiagabine hydrochloride in solvent(s) may be carried out at ambient or at elevated temperatures. Crystallization of tiagabine hydrochloride from the solution may be carried out at ambient or lower temperatures. Crystallization may be allowed to occur by chilling or seeding or scratching the glass of the reaction vessel or cooling and other such common techniques. Isolation of the novel polymorphic forms may be achieved by using techniques such as filtration/centrifugation and drying. Filtration may be carried out in the presence or absence of vacuum. Drying may be carried out at ambient or elevated temperature in the presence or absence of vacuum. The product may be dried using different techniques such as fluid bed drying, tray drying, spray freeze drying and rotatory drying techniques with or without application of vacuum and/or under inert conditions. For instance, polymorphic forms III or IV of tiagabine hydrochloride may be prepared by dissolving in polar aprotic solvent such as dimethylformamide or dimethylsulfoxide and the like. The dissolution may be carried out at ambient or higher temperature This is followed by addition of anti-solvent selected from aliphatic or aromatic hydrocarbon solvents such as hexane, heptane, cyclohexane, cycloheptane, benzene, toluene, xylene and the like to crystallize polymorphic forms III or IV within about 3 hrs at ambient or lower temperature, preferably −10 to 30° C. The new polymorphic forms III and IV of tiagabine hydrochloride are suitable for pharmaceutical formulations. According to yet another embodiment of the present invention of tiagabine hydrochloride acetonitrile solvate may be obtained, preferably crystalline tiagabine hydrochloride acetonitrile solvate. Crystalline form of tiagabine hydrochloride acetonitrile solvate is stable and isolable in good yields. Crystalline form of tiagabine hydrochloride acetonitrile solvate exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at approximately 7.9, 21.5, 22.0, 24.3, 24.9, 26.7, 27.8. Crystalline form of tiagabine hydrochloride acetonitrile solvate exhibits an x-ray diffraction pattern as depicted in FIG. 3. According to another embodiment of the present invention substantially amorphous tiagabine hydrochloride may be made available. Amorphous tiagabine hydrochloride may be prepared by various methods such as spray drying solution comprising tiagabine hydrochloride or freeze drying solution comprising tiagabine hydrochloride and the like XRD analysis of amorphous tiagabine hydrochloride as prepared by spray drying and freeze drying are as given in FIGS. 4 and 5. The process for the preparation of tiagabine hydrochloride acetonitrile solvate comprising dissolving in acetonitrile or mixture comprising acetontrile and crystallizing by cooling or standing at ambient temperature. We have also found that the solvates of tiagabine hydrochloride can also be employed for making the new forms for eg. stable acetonitrile solvate having 1 mole of acetonitrile when dried at 85-90° C. under vacuum yields form III of tiagabine hydrochloride. The polymorphic forms III, IV, acetonitrile solvate and amorphous form of tiagabine hydrochloride are obtained from organic solvents or from drying of the solvates and had solvent levels below the acceptable limits, meeting ICH requirements. The data was reported in Table-2. TABLE 2 RESIDUAL SOLVENT DATA Solvent S. no Exp. No. Form Solvent(s) used content Limits as 1. 630/12 IV DMF+ Not NMT 880 detected 2 630/16 III DMF+ Not NMT 880 detected 2. 630/37a I ETHYLACETA Not NMT 5000 detected 3. 630/37b IV ISOPROPANOL 10 ppm NMT 5000 4. 630/37c IV ACETONE 556 ppm NMT 5000 5. 616/20B IV METHANOL+ Not NMT 3000 detected 6 641/04a Aceto- ACETONITRIL Not NMT 410 nitrile detected Stable polymorphic forms III, IV and amorphous forms are substantially free of solvent. The invention is further illustrated but not restricted by the description in the following examples. EXAMPLES Example 1 Form-III of tiagabine hydrochloride 66 gm of tiagabine hydrochloride is dissolved in 135 ml DMF at 60-70° C. and the solution filtered. 1200 ml toluene is added to DMF solution containing tiagabine hydrochloride at 50-55° C. for a period of 15 min and the mixture is gradually cooled to room temperature in 1 hr period and further cooled to 0-5° C. and maintained at 0-5° C. for 1.5 hr. The material is filtered and washed with 150 ml toluene. Dried the material at 50-55° C. till LOD comes to less than 0.5%. X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at 6.4617, 9.3296, 11.3101, 12.9202, 13.7893, 14.4799, 14.9003, 15.3375, 15.9390, 16.2009, 16.5963, 16.7774, 18.5875, 19.4396, 20.3969, 22.4225, 23.0653, 23.6163, 23.9868, 24.6971, 25.2271, 25.9469, 26.4799, 27.0214, 27.2297, 28.8106, 29.6048, 31.4648, 32.4574, 33.5262, 33.8443, 35.6166, 36.6730. Example 2(a) Form-IV of tiagabine hydrochloride 650 gm of tiagabine hydrochloride is dissolved in 1.5 lit DMF at 70-80° C., and added to 6.5 lit toluene at room temperature for a period of 30 min and the mixture is gradually cooled to room temperature in 30 min time and further cooled to 5-10° C. in 30 min time and maintained at 5-10° C. for 2 hrs. The material is filtered and washed with 1.3 lit toluene. Dried the material at 55-58° C. till LOD comes to less than 0.5%. (LOD Result 0.1%). XRD analysis of form IV after 6 months storage at ambient conditions, matches the XRD of ‘0’ day sample. X-ray powder diffraction pattern of this product exhibited characteristic peaks expressed in degrees 2 theta 4.1162, 4.9336, 6.4616, 6.9249, 8.0731, 9.3211, 10.3290, 11.3203, 11.5021, 12.3275, 12.8948, 13.5577, 13.8687, 14.5032, 14.7572, 14.9428, 15.3449, 15.9370, 16.2314, 16.3377, 16.6598, 16.8500, 17.3261, 17.3037, 17.8229, 18.3380, 18.6349, 18.8832, 19.1816, 19.4174, 19.8286, 20.3221, 20.9559, 21.2182, 21.6159, 22.1136, 22.4293, 22.9777, 23.6307, 23.9568, 24.3669, 24.7233, 24.9424, 25.2110, 25.5718, 25.9348, 26.1401, 26.5171, 26.8243, 27.0467, 27.5428, 27.9526, 28.1313, 28.6444, 28.8638, 29.5891, 29.9740, 30.3277, 30.7402, 31.4942, 32.0050, 32.4651, 32.9536, 33.5620, 33.9135, 34.4093, 35.2921, 365.7069, 36.8032, 37.2098, 37.8744, 39.0016, 39.2218, 39.6847. Particle Size Analysis (Analysed by HELOS (H1551) & RODOS) Form IV of tiagabine hydrochloride exhibited VMD=16.7 and 19.8 microns for 2 batches. Form I of tiagabine hydrochloride exhibited VMD=60.2 microns. Example 2(b) Form-IV of tiagabine hydrochloride Charge filtered 2 parts by volume (w.r.t weight of crude tiagabine hydrochloride) of Dimethylformamide in to the RBF between 28° C.˜32° C. Charge filtered 2 parts by volume (w.r.t weight of crude tiagabine hydrochloride) of Toluene in to the RBF between 28° C.˜32° C. Start stirring & charge crude tiagabine hydrochloride into the RBF between 28° C.˜32° C. Stir the content for 10 min. between 28° C.˜32° C. in the RBF to get uniform slurry. Heat the content to 65° C.˜70° C. into RBF to get a clear solution. Charge filtered 18 parts by volume of toluene (w.r.t weight of crude tiagabine hydrochloride) into reaction mixture between 65° C.˜70° C. under stirring. Gradually cool the content between 28° C.˜32° C. Stir the content for 45˜60 min. between 28° C.˜32° C. in the RBF. Further cool the content between 0° C.‘5° C. Stir the content for 40 to 60 min. between 0° C.˜5° C. in the RBF. Filter the product between 0° C.˜5° C. through centrifuge. Spin dry product for 30 mins. Wash the cake twice with chilled toluene. Spin dry the product for 60 mins. X-ray powder diffraction pattern of this product exhibited characteristic peaks expressed in degrees 2 theta at 4.4552, 5.0280, 5.4800, 6.4618, 7.4555, 8.1120, 8.3469, 9.4458, 10.2976, 11.4113, 11.9400, 12.3205, 12.9051, 13.5866, 13.8336, 14.5237, 14.8525, 15.3566, 15.9704, 16.2550, 16.8324, 17.8470, 18.3616, 18.5960, 18.8520, 19.2462, 19.4466, 20.3582, 20.9813, 21.5955, 22.1478, 22.4936, 22.9961, 23.6666, 23.9563, 24.7460, 25.3288, 25.6240, 25.9657, 26.4322, 27.0201, 27.4772, 27.9365, 28.1570, 28.8818, 29.6343, 30.2723, 30.8721, 31.5401, 32.1129, 32.5239, 32.9663, 33.5206, 33.8931, 34.4505, 35.3347, 35.5891, 36.0204, 36.5288, 36.7720, 37.2771, 37.7485, 38.2364, 39.1197 Example 3 Amorphous form of tiapabine hydrochloride 25 gm tiagabine hydrochloride is dissolved in 125 ml methanol 30 water mixture in 1:1 ratio at room temperature and spray dried the material at 45-50° C. It can also be prepared by dissolving 25 gm tiagabine hydrochloride in 175 ml water at 50-55° C. temperature and spray dried the material at 60° C. Another method of preparing amorphous form is by dissolving 10 gm tiagabine hydrochloride in 110 ml distilled water at room temperature and freeze dried the material for 24 hrs. XRD analysis are given in FIG. 4. Example 4 Monoacetonitrile solvate of tiagabine hydrochloride 5 gm of tiagabine hydrochloride is dissolved in 5 ml of methanol at 50-55° C., 50 ml acetonitrile is added to the methanol solution at 40-55° C. and cooled to room temperature in 1 hr period and further cooled to 5-10° C. and stirred for 2 hrs. Allowed the product to settle down and decanted the clear liquid. 50 ml ethyl acetate is added to the solid mass and stirred at 5-10° C. for 30 min, allowed the product to settle down the and decanted the clear liquid. Once again 50 ml ethyl acetate is added to the solid mass and stirred at 5-10° C. for 30 min, allowed the product to settle down the and decanted the clear liquid and dried the product mass in rotavapour under mild vaccum at 50° C. for 2 hrs. The obtained acetonitrile solvate form was dried at 85-90° C. under vacuum to obtain form III of tiagabine hydrochloride. X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at 7.8620, 11.7636, 12.7349, 13.4762, 14.3981, 14.8732, 15.7568, 16.8937, 17.1116, 17.4938, 18.0955, 18.8451, 19.8842, 21.5213, 22.0078, 23.2299, 23.6888, 24.2776, 24.6823, 24.9106, 25.6034, 26.2117, 26.6924, 27.5132, 27.7983, 28.4213, 28.9876, 29.7388, 30.1996, 30.5997, 31.5065, 31.5065, 32.7371, 36.1356, 38.1619.

<SOH> BACKGROUND OF THE INVENTION <EOH>U.S. Pat. No. 5,010,090 (assigned to Novo Nordisk, referred to hereinafter as '090) discloses tiagabine hydrochloride and the process of its preparation. The process adopted herein is very laborious and expensive as it utilizes column chromatography for purification. Further, the product is crystallised using ethyl acetate, isopropanol, acetone or water yielding product contaminated with high levels of solvent. Use of alternative organic solvents such as acetonitrile, butylacetate, toluene, acetone, dichloromethane etc. also gives product containing various amounts of the used crystallization solvent. The crystallization solvents are unwanted as they affect the stability of pharmaceutical products and are toxic to humans. Further the product manufactured using ethylacetate and other organic solvents often forms clathrates, hence not usable as pharmaceutical material due to high levels of solvent contamination. This patent does not disclose the polymorphic form of tiagabine hydrochloride. U.S. Pat. No. 5,354,760 (assigned to Novo Nordisk, referred to hereinafter as '760) patent provides monohydrate form of tiagabine hydrochlrodie referred to herein as form I. The monohydrate form of tiagabine hydrochloride is stable, non-hygroscopic and is suitable for pharmaceutical formulations as the only residual solvent in the product is water. However, it is reported that the monohydrate crystalline form is less stable at elevated temperature making its use inconvenient during formulation. The '760 patent discloses a process of preparation of form I tiagabine hydrochloride (monohydrate) comprising crystallization of tiagabine hydrochloride form an aqueous solution. U.S. Pat. No. 5,958,951 (assigned to Novo Nordisk, referred to hereinafter as '951) claims anhydrous crystalline form of tiagabine hydrochloride referred to herein as form II. The product obtained was reported to be non-hygroscopic and thermally stable. The process for preparation of form II claimed in '951 was the same as the process disclosed in '760, however the examples differ with respect to the conditions of crystallization for example in the exemplified process of '951 the crystallization from aqueous solution may occur at high temperature of about 52° C. over a period of about 18 hours. Thus, the process for the preparation of anhydrous form is time consuming.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides novel stable polymorphic forms of tiagabine hydrochloride, an anticonvulsant. Particularly, the present invention provides novel stable polymorphic forms III and IV of tiagabine hydrochloride. More particularly, the present invention provides stable polymorph IV of tiagabine hydrochloride that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at about 13.6, 14.5, 15.4, 16.2, 16.8, 23.0, 24.7, 26.0 The present invention also provides tiagbine hydrochloride acetonitrile solvate. The present invention also provides amorphous tiagbine hydrochloride. The present invention also provides a process for the preparation of each of the polymorphic forms III and IV of tiagabine hydrochloride and amorphous tiagabine hydrochloride. detailed-description description="Detailed Description" end="lead"?

20060622

20100223

20070322

60795.0

A61K31445

YOO, SUN JAE

NOVEL STABLE POLYMORPHIC FORMS OF AN ANTICONVULSANT

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Image Display Screen and Method for Controlling Said Screen

The invention relates to an image display screen including: light emitters arranged as rows of light emitters and columns of light emitters, control means to control the emissions of the light emitters, including: a plurality of modulation transistors, each associated with one light emitter of the array, the said modulation transistors being positioned next to each other, along a guiding line, a plurality of compensating transistors intended to compensate for the threshold trigger voltage of the modulation transistors. A single compensating transistor is connected to all the modulation transistors of a column and is intended to compensate for the threshold trigger voltages of all the said modulation transistors of this column. This compensating transistor is formed in the extension of the said modulation transistors of a column along the same guiding line. The invention also relates to a method for driving this screen.

1. Display screen including: light emitters arranged as rows of light emitters and columns of light emitters to form an array of light emitters, a silicon substrate on which control means to control the emissions of the light emitters are fabricated, the said control means including: means for powering the light emitters, a plurality of addressing electrodes arranged according to the columns of light emitters, and intended to transmit a voltage representing an image datum to each column of light emitters, a plurality of selection electrodes arranged according to the rows of light emitters, and intended to transmit a selection signal to each row of light emitters, a plurality of modulation transistors, each associated with a light emitter of the array, the said modulation transistors including a gate electrode intended to be connected to an addressing electrode and two current-carrying electrodes, each modulation transistor intended to have a drain current pass through it to power the said light emitter for a voltage between its gate electrode and one of its current-carrying electrodes that is greater than or equal to a threshold trigger voltage, the said modulation transistors being arranged in columns associated with the columns of light emitters and being aligned on the substrate according to a guiding line, a load capacitor connected to the terminals of each modulation transistor and intended to set an electric potential at the gate electrode of the associated modulation transistor, and a plurality of compensating transistors intended to compensate for the threshold trigger voltage of the modulation transistors by adjusting the charge on the capacitor, wherein a single compensating transistor is connected to all the modulation transistors of a given column and is intended to compensate for the threshold trigger voltages of all the said modulation transistors of this column, and wherein the said compensating transistor is formed in the extension of the line-arrangement of the said modulation transistors of a given column according to the said same guiding line. 2. Display screen according to claim 1, wherein the control means do not include any means allowing the flow of current from any one of the addressing electrodes to the means for powering the light emitters. 3. Display screen according to claim 1, wherein the control means include at least one voltage generator connected to one or to each addressing electrode in order to transmit a voltage representing an image datum. 4. Display screen according to claim 1, wherein the compensating transistor of each column of light emitters includes two current-carrying electrodes, each current-carrying electrode being connected in series between the addressing electrode of this same column and the modulation transistors of this same column. 5. Display screen according to claim 1 wherein each compensating transistor includes a gate electrode and two current-carrying electrodes, the gate electrode of each compensating transistor being connected to the gate electrode of all the modulation transistors of the associated column, in that one current-carrying electrode of each compensating transistor is connected to the addressing electrode of the associated column of light emitters, and in that the other current-carrying electrode of each compensating transistor is connected to its gate electrode. 6. Display screen according to claim 1, wherein the said modulation transistors and the said associated compensating transistor are fabricated on a polycrystalline silicon substrate obtained by heating an amorphous silicon substrate, using a laser beam, the said beam being intended first to heat a first rectangular heating surface of the substrate, then to move in a direction of movement and then to heat a second rectangular heating surface, and in that the said modulation transistors associated with the light emitters of a given column and the associated compensating transistor are aligned in one and the same heating surface, the guiding alignment line extending approximately perpendicularly to the direction of movement of the laser beam. 7. Display screen according to claim 1, wherein the said modulation transistors and the said associated compensating transistor each include a channel between two layers of doped material, the said channel being connected to their gate electrode, and in that the channel of the modulation transistors of a column and the channel of the associated compensating transistor have a main axis approximately parallel to the said guiding line. 8. Display screen according to claim 1, wherein the control means include initialization means for initializing the load capacitors intended to discharge all the load capacitors connected to the modulation transistors of a column. 9. Display screen according to claim 8, wherein the initialization means include an initialization transistor having a gate electrode and two current-carrying electrodes, one current-carrying electrode of the said initialization transistor being connected to the gate electrode of the modulation transistors of the said column, the gate electrode of the said initialization transistor being connected to a current-carrying electrode and to the addressing electrode of a column of light emitters. 10. Display screen according to claim 8, wherein the initialization means include a diode, the cathode of which is connected to the gate electrode of the modulation transistors and the anode of which is connected to the addressing electrode of a column of light emitters. 11. Display screen according to claim 1, wherein the control means include a plurality of selection transistors having a gate electrode and two current-carrying electrodes, each selection transistor having one current-carrying electrode connected to a modulation transistor, a gate electrode connected to a selection electrode and one current-carrying electrode connected to the compensating transistor of a column of light emitters. 12. Display screen according to claim 1, wherein the light emitters are organic electroluminescent diodes. 13. Method for driving a display screen according to claim 1, wherein the method includes a step for applying a voltage representing an image datum to each addressing electrode of each column of light emitters.

The present invention relates to a display screen. In particular, the invention relates to an active matrix display screen of the type based on electroluminescent organic material, with thin film transistors. These transistors are produced by the crystallization of a polycrystalline silicon substrate obtained by a technique of heating an amorphous silicon substrate by a pulsed excimer laser. This technique for fabricating thin film transistors is very economical. However, the crystallization of amorphous silicon results in the formation of grains of monocrystalline silicon of different orientation and separated by grain boundaries. These grain boundaries introduce dispersions of threshold trigger voltages of transistors and non-uniformities in the levels of current flowing through them for a given voltage applied to their gates. Now, since the light emitters of a screen produce light that is directly proportional to the current flowing through them, the threshold trigger voltage dispersions result in variations of luminance on the screen. To compensate for these dispersions, there are known, particularly through documents WO 02/071379 and U.S. Pat. No. 6,359,605, display screens of the above-mentioned type. However, the compensating transistors of these screens are not formed in the extension of the line-arrangement of the modulation transistors of a column. This type of arrangement ensures in particular a voltage that is equal to or at least close to the threshold trigger voltages of the modulation transistors and the threshold trigger voltage of the compensating transistor(s) and consequently ensures improved uniformity of the luminance on the screen. There is also known, particularly through document EP 1 220 191, the technique of introducing a compensating transistor in each addressing circuit of a light emitter of the screen. Each compensating transistor of an addressing circuit is fabricated next to the modulation transistor of this same circuit. Thus, the modulation transistor and the compensating transistor of the same addressing circuit are produced under the same conditions by the same rectilinear laser beam such that their threshold trigger voltages have similar values intended to compensate for each other. However, with such a screen, an initialization transistor and a selection transistor also need to be fabricated, resulting in a total of four transistors to control the emission of each light emitter of the screen. Now, these transistors significantly reduce the useful emission surface area of the pixels. Furthermore, the fabrication of a large number of transistors is not an economical process. The invention aims to propose a screen of the abovementioned type that is simpler to produce and more economical. To this end, one subject of the invention is a display screen including: light emitters arranged as rows of light emitters and columns of light emitters to form an array of light emitters, a silicon substrate on which control means to control the emissions of the light emitters are fabricated, the said control means including: means for powering the light emitters, a plurality of addressing electrodes arranged according to the columns of light emitters, and intended to transmit a voltage representing an image datum to each column of light emitters, a plurality of selection electrodes arranged according to the rows of light emitters, and intended to transmit a selection signal to each row of light emitters, a plurality of modulation transistors, each associated with a light emitter of the array, the said modulation transistors including a gate electrode intended to be connected to an addressing electrode and two current-carrying electrodes, each modulation transistor intended to have a drain current pass through it to power the said light emitter for a voltage between its gate electrode and one of its current-carrying electrodes that is greater than or equal to a threshold trigger voltage, the said modulation transistors being arranged in columns associated with the columns of light emitters and being aligned on the substrate according to a guiding line, a load capacitor connected to the terminals of each modulation transistor and intended to set an electric potential at the gate electrode of the associated modulation transistor, and a plurality of compensating transistors intended to compensate for the threshold trigger voltage of the modulation transistors by adjusting the charge on the capacitor, characterized in that it includes a single compensating transistor connected to all the modulation transistors of a given column and intended to compensate for the threshold trigger voltages of all the said modulation transistors of this column; the said compensating transistor is formed in the extension of the line-arrangement of the said modulation transistors of a given column according to the said same guiding line. According to one characteristic of the invention, the control means do not include any means allowing the flow of current from any one of the addressing electrodes to the means for powering the light emitters. Each modulation transistor associated with a light emitter may carry a drain current to power the said light emitter, this powering current hence flowing between two powering electrodes which are different from the addressing electrodes. Thus, there is no need for any switches connecting an addressing electrode to a power generator for the light emitters. Such switches are however present in the control means described in document WO 02/071379 or in document U.S. Pat. No. 6,359,605. In the control means described in these documents, the addressing electrodes are for transmitting a current ID representing an image datum to the light emitters, whereas in the case of the invention they are for transmitting a voltage VD. Since programming is carried out by current (and not by voltage as in the invention), the above-mentioned connecting switches are needed to ensure that the programming current flows between each addressing electrode and the circuit for powering the light emitters, while the gate voltage of the modulator associated with this light emitter gradually settles on its set value, for example, by the known current mirror system. According to particular embodiments, the display screen has one or more of the following characteristics: the control means include at least one voltage generator connected to one or to each addressing electrode in order to transmit a voltage VD representing an image datum; the compensating transistor of each column of light emitters includes two current-carrying electrodes, each current-carrying electrode being connected in series between the addressing electrode of this same column and the modulation transistors of this same column; each compensating transistor includes a gate electrode and two current-carrying electrodes, the gate electrode of each compensating transistor being connected to the gate electrode of all the modulation transistors of the associated column; one current-carrying electrode of each compensating transistor is connected to the addressing electrode of the associated column of light emitters, and the other current-carrying electrode of each compensating transistor is connected to its gate electrode; the said modulation transistors and the said associated compensating transistor are fabricated on a polycrystalline silicon substrate obtained by heating an amorphous silicon substrate, using a laser beam, the said beam being intended first to heat a first rectangular heating surface of the substrate, then to move in a direction of movement and then to heat a second rectangular heating surface; and the said modulation transistors associated with the light emitters of a given column and the associated compensating transistor are aligned in one and the same heating surface, the guiding alignment line extending approximately perpendicularly to the direction of movement of the laser beam; the said modulation transistors and the said associated compensating transistor each include a channel between two layers of doped material, the said channel being connected to their gate electrode, and the channel of the modulation transistors of a column and the channel of the associated compensating transistor have a main axis approximately parallel to the said guiding line; the control means include initialization means for initializing the load capacitors intended to discharge all the load capacitors connected to the modulation transistors of a column; the initialization means include an initialization transistor having a gate electrode and two current-carrying electrodes, one current-carrying electrode of the said initialization transistor being connected to the gate electrode of the modulation transistors of the said column, the gate electrode of the said initialization transistor being connected to a current-carrying electrode and to the addressing electrode of a column of light emitters; the initialization means include a diode, the cathode of which is connected to the gate electrode of the modulation transistors and the anode of which is connected to the addressing electrode of a column of light emitters; the control means include a plurality of selection transistors having a gate electrode and two current-carrying electrodes, each selection transistor having one current-carrying electrode connected to a modulation transistor, a gate electrode connected to a selection electrode and one current-carrying electrode connected to the compensating transistor of a column of light emitters; the light emitters are organic electroluminescent diodes. Another subject of the invention is a method for driving a display screen, including: light emitters arranged as rows of light emitters and columns of light emitters to form an array of light emitters; a silicon substrate on which control means to control the emissions of the light emitters are fabricated, the said control means including: a plurality of addressing electrodes arranged according to the columns of light emitters, and intended to transmit a voltage representing an image datum to each column of light emitters, a plurality of selection electrodes arranged according to the rows of light emitters, and intended to transmit a selection signal to each row of light emitters, a plurality of modulation transistors, each associated with a light emitter of the array, the said modulation transistors including a gate electrode intended to be connected to an addressing electrode and two current-carrying electrodes, each modulation transistor intended to have a drain current pass through it to power the said light emitter for a voltage between its gate electrode and one of its current-carrying electrodes that is greater than or equal to a threshold trigger voltage, the said modulation transistors being arranged in columns associated with the columns of light emitters and being aligned on the substrate according to a guiding line, a load capacitor connected to the terminals of each modulation transistor and intended to set an electric potential at the gate electrode of the associated modulation transistor, and a plurality of compensating transistors intended to compensate for the threshold trigger voltage of the modulation transistors by adjusting the charge on the capacitor, characterized in that the method includes: a step for forming a single compensating transistor connected to all the modulation transistors of a given column, the said compensating transistor being formed in the extension of the line-arrangement of the said modulation transistors of this same column, according to the said same guiding line; and a step for compensating for the threshold trigger voltages of all the said modulation transistors of this same column, the said compensation being performed by the sole compensating transistor; and a voltage-based step for driving the light emitters of the screen, via the control means. The invention will be better understood upon reading the following description given only by way of example and with reference to the drawings in which: FIG. 1 is a partial schematic view of a screen according to the invention; FIG. 2 is a perspective view representing a silicon substrate heated by a laser beam during the fabrication process of the transistors arranged in the display screen according to the invention; and FIGS. 3A to 3E are graphs showing how the applied voltages change over time during the addressing method performed by the control means according to the invention; in particular: FIG. 3A is a graph showing a selection voltage applied to the first selection electrode of a first addressing circuit; FIG. 3B is a graph showing a voltage applied to an addressing electrode of a column of light emitters; FIG. 3C is a graph showing a selection voltage applied to a second selection electrode of a second addressing circuit; FIG. 3D is a graph showing a voltage stored by a load capacitor of a first addressing circuit; and FIG. 3E is a graph showing a voltage stored by a load capacitor of a second addressing circuit. FIG. 1 partially represents a display screen according to the invention. This screen includes means 2 for controlling the emission of light from a group of image elements or pixels. The screen includes light emitters 4, 6, 8 formed from organic electroluminescent diodes, known by the acronym OLED, the luminance of which is directly proportional to the current flowing through them. They are arranged in rows of light emitters and in columns of light emitters and form an array. The control means 2 include a plurality of addressing circuits 10, 20, 30 each connected to a light emitter 4, 6, 8, one addressing electrode 40 per column of light emitters, one selection electrode 42, 44, 46 per row of light emitters, one compensating transistor 48 and one initialization transistor 50 per column of light emitters. Each addressing electrode 40 is connected to a voltage generator specifically intended to apply to it a voltage representing an image datum. For the sake of simplicity, only three light emitters of a given column of light emitters and control means 2 for addressing these light emitters have been represented in FIG. 1. The first light emitter 2 of the column of light emitters is connected to a first addressing circuit 10. The second light emitter 4 of the column of light emitters is connected to a second addressing circuit 20. Lastly, the third light emitter 6 of the column of light emitters is connected to a third addressing circuit 30. The addressing circuits 10, 20, 30 of this column are connected to the same addressing electrode 40, but are each connected to a different selection electrode. The first 10, second 20 and third 30 addressing circuits are identical; they have the same electronic components, connected in the same way to perform the same functions. To simplify the description, only the first addressing circuit 10 will be described in detail. However, to differentiate between the components of the different addressing circuits, the reference labels of the other addressing circuits have the same unit digits as those of the first addressing circuit 10, but different tens. The addressing circuits 10, 20, 30 include a generator 12, 22, 32 for powering the light emitters, a current modulation transistor 14, 24, 34, a load capacitor 16, 26, 36 and a selection switch 18, 28, 38 formed from a transistor. The modulation transistor 14, the selection switch 18, the compensating transistor 48 and the initialization transistor 50 are p-type thin film transistors. They have a drain electrode, a source electrode and a gate electrode. Their gate electrode is connected to a drain channel formed between two layers of doped material. They are intended to have a current, called the drain current, pass through them from their source to their drain when a voltage that is greater than or equal to their threshold trigger voltage Vth is applied between their gate and their source. Alternatively, n-type thin film transistors may also be used for fabricating a screen according to the invention. In that case, their drain current flows from their drain to their source. The source of the modulation transistor 14 is connected to the generator 12. The drain of the modulation transistor 14 is connected to the anode of the light emitter 4. The cathode of the light emitter 4 is connected to a ground electrode. The gate of the modulation transistor 14 is connected to one terminal of the load capacitor 16 and to the drain electrode of the selection switch 18. The second terminal of the load capacitor 16 is connected to the generator 12. The gate of the switches 18, 28 and 38 of the first 10, second 20 and third 30 addressing circuits is connected to the first 42, second 44 and third 46 selection electrodes respectively. The compensating transistor 48 is connected in parallel with the initialization transistor 50 and is connected at one end to node B and at the other end to a node A for connecting to the column addressing electrode 40. The source electrode of the transistor 48 and the drain electrode of the transistor 50 are connected to the addressing electrode 40 of the column of light emitters. The drain electrode of the transistor 48 and the source electrode of the transistor 50 are connected together at node B. The gate electrode of the transistor 48 is connected to its drain. The gate electrode of the transistor 50 is also connected to its drain. Therefore, the compensating transistor 48 is equivalent to a diode, the cathode of which is connected to node B and the anode of which is connected to node A. This diode is conducting when the potential difference between node A and node B is greater than the threshold trigger voltage Vth48 of the transistor 48. The initialization transistor 50 is also equivalent to a diode. This diode is connected in the opposite sense compared to the diode that is equivalent to the transistor 48. Its cathode is connected to node A. Its anode is connected to node B. This diode is conducting when the potential difference between node A and node B is less than the threshold trigger voltage Vth50 of the transistor 50. The drain electrode of the transistor 48 and the source electrode of the transistor 50 are connected via a line 52 to each switch 18, 28, 38 of all the addressing circuits 10, 20, 30 of the column of light emitters. The gate of the compensating transistor 48 is connected to the gate of the modulation transistors 14, 24, 34 of all the addressing circuits 10, 20, 30 of a column of light emitters. Furthermore, the compensating transistor 48 is fabricated under the same conditions as all the modulation transistors 14, 24, 34 of a column of light emitters such that it can compensate for the threshold trigger voltages of all the modulation transistors 14, 24, 34 of this column. The addressing electrode 40 of a column of light emitters is designed to convey an addressing voltage representing an image datum to the addressing circuits of this column of light emitters. The selection electrodes 42, 44, 46 are specifically for selecting a defined addressing circuit 10, 20, 30 in a column of addressing circuits by applying a selection voltage to one of these row selection electrodes. FIG. 2 schematically shows a step in the low temperature process of fabrication of the poly-silicon forming the structure of the transistors used to generate a screen according to the invention. The modulation transistors 14, 24 and 34 and the compensating transistor 48 are formed in the same layer of polycrystalline silicon obtained after heating and crystallizing an amorphous silicon substrate. During the step of heating of the amorphous silicon substrate 62, a rectilinear excimer laser beam 60 heats a thin layer 62 of amorphous silicon deposited on a glass substrate 64. This pulsed laser beam 60 first heats a first rectangular surface 66 which extends longitudinally along a guiding line 72, then moves in a direction of movement 68 and then heats a second heating surface 70 that is next to the first heating surface 66 and of the same shape as the first heating surface 66. The modulation transistors of a column of light emitters and the compensating transistor 48 intended to compensate for the threshold trigger voltage of all the modulation transistors of this column have been represented schematically in dotted-line form in FIG. 2. The modulation transistors 14, 24, 34 of a column addressed by the same addressing electrode 40 and the compensating transistor 48 to which they are connected are formed in such a way that they are positioned one after the other in a line that is parallel to the long sides of the heating surfaces 66, 70 and perpendicular to the direction of movement 68 of the laser beam 60. Furthermore, these transistors are fabricated on one and the same heating surface 66 heated, at the same time, by the same laser beam 60. More specifically, the modulation transistors 14, 24 and 34 and the compensating transistor 48 are produced such that their drain channel has a main axis approximately perpendicular to the direction 68 of movement of the laser beam. Therefore, they present threshold trigger voltages having similar values such that the compensating transistor 48 is able to compensate for the threshold trigger voltages of all the modulation transistors 14, 24, 34 of a column of light emitters. FIGS. 3A to 3E represent the steps for addressing the light emitters of a display screen according to the invention. In a step A for initializing the modulation transistor 14, a selection voltage VS42 is applied to the electrode 42. The switch 18 closes. An addressing voltage VD, having a value of zero, from now on called the initialization voltage VI, is applied to the addressing electrode 40. The voltage at node A is less than the voltage at node B. The initialization transistor 50 becomes conducting, while the compensating transistor 48 stops conducting. The initialization voltage is then applied to the gate of the modulator 14 and to a terminal of the load capacitor 16 which discharges, as illustrated in FIG. 3D. In a step B for programming the load capacitor 16, an addressing voltage VD1, representing an image datum, is applied to the addressing electrode 40; this voltage is modulated by the compensating transistor 48 and is transmitted to node B. At node B, the value of the voltage modulated by the transistor 48 is equal to VD1−Vth48 where Vth48 is the threshold trigger voltage of the transistor 48. The selection voltage VS42 is still applied to the gate of the selection switch 18; the switch 18 is closed. The addressing voltage VD1 modulated by the compensating transistor 48, is applied to the gate of the modulation transistor 14 and to one terminal of the load capacitor 16. After an instant, the modulation transistor 14 is in the saturation regime of operation and its drain current Id is defined by the following equation: Id=β(Vgs14−Vth14)2 where Vgs14=V12−V16 and V16=VD1−Vth48 where Id is the drain current flowing through the modulation transistor 14, β is a constant that is a function of the technology adopted and of the characteristics of the channel of the transistors, Vgs14 is the voltage between the gate and the source of the modulation transistor 14, V12 is the powering voltage from the generator 12, V16 is the voltage across the terminals of the load capacitor 16, VD1 is the data addressing voltage, Vth48 is the threshold trigger voltage of the compensating transistor 48. Since the modulation transistors 14 and the compensating transistor 48 have been fabricated on the same heating surface, they have similar threshold trigger voltages. Vth48=Vth14 then Id=β×(V12−VD1)2 Thus, the drain current Id flowing through the modulation transistor 14 is independent of its threshold trigger voltage Vth14. The threshold trigger voltage Vth48 of the compensating transistor 48 compensates for the threshold trigger voltage of the modulation transistor Vth14 such that the luminance of the pixel associated with the light emitter 2 is constant for a given addressing voltage. In an intermediate step C, a selection voltage VS44 is applied to the second selection electrode 44. The switch 28 of the second addressing circuit 20 closes. At the end of step C, the selection voltage VS42 is no longer applied to the selection electrode 42 of the first addressing circuit 10 meaning that the switch 18 opens. The load capacitor 16 stores charge at the gate of the modulation transistor 14 such that the latter continues to power the light emitter 4 until the next initialization step VI of the modulator 14, as illustrated in FIG. 3D. In a step D for initializing the load capacitor 26 of the second addressing circuit 20, an addressing voltage VD, having a value of zero and called the initialization voltage VI, is applied to the column addressing electrode 40. Therefore, the voltage at node A becomes less than the voltage at node B. The initialization transistor 50 becomes conducting and the compensating transistor 48 stops conducting. The initialization voltage conveyed by the addressing electrode 40, modulated by the transistor 50, is then transferred to the terminals of the load capacitor 26 which discharges. In a step E for programming the load capacitor 26, an addressing voltage VD2 is applied to the addressing electrode 40. The voltage at node A becomes greater than the voltage at node B. The compensating transistor 48 becomes conducting again while the initialization transistor 50 stops conducting. The voltage at node B, modulated by the compensating transistor 48 is equal to VD2−Vth48 where Vth48 is the threshold trigger voltage of the compensating transistor 48. The voltage at node B is transmitted to the gate of the modulator 24 by the line 52 and the switch 28 which has been closed due to the application of a selection voltage VS44 to the selection electrode 44. Since the modulation transistors 24 and the compensating transistor 48 have been fabricated on the same heating surface along the same guiding line 72, the threshold voltage Vth48 of the transistor 48 is the same as the threshold voltage Vth24 of the transistor 24. Vth48=Vth24 Therefore, Id=β×(V22−VD2)2 where V22 is the powering voltage from the generator 22, VD2 is the data addressing voltage. Thus, the compensating transistor 48 is capable of compensating for the threshold trigger voltage of the modulation transistor 14 of the first addressing circuit 10, of the modulation transistor 24 of the second addressing circuit 20 and of all the modulation transistors of a given column when its transistors are obtained by the heating of a surface of silicon, at the same time, and arranged along the same line. Furthermore, the initialization transistor 50 for the load capacitors is intended to discharge all the load capacitors 16, 26, 36 of the addressing circuits of a given column. Alternatively, the initialization transistor 50 may be replaced by a diode, the cathode of which is connected to the gate electrode of the modulation transistors and the anode of which is connected to the addressing electrode of the light-emitter column associated with the said column of transistors. Advantageously, the addressing circuits of the screen according to the invention are voltage driven meaning that the pixels are addressed faster. Specifically, current-based programming times are no longer necessary since the voltage is directly applied to the gate of the modulators and to the load capacitors. In additions the voltage driven addressing circuits are simple to implement and have a fabrication cost that is favourable compared to current-based addressing circuits.

20060622

20120124

20080918

87551.0

G09G332

SIM, MATTHEW Y

IMAGE DISPLAY SCREEN AND METHOD FOR CONTROLLING SAID SCREEN

UNDISCOUNTED

ACCEPTED

G09G

ACCEPTED

Arrangement in connection with crosscutting saw of harvester

The present invention relates to an arrangement in connection with a crosscutting saw of a harvester (1). Herein, a lattice-like structure composed of strips (17) is provided in a saw casing (10) of the crosscutting saw, the structure being substantially on the same section plane as the rotational movement of a chain (12) of the crosscutting saw. The strips are arranged in the saw casing in such a manner that substantially each movement path tangent generated at a lower edge (16) in a guide bar (13) of the chain or at an outer track (20) on the side of the saw casing in the chain wheel is arranged to encounter a surface (19) in the strip. This provides a structure that enhances a controlled removal of sawdust or other pieces flowing to the saw casing (10) during sawing.

1-11. (canceled) 12. An arrangement in connection with a crosscutting saw of a harvester, a harvester head therein comprising a saw casing and a chainsaw, arranged therein in a rotational manner, and a guide bar and a chain wheel, the saw casing comprising strips on a cutting plane substantially flush with a rotational plane of a chain of the chainsaw, the strips being arranged in the saw casing in such a manner that their longitudinal axis is substantially parallel to the rotational axis of the chain wheel, wherein the strips are arranged to provide a lattice-like structure in the saw casing, the structure extending at least over the rotational plane of the chain of the chainsaw, substantially each movement path tangent generated at a lower edge in the guide bar of the chain or at an outer track on the side of the saw casing in the chain wheel being arranged to encounter a surface in the strip, however, such that the strips are arranged to overlap in the saw casing in such a manner that at least one gap deviating from said tangential movement path remains between the strips, from which sawdust or other impurities flowing to the saw casing during sawing are allowed to be discharged from the saw casing. 13. An arrangement as claimed in claim 12, wherein the strip is arranged substantially radially relative to the chain wheel. 14. An arrangement as claimed in claim 13, wherein the strip is arched or is bent onto an extension of a movement path tangent generated at a lower edge in the guide bar of the chain or at an outer track on the side of the saw casing in the chain wheel. 15. An arrangement as claimed in claim 12, wherein the strips are arranged in the saw casing as a cover-like structure that is substantially parallel to the rotational axis of the chain wheel, the strips being arranged substantially in the radial direction of the chain wheel on at least two planes in such a manner that at least one gap remains between the strips. 16. An arrangement as claimed in claim 12, wherein the strips are fastened substantially rigidly to the saw casing. 17. An arrangement as claimed in claim 16, wherein the strips are fastened to the saw casing in a manner not enabling disassembly, preferably by welding. 18. An arrangement as claimed in claim 16, wherein the strips are fastened to the saw casing in a manner enabling disassembly with a mechanical fastening, preferably a screw fastening. 19. An arrangement as claimed in claim 12, wherein the protective structure comprises strips arranged in a common frame structure for generating an integral whole to be fastened to the saw casing. 20. An arrangement as claimed in claim 12, wherein the strips are made from the same material as the surrounding saw casing. 21. An arrangement as claimed in claim 12, wherein the strips are made from a composite material. 22. An arrangement as claimed in claim 12, wherein the strips are coated with an elastic coating. 23. An arrangement as claimed in claim 18, wherein the mechanical fastening is a screw fastening.

BACKGROUND OF THE INVENTION The present invention relates to an arrangement in connection with a crosscutting saw of a harvester according to the preamble of claim 1. Such an arrangement is intended for use particularly in connection with a crosscutting saw at a harvester head of a harvester moving in the terrain. Since the tendency in modern harvesters is towards an optimally short time taken up by crosscut-sawing, there is a continuous trend in the field to increase the speed of rotation of chainsaws and, at the same time, the peripheral speed of the therein provided chain up to the maximum values set by the chain manufacturer. The ever-increasing speed of the chain increases the risk of the chain breaking during sawing or pieces being detached from it. If the chain breaks, it may cause a so-called chain blast, wherein the chain or parts thereof are thrown into the surroundings of the chainsaw with a high force and speed causing a significant safety risk in the working environment. There exist distinct findings that the number of such accidents has increased significantly. However, the saw casing of a chainsaw cannot be made entirely enclosed, even if that prevented such problems or at least significantly lessened the risks caused by a dangerous chain blast. When a tree trunk is felling or crosscut-sawn, much sawdust is produced, which is packed inside the saw casing during sawing. The problem is particularly emphasized in winter conditions when not only sawdust, but also snow is packed inside the saw casing. Accordingly, sawdust and snow would rapidly fill an encased saw casing, finally using up all the space required for the movement of the chainsaw. This is why prior art saw casings comprise a relatively open structure at that end of the chainsaw where the guide bar is hinged to the harvester head. Attempts have been made previously to solve this problem, whereby device parts are known that are arranged in connection with the crosscutting saw at the harvester head of the harvester and used to attempt to prevent the chain of the crosscutting saw or parts thereof from being thrown in directions hazardous to the driver or objects or people in the environment. For example, patent publication WO 02/071833 discloses a solution wherein one or more movably arranged guarding members are arranged in connection with the saw casing substantially on the same plane as the rotational movement of the chain of the crosscutting saw. In the solution according to said patent publication, these guarding members are, however, arranged movable. Accordingly, the guarding members are kept in different positions when felling a tree and when cutting the tree into logs. The purpose of this solution is to achieve a protective effect as covering as possible, but at the same time, attempt to prevent any damage to the guarding members during delimbing, for example. The solution presented does lead to a complex structure and will probably restrict the usage of the harvester head. The use of the guarding member according to the solution does not in spite of all bring about a complete security about the chain, when breaking or becoming detached from the sawing device, not causing a so-called chain blast in hazardous directions, since the tip of the guide bar of the crosscutting saw still propagates unprotected during most of the sawing. BRIEF DESCRIPTION OF THE INVENTION The object of the present invention is to eliminate prior art drawbacks and to provide a completely new solution for the structure and function of an arrangement in connection with the crosscutting saw of a harvester. More exactly, the arrangement according to the invention is mainly characterized by what is disclosed in the characterizing part of claim 1. The invention is based on the idea of arranging the chain wheel of the crosscutting saw to be partly surrounded by protective structures arranged in the saw casing. These protective structures are arranged to overlap and preferably to guide the sawdust and any loose pieces flying from the chainsaw downwards during crosscut-sawing. Thus, no straight-lined connection exists to the outside of the saw casing from any movement path tangent of the lower edge of the guide bar or the outer track on the side of the saw casing of the chain wheel. Preferred embodiments of the invention are described in the dependent claims. As employed in the description, terms, such as ‘up’, ‘down’, ‘over’, ‘under’ and so on, illustrate the features of the invention in directions relative to the arrangement according to the invention in connection with the crosscutting saw of a harvester as presented in the attached figures. The invention brings about significant advantages. Accordingly, according to studies conducted, in most cases when a chain blast takes place, the chain or a part detached from it is directed substantially in the direction of the longitudinal axis of the guide bar backwards in the direction of the chain wheel. It is easy to stop such a tangential movement with the overlapping protective structures of the invention. When hitting a protective structure, the chain or the part detached from it loses a significant part of its kinetic energy and is directed away from the control cabin or stops entirely at the protective structure and remains inside the saw casing. On the other hand, the frame structure of the saw casing designed in the present manner or the arrangement provided in the frame brings forth the advantage of preventing the sawdust produced by the chainsaw and the oil used for lubricating the chain from spreading widely into the surroundings of the harvester, where it would cause impaired visibility and increased need for cleaning the windows of the control cabin of the harvester. The arrangement in connection with the crosscutting saw of a harvester according to the invention is simple to connect to harvester heads of harvesters already in use, and it thereby significantly increases work safety. The present arrangement in connection with the crosscutting saw of a harvester does not affect the use of the harvester head in sawing, as do arrangements projecting from the saw casing, for example. It requires no extra work steps that would inconvenience work and does in no way complicate the servicing of the harvester head. The arrangement according to the invention does not either damage a chain detached from the guide bar as badly as do protective structures following the movements of the guide bar. Accordingly, the chain, when detached from the guide bar, can often be taken into use again after servicing operations. BRIEF DESCRIPTION OF THE FIGURES In the following, the invention will be described in more detail in connection with preferred embodiments with reference to the accompanying drawing, in which FIG. 1 schematically shows an overview of a harvester, known per se, FIG. 2 shows an arrangement at the harvester head of a harvester in connection with a crosscutting saw, with the harvester head shown from behind in a position during crosscut-sawing of a felled tree, and FIG. 3 shows another embodiment of an arrangement in connection with a crosscutting saw, also with the harvester head shown from behind. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS In the following, preferred embodiments of the invention will be described with reference to the above figures. Herein, the arrangement in connection with a crosscutting saw of a harvester comprises the structural parts denoted in the figures by reference numerals, corresponding to the reference numerals used in the present description. FIG. 1 shows a wheel-mounted harvester 1, known per se. It comprises a control cabin 2 and a crane 5 arranged via a rotating device 3 to an undercarriage 4 and arranged tiltable in the longitudinal direction of the machine. In addition to the fastening between the undercarriage and the crane, the crane is provided with a necessary number of degrees of freedom to enable effective harvesting within the entire movement range of the crane. A harvester head 7 supported by a rotator 6 is arranged in the crane, the harvester head being rotatable about its substantially vertical axis by means of the rotator. The harvester head is suspended from the rotator via a special link 8 hinged in a turning manner to the frame of the harvester head. This enables tilting of the harvester head and a tree trunk 9 processed therein after felling-sawing into a substantially horizontal position for the duration of the delimbing and crosscut-sawing of the tree. Felling and crosscut-sawing are performed with the crosscutting saw placed in a saw casing 10 at the harvester head, the crosscutting saw usually employed being a chainsaw 11. FIG. 2 schematically shows the harvester head 7 of the harvester 1. The harvester head supports the tree trunk 9 to be cut and being cut by means of a chain 13 revolving about a guide bar 12 in the chainsaw 11. The chain is driven with a chain wheel 14, which is placed at the fastening end of the guide bar in the saw casing 10 surrounding the chainsaw in a dormant state. The saw casing is rigidly fastened to the frame of the harvester head in a manner known per se. When the tree trunk 9 is being sawed, the chain 13 revolves, driven by the chain wheel 14, clockwise relative to the guide bar 12 in accordance with FIG. 2. Since the majority of the stresses the chain is subjected to is directed thereto in the actual sawing situation, this takes place in the contact area of the guide bar and the tree trunk, i.e. at a lower edge 15 of the guide bar. Consequently, in malfunction of the chain, i.e. when it breaks down or is displaced from the guide bar, this takes place mainly on the lower edge of the guide bar with the chain on the way towards the chain wheel and the saw casing 10. As a result of the malfunction, the entire chain or part thereof is thrown at a high velocity towards the saw casing and via conventional sawdust openings therein further to the environment. In order to avoid a dangerous situation caused by malfunction, a special protective structure 16, i.e. an arrangement in connection with the crosscutting saw, is arranged in the saw casing 10, its purpose being to prevent the chain 13 or a part thereof from being thrown further to the outside of the harvester head 7. The present arrangement comprises a lattice-like structure composed of strips 17 in the saw casing, the structure being substantially on the same section plane as the rotational movement of the chain. Such strips are arranged in the saw casing such that their longitudinal axis is substantially parallel to the rotational axis of the chain wheel. However, the strips are arranged to overlap in the saw casing such that at least one gap 18 remains between the strips, allowing sawdust or other impurities flowing into the saw casing during sawing to be removed from the saw casing. Thus, it may be stated that the strips 17 are partly overlapping and at an angle to the tangent of the chain wheel 14 which extends to the strips at the point where the chain 13 touches the chain wheel for the first time when coming from the guide bar 12. This being so, seen in the direction of said tangent, the opposite edges of adjacent strips are preferably approximately at the same point. However, seen perpendicularly to this direction, the gap 18 enabling the removal of sawdust is formed between the edges of the strips. During sawing, when the guide bar turns, the tangents generated at each particular point of the guide bar form a substantially circular sector, and the strips preferably form a circular arc relative to the midpoint of the chain wheel. However, for removal of sawdust, these strips 17 do not necessarily have to be of the width of the entire saw casing 10. It is indeed sufficient that the strips are arranged symmetrically relative to the cutting plane formed by the rotational plane of the guide bar 12 and the chain 13 such that they cover the chain line on said plane with sufficient certainty. In this case, the strips are able to stop a broken chain at the same time as they guide the fastest and farthest flying middle part of a stream generated from sawdust away from the cabin 2. The orientation angle formed by an outer surface 19 in the strips 17 has to be as obtuse as possible in order for a sufficiently efficient sawdust removal to be achieved. On the other hand, this orientation angle has to be acute enough for such a gap 18 not to remain between the strips that would allow the part being detached during a chain blast to penetrate the protective structure 16. Accordingly, the gap between the strips cannot be substantially larger than 1 to 5 mm when observed from the direction of a movement path tangent of the lower edge of the guide bar or of an outer track 20 on the side of the saw casing of the chain wheel. Consequently, the strips 17 of the present arrangement are arranged in accordance with FIG. 2 substantially radially relative to the chain wheel 14. However, in such a manner that each strip is arched or bent in such a manner than one surface 19 therein is arranged to settle to the movement path of the detached chain 13 or a part detaching from the chain. At each point of the protective lattice according to the arrangement is thus provided a strip whose surface is on the extension of some tangential movement path provided by the chain moving on the guide bar. Such a design of the protective structure 16 also ensures that during felling-sawing, the sawdust stream generated in the sawing is guided from the strips away from the control cabin 2 and during crosscut-sawing as directly as possible to the ground. On the other hand, in connection with crosscut-sawing, the present arrangement can also be implemented in the manner of the embodiment according to FIG. 3. In this embodiment, the above-mentioned strips 17 are arranged to create a cover-like structure in the saw casing 10, the structure being substantially parallel to the rotational axis of the chain wheel 14. However, to enable removal of sawdust or other impurities flowing to the saw casing during sawing, the strips are arranged substantially in the radial direction of the chain wheel on at least two planes such that at least one gap 18 remains between the strips. The structures of the present arrangements are achieved by fastening the strips 17 substantially rigidly in the saw casing 10, either in a manner preventing disassembly e.g. by welding or in a manner allowing disassembly with some mechanical fastening known per se, such as screw fastening. The strips 17 of the present arrangement are preferably made from the same material as the surrounding saw casing, but, naturally, nothing prevents them from being made from some other, for instance lighter composite material. The strips can also be coated for instance with an elastic or yielding material or another coating suitable for this purpose, to dampen the speed of movement of flying pieces. The protective structure 16 of the above-described kind can also be implemented by the strips 17 constituting an integral whole to be fastened to the saw casing 10, for instance by arranging the strips in a common frame structure. This allows the installation and servicing of the protective structure to be significantly facilitated. Such a protective structure constituting a separate whole is also significantly simple to install in saw casings already in use. It is to be understood that the above specification and the related figures are only intended to illustrate the present invention. The solution is thus not restricted solely to the embodiment described above or in the claims, but different variations and modifications of the invention will be apparent to those skilled in the art, without deviating from the idea disclosed in the attached claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to an arrangement in connection with a crosscutting saw of a harvester according to the preamble of claim 1 . Such an arrangement is intended for use particularly in connection with a crosscutting saw at a harvester head of a harvester moving in the terrain. Since the tendency in modern harvesters is towards an optimally short time taken up by crosscut-sawing, there is a continuous trend in the field to increase the speed of rotation of chainsaws and, at the same time, the peripheral speed of the therein provided chain up to the maximum values set by the chain manufacturer. The ever-increasing speed of the chain increases the risk of the chain breaking during sawing or pieces being detached from it. If the chain breaks, it may cause a so-called chain blast, wherein the chain or parts thereof are thrown into the surroundings of the chainsaw with a high force and speed causing a significant safety risk in the working environment. There exist distinct findings that the number of such accidents has increased significantly. However, the saw casing of a chainsaw cannot be made entirely enclosed, even if that prevented such problems or at least significantly lessened the risks caused by a dangerous chain blast. When a tree trunk is felling or crosscut-sawn, much sawdust is produced, which is packed inside the saw casing during sawing. The problem is particularly emphasized in winter conditions when not only sawdust, but also snow is packed inside the saw casing. Accordingly, sawdust and snow would rapidly fill an encased saw casing, finally using up all the space required for the movement of the chainsaw. This is why prior art saw casings comprise a relatively open structure at that end of the chainsaw where the guide bar is hinged to the harvester head. Attempts have been made previously to solve this problem, whereby device parts are known that are arranged in connection with the crosscutting saw at the harvester head of the harvester and used to attempt to prevent the chain of the crosscutting saw or parts thereof from being thrown in directions hazardous to the driver or objects or people in the environment. For example, patent publication WO 02/071833 discloses a solution wherein one or more movably arranged guarding members are arranged in connection with the saw casing substantially on the same plane as the rotational movement of the chain of the crosscutting saw. In the solution according to said patent publication, these guarding members are, however, arranged movable. Accordingly, the guarding members are kept in different positions when felling a tree and when cutting the tree into logs. The purpose of this solution is to achieve a protective effect as covering as possible, but at the same time, attempt to prevent any damage to the guarding members during delimbing, for example. The solution presented does lead to a complex structure and will probably restrict the usage of the harvester head. The use of the guarding member according to the solution does not in spite of all bring about a complete security about the chain, when breaking or becoming detached from the sawing device, not causing a so-called chain blast in hazardous directions, since the tip of the guide bar of the crosscutting saw still propagates unprotected during most of the sawing.

<SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>The object of the present invention is to eliminate prior art drawbacks and to provide a completely new solution for the structure and function of an arrangement in connection with the crosscutting saw of a harvester. More exactly, the arrangement according to the invention is mainly characterized by what is disclosed in the characterizing part of claim 1 . The invention is based on the idea of arranging the chain wheel of the crosscutting saw to be partly surrounded by protective structures arranged in the saw casing. These protective structures are arranged to overlap and preferably to guide the sawdust and any loose pieces flying from the chainsaw downwards during crosscut-sawing. Thus, no straight-lined connection exists to the outside of the saw casing from any movement path tangent of the lower edge of the guide bar or the outer track on the side of the saw casing of the chain wheel. Preferred embodiments of the invention are described in the dependent claims. As employed in the description, terms, such as ‘up’, ‘down’, ‘over’, ‘under’ and so on, illustrate the features of the invention in directions relative to the arrangement according to the invention in connection with the crosscutting saw of a harvester as presented in the attached figures. The invention brings about significant advantages. Accordingly, according to studies conducted, in most cases when a chain blast takes place, the chain or a part detached from it is directed substantially in the direction of the longitudinal axis of the guide bar backwards in the direction of the chain wheel. It is easy to stop such a tangential movement with the overlapping protective structures of the invention. When hitting a protective structure, the chain or the part detached from it loses a significant part of its kinetic energy and is directed away from the control cabin or stops entirely at the protective structure and remains inside the saw casing. On the other hand, the frame structure of the saw casing designed in the present manner or the arrangement provided in the frame brings forth the advantage of preventing the sawdust produced by the chainsaw and the oil used for lubricating the chain from spreading widely into the surroundings of the harvester, where it would cause impaired visibility and increased need for cleaning the windows of the control cabin of the harvester. The arrangement in connection with the crosscutting saw of a harvester according to the invention is simple to connect to harvester heads of harvesters already in use, and it thereby significantly increases work safety. The present arrangement in connection with the crosscutting saw of a harvester does not affect the use of the harvester head in sawing, as do arrangements projecting from the saw casing, for example. It requires no extra work steps that would inconvenience work and does in no way complicate the servicing of the harvester head. The arrangement according to the invention does not either damage a chain detached from the guide bar as badly as do protective structures following the movements of the guide bar. Accordingly, the chain, when detached from the guide bar, can often be taken into use again after servicing operations.

20060621

20080226

20070329

88569.0

A01G2308

SELF, SHELLEY M

ARRANGEMENT IN CONNECTION WITH CROSSCUTTING SAW OF HARVESTER

UNDISCOUNTED

ACCEPTED

A01G

ACCEPTED

Block for filtering particles contained in exhaust gases of an internal combustion engine

A filter block, particularly for filtering particulates present in the exhaust gases of an internal combustion engine, including peripheral inlet (50,14p2) and outlet (52,14p1) channels arranged alternately at the periphery of the block and each including an external wall (44;54 ;401,402;403) exposed to the exterior of the block and an internal wall (46 ;56 ;404,405 ;406,407,408) arranged inside the block. The block according to the invention is remarkable in that it includes at least one group (G) of two adjacent peripheral channels (50,52) such that, in a transverse plane of section (P), the ratio R of the average thickness “E” of all the external walls (44,54) of the group (G) to the average thickness “e” of all the internal walls (46,56) of the (G) is greater than 1.2.

1-15. (canceled) 16. A filter block, particularly for filtering particulates present in the exhaust gases of an internal combustion engine, comprising peripheral inlet (50,14p2) and outlet (52,14p1) channels arranged alternately at the periphery of said block and each comprising an external wall (44;54 ;401,402;403) exposed to the exterior of said block and an internal wall (46 ;56 ;404,405 ;406,407,408) arranged inside said block, said filter block comprising at least one group (G) of two adjacent peripheral channels (50,52) such that, in a transverse plane of section (P), the ratio “R” of the average thickness “E” of all the external walls (44,54) of said group (G) to the average thickness “e” of all the internal walls (46,56) of said group (G) is greater than 1.2. 17. The filter block as claimed in claim 16, wherein, in said transverse plane of section (P), the ratio “R*” of the minimum thickness “Emin” of all the external walls (44,54) of said group (G) to the average thickness “e” of all the internal walls (46,56) of said group (G) is greater than 1.2. 18. The filter block as claimed in claim 16, wherein said ratio “R”, is constant irrespective of the transverse plane of section (P) considered. 19. The block as claimed in claim 17, wherein the transverse cross section of said inlet (50) and/or outlet (52) channel of said group (G) and/or said average thickness “E”, and said minimum thickness “Emin”, is substantially constant along the whole length (L) of said block (11). 20. The filter block as claimed in claim 17, wherein said ratio “R” is between 1.9 and 2.1, preferably is substantially equal to 2. 21. The filter block as claimed in claim 16, wherein the average thickness of the external wall of the outlet channel of said group (G) is greater than the average thickness of the external wall of the inlet channel of said group (G). 22. The filter block as claimed in claim 16, wherein, in any transverse plane of section (P), all said inlet channels (14e) have an identical transverse cross section, and all said outlet channels (14s) have an identical transverse cross section, said transverse cross section of said inlet channels being different, preferably with a greater surface area, from that of said outlet channels. 23. The filter block as claimed in claim 16, which comprises at least one inlet channel (14e) and one outlet channel (14s) separated by a nonplane wall element (40). 24. The filter block as claimed in claim 23, wherein said nonplane wall element (40) has, in transverse cross section, at least one face having the shape of a sinusoid or a fraction of sinusoid. 25. The filter block as claimed in claim 16 wherein said external walls (44,54) of said group (G) have a plane external face (60). 26. The filter block as claimed in claim 16, wherein each set of two adjacent peripheral channels of said block not comprising a channel (14p1) bounding an edge (11′) of said block is a said group (G). 27. The filter block as claimed in claim 16, wherein each set of two adjacent peripheral channels of said block comprising a channel bounding an edge of said block is a said group (G). 28. The filter block as claimed in claim 16, wherein, in said plane of section (P), the average thickness of a peripheral wall (30) of said block (11) is substantially equal to said thickness “E” of any group of two adjacent peripheral channels not comprising a corner channel. 29. A filter body for a particulate filter, which comprises at least one filter block as claimed in claim 16. 30. An extrusion die conformed in order to form, by extrusion of a ceramic material, a structure provided with channels suitable for the fabrication of a filter block as claimed in claim 16.

The invention relates to a filter block, particularly for filtering particulates present in the exhaust gases of an internal combustion engine, comprising peripheral inlet and outlet channels arranged alternately at the periphery of said block and each comprising an external wall exposed to the exterior of said block and an internal wall arranged inside said block. The invention also relates to a body formed by assembling a plurality of said blocks, and to a die for extruding blocks according to the invention. Conventionally, before being released to the open air, the exhaust gases may be purified by means of a particulate filter like the one shown in FIGS. 1 and 2, known in the prior art. A particulate filter 1 is shown in FIG. 1 in transverse cross section, along the plane of section B-B shown in FIG. 2, and in FIG. 2 in longitudinal cross section along the plane of section A-A shown in FIG. 1. The particulate filter 1 conventionally comprises at least one filter body 3, inserted in a metal housing 5. The filter body 3 results from the assembly and machining of a plurality of blocks 11, referenced 11a-11. To fabricate a block 11, a ceramic material (cordierite, silicon carbide, etc.) is extruded to form a porous honeycomb structure. The extruded porous structure conventionally has the shape of a rectangular parallelepiped, comprising four longitudinal edges 11′, extending along an axis D-D between two substantially square upstream 12 and downstream 13 faces on which a plurality of adjacent, square section, straight channels 14 terminate, parallel to the axis D-D. After extrusion, the extruded porous structures are alternately plugged on the upstream face 12 or on the downstream face 13 by upstream 15s and downstream 15e plugs, respectively, as is well known, to form channels of the “outlet channel” 14s and “inlet channel” 14e types, respectively. At the opposite end of the outlet 14s and inlet 14e channels from the upstream 15s and downstream 15e plugs, respectively, the outlet 14s and inlet 14e channels terminate outwardly in outlet 19s and inlet 19e openings, respectively, extending on the downstream 13 and upstream 12 faces, respectively. Each channel 14 thereby defines an internal volume 20 bounded by the side wall 22, a plug 15s or 15e, and an outwardly terminating opening 19s or 19e. The inlet 14e and outlet 14s channels are in fluid communication via their side walls 22. The blocks 11a-11i are assembled together by bonding using seals 27 of ceramic cement generally consisting of silica and/or silicon carbide and/or aluminum nitride. The assembly thus formed can then be machined to obtain, for example, a round cross section. Thus the external blocks 11a, 11b, 11c, 11d, 11e, 11f, 11g, 11h have an external face that is rounded by machining. This produces a cylindrical filter body 3 with axis C-C, which can be inserted into the housing 5, a peripheral seal 28, gastight to the exhaust gases, being arranged between the external filter blocks 11a-11h and the housing 5. As indicated by the arrows shown in FIG. 2, the flow F of exhaust gases enters the filter body 3 via the openings 19e of the inlet channels 14e, passes through the filtering side walls 22 of these channels to join the outlet channels 14s, and then escapes to the exterior via the openings 19s. After a certain period of use, the particulates, or “soot”, accumulated in the inlet channels 14e of the filter body 3, impair the performance of the engine. This is why the filter body 3 must be regenerated regularly, for example every 500 kilometers. The regeneration, or “unclogging”, consists in oxidizing the soot by heating it to a temperature permitting its ignition. During the regeneration phases, the exhaust gases transport downstream all the heat energy liberated by the combustion of the soot. Moreover, since the soot is not uniformly deposited in the various channels, the combustion zones are not uniformly distributed in the filter body 3. Finally, the peripheral zones of the filter body 3 are cooled, via the metal housing 5, by the surrounding air. As a result, the temperature differs according to the zones of the filter body 3 and does not vary uniformly. The nonuniformity of the temperatures within the filter body 3 and the differences in the nature of the materials used for the filter blocks 11a-11i on the one hand, and for the seals 27 on the other, generate high amplitude local stresses, which can cause local breakage or cracks. In particular, the local stresses at the interfaces between the blocks 11a-11h and the housing 5, and between the blocks 11a-11i and the seals 27, can cause cracks in the blocks 11a-11i thereby shortening the service life of the particulate filter 1. It is the object of the invention to provide a novel block 11 able to decrease this risk of cracking. This object is achieved by means of a filter block, particularly for filtering particulates present in the exhaust gases of an internal combustion engine, comprising peripheral inlet and outlet channels arranged alternately at the periphery of said block and each comprising an external wall exposed to the exterior of said block and an internal wall arranged inside said block. The filter block according to the invention is remarkable in that it comprises at least one group of two adjacent peripheral channels such that, in a transverse plane of section, the ratio R of the average thickness “E” of all the external walls of said group to the average thickness “e” of all the internal walls of said group is greater than 1.2. As will be seen in greater detail in the rest of the description, the average thickness of the peripheral wall formed by the external walls of the channels of said group is thus increased, thereby locally reinforcing the block and thereby advantageously limiting the risks of cracking. At the peripheral channels that it overlaps, the peripheral wall locally has an average thickness greater than the average thickness of the internal walls of these channels. The peripheral wall thus has an “average reinforcement”, which does not exclude the possibility that, over a portion of the external walls considered, for example over the width of one of said channels, or even beyond, the thickness of the peripheral wall may be less than 1.2 times the average thickness of the internal walls of these channels. Preferably, however, in said transverse plane of section, the thickness of the external walls of the channels of said group is, at any point, greater than or equal to the average thickness “e” of all the internal walls of these channels. More preferably, in said transverse plane of section, the ratio R* of the minimum thickness “Emin” of all the external walls of said group to the average thickness “e” of all the internal walls of said group is greater than 1.2. The cracking resistance is thereby further improved. The invention also relates to a filter body for a particulate filter which is remarkable in that it comprises at last one filter block according to the invention. The invention also relates to an extrusion die conformed in order to form, by extrusion of a ceramic material, a structure provided with channels suitable for the fabrication of a filter block according to the invention. The description that follows, with reference to the drawings appended hereto, will help to better understand and appreciate the advantages of the invention. In these drawings: FIG. 1 shows a particulate filter of the prior art, in transverse cross section along the transverse plane of section B-B shown in FIG. 2; FIG. 2 shows the same particulate filter, along the longitudinal plane of section A-A shown in FIG. 1; FIG. 3 shows a perspective view of a block according to the invention, in the preferred embodiment; FIG. 4 schematically shows a filter block according to the invention in transverse cross section along a transverse plane P. viewed towards the downstream face of the block; FIG. 5 shows a detail of FIG. 4; FIGS. 6 and 7 show, in plan view, longitudinal cross sections, along a median plane M as shown in FIG. 8, of filter bodies consisting of 16 blocks according to and not according to the invention, respectively, after having undergone severe regeneration tests; and FIG. 8 shows, in transverse cross section, a filter body used for said tests. To improve the clarity of FIG. 4, the number of channels shown is much smaller than that of the filter blocks conventionally marketed. In these figures, which are nonlimiting, the various elements are not necessarily shown to the same scale. In particular, the thickness of the walls separating the various channels is not to scale and does not constitute a limit to the invention. Identical references have been used in the various figures to denote identical or similar elements. FIGS. 1, 2 and 3 having been described in the preamble, we shall now refer to FIG. 4, also partially described above. The block 11 shown in detail in FIG. 4 comprises sets of adjacent inlet channels 14e and outlet channels 14s, arranged with respect to each other so that all the gas filtered by any inlet channel passes into outlet channels adjacent to said inlet channel. Advantageously, there is no zone of one or more inlet channel(s) that terminates in another inlet channel, which zone cannot be useful for filtration because the exhaust gases can pass through it in both directions. The filtration area available for a given volume of filter block is thereby optimized. Preferably, the inlet 14e and outlet 14s channels are parallel and straight along the length L of the filter block. Advantageously, it is thereby possible by extrusion to fabricate the honeycomb structure suitable for the fabrication of a filter block according to the invention. The sets of inlet channels 14e and outlet channels 14s are interpenetrating in order to form, in transverse cross section, a checkerboard pattern in which said inlet channels alternate with said outlet channels, in the height direction (direction y) and in the width direction (direction x). The expression “corner channels” is applied to the inlet 29e and outlet 29s channels which bound an edge 11′ of the block 11. In any transverse plane of section, all the inlet channels 14e have an identical transverse cross section, substantially constant along the whole length L of the block. Similarly, all the outlet channels 14s have an identical transverse cross section, substantially constant along the whole length L of the block. This facilitates the fabrication of the filter blocks. In the preferred embodiment of the invention, shown in FIG. 4, the transverse cross section of the inlet channels 14e is different from that of the outlet channels 14s. Preferably, the transverse cross sections of the inlet channels 14e are greater than those of the outlet channels 14s, in order to increase the overall volume of the inlet channels at the expense of that of the outlet channels. The soot storage capacity is thereby advantageously increased. For this purpose, the inlet 14e and outlet 14s channels are bounded by nonplane wall elements 40, preferably concave on the inlet channel 14e side and convex on the outlet channel 14s side. The expression “wall element” is applied to a portion of the side wall 22 of a channel bounded by splices 42. The term “splice” is applied to the boundary of a portion of side wall shared with an adjacent channel. For an internal channel, this line corresponds to a junction zone between the side walls of two channels of the same type. For a network of square section channels, the splices of one channel are therefore the “corners” of the internal volume 20. Preferably, the wall elements 40 follow each other, in transverse cross section and along a horizontal row (along the x axis) or vertical row (along the y axis) of channels, to define a sinusoidal or “wavy” shape. The wall elements 40 undulate substantially by a sinusoid semiperiod over the width of a channel. The expression “peripheral channels” 14p is applied to the channels located at the periphery of a block 11. The side wall 22 of the peripheral channels 14p comprises an external wall 44, that is, one in contact with the exterior of the block 11, and an internal wall 46, that is, one shared with adjacent channels. The external wall 44 comprises two (401, 402) or one (403) wall element(s), according to whether the channel considered, 14p1, and 14p2 respectively, is a corner channel or not. Similarly, the internal wall 44 comprises two (404 and 405) or three (406, 407, 408) wall element(s) respectively, according to whether the channel considered, 14p1 and 14p2 respectively, is a corner channel or not. The external walls 44 of the peripheral channels constitute a peripheral side wall 30 forming the four faces 16a-d of the external surface 16 of the filter block 11. Consider a group G of two adjacent peripheral channels 50 and 52. The side wall of channel 50 consists of an external wall 44 and an internal wall 46. The side wall of channel 52 consists of an external wall 54 and an internal wall 56. This group necessarily comprises an inlet channel 50 and an outlet channel 52, separated by a common wall element 58. “E” and “e” denote the average thickness of the two external walls 44 and 54 and of the two internal walls 46 and 56 of this group, respectively, measured in the transverse plane of section P. A thickness of a wall of a channel is measured by taking a position perpendicular to this wall, thereby excluding any thickness measurement in the corners of the internal volume of this channel. R denotes the ratio E/e and R* the ratio Emin/e of the minimum thickness “Emin” of all the external walls 44 and 54 of said group G to the average thickness “e”. According to the invention, R, and preferably R*, is greater than 1.2, preferably greater than 1.5. More preferably, the ratio R, and preferably R*, is greater than 1.9 and, preferably, less than 2.1. A ratio R, and preferably R*, substantially equal to 2, is the most preferred. Preferably, the ratio R and/or the ratio R* is constant irrespective of said transverse plane of section P considered. Preferably, all the possible groups G of two adjacent peripheral channels not comprising a corner channel have a ratio R or R* according to the invention, preferably identical for all these groups. More preferably, all the groups comprising a corner channel also have a ratio R or R* according to the invention, preferably identical for all these groups. Preferably, the wall elements of the external walls of the corner channels have an identical profile to the wall elements of the external walls of the channels of the same type of the groups not comprising a corner channel. Preferably, in the plane of section P, the average thickness of the peripheral wall of the block 11 is substantially equal to the average thickness “E” of any group G of two adjacent peripheral channels not comprising a corner channel. Preferably, the average thickness E and/or the minimum thickness Emin is constant along the whole length L of the block. The peripheral wall 30 of the block 11 is thus reinforced by an “average reinforcement” of material arranged uniformly on the four faces 16a-d, and extending along the whole length “L” of the block 11, from the upstream face 12 to the downstream face 13. Preferably, considering a group of two adjacent peripheral channels, the average thickness of the external wall of the outlet channel is greater than the average thickness of the external wall of the inlet channel. Preferably, the external face 60 of the external walls 44 and 54 of the peripheral channels 50 and 52 is substantially plane and the internal face 62 has the shape of a sinusoid or a fraction of sinusoid. More preferably, the external walls of the peripheral channels are conformed so that the four faces 16a-d of the block 11 are plane. Advantageously, this facilitates the handling and storage of the block, which is particularly useful if the fabrication is automated. The expression “internal channels” 14i is applied to the channels located inside the block 11, that is to say not comprising an external wall. Preferably, the average reinforcement of the peripheral wall of the block is arranged so that, in any transverse plane of section P, the flow cross sections of the peripheral inlet and outlet channels 14p are substantially identical to those of the internal inlet and outlet channels 14i, respectively. Advantageously, the application of a reinforcement therefore does not alter the volumes of the peripheral channels 14p and therefore the overall efficiency of the filter block 11. Preferably, the block according to the invention is one-piece and fabricated by extrusion using an appropriate die, by techniques known to a person skilled in the art. The “average reinforcement” of the peripheral wall is not added on to the filter block, but is of one piece with it. The stiffness of the filter block and its resistance to cracking are thereby advantageously improved. Furthermore, any risk of delamination of material forming the reinforcement is thereby advantageously eliminated. Finally, the fabrication of the filter block is thereby simplified. After assembly, a set of filter blocks according to the present invention forms a structure having local reinforcements. Preferably, these reinforcements are substantially uniformly distributed. After optional machining of this structure in order to form a filter body, a material reinforcement may be added at the periphery of the filter body. The risk of cracking is thereby further decreased. Preferably, the assembled blocks comprise peripheral walls 30 having “average reinforcements” (that is, considering the average of the thickness of the external walls of groups of two peripheral channels) that are uniformly distributed on the external surface of the blocks. The assembly of the blocks thereby produces an internal network of reinforcements inside the filter body, improving its resistance to cracking. In one embodiment of the invention, all the peripheral walls 30 of all the assembled blocks have a constant thickness at least 1.2 times larger than the average thickness of the internal walls of the internal channels of these blocks. After assembly, the peripheral reinforcements of the blocks thereby form, in transverse cross section, a grid considerably enhancing the cracking resistance compared to a filter body that does not have a reinforcement at its periphery. It is preferable for the reinforcement around the blocks to vary uniformly, preferably in a substantially sinusoidal manner, in order to increase the volume of the inlet channels compared to the volume of the outlet channels, as shown in FIG. 4. More preferably, irrespective of the embodiment, the thickness of the internal walls 56 of the peripheral channels is identical to the thickness of the walls of the internal channels. The efficiency of filtration across all the internal walls is thereby substantially the same, irrespective of the internal wall considered. The fabrication of the filter body is thereby also simplified, because the filter blocks can be assembled interchangeably at any position inside the filter body. Tests have been conducted to evaluate the cracking resistance of a filter body comprising 16 conventional filter blocks (FIG. 7) and of a filter body comprising 16 blocks of the same type but comprising, like the block shown in FIG. 4, a peripheral wall 30 reinforced according to the invention (FIG. 6). These two filter bodies were subjected to severe regeneration (corresponding to an engine speed of 120 km/hour, followed by transition to idling speed followed by post-injection) to 5 g/l on an engine test bench. The filter blocks were then cut longitudinally along a median plane. The longitudinal sections of four filter blocks are thus observed. A comparison of the longitudinal sections shown in FIGS. 6 and 7 clearly shows that the blocks according to the invention do not have any cracks, unlike the blocks according to the prior art, which have cracks “f” of a length generally greater than 0.5 mm and possibly extending along the whole length L of the block. Cracks are visible to the naked eye and under the microscope. As is clearly apparent now, the filter block with reinforced structure according to the invention has better resistance to cracking than the blocks of the prior art. Obviously, the present invention is not limited to the embodiment described and shown above, which is provided for illustration and is nonlimiting. Thus, all the groups of two adjacent peripheral channels do not necessarily have the same conformation. The reinforcement of the external walls of a group of two adjacent peripheral channels does not necessarily extend along the whole length L of the block. The reinforcement can also evolve, periodically or not, in a longitudinal or transverse plane. Advantageously, it is thereby possible to adapt the thickness of the reinforcing partition to the intensity of the local thermomechanical stresses. The transverse cross section of a channel could also evolve, periodically or not, along this channel. Nor do all the groups of two adjacent peripheral channels of the block comprise external walls having a reinforcement, even if this is preferable to improve the cracking resistance of the block. Preferably, at least the groups of two adjacent peripheral channels comprising a corner channel have a reinforcement according to the invention. The shape, particularly the cross section, dimensions and number of channels are nonlimiting. The cross section of the inlet channels could also be identical to that of the outlet channels. The peripheral channels may also have a different cross section from the internal channels of the same type, for example because they have been truncated during the machining of the block. The filter block 11 may have any shape. It is also possible to arrange a reinforcement on the surface of the block 11 by fixing additional material thereon by bonding, welding or any other known technique. The material added on may be identical or different to the material of the block 11. A material reinforcement is preferably applied, after extrusion and before sintering, to those faces of the block having been machined, for example, to the rounded external faces of the blocks 11a-11b. The method for fabricating a filter block according to the invention may thus comprise the following successive steps: a) extrusion of a ceramic material to form a porous honeycomb structure; b) application of a reinforcement of a material, identical or different from said ceramic material, to at least part of the external surface of said porous structure; and c) drying and sintering of said porous structure to obtain a filter block. Optionally, the porous structure may be dried between steps a) and b), and then machined, the material reinforcement being preferably applied to at least part of said external surface having been machined.

20060907

20110315

20070628

95648.0

B01D3920

ORLANDO, AMBER ROSE

BLOCK FOR FILTERING PARTICLES CONTAINED IN EXHAUST GASES OF AN INTERNAL COMBUSTION ENGINE

UNDISCOUNTED

ACCEPTED

B01D

ACCEPTED

Resin Tube-Equipped Quick Connector

There is provided a resin tube-equipped quick connector capable of connecting a fuel-transporting resin tube to a mating pipe without hindrance even if the resin tube has a small diameter. The quick connector 16 is constructed such that it includes a connector body 18 having a press-fitting portion 28, and a retainer 20. On the other hand, a press-fit undergoing portion 10A of the resin tube 10 into which the press-fitting portion 28 is to be press-fitted is beforehand expanded in tube diameter prior to the press-fitting, and the press-fitting portion 28 is press-fitted into the expanded press-fit undergoing portion 10A in a withdrawal-preventing condition to provide the quick connector 16 equipped with the resin tube 10.

1. A resin tube-equipped quick connector for connecting a fuel-transporting resin tube to a mating pipe, comprising a connector body, a retainer and a seal member; characterized in that: the connector body has a generally tubular shape as a whole, and has a retainer holding portion at one axial side thereof, and also has at the other side thereof a press-fitting portion which is press-fitted into the interior of the resin tube from one end thereof; the retainer is a member for being held in the retainer holding portion, and is engaged with a convex or concave pipe-side engagement portion, formed on an outer peripheral surface of the mating pipe and spaced from an axial insertion-side end thereof, so as to fix the inserted mating pipe in the axial direction; the seal member is mounted within the connector body at an inner region thereof disposed closer to the press-fitting portion than the retainer holding portion is disposed, and the seal member is brought into contact with an outer peripheral surface of an insertion end portion of the inserted mating pipe disposed closer to the distal end of the mating pipe than the pipe-side engagement portion is disposed, thereby forming an air-tight seal between the insertion end portion and an inner surface of the connector body; and a press-fit undergoing portion of the resin tube into which the press-fitting portion is to be press-fitted is beforehand expanded in tube diameter prior to the press-fitting, and the press-fitting portion is press-fitted in the tube diameter-expanded press-fit undergoing portion to be integrated therewith in a withdrawal-preventing condition. 2. The resin tube-equipped quick connector as claimed in claim 1, characterized in that the retainer is elastically deformable radially, and includes a retainer-side retaining engagement portion which can be fitted to a body-side retaining engagement portion, formed at the retainer holding portion of the connector body, from a radially-inward side to be retained and fixed in the axial direction, and at least one of an inner peripheral cam surface for elastically expanding the retainer when inserting the mating pipe into the retainer and an outer peripheral cam surface for elastically reducing the diameter of the retainer when inserting the retainer into the retainer holding portion. 3. (canceled) 4. The resin tube-equipped quick connector as claimed in claim 1 or 2, characterized in that a protector is fitted on the resin tube to cover an outer peripheral surface of the resin tube. 5. The resin tube-equipped quick connector as claimed in claim 1 or 2, characterized in that the resin tube has a multi-layer structure an inner layer of the resin tube is more excellent in gasoline resistance than an outer layer.

TECHNICAL FIELD This invention relates to a resin tube-equipped quick connector, and more specifically to a resin tube-equipped quick connector for connecting a fuel-transporting resin tube to a mating pipe. BACKGROUND ART A resin tube has heretofore been widely used for fuel transporting purposes, for example, for transporting fuel within a fuel tank to an engine. This resin tube is connected to a vehicle body-side mating pipe to form a piping system for fuel transporting purposes. Heretofore, for connecting this resin tube and the mating pipe together, a quick connector capable of effecting this connection with a one-touch operation has been used. A quick connector of this kind is disclosed, for example, in JP-A-11-201355. FIGS. 8A, 8B, 9A and 9B show a specific example of the construction of this quick connector. In these Figures, 200 denotes a resin tube, and 202 denotes a mating pipe to which this resin tube 200 is to be connected. An engagement convex portion (pipe-side engagement portion) 204, projecting in an annular shape, is formed on an outer peripheral surface of the mating pipe 202. 206 denotes the quick connector which includes a connector body (here made entirely of a resin) 208, a retainer 210, and O-rings 212 and a bushing 214 which serve as seal members. The connector body 208 has a retainer holding portion 216 at one axial side thereof, and also has a press-fitting portion 218 at the other side thereof. The press-fitting portion 218 is a portion for being press-fitted into the interior of the resin tube 200 in the axial direction, and annular projections 220 of a sawtooth-like cross-section, each having an acute-angled distal end, are formed respectively on a plurality of axially-different portions of an outer peripheral surface of this press-fitting portion. By press-fitting this press-fitting portion 218 into the interior of the resin tube 200, the connector body 208 is connected to this resin tube 200. At this time, the annular projections 220, formed on the outer peripheral surface of the press-fitting portion 218, bite into an inner surface of an end portion of the resin tube 200 bulgingly deformed as a result of the pressing fitting, thereby preventing the withdrawal of the resin tube 200. Incidentally, an annular groove is formed in the press-fitting portion 218, and an O-ring 222 is held in this groove, and this O-ring 222 forms an airtight seal between the press-fitting portion 218 and the resin tube 200. The retainer holding portion 216 is a portion for receiving the retainer 210 therein to hold the same, and the connector body 208 is connected to the mating pipe 202 through this retainer 210. A retaining engagement portion (body-side retaining engagement portion) 224 for retaining engagement with the retainer 210 is formed at a front end of this retainer holding portion 216. On the other hand, the retainer 210 is a resin-made member having a generally annular shape as a whole, and can be elastically deformed radially. An engagement recess portion (retainer-side engagement portion) 225 with which the engagement convex portion 204 of the mating pipe 202 can be engaged from a radially-inward side, as well as a retaining engagement groove (retainer-side retaining engagement portion) 226 which can be fitted to the retaining engagement portion 224 of the connector body 208 also from the radially-inward side to be retained in the axial direction, is provided on this retainer 210. This retaining engagement groove 226 is retainingly engaged with the retaining engagement portion 224 of the retainer holding portion 216, so that the retainer 210 is held in a fixed condition in the axial direction by this retainer holding portion 216. Further, an inner peripheral cam surface 228 and an outer peripheral cam surface 230, each having a tapering shape, are formed respectively on an inner peripheral surface and an outer peripheral surface of this retainer 210. When the mating pipe 202 is inserted into the interior of the retainer 210 in the axial direction, the inner peripheral cam surface 228 abuts against the engagement convex portion 204 to guide the movement thereof, and also causes the retainer 210 to make an expanding motion elastically as a whole by a cam effect in accordance with the movement of the engagement convex portion 204, thereby allowing the passage of the engagement convex portion 204. Then, when the engagement convex portion 204 reaches the position of the engagement recess portion 225, the retainer 210 is restored into its original shape as a whole, and simultaneously with this, the engagement convex portion 204 is fitted in the engagement recess portion 225, so that these portions are fixed to each other in the axial direction. On the other hand, when the retainer 210 is inserted into the retainer holding portion 216 of the connector body 208 in the axial direction, the outer peripheral cam surface 230 abuts against the retaining engagement portion 224 to cause the retainer 210 to make a diameter-reducing motion elastically as a whole, and causes the retaining engagement groove 226 to be retainingly engaged with the retaining engagement portion 224 with this diameter-reducing motion. Operating finger grips 231 are provided at a front end portion of the retainer 210, and by applying a force to the operating finger grips 231, the retainer 210 can be caused to make a diameter-reducing motion. In this quick connector 206, the retainer 210 is held in the retainer holding portion 216 of the connector body 208, and in this condition the mating pipe 202 is inserted into the interior of the retainer 210 in the axial direction. At this time, the retainer 210 is elastically forced open in an expanding direction by the engagement convex portion 204 of the mating pipe 202, and then makes a diameter-reducing motion when the engagement convex portion 204 reaches the engagement recess portion 225, and also the engagement convex portion 204 is engaged in the engagement recess portion 225. Incidentally, the retainer 210 may be beforehand attached to the mating pipe 202, and in this condition the mating pipe 202 may be inserted, together with the retainer 210, into the connector body 208. At this time, the retainer 210 once makes a diameter-reducing motion, and thereafter makes an expanding motion when the retaining engagement groove 226 reaches the position of the retaining engagement portion 224, so that the retaining engagement groove 226 is retainingly engaged with the retaining engagement portion 224. The O-rings 212 and the bushing 214 which serve as the seal members are mounted within the connector body 208 at a region deeper than the retainer holding portion 216, and are held therein. When the mating pipe 202 is inserted into the connector body 208, the O-rings 212 and the bushing 214 are brought into air-tight contact with an insertion end portion 232 of the mating pipe 202, that is, the outer peripheral surface of the insertion end portion 232 disposed closer to the distal end of the mating pipe than the engagement convex portion 204 is disposed, thereby forming an air-tight seal between the mating pipe 202 and the connector body 208. Although the two O-rings 212 are used in FIG. 8A, there are occasions when only one O-ring 212 is used in order to achieve a compact design as shown in FIG. 8B. As will be appreciated from the foregoing, in the connection using such quick connector 206, the resin tube 200 can be easily connected to the mating pipe 202 with a one-touch operation. For example, a tube, having an inner diameter of 6 mm and an outer diameter of about 8 mm, has been used as the above conventional resin tube 200, and it has been used in a piping system as shown in FIG. 10. In this piping system, fuel within a fuel tank 234 is supplied via a supply passage 238 under a constant pressure by a fuel pump 236, and this fuel is injected from an injector 240 into a cylinder 242 of an engine, and excess fuel is retuned to the fuel tank 234 via a return passage 244. From the viewpoint of the design of the piping system or from the viewpoint of cost reduction, it is considered preferable that the above pipes and resin tube should be lightweight and small in diameter. On the other hand, in recent years, there has been used a piping system (a so-called fuel returnless system) in which only a necessary amount of fuel, that is, an amount to be consumed, is supplied to the engine without supplying excess fuel from the fuel tank 234, and the returning of the excess fuel to the fuel tank 234 as in the piping system (a so-called fuel return system) of FIG. 10 is not carried out. In this fuel returnless system, only the necessary amount of fuel is supplied, and therefore when a resin tube, having the same inner diameter as that of the resin tube of the piping system of FIG. 10, is used, the accumulation of the fuel is liable to occur, and the accumulated fuel is vaporized within the piping by the atmosphere within an engine room, so that an engine speed is liable to become unstable. In this case, it is preferred to use a small-diameter resin tube with an inner diameter, for example, of not larger than 5 mm as the resin tube so that the accumulation of the fuel will not occur. With respect to so-called compact vehicles with a small engine displacement, such as a mini-vehicle, an automotive two-wheeled vehicle, an automotive three-wheeled vehicle and an ATV (All Terrain Vehicle), it is preferred to use a small-diameter resin tube with an inner diameter of not larger than 4 mm (for example, 3.5 mm) for the purpose of suppressing the accumulation of fuel, and it is more preferred to use a small-diameter resin tube with an inner diameter of not larger than 3 mm (for example, 2.5 mm). However, in the case of using such a small-diameter resin tube, when the press-fitting portion 218 of the quick connector 206 is press-fitted directly into the resin tube, this press-fitting operation fails halfway, and when trying to forcibly press-fit it, the resin tube is buckled, so that the resin tube cannot be connected to the mating pipe 202 by the use of such a quick connector 206. DISCLOSURE OF THE INVENTION This invention has been made in view of the background of the above circumstances, and its object is to provide a resin tube-equipped quick connector capable of connecting even such a small-diameter resin tube as described above to a mating pipe without hindrance. According to one aspect of the present invention, there is provided a resin tube-equipped quick connector for connecting a fuel-transporting resin tube to a mating pipe, comprising a connector body, a retainer and a seal member; characterized in that the connector body has a generally tubular shape as a whole, and has a socket-like retainer holding portion at one axial side thereof, and also has at the other side thereof a press-fitting portion which is press-fitted into the interior of the resin tube from one end thereof; the retainer is a member for being held in the retainer holding portion, and is engaged with a convex or concave pipe-side engagement portion, formed on an outer peripheral surface of the mating pipe and spaced from an axial insertion-side end thereof, so as to fix the inserted mating pipe in the axial direction; the seal member is mounted within the connector body at an inner region thereof disposed closer to the press-fitting portion than the retainer holding portion is disposed, and the seal member is brought into contact with an outer peripheral surface of an insertion end portion of the inserted mating pipe disposed closer to the distal end of the mating pipe than the pipe-side engagement portion is disposed, thereby forming an air-tight seal between the insertion end portion and an inner surface of the connector body; and a press-fit undergoing portion of the resin tube into which the press-fitting portion is to be press-fitted is beforehand expanded in tube diameter prior to the press-fitting, and the press-fitting portion is press-fitted in the tube diameter-expanded press-fit undergoing portion to be integrated therewith in a withdrawal-preventing condition. According to a second aspect of the present invention, the retainer is the member which is elastically deformable radially, and includes a retainer-side retaining engagement portion which can be fitted to a body-side retaining engagement portion, formed at the retainer holding portion of the connector body, from a radially-inward side to be retained and fixed in the axial direction, and at least one of an inner peripheral cam surface for elastically expanding the retainer when inserting the mating pipe into the retainer and an outer peripheral cam surface for elastically reducing the diameter of the retainer when inserting the retainer into the retainer holding portion. According to a third aspect of the present invention, the resin tube is a small-diameter one having an inner diameter of not larger than 5 mm. According to a fourth aspect of the invention, a protector is fitted on the resin tube to cover an outer peripheral surface of the resin tube. According to a fifth aspect of the present invention, the resin tube has such a structure that a plurality of layers are layered together in the radial direction, and the layer on the inner surface of the resin tube is formed by a resin layer which is more excellent in gasoline resistance than the layer on the outside thereof. As described above, in the present invention, the press-fit undergoing portion of the resin tube, that is, the press-fit undergoing portion into which the press-fitting portion of the connector body is to be press-fitted, is beforehand expanded in tube diameter prior to the press-fitting, and the press-fitting portion is press-fitted into this expanded press-fit undergoing portion in a withdrawal-preventing condition, thus beforehand providing the quick connector equipped with the resin tube. In the present invention, even the small-diameter resin tube can be easily connected to the mating pipe with a one-touch operation. Here, the retainer is the member which can be elastically deformed radially, and can be constructed to have the retainer-side retaining engagement portion for retaining engagement with the body-side (connector body-side) retaining engagement portion and the inner peripheral cam surface or the outer peripheral cam surface. The present invention is suitably applied particularly to the connection of the small-diameter resin tube having the inner diameter of not larger than 5 mm. The protector can be fitted on the resin tube to cover the outer peripheral surface thereof. By doing so, chipping due to a flying stone can be prevented, and also the resin tube can be prevented from damage when the resin tube is fixed to a predetermined portion of a vehicle body by a clamp. In the present invention, the resin tube can have such a structure that the plurality of layers are layered together in the radial direction, and the layer on the inner surface of the resin tube can be formed by a resin layer having an excellent gasoline resistance. With this layered structure of the resin tube, the layer on the inner surface thereof can impart a good gasoline resistance, and besides by providing the high-strength layer on the outside thereof, the strength of the resin tube itself can be increased to a high strength. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view showing one preferred embodiment of a resin tube-equipped quick connector of the present invention connected to a mating pipe. FIG. 2 is a view showing the quick connector of the above embodiment disassembled into a connector body and a retainer, and also showing a condition before the connector is connected to the mating pipe. FIG. 3 is a view showing the quick connector of the above embodiment disassembled into the connector body and the retainer, and also showing the mating pipe in a condition before the connection and a resin tube in a condition before the press-fitting. FIG. 4 is a view showing a press-fitting portion of the connector body and the resin tube of the above embodiment, showing a condition before they are press-fitted together. FIGS. 5A, 5B and 5C are views showing a method of forming a press-fit undergoing portion of the resin tube of the above embodiment. FIGS. 6A and 6B are views showing other embodiments of the present invention, respectively. FIG. 7 is a view showing a further embodiment of the present invention. FIGS. 8A and 8B are views showing one example of a conventional quick connector which is press-fitted in a resin tube, but is not yet connected to a mating pipe. FIGS. 9A and 9B are views showing important portions of the quick connector of FIGS. 8A and 8B. FIG. 10 is a conceptual view of a fuel return system. BEST MODE FOR CARRYING OUT THE INVENTION Next, an embodiment of the present invention will be described in detail with reference to the drawings. In FIGS. 1 to 3, 10 denotes a small-diameter resin tube used for transporting fuel, and it is used in a compact vehicle such as e.g. a mini-vehicle and an automotive two-wheeled vehicle, and is suitably used both in a fuel returnless system and a fuel return system in which excess gasoline is returned to a fuel tank. Here, an inner diameter d1 (see FIG. 4) is 2.5 mm, and an outer diameter d2 is 4 mm. In the present invention, the compact vehicle means an automotive two-wheeled vehicle, an automotive three-wheeled vehicle, an ATV (All Terrain Vehicle) and the like. 12 denotes a mating pipe (here made of metal) to which the resin tube 10 is to be connected, and an engagement convex portion (pipe-side engagement portion) 14, projecting in an annular shape, is formed on an outer peripheral surface of this mating pipe. 16 denotes the quick connector which includes a connector body (here made entirely of a resin) 18 having a generally tubular shape as a whole, a retainer 20, and O-rings 22 and a bushing 24 which serve as seal members. In this embodiment, the quick connector 16 (except the seal members) and the resin tube 10 are composed of polyamide. However, the material for the quick connector 16 and the resin tube 10 is suitably selected from the viewpoints of heat resistance, anti-fuel-penetrability, gasoline resistance (hardly swelling even upon contact with gasoline) and a cost. Specifically, polyamide series (PA11, PA12, P6, PA66, PPA, etc.,) and PPS are excellent in heat resistance, and polyester series (PBT, PET, PEN, etc.,) are excellent in anti-fuel-penetrability and gasoline resistance. POM, while securing heat resistance, anti-fuel-penetrability and gasoline resistance, is relatively inexpensive. The above materials are used as they are, and in other cases it is desirable to add glass fibers in order to enhance the strength or to add a nano-composite material such as clay in order to enhance the anti-fuel-penetrability. It is desirable that the material for the quick connector 16 be the same as the material for the resin tube 10, and with respect to the material for the resin tube 10, an alloyed elastomer is used in any of the above resin materials (the polyamide series, the polyester series, the POM, etc.,), and by doing so, in addition to the heat resistance and the anti-fuel-penetrability inherent to the resin, flexibility can be imparted to the resin tube 10. The connector body 18 has a socket-like retainer holding portion 26 at one axial side thereof, and also has a press-fitting portion (nipple portion) 28 at the other side thereof. The retainer holding portion 26 is a portion for receiving the retainer 20 therein to hold the same, and the connector body 18 is connected to the mating pipe 12 through this retainer 20. Open windows 30 and a front-end retaining engagement portion (body-side retaining engagement portion) 32 for retaining engagement with the retainer 20 are provided on this retainer holding portion 26. On the other hand, the retainer 20 is a resin-made member having a generally annular shape (here a generally cross-sectionally C-shape) as a whole, and can be elastically deformed radially. An engagement recess portion (retainer-side engagement portion) 34 with which the engagement convex portion 14 of the mating pipe 12 can be engaged from a radially-inward side, as well as a retaining engagement groove (retainer-side retaining engagement portion) 36 which can be fitted to the retaining engagement portion 32 of the connector body 18 also from the radially-inward side to be retained in the axial direction, are provided on this retainer 20. This retaining engagement groove 36 is retainingly engaged with the retaining engagement portion 32 of the retainer holding portion 26, so that the retainer 20 is held in a fixed condition in the axial direction by this retainer holding portion 26. Further, an inner peripheral cam surface 38 and an outer peripheral cam surface 40, each having a tapering shape, are formed respectively on an inner peripheral surface and an outer peripheral surface of this retainer 20. When the mating pipe 12 is inserted into the interior of the retainer 20 in the axial direction, the inner peripheral cam surface 38 abuts against the engagement convex portion 14 to guide the movement thereof, and also causes the retainer 20 to make an expanding motion elastically as a whole by a cam effect in accordance with the movement of the engagement convex portion 14, thereby allowing the passage of the engagement convex portion 14. Then, when the engagement convex portion 14 reaches the position of the engagement recess portion 34, the retainer 20 is restored into its original shape as a whole, and simultaneously with this, the engagement convex portion 14 is fitted in the engagement recess portion 34, so that these portions are fixed to each other in the axial direction. On the other hand, when the retainer 20 is inserted into the retainer holding portion 26 of the connector body 18 in the axial direction, the outer peripheral cam surface 40 abuts against the retaining engagement portion 32 to cause the retainer 20 to make a diameter-reducing motion elastically as a whole, and causes the retaining engagement groove 36 to be retainingly engaged with the retaining engagement portion 32 with this diameter-reducing motion. Operating finger grips 42 are provided at the front end portion of the retainer 20, and by applying a force to the operating finger grips 42, the retainer 20 can be caused to make a diameter-reducing motion. In this quick connector 16, the retainer 20 is held in the retainer holding portion 26 of the connector body 18, and in this condition the mating pipe 12 is inserted into the interior of the retainer 20 in the axial direction. At this time, the retainer 20 is elastically forced open in an expanding direction by the engagement convex portion 14 of the mating pipe 12, and then makes a diameter-reducing motion when the engagement convex portion 14 reaches the engagement recess portion 34, and also the engagement convex portion 14 is engaged in the engagement recess portion 34. Incidentally, the retainer 20 may be beforehand attached to the mating pipe 12, and in this condition the mating pipe 12 may be inserted, together with the retainer 20, into the connector body 18. At this time, the retainer 20 once makes a diameter-reducing motion, and thereafter makes an expanding motion when the retaining engagement groove 36 reaches the position of the retaining engagement portion 32, so that the retaining engagement groove 36 is retainingly engaged with the retaining engagement portion 32. The O-rings 22 and the bushing 24 which serve as the seal members are mounted within the connector body 18 at a region deeper than the retainer holding portion 26, and are held therein. When the mating pipe 12 is inserted into the connector body 18, the O-rings 22 and the bushing 24 are brought into air-tight contact with an insertion end portion 44 of the mating pipe 12, that is, the outer peripheral surface of the insertion end portion 44 disposed closer to the distal end of the mating pipe than the engagement convex portion 14 is disposed, thereby forming an air-tight seal between the mating pipe 12 and the connector body 18. The above press-fitting portion 28 is a portion for being press-fitted into the interior of the resin tube 10 in the axial direction. Annular projections 46 of a sawtooth-like cross-section, each having an acute-angled distal end, are formed respectively on a plurality of axially-different portions of an outer peripheral surface of this press-fitting portion. By press-fitting this press-fitting portion 28 into the interior of the resin tube 10 from one end thereof, the connector body 18 is connected to this resin tube 10. As shown in FIGS. 3 and 4, the end portion of the resin tube 10, that is, a press-fit undergoing portion 10A thereof into which the press-fitting portion 28 of the connector body 18 is to be press-fitted, is beforehand expanded in tube diameter prior to the press-fitting. The press-fitting portion 28 is press-fitted into the press-fit undergoing portion 10A of the expanded tube-shape in the axial direction, and by this press-fitting operation, the resin tube 10 and the connector body 18 are combined in an integrated manner in a withdrawal-preventing condition. In this condition, the resin tube 10 is connected to the mating pipe 12 through the quick connector 16. In this embodiment, an inner diameter d4 of the press-fitting portion 28 is 2.0 mm, and an outer diameter d5 of the annular projection 46 is 4.5 mm, and an outer diameter d6 of a root portion between the annular projections 46 and 46 is 3.5 mm. A height h of projecting of the annular projection 46 is 0.5 mm. On the other hand, an inner diameter d3 of the press-fit undergoing portion 10A is 3.5 mm. Namely, in this embodiment, the outer diameter d6 of the root portion of the press-fitting portion 28 between the annular projections 46 and 46 is the same as the inner diameter d3 of the press-fit undergoing portion 10A of the expanded tube-shape. Here, an axial length L of the press-fitting portion 28 is 14.5 mm. An axial length of the press-fit undergoing portion 10A is also L (14.5 mm). As a result, in this embodiment, the press-fitting portion 28 is press-fitted into the press-fit undergoing portion 10A of the resin tube 10, while radially outwardly bulging and deforming the press-fit undergoing portion 10A by an amount corresponding to the projecting height h of the annular projection 46, and after the press-fitting, the annular projections 46 are kept in a biting condition relative to an inner surface of the bulgingly-deformed press-fit undergoing portion 10A, thereby preventing the withdrawal of the resin tube 10. As described above, in this embodiment, the end portion of the resin tube 10, having the inner diameter smaller than the outer diameter d6 of the root portion of the press-fitting portion 28, is expanded in tube diameter to form the press-fit undergoing portion 10A having the inner diameter which is the same as the outer diameter d6 of the root portion, and is smaller than the outer diameter d5 of the annular projection 46. FIGS. 5A to 5C show one example of a method of expanding the end portion of the resin tube 10 to form the press-fit undergoing portion 10A. As illustrated, here, a beforehand-heated diameter-enlarging pin 48, having a shape corresponding to the shape of the inner surface of the press-fit undergoing portion 10A, is inserted into the end portion of the resin tube 10 in the axial direction. Namely, the diameter-enlarging pin 48 is inserted into the interior of the resin tube 10 while softening the end portion of the resin tube 10 by heat stored in the diameter-enlarging pin 48 and enlarging the diameter of this end portion. Thereafter, by withdrawing the diameter-enlarging pin 48 from the resin tube 10, the press-fit undergoing portion 10A of the expanded tube-shape can be formed at the end portion of the resin tube 10. However, this is merely one example, and various other methods can be used. As is clear from the foregoing, the quick connector 16 of this embodiment is of the type equipped with the resin tube 10, in which the resin tube 10 is beforehand integrated therewith in a withdrawal-preventing condition. At the time of connecting this resin tube 10 to the mating pipe 12, the resin tube 10 can be easily connected to the mating pipe 12 with the one-touch operation merely by inserting the mating pipe 12 into the interior of the quick connector 16 even if the resin tube 10 has the small diameter as in this embodiment. Next, FIGS. 6A and 6B show other embodiments of the present invention. FIG. 6A shows an example in which a protector 50 is fitted on a resin tube 10 to cover an outer peripheral surface thereof. A wall thickness of the protector 50 is, for example, about 0.5 mm to about 1.0 mm. In this embodiment, chipping due to a flying stone can be prevented, and also the resin tube 10 can be prevented from being damaged when the resin tube 10 is fixed to a predetermined portion of a vehicle body by a clamp. EPDM or a thermoplastic resin such as TPE can be used as the protector 50. Here, EPDM is advantageous in that it is inexpensive, and is excellent in weather resistance. On the other hand, the thermoplastic resin does not need curing after it is extruded as a protector material, and therefore it is excellent in productivity. Theses are given merely as one example, and other materials can, of course, be used. FIG. 6B shows the further embodiment. In this embodiment, a resin tube 10 is formed into a two-layer layered structure having an outer layer 10-1 and an inner layer 10-2. Here, the above-mentioned materials such as polyamide can be used for the outer layer 10-1. On the other hand, a resin with an excellent sour gasoline resistance, such as ETFE, is used to form the inner layer 10-2. Here, sour gasoline is gasoline whose sulfur content is increased by oxidation, and it exerts adverse effects such as the corrosion of metal parts and the deterioration of the resin tube. Therefore, in this embodiment, the resin tube 10 has the two-layer layered structure, and the outer layer 10-1 is composed of polyamide or the like having a pressure-withstanding strength, while the inner layer 10-2 is composed of a material more excellent in gasoline resistance (particularly sour gasoline resistance) than the outer layer 10-1. Therefore, the strength of the resin tube 10 itself can be increased to a high strength by the outer layer 10-1 while preventing the deterioration of the resin tube 10 due to sour gasoline or the like. FIG. 7 shows a still further embodiment of the present invention. In the above embodiments, the withdrawal prevention and the sealing are both effected merely by press-fitting the press-fitting portion 28 with the annular projections 46 into the press-fit undergoing portion 10A of the resin tube 10. In the embodiment of FIG. 7, however, an annular groove is formed in a press-fitting portion 28, and an O-ring 52 serving as a seal member is mounted in this groove, and the ability of sealing between the press-fitting portion 28 and the press-fit undergoing portion 10A is enhanced by this O-ring 52. The embodiments of the present invention have been described above in detail, but these are merely illustrated by way of examples, and in the present invention, the quick connector 16, including the above retainer 20 and retainer holding portion 26, can be constructed in various forms, and also the shape and dimensions of the press-fitting portion 28 of the connector body 18 and the shape and dimensions of the press-fit undergoing portion 10A of the resin tube 10 can be changed to various other shapes and dimensions than those of the above examples, and thus the present invention can be constructed in forms with various changes without departing from the spirit of the present invention.

<SOH> BACKGROUND ART <EOH>A resin tube has heretofore been widely used for fuel transporting purposes, for example, for transporting fuel within a fuel tank to an engine. This resin tube is connected to a vehicle body-side mating pipe to form a piping system for fuel transporting purposes. Heretofore, for connecting this resin tube and the mating pipe together, a quick connector capable of effecting this connection with a one-touch operation has been used. A quick connector of this kind is disclosed, for example, in JP-A-11-201355. FIGS. 8A, 8B , 9 A and 9 B show a specific example of the construction of this quick connector. In these Figures, 200 denotes a resin tube, and 202 denotes a mating pipe to which this resin tube 200 is to be connected. An engagement convex portion (pipe-side engagement portion) 204 , projecting in an annular shape, is formed on an outer peripheral surface of the mating pipe 202 . 206 denotes the quick connector which includes a connector body (here made entirely of a resin) 208 , a retainer 210 , and O-rings 212 and a bushing 214 which serve as seal members. The connector body 208 has a retainer holding portion 216 at one axial side thereof, and also has a press-fitting portion 218 at the other side thereof. The press-fitting portion 218 is a portion for being press-fitted into the interior of the resin tube 200 in the axial direction, and annular projections 220 of a sawtooth-like cross-section, each having an acute-angled distal end, are formed respectively on a plurality of axially-different portions of an outer peripheral surface of this press-fitting portion. By press-fitting this press-fitting portion 218 into the interior of the resin tube 200 , the connector body 208 is connected to this resin tube 200 . At this time, the annular projections 220 , formed on the outer peripheral surface of the press-fitting portion 218 , bite into an inner surface of an end portion of the resin tube 200 bulgingly deformed as a result of the pressing fitting, thereby preventing the withdrawal of the resin tube 200 . Incidentally, an annular groove is formed in the press-fitting portion 218 , and an O-ring 222 is held in this groove, and this O-ring 222 forms an airtight seal between the press-fitting portion 218 and the resin tube 200 . The retainer holding portion 216 is a portion for receiving the retainer 210 therein to hold the same, and the connector body 208 is connected to the mating pipe 202 through this retainer 210 . A retaining engagement portion (body-side retaining engagement portion) 224 for retaining engagement with the retainer 210 is formed at a front end of this retainer holding portion 216 . On the other hand, the retainer 210 is a resin-made member having a generally annular shape as a whole, and can be elastically deformed radially. An engagement recess portion (retainer-side engagement portion) 225 with which the engagement convex portion 204 of the mating pipe 202 can be engaged from a radially-inward side, as well as a retaining engagement groove (retainer-side retaining engagement portion) 226 which can be fitted to the retaining engagement portion 224 of the connector body 208 also from the radially-inward side to be retained in the axial direction, is provided on this retainer 210 . This retaining engagement groove 226 is retainingly engaged with the retaining engagement portion 224 of the retainer holding portion 216 , so that the retainer 210 is held in a fixed condition in the axial direction by this retainer holding portion 216 . Further, an inner peripheral cam surface 228 and an outer peripheral cam surface 230 , each having a tapering shape, are formed respectively on an inner peripheral surface and an outer peripheral surface of this retainer 210 . When the mating pipe 202 is inserted into the interior of the retainer 210 in the axial direction, the inner peripheral cam surface 228 abuts against the engagement convex portion 204 to guide the movement thereof, and also causes the retainer 210 to make an expanding motion elastically as a whole by a cam effect in accordance with the movement of the engagement convex portion 204 , thereby allowing the passage of the engagement convex portion 204 . Then, when the engagement convex portion 204 reaches the position of the engagement recess portion 225 , the retainer 210 is restored into its original shape as a whole, and simultaneously with this, the engagement convex portion 204 is fitted in the engagement recess portion 225 , so that these portions are fixed to each other in the axial direction. On the other hand, when the retainer 210 is inserted into the retainer holding portion 216 of the connector body 208 in the axial direction, the outer peripheral cam surface 230 abuts against the retaining engagement portion 224 to cause the retainer 210 to make a diameter-reducing motion elastically as a whole, and causes the retaining engagement groove 226 to be retainingly engaged with the retaining engagement portion 224 with this diameter-reducing motion. Operating finger grips 231 are provided at a front end portion of the retainer 210 , and by applying a force to the operating finger grips 231 , the retainer 210 can be caused to make a diameter-reducing motion. In this quick connector 206 , the retainer 210 is held in the retainer holding portion 216 of the connector body 208 , and in this condition the mating pipe 202 is inserted into the interior of the retainer 210 in the axial direction. At this time, the retainer 210 is elastically forced open in an expanding direction by the engagement convex portion 204 of the mating pipe 202 , and then makes a diameter-reducing motion when the engagement convex portion 204 reaches the engagement recess portion 225 , and also the engagement convex portion 204 is engaged in the engagement recess portion 225 . Incidentally, the retainer 210 may be beforehand attached to the mating pipe 202 , and in this condition the mating pipe 202 may be inserted, together with the retainer 210 , into the connector body 208 . At this time, the retainer 210 once makes a diameter-reducing motion, and thereafter makes an expanding motion when the retaining engagement groove 226 reaches the position of the retaining engagement portion 224 , so that the retaining engagement groove 226 is retainingly engaged with the retaining engagement portion 224 . The O-rings 212 and the bushing 214 which serve as the seal members are mounted within the connector body 208 at a region deeper than the retainer holding portion 216 , and are held therein. When the mating pipe 202 is inserted into the connector body 208 , the O-rings 212 and the bushing 214 are brought into air-tight contact with an insertion end portion 232 of the mating pipe 202 , that is, the outer peripheral surface of the insertion end portion 232 disposed closer to the distal end of the mating pipe than the engagement convex portion 204 is disposed, thereby forming an air-tight seal between the mating pipe 202 and the connector body 208 . Although the two O-rings 212 are used in FIG. 8A , there are occasions when only one O-ring 212 is used in order to achieve a compact design as shown in FIG. 8B . As will be appreciated from the foregoing, in the connection using such quick connector 206 , the resin tube 200 can be easily connected to the mating pipe 202 with a one-touch operation. For example, a tube, having an inner diameter of 6 mm and an outer diameter of about 8 mm, has been used as the above conventional resin tube 200 , and it has been used in a piping system as shown in FIG. 10 . In this piping system, fuel within a fuel tank 234 is supplied via a supply passage 238 under a constant pressure by a fuel pump 236 , and this fuel is injected from an injector 240 into a cylinder 242 of an engine, and excess fuel is retuned to the fuel tank 234 via a return passage 244 . From the viewpoint of the design of the piping system or from the viewpoint of cost reduction, it is considered preferable that the above pipes and resin tube should be lightweight and small in diameter. On the other hand, in recent years, there has been used a piping system (a so-called fuel returnless system) in which only a necessary amount of fuel, that is, an amount to be consumed, is supplied to the engine without supplying excess fuel from the fuel tank 234 , and the returning of the excess fuel to the fuel tank 234 as in the piping system (a so-called fuel return system) of FIG. 10 is not carried out. In this fuel returnless system, only the necessary amount of fuel is supplied, and therefore when a resin tube, having the same inner diameter as that of the resin tube of the piping system of FIG. 10 , is used, the accumulation of the fuel is liable to occur, and the accumulated fuel is vaporized within the piping by the atmosphere within an engine room, so that an engine speed is liable to become unstable. In this case, it is preferred to use a small-diameter resin tube with an inner diameter, for example, of not larger than 5 mm as the resin tube so that the accumulation of the fuel will not occur. With respect to so-called compact vehicles with a small engine displacement, such as a mini-vehicle, an automotive two-wheeled vehicle, an automotive three-wheeled vehicle and an ATV (All Terrain Vehicle), it is preferred to use a small-diameter resin tube with an inner diameter of not larger than 4 mm (for example, 3.5 mm) for the purpose of suppressing the accumulation of fuel, and it is more preferred to use a small-diameter resin tube with an inner diameter of not larger than 3 mm (for example, 2.5 mm). However, in the case of using such a small-diameter resin tube, when the press-fitting portion 218 of the quick connector 206 is press-fitted directly into the resin tube, this press-fitting operation fails halfway, and when trying to forcibly press-fit it, the resin tube is buckled, so that the resin tube cannot be connected to the mating pipe 202 by the use of such a quick connector 206 .

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a view showing one preferred embodiment of a resin tube-equipped quick connector of the present invention connected to a mating pipe. FIG. 2 is a view showing the quick connector of the above embodiment disassembled into a connector body and a retainer, and also showing a condition before the connector is connected to the mating pipe. FIG. 3 is a view showing the quick connector of the above embodiment disassembled into the connector body and the retainer, and also showing the mating pipe in a condition before the connection and a resin tube in a condition before the press-fitting. FIG. 4 is a view showing a press-fitting portion of the connector body and the resin tube of the above embodiment, showing a condition before they are press-fitted together. FIGS. 5A, 5B and 5 C are views showing a method of forming a press-fit undergoing portion of the resin tube of the above embodiment. FIGS. 6A and 6B are views showing other embodiments of the present invention, respectively. FIG. 7 is a view showing a further embodiment of the present invention. FIGS. 8A and 8B are views showing one example of a conventional quick connector which is press-fitted in a resin tube, but is not yet connected to a mating pipe. FIGS. 9A and 9B are views showing important portions of the quick connector of FIGS. 8A and 8B . FIG. 10 is a conceptual view of a fuel return system. detailed-description description="Detailed Description" end="lead"?

20070420

20120501

20070830

79940.0

F16L3700

DUNWOODY, AARON M

RESIN TUBE-EQUIPPED QUICK CONNECTOR

UNDISCOUNTED

ACCEPTED

F16L

ACCEPTED

Wafer with optical control modules in ic fields

In a wafer (1) with a number of exposure fields (2), each of which exposure fields comprises a number of lattice fields (3) with an IC (4) located therein, two groups (5, 7) of saw paths (6, 8) are provided and two control module fields (A1, A2, B1, B2, C1, C2, D1, D2) are assigned to each exposure field, each of which control module fields contains at least one optical control module (OCM-A1, OCM-A2, OCM-B1, OCM-B2, OCM-C1, OCM-C2, OCM-D1, OCM-D2) and lies within the exposure field in question and comprises a plurality of control module field sections (A11, A12 . . . AIN and A21, A22 . . . A2N and B11, B12 . . . B1N and B21, B22 . . . B2N and C1N and C2N and D1N and D2N) and is distributed among several lattice grids (3), wherein each control module field section (A11 to D2N) is located in a lattice field and contains at least one control module component (10,11,12,13,14,15,16,17,18).

1. A wafer which wafer comprises a number of exposure fields and which wafer comprises a number of lattice fields in each exposure field, wherein each lattice field contains an IC and each IC contains a plurality of IC components, and which wafer comprises a first group of first saw paths and a second group of second saw paths wherein all of the first saw paths of the first group run parallel to a first direction and have a first path width and wherein all of the second saw paths of the second group run parallel to a second direction intersecting the first direction and have a second path width and wherein the first saw paths and the second saw paths are provided and designed for a subsequent segregation of the lattice fields and the ICs contained therein, and wherein in each exposure field at least two control module fields are provided, each of which control module fields runs parallel to the first direction and thus to the first saw paths and contains at least one optical control module, wherein each control module contains a plurality of control module components, and wherein each control module field within an exposure field comprises a plurality of control module field sections and is distributed among several lattice grids, and wherein each control module field section is located in a lattice field and contains at least one control module component 2. A wafer as claimed in claim 1, wherein each control module field section in each lattice field is located in the same position, in which position the IC in the lattice field in question does not have any IC components. 3. A wafer as claimed in claim 1, wherein the at least two control module fields of each exposure field are arranged at an average distance from one another extending in the second direction, which average distance is equal to at least a quarter of the side length of a side of the exposure field which extends in the second direction 4. Wafer as claimed in claim 3, wherein the average distance is equal to the whole side length of a side of the exposure field which area extends in the second direction minus the side length of a side of a lattice field which extends in the second direction

The invention relates to a wafer, which wafer comprises a number of exposure fields and which wafer comprises a number of lattice fields in each exposure field, wherein each lattice field contains an IC and each IC contains a plurality of IC components, and which wafer comprises a first group of first saw paths and a second group of second saw paths, wherein all of the first saw paths of the first group run parallel to a first direction and have a first path width and wherein all of the second saw paths of the second group run parallel to a second direction intersecting the first direction and have a second path width, and wherein the first saw paths and the second saw paths are provided and designed for a subsequent segregation of the lattice fields and the ICs contained therein, and wherein in each exposure field at least two control module fields are provided, each of which control module fields runs parallel to the first direction and thus to the first saw paths and contains at least one optical control module, wherein each control module contains a plurality of control module components. Such a wafer according to the design described in the first paragraph is known, for instance, from patent specification U.S. Pat. No. 6,114,072 A, wherein the design described with reference to FIG. 21 deserves particular attention. The known wafer is so designed that a first control module field of each exposure field immediately adjoins a first edge of the exposure field in question and that a second control module field of each exposure field immediately adjoins the second edge of the exposure field in question. Each control module field lies in a half of a first saw path. As a result of this design, a first control module field and a second control module field of the two exposure fields in question lie between two rows of lattice fields of two exposure fields, which are arranged immediately adjacent to one another in the second direction, so that the distance extending in the second direction between two rows of lattice fields of two exposure fields, which are arranged immediately adjacent to one another in the second direction, is determined by the double value of the width of a control module field. Owing to the fact that two such first control module fields lie between two rows of lattice fields of two exposure fields, which are arranged immediately adjacent to one another in the second direction, and of the fact that each control module field lies in a half of a first saw path and two adjacent control module fields, therefore determine the width of a whole first saw path and that all parallel saw paths of a wafer, including the first saw paths between the lattice fields within each exposure field, which run parallel to the first direction, must be of equal width if the stepper steps required in the production of the wafer and the production of the ICs are to be completed precisely in the testing, sawing and assembly phases, the first saw paths running between the ICs of each exposure field also have to have the double width of the control module fields. As a result, a not insignificant proportion of the wafer surface is required for the totality of all saw paths, which constitutes undesirable waste. It is an object of the invention to eliminate the facts described above and to create an improved wafer. To solve this problem, features according to the invention are provided in a wafer according to the invention, so that a wafer according to the invention can be characterized in the following way: Wafer, which wafer comprises a number of exposure fields and which wafer comprises a number of lattice fields in each exposure field, wherein each lattice field contains an IC and each IC contains a plurality of IC components, and which wafer comprises a first group of first saw paths and a second group of second saw paths, wherein all of the first saw paths of the first group run parallel to a first direction and have a first path width and wherein all of the second saw paths of the second group run parallel to a second direction intersecting the first direction and have a second path width, and wherein the first saw paths and the second saw paths are provided and designed for a subsequent segregation of the lattice fields and the ICs contained therein, and wherein in each exposure field at least two control module fields are provided, each of which control module fields runs parallel to the first direction and thus to the first saw paths and contains at least one optical control module, wherein each control module contains a plurality of control module components, and wherein each control module field located within an exposure field comprises a plurality of control module field sections and is distributed among several lattice fields, and wherein each control module field section is located in a lattice field and contains at least one control module component. By the provision of the features according to the invention, it can be achieved in a simple way and without any additional costs that there is no control module field between two exposure fields immediately adjacent to one another in the second direction, so that the distance extending in the second direction between two exposure fields is determined only by the width of a first saw path. As a result, the width of the saw paths provided between adjacent lattice fields is expediently likewise determined by the width of a first saw path only, so that the surface area of a wafer according to the invention can be utilized much better than that of a wafer according to prior art. In a wafer according to prior art, the width of the first saw paths running between the lattice fields and of the control module fields are known to lie in the range between 90 μm and 120 μm, whereas in a wafer according to the invention—depending on the wafer manufacturing technology and the wafer process technology used—the widths of the first saw paths and of the control module fields are or can be reduced to values between 80 μm and 20 μm or 15 μm or 10 μm respectively, wherein particularly thin saw blades are used for widths between 80 μm and 50 μm and the very small widths are subject to the precondition that so-called laser saws are used for the subsequent segregation of the lattice fields or ICs, wherein so-called “red lasers” or “blue lasers” are used. The technologies known among experts under the names of “stealth dicing” and “scribe & break dicing” can also be applied. Added to this is the advantage that virtually the whole of all lattice fields can be and is used to implement at least one IC each and only a very small area in all lattice fields, i.e. in each IC of each lattice field, is required for the implementation of the control modules. In a wafer according to the invention, it has been found to be particularly advantageous if each control module field section in each lattice field is located in the same position, in which position the IC in the lattice field in question does not have any IC components. In this way, an area in a lattice field, which area is not used for the implementation of the IC contained in said lattice field, which is, however, too small for the implementation of a complete control module, can expediently be used to implement at least one control module component. In a wafer according to the invention, it has further been found to be very advantageous if the at least two control module fields of each exposure field are arranged at an average distance from one another extending in the second direction, which average distance is equal to at least a quarter of the side length of a side of the exposure field which extends in the second direction. In this way, the distance between the at least two control module fields of each exposure field is large enough to fulfill the minimum requirements of manufacturing accuracy, which is advantageous with regard to the precise execution of the process steps executable or executed while using the optical control modules. In a wafer according to the invention, the average distance can be equal to slightly more than a quarter (¼) or slightly less or slightly more than a half (½) or slightly less or slightly more than three quarters (¾) of the side length of a side of the exposure field which extends in the second direction. It has, however, been found to be particularly advantageous if the average distance is equal to the whole side length of a side of the exposure field which extends in the second direction minus the side length of a side of a lattice field which extends in the second direction. This ensures as large a distance as possible between the at least two control module fields of each exposure field, which is advantageous with regard to the highly precise execution of the process steps executable or executed while using the optical control modules. It is advantageous if only two control module fields are provided in each exposure field and if these two control module fields are located at as large a distance as possible from one another. This ensures a high precision in the process steps executed while utilizing the control modules or the control module components. It can be mentioned that three or four control module fields can be provided in each exposure field, with their control module field sections being distributed among ICs in the exposure field in question. It can further be mentioned that each exposure field can have the shape of a triangle, with a control module field located near each corner region or a control module field being provided near two corner regions only. It should finally be mentioned that the use of the measures according to the invention has been or is found to be most useful if the wafer is provided and used for the implementation of ICs with an IC surface area of approximately 0.5 to 10.0 mm×0.5 to 10.0 mm, i.e. approximately 0.25 to 100.0 mm2. It is further useful if the exposure fields are approximately 21.0 mm×21.0 mm in size and if approximately 320 to 128 000 ICs (chips) are implemented on the wafer if its diameter is, for instance, 8.0 inches, amounting to a usable area of approximately 32 000 mm2 for ICs. The measures according to the invention can, however, also be applied in wafers with a diameter of 4.0, 5.0, 6.0 and 12.0 inches. These and other aspects of the invention are apparent from and will be elucidated with reference to the embodiments described hereinafter. The invention is described further below with reference to an embodiment illustrated in the drawings, to which embodiment the invention is, however, not restricted. In the drawings, FIG. 1 is a diagrammatic top view of a wafer according to an embodiment of the invention. FIG. 2 is a section of the wafer according to FIG. 1, which is considerably enlarged compared to FIG. 1. FIG. 1 shows a wafer 1. The wafer 1 has semi-conductor characteristics in the known way. The wafer 1 is based on silicon. The wafer 1 can, however, alternatively based on a polymer to obtain so-called polymer ICs with the aid of the wafer. The wafer 1 comprises a number of exposure fields 2. In FIG. 1, the exposure fields 2 are shown without the components they contain. FIG. 2 only shows two complete exposure fields 2 by means of broken lines. As FIG. 2 illustrates, the wafer 1 has a number of intersecting and lattice-like saw path sections 6A, 6B, 6C, 8A, 8B 8C, 8D in each exposure field 2. The wafer 1 further comprises a number of lattice fields 3 between the saw path sections 6A, 6B, 6C, 8A, 8B 8C, 8D, wherein each lattice field 3 contains one IC 4. Each IC 4 includes a plurality of IC components as has been known for a long time. The IC components are not shown in FIGS. 1 and 2. Small areas of each IC 4 do not contain any IC components. The wafer 1 comprises a first group 5 of first saw paths 6 and a second group 7 of second saw paths 8. All of the first saw paths 6 of the first group 5 run parallel to a first direction X indicated by a dot-dash line in FIG. 1. All of the second saw paths 8 of the second group 7 run parallel to a second direction Y intersecting the first direction X and likewise indicated by a dot-dash line in FIG. 1. In the wafer 1, the first direction X and the second direction Y intersect at right angles. This is, however, not absolutely necessary, and the two directions X and Y can intersect at an angle other than 90°, for instance at an angle of 85°, 80°, 75° or 70°. All of the first saw paths 6 have a first path width W1. All of the second saw paths 8 have a path width W2. In the wafer 1, the two path widths W1, W2 are different, the first path width W1 being less than the second path width W2. This is, however, not absolutely necessary, and the two path widths W1 and W2 may be equal, which is usually preferred. It is also possible to choose a first path width W1 larger than the second path width W2. The first saw paths 6 comprise several first saw path sections 6A, 6B, 6C arranged consecutively in the first direction X, while the second saw paths 8 comprise several second saw path sections 8A, 8B, 8C, 8D arranged consecutively in the second direction Y. The first saw paths 6 and the second saw paths 8 are provided and designed for the subsequent segregation of the lattice fields 3 and thus of the ICs contained therein. With regard to the saw paths, it should here be mentioned that in a wafer wherein the first saw paths and the second saw paths intersect at an angle other than 90°, a third group of third saw paths can be provided, resulting in a wafer with triangular lattice fields and triangular ICs. In this case, the design can be so chosen that the saw paths of the three groups intersect at an angle of 60°, giving the lattice fields and the ICs the planar shape of an equilateral triangle. This is, however, not necessary, because other angular relationships and thus other triangle shapes are feasible as well. The first, second and third saw paths can have equal or different path widths. The wafer 1 comprises control module fields, each of which contains an optical control module. The provision of optical control modules on a wafer as such has been known for some time. These optical control modules contain square or rectangular interference fields detectable, depending on size, either by the naked eye or by computer-aided detection devices and used for mask adjustment and layer thickness testing. The design of the control module fields and the optical control modules contained therein in the wafer 1 according to FIG. 1 is described in detail below with reference to FIG. 2. In the wafer 1 according to FIGS. 1 and 2, two control module fields A1, A2, B1, B2, C1, C2, D1, D2 are assigned to each exposure field 2. Each of these control module fields A1, A2, B1, B2, C1, C2, D1, D2 runs parallel to the first direction and thus to the first saw paths 6. Each of the control module fields A1, A2, B1, B2, C1, C2, D1, D2 contains an optical control module. An optical control module of this type has a known three-dimensional structure, because a control module component is implemented in each process step, with the result that at least a control module component of an optical control module which is implemented in a last process step is visible from outside of the wafer 1 or detectable by means of a computer-based detection device, whereas any control module components of a control module which have been implemented in a process step executed before the last process step are not visible or detectable from outside of the wafer. In FIG. 2, the control modules in the control module fields A1, A2, B1, B2, C1, C2, D1, D2 are identified by the reference numbers OCM-A1, OCM-A2, OCM-B1, OCM-B2, OCM-C1, OCM-C2, OCM-D1, OCM-D2. Reference numbers for the control module components are only entered for the optical control module OCM-B1 in FIG. 2. The control module components located deeper inside the wafer 1 and therefore less visible from outside of the wafer 1 and indicated by broken lines have been given the reference numbers 10, 11, 12, 13, 14 and 15. The three control module components located higher in the wafer 1 and therefore visible from outside of the wafer 1 have been given the reference numbers 16, 17 and 18. As FIG. 2 indicates, the two control module fields A1, A2, B1, B2, C1, C2, D1, D2 of each exposure field 2 are located within the exposure field 2 in question, and each control module field A1, A2, B1, B2, C1, C2, D1, D2 within an exposure field 2 comprises several control module field sections A11, A12, . . . A1N and A21, A22, . . . A2N and B11, B12, . . . B1N and B21, B22, . . . B2N and C1N and C2N and D1N and D2N. Each control module field section A11 to D2N is located in a lattice field 3. Each control module field section A11 to D2N contains at least one control module component 10, 11, 12, 13, 14, 15, 16, 17, 18. FIG. 2 shows that each control module field section A11 to D2N contains the same number of control module components, i.e. three control module components. This is not absolutely necessary, because the control module field sections A11 to D2N can contain different numbers of control module components, for instance only one or two control module components, but also four, five, six or more such control module components. In the wafer 1, the control module field sections A11 to D2N are so arranged that each control module field section A11 to D2N is located in the same position in each lattice field 3. In this position, the IC 4 in the lattice field 3 in question does not have any IC components. In other words, a wafer area not required for the implementation of the IC 4 in question is used to implement the control module components contained in each control module field section A11 to D2N. As FIG. 2 further shows, the control module fields A1, A2, B1, B2, C1, C2, D1, D2 of each exposure field 2, which are arranged consecutively in the second direction Y, are, if viewed in the second direction Y, arranged at an average distance K from one another in the second direction Y. In the present case, this average distance K is equal to the whole side length L of a side M of an exposure field 2 which extends in the second direction Y minus the side length N of a side P of a lattice field 3 which extends in the second direction Y. Though the average distance K may be smaller, it has been found to be advantageous if the average distance K is equal to at least a quarter of the side length L of a side K of an exposure field 2 which extends in the second direction Y. The wafer 1 offers the great advantage that each control module field A1, A2, B1, B2, C1, C2, D1, D2 is located within an exposure field 2, so that no space is required for the control module fields A1, A2, B1, B2, C1, C2, D1, D2 outside of the exposure fields 2, with the result that the saw paths 6 running parallel to the first direction X can be designed particularly narrow and are therefore designed narrow. In a wafer 1 according to FIGS. 1 and 2, all saw paths 6 have a first path width W1 of 50 μm. The first path width may alternatively be 60 μm or 70 μm or 40 μm or even less, for instance 30 μm or 20 μm or in future technologies even only 10 μm, because the first path width W1 is in the present case exclusively determined by the cutting or separation equipment with which the wafer is cut or divided to segregate the ICs. The wafer 1 further offers the advantage that no lattice fields 3 are required for the implementation of the control modules OCM-A1, OCM-A2, OCM-B1, OCM-B2, OCM-C1, OCM-C2, OCM-D1, OCM-D2, but the whole area of an exposure field 2 is available for the implementation of ICs 4, allowing for the optimum utilization of the whole wafer surface for the production of ICs 4. With regard to the control modules OCM-A1, OCM-A2, OCM-B1, OCM-B2, OCM-C1, OCM-C2, OCM-D1, OCM-D2, is should finally be mentioned that the control modules OCM-A1, OCM-A2, OCM-B1, OCM-B2, OCM-C1, OCM-C2, OCM-D1, OCM-D2 preferably have the dimensions stated below, i.e. a dimension of approximately 40.0 μm in the first direction X and a dimension of approximately 40.0 μm in the second direction Y. Since actual dimensions depend on the technology used, smaller dimensions, such as approximately 30.0 μm or 20.0 μm, are achievable in highly modern technologies and developing technologies. In the wafer 1, the surface areas of the ICs 4 are slightly smaller than those of the lattice fields 3. The surface areas of the ICs 4 may, however, be equal to the surface areas of the lattice fields if preferred. In a wafer according to the invention, three, four, five, six or more control module fields can be provided instead of a total of two control module fields per exposure field. The number of control modules is determined by the technology used in the production of the wafer and of the ICs located thereon. It can finally be mentioned that the wafer 1 further includes so-called process control modules (PCMs) located in the second saw paths 8 running parallel to the second direction Y. A solution as described in patent specification WO 02/069.389 A2 can, however, be provided as an alternative.

20060622

20081125

20070712

93491.0

H01L2302

NGUYEN, CUONG QUANG

WAFER WITH OPTICAL CONTROL MODULES IN IC FIELDS

UNDISCOUNTED

ACCEPTED

H01L

ACCEPTED

Acidic quinoline derivatives and their use for the prevention and/or treatment of hyperglycaemia-related pathologies

The invention relates to compounds of the general formula (I): in which R1, R2, X, and A are as defined in claim 1. These compounds can be used in the treatment of hyperglycaemia-related pathologies.

1. Use of a derivative of the general formula (I) for the preparation of a medicament for the prevention of and/or treating hyperglycaemia-related pathologies: in which: X represents, independently of each other, a carbon atom, optionally substituted by a group chosen from: alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, heteroaryl, —CN, halogen, —O-aryl, —O-heteroaryl, cycloalkyl, heterocyclyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2, or two adjacent carbon atoms may form an aromatic ring fused to the aryl nucleus, or a nitrogen, oxygen or sulfur atom; R1 and R2, which may be identical or different, independently represent a group chosen from: Hydrogen, alkyl, alkenyl, alkynyl, each optionally and independently substituted by one or more of the following groups: —CN, halogen, aryl, biaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, cycloalkyl, heterocycloalkyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2; in which: aryl is optionally and independently substituted by one or more groups chosen from: —CN, halogen, aryl, alkyl, —O-alkyl, -alkyl-C(═O)O-alkyl, -alkyl-C(═O)OH, —O-alkylaryl, heterocycloalkyl, —NRR′, —OH, —S(O)pR, in which p represents 0, 1 or 2; —O-aryl, perhaloalkyl, —COOH, COOR; heteroaryl is optionally and independently substituted by one or more groups chosen from halogen, —COOH, —COOR and heterocycloalkyl; heterocycloalkyl is optionally and independently substituted by one or more alkyl or ═O; cycloalkyl or heterocycloalkyl, each optionally and independently substituted by alkyl or alkoxy; aryl or heteroaryl, each optionally and independently substituted by one or more groups chosen from —CN, halogen, aryl, alkyl, —O-alkyl, -alkyl-C(═O)O-alkyl, —O-alkylaryl, heterocycloalkyl; —NRR′, —OH, —S(O)pR, in which p represents 0, 1 or 2; —O-aryl, perhaloalkyl, —COOH, COOR; R and R′ are chosen from H and alkyl; represents a single bond or a double bond; and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. 2. Use according to claim 1, for which, in formula (I), each of the X represents a carbon atom, optionally substituted by a halogen atom. 3. Use according to claim 1, in which the carbon in position 6 of the quinoline ring is substituted by a halogen atom. 4. Use according to claim 1, for which the halogen substituent of X is a fluorine atom. 5. Use according to claim 1, for which R1 and/or R2 independently represent(s) a hydrogen atom, alkyl, alkenyl, alkynyl, optionally substituted by —CN, halogen, —O-aryl, —O-heteroaryl, cycloalkyl, heterocycloalkyl, —COOH, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, biaryl or aryl, in which aryl is optionally substituted by —CN, halogen, aryl, alkyl, —O-alkyl, -alkyl-C(═O)O-alkyl, alkylCOOH, —O-alkylaryl or heterocycloalkyl. 6. Use according to claim 1, for which R1 represents alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylaryl, aryl or heteroaryl, which are optionally substituted, as defined in claim 1. 7. Use according to claim 1, for which R1 represents alkyl or alkenyl, optionally substituted as defined in claim 1. 8. Use according to claim 1, for which R1 represents alkyl, optionally and independently substituted by one or more groups chosen from: —CN, aryl, heterocycloalkyl, biaryl, halogen, —C(═O)-aryl, —O-aryl, —C(═O)-alkyl, cycloalkyl, —C(═O)-alkyl, —COOH, —O-heteroaryl, —C(═O)NRR′, —C(═O)-cycloalkyl, —O-heterocycloalkyl; in which aryl is optionally and independently substituted by one or more halogen, —CN, —O-alkylaryl, aryl, alkyl, —O-alkyl, heterocycloalkyl, -alkyl-C(═O)—OH or -alkyl-C(═O)O-alkyl; heteroaryl is optionally substituted by heterocycloalkyl, halogen or —COOH. heterocycloalkyl is optionally and independently substituted by one or more groups chosen from ═O and alkyl. 9. Use according to claim 1, for which R1 represents alkyl or alkenyl, in which the carbon α to the oxygen atom is substituted by —COOH, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl or —C(═O)NRR′, in which alkyl and aryl are optionally substituted as in claim 1, and RR′ are defined as in claim 1. 10. Use according to claim 1, for which R1 represents alkyl or alkenyl, each optionally substituted by one or more substituents chosen from halogen, —O-heteroaryl or —C(═O)-aryl, in which aryl is optionally substituted by one or more —O-alkyl and heteroaryl is optionally substituted by one or more —COOH or halogen. 11. Use according to claim 1, for which R2 represents a hydrogen atom or an alkyl group. 12. Use according to claim 1, for which R2 represents a methyl radical. 13. Use according to claim 1, for which R and R′ represent a hydrogen atom or a methyl or ethyl radical. 14. Use according to claim 1, for which the compounds of the formula (I) are represented by the general formula (II) below: in which R1 and R2 are as defined in claim 1; R3 and R4, which may be identical or different, independently represent groups chosen from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, heteroaryl, —CN, halogen, —O-aryl, —O-heteroaryl, cycloalkyl, heterocyclyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)cyclo-alkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′ and —S(O)pR, in which p represents 0, 1 or 2; or R3 and R4 may together also form a heterocycle adjacent to the phenyl ring and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. 15. Use according to claim 14, for which R3 and R4 represent H, —O-alkyl and/or a halogen atom or R3 and R4 together form a heterocycle adjacent to the phenyl ring. 16. Use according to claim 14, for which R3 and R4 represent the ring —O—(CH2)n—O—, n being an integer ranging from 1 to 4. 17. Use according to claim 15, for which R3 and R4 represent, respectively, a fluorine atom in position 6 and a hydrogen atom. 18. Use according to claim 1, for which the compounds of the general formula (I) are chosen from: methyl 4-(1,3-benzothiazol-2-ylmethoxy)-6-fluoroquinoline-2-carboxylate methyl 4-[(4-bromo-2-fluorobenzyl)oxy]-6-fluoroquinoline-2-carboxylate methyl 4-ethoxy-6-fluoroquinoline-2-carboxylate methyl 4-[(4-bromo-2-fluorobenzyl)oxy]-6-methoxyquinoline-2-carboxylate methyl 6-fluoro-4-[(3-methylbut-2-en-1-yl)oxy]quinoline-2-carboxylate methyl 4-[(2′-cyanobiphenyl-4-yl)methoxy]-6-fluoroquinoline-2-carboxylate methyl 4-(cyanomethoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(2-chloroethoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(2-amino-2-oxoethoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(allyloxy>6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-(pentyloxy)quinoline-2-carboxylate methyl 4-[2-(4-chlorophenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-(2-oxo-2-phenylethoxy)quinoline-2-carboxylate methyl 6-fluoro-4-[2-(4-fluorophenoxy)ethoxy]quinoline-2-carboxylate methyl 6-fluoro-4-(2-phenylethoxy)quinoline-2-carboxylate methyl 6-fluoro-4-(2-phenoxyethoxy)quinoline-2-carboxylate methyl 6-fluoro-4-(3-phenylpropoxy)quinoline-2-carboxylate methyl 4-(2-biphenyl-4-yl-2-oxoethoxy)-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(4-methylphenyl)-2-oxoethoxy]quinoline-2-carboxylate methyl 6-fluoro-4-[2-(4-methoxyphenyl)-2-oxoethoxy]quinoline-2-carboxylate methyl 4-[2-(1-adamantyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(4-fluorophenyl)-2-oxoethoxy]quinoline-2-carboxylate methyl 4-[2-(3,4-dichlorophenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(3-methoxyphenyl)-2-oxoethoxy]quinoline-2-carboxylate methyl 4-[4-(4-chlorophenoxy)butoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(3-fluorophenoxy)ethoxy]quinoline-2-carboxylate methyl 4-[2-(4-bromophenoxy)ethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-{[5-(4-fluorophenoxy)pentyl]oxy}quinoline-2-carboxylate methyl 4-[2-(4-cyanophenoxy)ethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-{2-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]ethoxy}quinoline-2-carboxylate methyl 6-fluoro-4-{2-[4-(3-methoxy-3-oxopropyl)phenoxy]ethoxy}quinoline-2-carboxylate methyl 6-fluoro-4-[2-(1-naphthyloxy)ethoxy]quinoline-2-carboxylate methyl 6-fluoro-4-[2-(2-methoxyphenoxy)ethoxy]quinoline-2-carboxylate methyl 4-{2-[2-(benzyloxy)phenyl]-2-oxoethoxy}-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(2-naphthyloxy)ethoxy]quinoline-2-carboxylate methyl 4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]-6-fluoroquinoline-2-carboxylate methyl 4-[1-(ethoxycarbonyl 3-phenylpropoxy]-6-fluoroquinoline-2-carboxylate methyl 4-[2-(2,3-dimethylphenoxy)ethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-{2-[4-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethoxy}quinoline-2-carboxylate methyl 4-{2-[4-(benzyloxy)phenyl]-2-oxoethoxy}-6-fluoroquinoline-2-carboxylate methyl 4-[2-(3,4-dimethoxyphenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 4-(3-chloropropoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(3-chloro-2-methylpropoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(1-methylpropoxy)-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[(1-methylhexyl)oxy]quinoline-2-carboxylate methyl 4-[2-(2,4-dimethoxyphenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 4-(3,3-dimethyl-2-oxobutoxy)-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-(3-phenoxypropoxy)quinoline-2-carboxylate methyl 4-[(4-bromo-2-fluorobenzyl)oxy]-6-fluoroquinoline-2-carboxylic acid methyl 4-(1,3-benzothiazol-2-ylmethoxy)-6-fluoroquinoline-2-carboxylic acid 4-ethoxy-6-fluoroquinoline-2-carboxylic acid 4,4′-[(2E)-but-2-ene-1,4-diylbis(oxy)]bis(6-fluoroquinoline-2-carboxylic acid) 6-fluoro-4-[(3-methylbut-2-en-1-yl)oxy]quinoline-2-carboxylic acid 4-[(2′-cyanobiphenyl-4-yl)methoxy]-6-fluoroquinoline-2-carboxylic acid sodium 4-[(4-bromo-2-fluorobenzyl)oxy]-6-methoxyquinoline-2-carboxylate 4-(cyanomethoxy)-6-fluoroquinoline-2-carboxylic acid 4-(2-chloroethoxy)-6-fluoroquinoline-2-carboxylic acid 4-(2-amino-2-oxoethoxy)-6-fluoroquinoline-2-carboxylic acid 4-(allyloxy)-6-fluoroquinoline-2-carboxylic acid 4-(3-chloropropoxy)-6-fluoroquinoline-2-carboxylic acid 4-(3-chloro-2-methylpropoxy)-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-(pentyloxy)quinoline-2-carboxylic acid 4-(cyclohexylmethoxy)-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-[2-(4-fluorophenoxy)ethoxy]quinoline-2-carboxylic acid 6-fluoro-4-(2-phenylethoxy)quinoline-2-carboxylic acid 6-fluoro-4-(3-phenylpropoxy)quinoline-2-carboxylic acid 4-[2-(1-adamantyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-[2-(4-fluorophenyl)-2-oxoethoxy]quinoline-2-carboxylic acid 6-fluoro-4-[2-(3-methoxyphenyl)-2-oxoethoxy]quinoline-2-carboxylic acid 4-[4-(4-chlorophenoxy)butoxy]-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-[2-(3-fluorophenoxy)ethoxy]quinoline-2-carboxylic acid 4-[2-(4-bromophenoxy)ethoxy]-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-{[5-(4-fluorophenoxy)pentyl]oxy}quinoline-2-carboxylic acid 4-[2-(4-cyanophenoxy)ethoxy]-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-{2-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]ethoxy}quinoline-2-carboxylic acid 4-{2-[4-(2-carboxyethyl)phenoxy]ethoxy}-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-[2-(2-methoxyphenoxy)ethoxy]quinoline-2-carboxylic acid 4-(1-carboxy-3-phenylpropoxy)-6-fluoroquinoline-2-carboxylic acid 4-[2-(2,3-dimethylphenoxy)ethoxy]-6-fluoroquinoline-2-carboxylic acid 4-[2-(3,4-dimethoxyphenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylic acid and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. 19. Use according to claim 1, for which the compounds of the general formula (I) are chosen from: 4-(4-bromo-2-fluorobenzyloxy)-6-fluoroquinoline-2-carboxylic acid 4-(benzothiazol-2-ylmethoxy)-6-fluoroquinoline-2-carboxylic acid 4-ethoxy-6-fluoroquinoline-2-carboxylic acid 4-(4-bromo-2-fluorobenzyloxy)-6-methoxyquinoline-2-carboxylic acid (sodium salt) 4-({(E)-4-[(2-carboxy-6-fluoro-4-quinolinyl)oxy]-2-butenyl}oxy)-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-(3-methylbut-2-enyloxy)quinoline-2-carboxylic acid 4-(2′-cyanobiphenyl-4-ylmethoxy)-6-fluoroquinoline-2-carboxylic acid 4-[2-(3,4-dimethoxyphenyl)-2-oxo-ethoxy]-6-fluoroquinoline-2-carboxylic acid methyl 4-(3-chloropropoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(3-chloro-2-methylpropoxy)-6-fluoroquinoline-2-carboxylate and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. 20. Use according to claim 1, for which the said pharmaceutical composition is suitable for the treatment of diabetes. 21. Use according to claim 1, for which the said pharmaceutical composition is suitable for the treatment of type II diabetes. 22. Use according to claim 1, for which the pharmaceutical composition is suitable for the treatment of diseases chosen from dyslipidaemia and obesity. 23. Use according to claim 1, for which the pharmaceutical composition is suitable for the treatment of diseases chosen from diabetes-related microvascular and macrovascular complications. 24. Use according to claim 1, for which the said complications include arterial hypertension, atherosclerosis, inflammatory processes, microangiopathy, macroangiopathy, retinopathy and neuropathy. 25. Use according to claim 1, for which the pharmaceutical composition is suitable for reducing hyperglycaemia. 26. Compounds of the general formula (I) as defined in claim 1, for which R1 represents alkyl in which the carbon a to the oxygen atom is substituted by —COOH, —C(═O)alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl or —C(═O)NRR′, in which alkyl and/or aryl are optionally substituted as defined in claim 1, and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. 27. Compounds according to claim 26 represented by the general formula (III): in which X, R2, R, R′ and are as defined in claim 26, ALK represents an alkyl or alkenyl radical optionally substituted by one or more of the following groups: —CN, halogen, aryl, biaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, cycloalkyl, heterocycloalkyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2; R″ is chosen from —OH, alkyl, aryl, cycloalkyl, —O-alkyl and —NRR′, in which: alkyl is optionally substituted by one or more of the following groups: —CN, halogen, aryl, biaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, cycloalkyl, heterocycloalkyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2; aryl is optionally substituted by one or more groups chosen from: —CN, halogen, aryl, alkyl, —O-alkyl, -alkyl-C(═O)O-alkyl, -alkyl-C(═O)OH, —O-alkylaryl, heterocycloalkyl, —NRR′, —OH, —S(O)pR, in which p represents 0, 1 or 2; —O-aryl, perhaloalkyl, —COOH, COOR; heteroaryl is optionally and independently substituted by one or more groups chosen from halogen, —COOH and heterocycloalkyl; heterocycloalkyl is optionally and independently substituted by one or more alkyl or ═O; R′″ is H, alkyl or alkenyl optionally substituted by one or more of the following groups: —CN, halogen, aryl, biaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, cycloalkyl, heterocycloalkyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2; and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. 28. Compounds according to claim 26, for which R″ represents —OH, alkyl, aryl, cycloalkyl, —O-alkyl or —NRR′, in which aryl is optionally substituted by —O-alkylaryl, —O-alkyl, alkyl, aryl or halogen; ALK represents alkyl optionally substituted by aryl; R′″ represents H; X each represent a carbon atom, optionally substituted by a halogen atom, R2 represents H or an alkyl radical, R and R′ represent a hydrogen atom or an alkyl radical. 29. Compounds according to claim 26, for which X represents a carbon atom optionally substituted in position 6 of the quinoline ring system with a fluorine atom. 30. Process for the preparation of the compounds of the formula (I) or (III) defined according to claim 26, comprising the step consisting in reacting compound (3): in which X and are as defined in claim 26, with a compound of the formula R1-Hal, in which Hal represents a halogen atom, and R1 is as defined in claim 26, in a suitable organic solvent, in alkaline medium, at a temperature of between room temperature and the boiling point of the solvent, and optionally the step consisting in saponifying the product obtained, in an alcoholic solvent, in the presence of a base, optionally followed by the step consisting in esterifying the product obtained with a corresponding alcohol of the formula R2-OH, in which R2 is as defined in claim 26, in an alcoholic solvent, in acidic medium. 31. Process according to claim 30, comprising the step consisting in isolating the product obtained. 32. Pharmaceutical compositions comprising, as active ingredient, at least one derivative of the general formula I or III as defined in claim 26.

The present invention relates to the use of quinoline derivatives in the treatment of pathologies associated with hyperglycaemia and/or insulin resistance syndrome, in particular non-insulin-dependent diabetes or type II diabetes. Kynurenines represent the main pathway of tryptophan metabolism. T. W. Stone et al. have put forward the hypothesis of the possible roles of kynurenines in diabetes (T. W. Stone et al., Nature Reviews, vol. 1, August 2002, pp. 609-620), without, however, suggesting the use of quinoline derivatives as antidiabetic agents. Moreover, D. Edmont et al. have described the antidiabetic effect of 2-carboxyguanidine derivatives of quinoline (D. Edmont et al, Bioorganic & Medicinal Chemistry Letters, vol. 10, 16, 2000, 1831-1834). However, the antidiabetic effect of quinoline derivatives not containing a carboxyguanidine group is not suggested. The present invention relates to the use of derivatives of the general formula (I) below for manufacturing a medicament for the prevention of and/or treating hyperglycaemia-related pathologies: in which: X represents, independently of each other, a carbon atom, or a nitrogen, oxygen or sulfur atom; if X represents a carbon atom, it may be optionally substituted by a group chosen from: alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, heteroaryl, —CN, halogen, —O-aryl, —O-heteroaryl, cyclo-alkyl, heterocyclyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2; or two adjacent carbon atoms may form an aromatic ring fused to the aryl nucleus. R1 and R2, which may be identical or different, independently represent a group chosen from: Hydrogen, alkyl, alkenyl, alkynyl, each optionally and independently substituted by one or more of the following groups: —CN, halogen, aryl, biaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, cycloalkyl, heterocycloalkyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2; in which: aryl is optionally and independently substituted by one or more groups chosen from: —CN, halogen, aryl, alkyl, —O-alkyl, -alkyl-C(═O)O-alkyl, -alkyl-C(═O)OH, —O-alkylaryl, heterocycloalkyl, —NRR′, —OH, —S(O)pR, in which p represents 0, 1 or 2; —O-aryl, perhaloalkyl, —COOH, COOR; heteroaryl is optionally and independently substituted by one or more groups chosen from halogen, —COOH, COOR and heterocycloalkyl; heterocycloalkyl is optionally and independently substituted by one or more alkyl or ═O; cycloalkyl or heterocycloalkyl, each optionally and independently substituted by alkyl or alkoxy; aryl or heteroaryl, each optionally and independently substituted by one or more groups chosen from —CN, halogen, aryl, alkyl, —O-alkyl, -alkyl-C(═O)O-alkyl, —O-alkylaryl, heterocycloalkyl; —NRR′, —OH, —S(O)pR, in which p represents 0, 1 or 2; —O-aryl, perhaloalkyl, —COOH, COOR; R and R′ are chosen from H and alkyl; represents a single bond or a double bond and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. Preferably, each of the X represents a carbon atom; preferably, each of the X represents a carbon atom optionally substituted by a halogen atom; preferably, the carbon in position 6 of the quinoline ring is substituted by a halogen atom, preferably fluorine; If R1 and/or R2 represent(s) alkyl, alkenyl or alkynyl, they are preferably optionally substituted by —CN, halogen, —O-aryl, —O-heteroaryl, cycloalkyl, heterocycloalkyl, —COOH, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, biaryl or aryl, in which aryl is optionally substituted by —CN, halogen, aryl, alkyl, —O-alkyl, -alkyl-C(═O)O-alkyl, alkylCOOH, —O-alkylaryl or heterocycloalkyl. Preferably, R1 represents alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylaryl, aryl or heteroaryl, which are optionally substituted, as defined hereinabove or hereinbelow. Preferably, R1 represents alkyl or alkenyl, which are optionally substituted, as defined hereinabove or hereinbelow. Preferably, R1 represents alkyl or alkenyl, preferably alkyl, optionally and independently substituted by one or more groups chosen from: —CN, aryl, heterocycloalkyl, biaryl, halogen, —C(═O)-aryl, —O-aryl, —C(═O)-alkyl, cycloalkyl, —C(═O)-alkyl, —COOH, —O-heteroaryl, —C(═O)NRR′, —C(═O)-cycloalkyl, —O-heterocycloalkyl; in which aryl is optionally and independently substituted by one or more halogen, —CN, —O-alkylaryl, aryl, alkyl, —O-alkyl, heterocycloalkyl, -alkyl-C(═O)—OH, -alkyl-C(═O)O-alkyl; heteroaryl is optionally substituted by heterocycloalkyl, halogen or —COOH. heterocycloalkyl is optionally and independently substituted by one or more groups chosen from ═O and alkyl. Preferably, R1 represents alkyl or alkenyl in which the carbon a to the oxygen atom is substituted by —COOH, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl or —C(═O)NRR′, in which alkyl and aryl are optionally substituted as defined hereinabove or hereinbelow, and RR′ are as defined hereinabove or hereinbelow. Preferably, R1 represents alkyl or alkenyl, each optionally substituted by halogen, —O-heteroaryl or —C(═O)-aryl, in which aryl is optionally substituted by one or more —O-alkyl and heteroaryl is optionally substituted by one or more —COOH or halogen. Preferably, R2 represents a hydrogen atom or an alkyl group, preferably methyl. Preferably, R and R′ represent a hydrogen atom or a methyl or ethyl radical. Preferably, the compounds of the formula (I) are represented by the general formula (II) below: in which R1 and R2 are as defined above and R3 and R4, which may be identical or different, independently represent groups chosen from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, heteroaryl, —CN, halogen, —O-aryl, —O-heteroaryl, cycloalkyl, heterocyclyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′ and —S(O)pR, in which p represents 0, 1 or 2, or R3 and R4 may together also form a heterocycle adjacent to the phenyl ring, and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. Preferably, R3 and R4 represent H, —O-alkyl and/or a halogen atom, preferably halogen in position 6; preferably, R3 and/or R4 represent(s) fluorine or H. If R3 and R4 together form a heterocycle adjacent to the phenyl ring, they may especially represent the ring —O—(CH2)n—O—, n being an integer ranging from 1 to 4. The compounds of the formula (I) in which: X and R2 are defined as above and R1 represents alkyl in which the carbon α to the oxygen atom is substituted by —COOH, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl or —C(═O)NRR′, in which alkyl and aryl are optionally substituted as defined herein-above or hereinbelow, and RR′ are as defined hereinabove or hereinbelow, are of most particular interest and as such form part of the present invention. They are represented by the general formula (III) below: in which X, R2, R, R′ and are as defined above; ALK represents an alkyl or alkenyl radical optionally substituted by one or more of the following groups: —CN, halogen, aryl, biaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, cycloalkyl, heterocycloalkyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2; R″ is chosen from —OH, alkyl, aryl, cycloalkyl, —O-alkyl and —NRR′, in which: alkyl is optionally substituted by one or more of the following groups: —CN, halogen, aryl, biaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, cycloalkyl, hetero-cyclo-alkyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2; and aryl is optionally substituted by one or more groups chosen from: —CN, halogen, aryl, alkyl, —O-alkyl, -alkyl-C(—O)O-alkyl, -alkyl-C(═O)OH, —O-alkylaryl, hetero-cycloalkyl, —NRR′, —OH, —S(O)pR, in which p represents 0, 1 or 2, —O-aryl, perhaloalkyl, —COOH, COOR; heteroaryl is optionally and independently substituted by one or more groups chosen from halogen, —COOH and heterocycloalkyl; heterocycloalkyl is optionally and independently substituted by one or more alkyl or ═O; R′″ is H, alkyl or alkenyl optionally substituted by one or more of the following groups: —CN, halogen, aryl, biaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, cycloalkyl, heterocycloalkyl, —CO2H, —C(═O)-alkyl, —C(═O)-aryl, —C(═O)-cycloalkyl, —C(═O)O-alkyl, —C(═O)NRR′, —OH, —O-alkyl, —O-alkylaryl, —C(═O)O-aryl, —NRR′, —S(O)pR, in which p represents 0, 1 or 2; and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. In the general formula (III), preferably, X and R2 are as defined above, R″ represents —OH, alkyl, aryl, cycloalkyl, —O-alkyl or —NRR′, in which aryl is optionally substituted by —O-alkylaryl, —O-alkyl, alkyl, aryl or halogen; ALK represents alkyl optionally substituted by aryl; R′″ represents H; X each represent a carbon atom, optionally substituted by a halogen atom, preferably fluorine; even more preferably in position 6 of the quinoline ring system; R2 represents H or an alkyl radical, preferably methyl. The compounds of the formula (I) may especially be chosen from: methyl 4-(1,3-benzothiazol-2-ylmethoxy)-6-fluoroquinoline-2-carboxylate methyl 4-[(4-bromo-2-fluorobenzyl)oxy]-6-fluoroquinoline-2-carboxylate methyl 4-ethoxy-6-fluoroquinoline-2-carboxylate methyl 4-[(4-bromo-2-fluorobenzyl)oxy]-6-methoxyquinoline-2-carboxylate methyl 6-fluoro-4-[(3-methylbut-2-en-1-yl)oxy]quinoline-2-carboxylate methyl 4-[(2′-cyanobiphenyl-4-yl)methoxy]-6-fluoroquinoline-2-carboxylate methyl 4-(cyanomethoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(2-chloroethoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(2-amino-2-oxoethoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(allyloxy)-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-(pentyloxy)quinoline-2-carboxylate methyl 4-[2-(4-chlorophenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-(2-oxo-2-phenylethoxy)quinoline-2-carboxylate methyl 6-fluoro-4-[2-(4-fluorophenoxy)ethoxy]quinoline-2-carboxylate methyl 6-fluoro-4-(2-phenylethoxy)quinoline-2-carboxylate methyl 6-fluoro-4-(2-phenoxyethoxy)quinoline-2-carboxylate methyl 6-fluoro-4-(3-phenylpropoxy)quinoline-2-carboxylate methyl 4-(2-biphenyl-4-yl-2-oxoethoxy)-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(4-methylphenyl)-2-oxoethoxy]quinoline-2-carboxylate methyl 6-fluoro-4-[2-(4-methoxyphenyl)-2-oxoethoxy]quinoline-2-carboxylate methyl 4-[2-(1-adamantyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(4-fluorophenyl)-2-oxoethoxy]quinoline-2-carboxylate methyl 4-[2-(3,4-dichlorophenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(3-methoxyphenyl)-2-oxoethoxy]quinoline-2-carboxylate methyl 4-[4-(4-chlorophenoxy)butoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(3-fluorophenoxy)ethoxy]quinoline-2-carboxylate methyl 4-[2-(4-bromophenoxy)ethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-{[5-(4-fluorophenoxy)pentyl]oxy}quinoline-2-carboxylate methyl 4-[2-(4-cyanophenoxy)ethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-{2-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]ethoxy}quinoline-2-carboxylate methyl 6-fluoro-4-{2-[4-(3-methoxy-3-oxopropyl)phenoxy]ethoxy}quinoline-2-carboxylate methyl 6-fluoro-4-[2-(1-naphthyloxy)ethoxy]quinoline-2-carboxylate methyl 6-fluoro-4-[2-(2-methoxyphenoxy)ethoxy]quinoline-2-carboxylate methyl 4-{2-[2-(benzyloxy)phenyl]-2-oxoethoxy}-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[2-(2-naphthyloxy)ethoxy]quinoline-2-carboxylate methyl 4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]-6-fluoroquinoline-2-carboxylate methyl 4-[1-(ethoxycarbonyl)-3-phenylpropoxy]-6-fluoroquinoline-2-carboxylate methyl 4-[2-(2,3-dimethylphenoxy)ethoxy]-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-{2-[4-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethoxy}quinoline-2-carboxylate methyl 4-{2-[4-(benzyloxy)phenyl]-2-oxoethoxy}-6-fluoroquinoline-2-carboxylate methyl 4-[2-(3,4-dimethoxyphenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 4-(3-chloropropoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(3-chloro-2-methylpropoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(1-ethylpropoxy)-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-[(1-methylhexyl)oxy]quinoline-2-carboxylate methyl 4-[2-(2,4-dimethoxyphenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylate methyl 4-(3,3-dimethyl-2-oxobutoxy)-6-fluoroquinoline-2-carboxylate methyl 6-fluoro-4-(3-phenoxypropoxy)quinoline-2-carboxylate 4-[(4-bromo-2-fluorobenzyl)oxy]-6-fluoroquinoline-2-carboxylic acid 4-(1,3-benzothiazol-2-ylmethoxy)-6-fluoroquinoline-2-carboxylic acid 4-ethoxy-6-fluoroquinoline-2-carboxylic acid 4,4′-[(2E)-but-2-ene-1,4-diylbis(oxy)]bis(6-fluoroquinoline-2-carboxylic acid) 6-fluoro-4-[(3-methylbut-2-en-1-yl)oxy]quinoline-2-carboxylic acid 4-[(2′-cyanobiphenyl-4-yl)methoxy]-6-fluoroquinoline-2-carboxylic acid sodium 4-[(4-bromo-2-fluorobenzyl)oxy]-6-methoxyquinoline-2-carboxylate 4-(cyanomethoxy)-6-fluoroquinoline-2-carboxylic acid 4-(2-chloroethoxy)-6-fluoroquinoline-2-carboxylic acid 4-(2-amino-2-oxoethoxy)-6-fluoroquinoline-2-carboxylic acid 4-(allyloxy)-6-fluoroquinoline-2-carboxylic acid 4-(3-chloropropoxy)-6-fluoroquinoline-2-carboxylic acid 4-(3-chloro-2-methylpropoxy)-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-(pentyloxy)quinoline-2-carboxylic acid 4-(cyclohexylmethoxy)-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-[2-(4-fluorophenoxy)ethoxy]quinoline-2-carboxylic acid 6-fluoro-4-(2-phenylethoxy)quinoline-2-carboxylic acid 6-fluoro-4-(3-phenylpropoxy)quinoline-2-carboxylic acid 4-[2-(1-adamantyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-[2-(4-fluorophenyl)-2-oxoethoxy]quinoline-2-carboxylic acid 6-fluoro-4-[2-(3-methoxyphenyl)-2-oxoethoxy]quinoline-2-carboxylic acid 4-[4-(4-chlorophenoxy)butoxy]-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-[2-(3-fluorophenoxy)ethoxy]quinoline-2-carboxylic acid 4-[2-(4-bromophenoxy)ethoxy]-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-{[5-(4-fluorophenoxy)pentyl]oxy}quinoline-2-carboxylic acid 4-[2-(4-cyanophenoxy)ethoxy]-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-{2-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]ethoxy}quinoline-2-carboxylic acid 4-{2-[4-(2-carboxyethyl)phenoxy]ethoxy}-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-[2-(2-methoxyphenoxy)ethoxy]quinoline-2-carboxylic acid 4-(1-carboxy-3-phenylpropoxy)-6-fluoroquinoline-2-carboxylic acid 4-[2-(2,3-dimethylphenoxy)ethoxy]-6-fluoroquinoline-2-carboxylic acid 4-[2-(3,4-dimethoxyphenyl)-2-oxoethoxy]-6-fluoroquinoline-2-carboxylic acid and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. More preferably, the compounds of the formula (I) may be chosen from: 4-(4-bromo-2-fluorobenzyloxy)-6-fluoroquinoline-2-carboxylic acid 4-(benzothiazol-2-ylmethoxy)-6-fluoroquinoline-2-carboxylic acid 4-ethoxy-6-fluoroquinoline-2-carboxylic acid 4-(4-bromo-2-fluorobenzyloxy)-6-methoxyquinoline-2-carboxylic acid (sodium salt) 4-({(E)-4-[(2-carboxy-6-fluoro-4-quinolinyl)oxy]-2-butenyl}oxy)-6-fluoroquinoline-2-carboxylic acid 6-fluoro-4-(3-methylbut-2-enyloxy)quinoline-2-carboxylic acid 4-(2′-cyanobiphenyl-4-ylmethoxy)-6-fluoroquinoline-2-carboxylic acid 4-[2-(3,4-dimethoxyphenyl)-2-oxo-ethoxy]-6-fluoroquinoline-2-carboxylic acid methyl 4-(3-chloro-propoxy)-6-fluoroquinoline-2-carboxylate methyl 4-(3-chloro-2-methylpropoxy)-6-fluoroquinoline-2-carboxylate and also the tautomeric forms, enantiomers, diastereoisomers and epimers, and the pharmaceutically acceptable salts. According to the present invention, the alkyl radicals represent saturated hydrocarbon-based radicals in a straight or branched chain of 1 to 20 carbon atoms and preferably of 1 to 5 carbon atoms. If they are linear, mention may be made especially of methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, hexadecyl and octadecyl radicals. If they are branched or substituted by one or more alkyl radicals, mention may be made especially of isopropyl, tert-butyl, 2-ethylhexyl, 2-methylbutyl, 2-methylpentyl, 1-methylpentyl and 3-methylheptyl radicals. The alkoxy radicals according to the present invention are radicals of the formula —O-alkyl, the alkyl being as defined above. Among the halogen atoms, mention is made more particularly of fluorine, chlorine, bromine and iodine atoms, preferably fluorine. The alkenyl radicals represent hydrocarbon-based radicals in a straight or linear chain, and comprise one or more ethylenic unsaturations. Among the alkenyl radicals that may especially be mentioned are allyl or vinyl radicals. The alkynyl radicals represent hydrocarbon-based radicals in a straight or linear chain, and comprise one or more acetylenic unsaturations. Among the alkynyl radicals, mention may be made especially of acetylene. The cycloalkyl radical is a mono-, bi- or tricyclic, saturated or partially unsaturated, non-aromatic hydrocarbon-based radical of 3 to 10 carbon atoms, such as, especially, cyclopropyl, cyclopentyl, cyclohexyl or adamantyl, and also the corresponding rings containing one or more unsaturations. Aryl denotes a mono- or bicyclic hydrocarbon-based aromatic system of 6 to 10 carbon atoms. Among the alkyl radicals that may especially be mentioned are the phenyl or naphthyl radical, more particularly substituted by at least one halogen atom. Among the alkylaryl radicals that may especially be mentioned are the benzyl or phenethyl radical. The heteroaryl radicals denote mono- or bicyclic aromatic systems of 5 to 10 carbon atoms, comprising one or more hetero atoms chosen from nitrogen, oxygen and sulfur. Among the heteroaryl radicals that may be mentioned are pyrazinyl, thienyl, oxazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, naphthyridinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridyl, imidazo[2,1-b]thiazolyl, cinnolinyl, triazinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzazaindolyl, 1,2,4-triazinyl, benzothiazolyl, furanyl, imidazolyl, indolyl, triazolyl, tetrazolyl, indolizinyl, isoxazolyl, isoquinolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, purinyl, quinazolinyl, quinolyl, isoquinolyl, 1,3,4-thiadiazolyl, thiazolyl, triazinyl, isothiazolyl and carbazolyl, and also the corresponding groups derived from their fusion or from fusion with the phenyl nucleus. The preferred heteroaryl groups comprise thienyl, pyrrolyl, quinoxalinyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, thiazolyl, carbazolyl and thiadiazolyl, and groups derived from fusion with a phenyl nucleus, and more particularly quinolyl, carbazolyl and thiadiazolyl. The heterocycloalkyl radicals denote mono- or bicyclic, saturated or partially unsaturated, non-aromatic systems of 5 to 10 carbon atoms, comprising one or more hetero atoms chosen from N, O and S. Among the heterocycloalkyls that may especially be mentioned are epoxyethyl, oxiranyl, aziridinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, dithiolanyl, thiazolidinyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidyl, piperazinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl, dihydrofuranyl, 2-imidazolinyl, 2,3-pyrrolinyl, pyrazolinyl, dihydrothiophenyl, dihydropyranyl, pyranyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrimidinyl and dihydrothiopyranyl, and the corresponding groups derived from fusion with a phenyl nucleus, and more particularly morpholinyl, dioxalanyl, benzothiazolidinyl, pyrrolidinyl and benzopyrrolidinyl rings. The expression “pharmaceutically acceptable salts” refers to the relatively non-toxic mineral and organic acid-addition salts, and the base-addition salts, of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, the acid-addition salts can be prepared by separately reacting the purified compound in its purified form with an organic or mineral acid and isolating the salt thus formed. Among the examples of acid-addition salts are the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, sulfamates, malonates, salicylates, propionates, methylenebis-b-hydroxynaphthoates, gentisic acid, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and quinates-laurylsulfonate, and analogues. (See for example S. M. Berge et al. “Pharmaceutical Salts” J. Pharm. Sci, 66: pp. 1-19 (1977) which is incorporated herein by reference). The acid-addition salts can also be prepared by separately reacting the purified compound in its acid form with an organic or mineral base and isolating the salt thus formed. The acid-addition salts include amine salts and metal salts. The suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium and aluminium salts. The sodium and potassium salts are preferred. The suitable mineral base-addition salts are prepared from metallic bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide and zinc hydroxide. The suitable amine base-addition salts are prepared from amines whose basicity is sufficient to form a stable salt, and preferably include amines that are often used in medicinal chemistry on account of their low toxicity and their acceptability for medical use: ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzyl-phenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, for example lysine and arginine, and dicyclohexylamine, and analogues. The invention also relates to the tautomeric forms, enantiomers, diastereoisomers, epimers and organic or mineral salts of the compounds of the general formula (I). The compounds of the invention of the formula (I) as defined above containing a sufficiently acidic function or a sufficiently basic function, or both, can include the corresponding pharmaceutically acceptable salts of an organic or mineral acid or of an organic or mineral base. The compounds of the general formula (I) can be prepared by application or adaptation of any method known per se and/or within the capacity of a person skilled in the art, especially those described by Larock in Comprehensive Organic Transformations, VCH Pub., 1989, or by application or adaptation of the processes described in the examples that follow, or alternatively, more particularly, according to the following method described in Bioorganic & Medicinal Chemistry Letters 10(16), 2000, 1831-34: Compound (1) is condensed with the acetylenedicarboxylate by heating in alcoholic medium, preferably in methanol. Compound (2) obtained is cyclized at reflux in a solvent, such as diphenyl ether or Dowtherm A. Compound (3) obtained is O-alkylated in alkaline medium, preferably in DMF in the presence of potassium carbonate at 50° C., and the ester (4) obtained is then saponified, preferably with caustic soda in alcoholic medium. The compounds of the formula (I) for which R2 is other than H are then obtained by esterification of (4) with the corresponding alcohol R2-OH. According to another subject, the present invention thus also relates to the process for the preparation of the compounds of the formula (III) described above, comprising the step consisting in reacting a compound of the formula (3) in which X and are as defined above, with a compound of the formula R1-Hal, in which Hal represents a halogen atom, and R1 is as defined above, in a suitable organic solvent, in alkaline medium, at a temperature of between room temperature and the boiling point of the solvent, and optionally, if R2 is other than methyl, the step consisting in saponifying the product obtained, in an alcoholic solvent, in the presence of a base, optionally followed, if R2 is other than H, by the step consisting in esterifying the product obtained with a corresponding alcohol of the formula R2-OH, in which R2 is as defined above, in an alcoholic solvent, in acidic medium. Optionally, the said process may also include the step consisting in isolating the product obtained. In the reactions described hereinbelow, it may be necessary to protect reactive functional groups, for example hydroxyl, amino, imino, thio or carboxyl groups, if they are desired in the final product, to avoid their unwanted participation in the reactions. The conventional protecting groups can be used in accordance with the standard practice; for examples, see T. W. Green and P. G. M. Wuts in Protective Groups in Organic Chemistry, John Wiley and Sons, 1991; J. F. W. McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973. The compound thus prepared can be recovered from the reaction mixture via the conventional means. For example, the compounds can be recovered by distilling the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the mixture of the solution, pouring the remainder into water, followed by extraction with a water-immiscible organic solvent, and distilling the solvent from the extract. In addition, the product can also be purified, if so desired, by various techniques, such as recrystallization, reprecipitation or various chromatographic techniques, especially column chromatography or preparative thin-layer chromatography. It will be appreciated that the compounds that are useful according to the present invention may contain asymmetric centres. These asymmetric centres can be, independently, of R or S configuration. It will be apparent to a person skilled in the art that certain compounds that are useful according to the invention may also exhibit geometrical isomerism. It should be understood that the present invention includes individual geometrical isomers and stereoisomers, and mixtures thereof, including racemic mixtures, of compounds of the formula (I) above. Isomers of this type can be separated from their mixtures by application or adaptation of known processes, for example chromatography techniques or recrystallization techniques, or they are prepared separately from suitable isomers of their intermediates. For the purposes of the present text, it is understood that the tautomeric forms are included in the citation of a given group, for example thio/mercapto or oxo/hydroxyl. The acid-addition salts are formed with the compounds that are useful according to the invention in which a basic function, such as an amino, alkylamino or dialkylamino group is present. The pharmaceutically acceptable, i.e. non-toxic, acid-addition salts are preferred. The selected salts are optimally chosen so as to be compatible with the usual pharmaceutical vehicles and suitable for oral or parenteral administration. The acid-addition salts of the compounds that are useful according to the present invention can be prepared by reacting the free base with the appropriate acid, by application or adaptation of known processes. For example, the acid-addition salts of the compounds that are useful according to the present invention can be prepared either by dissolving the free base in water or in a basified aqueous solution or suitable solvents containing the appropriate acid, and isolating the solvent by evaporating the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt separates out directly or can be obtained by concentrating the solution. Among the acids that are suitable for use in the preparation of these salts are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, various organic carboxylic and sulfonic acids, such as acetic acid, citric acid, propionic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, toluenesulfonic acid, fatty acids, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, cyclopentanepropionate, digluconate, dodecyl sulfate, bisulfate, butyrate, lactate, laurate, lauryl sulfate, malate, hydriodide, 2-hydroxyethanesulfonate, glycerophosphate, picrate, pivalate, pamoate, pectinate, persulfate, 3-phenylpropionate, thiocyanate, 2-naphthalenesulfonate, undecanoate, nicotinate, hemisulfate, heptonate, hexanoate, camphorate, camphorsulfonate and the like. The acid-addition salts of the compounds that are useful according to the present invention can be regenerated from the salts by application or adaptation of known processes. For example, the parent compounds that are useful according to the invention can be regenerated from their acid-addition salts by treatment with an alkali, for example aqueous sodium bicarbonate solution or aqueous ammonia solution. The compounds that are useful according to the present invention can be regenerated from their base-addition salts by application or adaptation of known processes. For example, the parent compounds that are useful according to the invention can be regenerated from their base-addition salts by treatment with an acid, for example hydrochloric acid. The base-addition salts can be formed if the compound that is useful according to the invention contains a carboxyl group, or a sufficiently acidic bio-isostere. The bases that can be used to prepare the base-addition salts preferably include those that produce, if they are combined with a free acid, pharmaceutically acceptable salts, i.e. salts whose cations are not toxic to the patient in the pharmaceutical doses of the salts, such that the beneficial inhibitory effects intrinsic to the free base are not negated by the side effects attributable to the cations. The pharmaceutically acceptable salts, including those derived from alkaline-earth metal salts, within the scope of the present invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide and the like. The compounds that are useful according to the present invention can be readily prepared, or formed during the process of the invention, in the form of solvates (for example hydrates). The hydrates of the compounds that are useful according to the present invention can be readily prepared by recrystallization of an aqueous/organic solvent mixture, using organic solvents, such as dioxane, tetrahydrofuran or methanol. The basic products or the intermediates can be prepared by application or adaptation of known processes, for example processes as described in the Reference Examples or obvious chemical equivalents thereof. According to the present invention, the compounds of the formula (I) have hypoglycaemiant activity. They can reduce hyperglycaemia, more particularly the hyperglycaemia of non-insulin-dependent diabetes. Insulin resistance is characterized by a reduction in the action of insulin (cf. Presse Médicale, 1997, 26 (No 14), 671-677) and is involved in a large number of pathological conditions, such as diabetes and more particularly non-insulin-dependent diabetes (type II diabetes or NIDDM), dyslipidaemia, obesity and certain microvascular and macrovascular complications, for instance atheroscleroS is, arterial hypertension, inflammatory processes, macroangiopathy, microangiopathy, retinopathy and neuropathy. In this respect, reference will be made, for example, to Diabetes, vol. 37, 1988, 1595-1607; Journal of Diabetes and Its Complications, 1998, 12, 110-119 or Horm. Res., 1992, 38, 28-32. In particular, the compounds of the invention show strong anti-hyperglycaemic activity. The compounds of the formula (I) are thus useful in the treatment of hyperglycaemia-related pathologies. The present invention also relates to the use of compounds of the general formula (I) for the preparation of pharmaceutical compositions for the prevention of and/or treating hyperglycaemia-related pathologies, more particularly diabetes. The pharmaceutical compositions according to the invention can be presented in forms intended for parenteral, oral, rectal, permucous or percutaneous administration. They will thus be presented in the form of injectable solutions or suspensions or multi-dose bottles, in the form of plain or coated tablets, sugar-coated tablets, wafer capsules, gel capsules, pills, cachets, powders, suppositories or rectal capsules, solutions or suspensions, for percutaneous use in a polar solvent, or for permucous use. The excipients that are suitable for such administrations are cellulose or microcrystalline cellulose derivatives, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches and lactose for solid forms. For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients. For parenteral use, water, aqueous solutions, physiological saline and isotonic solutions are the vehicles most appropriately used. The dosage can vary within wide ranges (0.5 mg to 1000 mg) according to the therapeutic indication and the route of administration, and also to the age and weight of the patient. The examples that follow illustrate the invention without, however, limiting it. The starting materials used are known products or are prepared according to known procedures. Unless otherwise mentioned, the percentages are expressed on a weight basis. EXAMPLE 1 4-Ethoxy-6-fluoroquinoline-2-carboxylic acid 2-(4-Fluorophenylamino)but-2-enedioic Acid Dimethyl Ester 50 ml (0.51 M) of 4-fluoroaniline (at 98%) are introduced into 500 ml of anhydrous methanol, followed by dropwise addition of 70.5 ml (0.56 M) of methyl acetylenedicarboxylate (at 98%). The reaction mixture is heated at 55° C. with stirring for 3 hours, and then evaporated under reduced pressure. The residue is purified by evolution through silica. 113.2 g of yellow oil are obtained. Yield: 87% 1H NMR (CDCl3): 9.74 (1H, s); 7.06 (4H, m); 5.55 (1H, s); 3.88 (3H, s); 3.84 (3H, s); Methyl 6-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylate 250 ml de Dowtherm-A are brought to reflux (about 235° C.) under a nitrogen atmosphere. 41 g (0.16 M) of 2-(4-fluorophenylamino)but-2-enedioic acid dimethyl ester are then introduced dropwise. The methanol formed is separated out. Refluxing is maintained for 10 minutes after the end of introduction. The reaction mixture is then cooled to about 50° C., followed by addition of 250 ml of petroleum ether: a solid precipitates out. It is filtered off by suction, washed three times with petroleum ether and then dried under reduced pressure. 27.4 g of a beige-coloured solid are obtained. A second crop is obtained by evaporating off, under reduced pressure, the petroleum ether and the residual methanol from the reaction medium, which is heated again to 240° C. for 30 minutes. After cooling and diluting with petroleum ether (2 volumes), the precipitate obtained is worked up as previously, to obtain 2.6 g of solid. The two crops are combined and washed with 400 ml of hot butanol After filtration by suction and drying under reduced pressure: 26.3 g of solid. Yield: 73% m.p.: >250° C. 1H NMR (DMSO-d6): 12.2 (1H, s); 7.9 (1H, m); 7.7 (1H, m); 7.5 (1H, m); 3.85 (3H, s) Methyl 4-ethoxy-6-fluoroquinoline-2-carboxylate 8.0 g (0.036 M) of methyl 6-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylate and 15.0 g (0.108 M) of potassium carbonate are introduced into 80 ml of DMF. The reaction mixture is stirred for 1 hour at 50° C. After addition of 3.0 ml (0.037 M) of iodoethane and heating for 12 hours at 50° C., the reaction medium is poured into 400 ml of demineralized water. A brown solid precipitates out. The solid is filtered off, washed thoroughly with water and then with isopropyl ether, and finally dried under vacuum at 40° C. 5.54 g of brown solid are obtained. Yield: 61% m.p.=149° C. 1H NMR (DMSO-d6): 8.35 (1H, m); 7.9 (2H, m); 7.7 (1H, m); 4.6 (2H, q); 4.2 (3H, s); 1.75 (3H, t) 4-Ethoxy-6-fluoroquinoline-2-carboxylic acid (1) A suspension of 14.0 g (0.056 M) of methyl 4-ethoxy-6-fluoro-2-quinoline-carboxylate in 100 ml of a solution comprising 2.32 g (0.056 M) of sodium hydroxide (at 97%) in 100 ml of methanol and 100 ml of demineralized water is refluxed for 5 hours. The solution, which has become clear, is cooled and then acidified to pH=1 with 6N hydrochloric acid solution. The reaction medium is then poured into 700 ml of an ice-water mixture. The precipitate formed is stirred for a further 1 hour, filtered off, washed with demineralized water until the filtrate is neutral, and then with isopropyl ether, and finally dried under vacuum. 11.66 g of white solid are obtained. Yield: 88% m.p.=207° C. 1H NMR (DMSO-d6): 8 (1H, m); 7.65 (2H, m); 7.42 (1H, s); 4.27 (2H, q); 1.39 (3H, t) By way of example, the following compounds are prepared according to the procedure of Example 1: (2): 4-(4-Bromo-2-fluorobenzyloxy)-6-fluoroquinoline-2-carboxylic acid m.p.=>250° C. 1H NMR (DMSO-d6): 8.5-7.7 (7H, m); 5.75 (2H, s); (3): 4-(Benzothiazol-2-ylmethoxy)-6-fluoroquinoline-2-carboxylic acid m.p.=>250° C. 1H NMR (DMSO-d6): 8.15-7.3 (8H, m); 5.85 (2H, s); (4): 4-(4-Bromo-2-fluorobenzyloxy)-6-methoxyquinoline-2-carboxylic acid, sodium salt m.p.=>250° C. 1H NMR (DMSO-d6): 28.3 (1H, m); 7.85-7.45 (6H, m); 5.55 (2H, s); 4 (3H, s) (5): 4-({(E)-4-[(2-Carboxy-6-fluoro-4-quinolinyl)oxy]-2-butenyl}oxy)-6-fluoro-2-quinolinecarboxylic acid m.p.=>250° C. 1H NMR (TFA): 9.07-8.57 (8H, m), 7.06 (2H, s); 6.11 (4H, s); (6): 6-Fluoro-4-(3-methylbut-2-enyloxy)quinoline-2-carboxylic acid m.p.=>250° C. 1H NMR (DMSO-d6): 8.5 (1H, m) 7.86 (3H, m); 5.8 (1H, m); 5.08 (1H, s); 5.05 (1H, s); 2.02 (6H, s) (7): 4-(2′-Cyanobiphenyl-4-ylmethoxy)-6-fluoroquinoline-2-carboxylic acid m.p.=>250° C. 1H NMR (DMSO-d6): 8.35 (1H, m); 7.99-7.34 (12H, m); 5.57 (2H, s) 4-Ethoxy-6-fluoroquinoline-2-carboxylic acid m.p.=205° C. 1H NMR (DMSO-d6): 8.01 (1H, m); 7.69-7.42 (3H, m); 4.27 (2H, q); 1.40 (3H, t) EXAMPLE 2 4-Allloxy-6-fluoroquinoline-2-carboxylic acid 4-Allyloxy-6-fluoroquinoline-2-carboxylic Acid Methyl Ester 374 mg (2.7 mM) of potassium carbonate and then a solution of 199.95 mg (0.904 mM) of methyl 6-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylate dissolved in 4 ml of hot dimethylformamide, are respectively added into a container. After heating at 50° C. with stirring for one hour, 109.36 (0.904 mM) of allyl bromide are added to the reaction medium. Stirring is continued for 4 hours at 50° C. and then for 8 hours at room temperature. The medium is diluted with 20 ml of demineralized water. A solid precipitates out with stirring. It is filtered off, washed with demineralized water and then dried. 4-Allyloxy-6-fluoroquinoline-2-carboxylic acid The above ester is hydrolysed with one equivalent of normal caustic soda comprising an equal volume of methanol, for one hour at 60° C. The reaction medium is then taken up in 15 ml of demineralized water, washed twice with ethyl acetate, acidified with normal hydrochloric acid solution and then extracted twice with ethyl acetate. The organic phases are combined and then concentrated under reduced pressure. The solid obtained is analysed. By way of example, the following compounds are prepared according to the procedure of Example 2: Theo- ret- Com- ical Mass pound Structure mass found 8 260.2 260.1 9 283.7 283.9 10 278.2 278.9 11 261.3 261.9 12 373.8 373.9 13 339.3 340 14 359.3 360 15 325.3 326 16 341.3 342 17 415.4 416 18 353.4 354 19 369.4 370 20 357.3 358 21 408.2 407.9 22 369.4 370 23 403.8 404 24 359.3 360 25 401.4 402 26 366.4 368 27 434.4 435 28 427.4 428 29 391.4 392 30 371.4 372 31 445.5 446 32 391.4 392 33 394.4 395 34 411.4 412 35 369.4 370 36 411.4 412 37 445.5 446 38 399.4 400 39 246.2 245 40 269.7 268 41 264.2 263 42 247.2 246.1 43 283.7 282 44 297.7 296 45 277.3 46 303.3 302.1 47 345.3 344 48 311.3 310 49 325.3 324 50 383.4 382.1 51 343.3 342 52 355.3 354 53 389.8 388 54 345.3 344 55 406.2 406 56 387.4 386 57 352.3 351 58 420.4 419.1 59 399.4 398 60 357.3 356 61 369.4 368 62 355.4 354.1 63 385.4 384 64 297.7 65 311.7 66 291.3 67 319.4 68 399.4 69 319.3 70 355.4 INSULIN SECRETION TEST According to the method described in Endocrinology, 1992 vol. 130 (1) pp. 167-178 COM- INS. POUND STRUCTURE C SEC. 1 10−5 M 172% 63 10−5 M 192% 64 10−5 M 179% 65 10−5 M 161% C corresponds to the concentration of test compound according to the invention INS. SEC. corresponds to the percentage of insulin secretion STUDY OF THE ANTIDIABETIC ACTIVITY IN NOSTZ RATS The antidiabetic activity of the compounds of the formula (I) via the oral route, on an experimental model of non-insulin-dependent diabetes induced in rats by means of steptozotocin, was determined as follows. The model of non-insulin-dependent diabetes is obtained in the rats by means of a neonatal injection (on the day of birth) of steptozotocin The diabetic rats used are eight weeks old. The animals are housed, from the day of birth to the day of the experiment, in an animal house at a regulated temperature of 21 to 22° C. and subjected to a fixed cycle of light (from 7 a.m. to 7 p.m.) and darkness (from 7 p.m. to 7 a.m.). Their food consisted of a maintenance diet, and water and food were given “ad libitum”, with the exception of fasting two hours before the tests, during which period the food is removed (postabsorptive state). The rats are treated orally for one (D1) or four (D4) days with the test product. Two hours after the final administration of the product and 30 minutes after anaesthetizing the animals with pentobarbital sodium (Nembutal®), a 300 μl blood sample is taken from the end of the tail. By way of example, the results obtained are collated in the table below. These results show the efficacy of the compounds mentioned in reducing glycaemia in the case of diabetic animals. These results are expressed as a percentage change in the glycaemia on D4 (number of days of treatment) relative to D0 (before the treatment). IN-VIVO TEST (N0 STZ RAT) REFERENCE STRUCTURE Percentage decrease in glycaemia at 200 mg/kg 1 −27 5 −17 6 −10

20060622

20081230

20070628

62410.0

A61K314704

SOLOLA, TAOFIQ A

ACIDIC QUINOLINE DERIVATIVES AND THEIR USE FOR THE PREVENTION AND/OR TREATMENT OF HYPERGLYCAEMIA-RELATED PATHOLOGIES

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Apparatus for determining type of liquid in a container and method for controlling the apparatus

A technique for quickly determining the type of liquid in a container externally regardless of the material of the container, preferably contactlessly. A halogen heater 102 and an infrared thermopile 103 are disposed outside an electrically conductive container 101 made of aluminum, for example. The surface temperature of the container 101 is measured when the halogen heater 102 is off, followed by the turning-on of the halogen heater 102 for two seconds, for example. The surface temperature of the container 101 is then measured, and a difference from the previous result of measurement is calculated. If the difference is smaller than a threshold value, the liquid in the container is determined to be a safe liquid consisting primarily of water, and a blue lamp is activated. If the difference is greater than the threshold value, the liquid in the container cannot be determined to be a safe liquid consisting primarily of water, and a red lamp is activated, indicating abnormality.

1. An apparatus for determining the type of liquid in a container comprising: a heat source disposed outside a container; a temperature sensor disposed near said heat source for converting the temperature of an outer wall of said container into a voltage or a current; a notification means capable of issuing an alert indicating that the content of said container is dangerous; and a control determination circuit whereby the supply of power to said heat source is controlled, the difference between the value of an output of said temperature sensor at time t1 which is before or upon the supply of power to said heat source and the value of an output of said temperature sensor at time t1+t2, which is when a predetermined time has elapsed after said time t1, is compared with a predetermined threshold value, and an alert signal is outputted to said notification means. 2. The apparatus for determining the type of liquid in a container according to claim 1, wherein said control determination circuit comprises: a timer; a power supply circuit capable of supplying power to said heat source; a notification signal generating circuit for outputting said alert signal to said notification means; an AD converter for converting an output of said temperature sensor into digital data; a data storage unit for recording a program and data; and an arithmetic processing unit for carrying out processes in accordance with said program recorded in said data storage unit, wherein said program causes said arithmetic processing unit to carry out: a first procedure in which, on the condition that no power is being supplied from said power supply circuit to said heat source, the current time t1 is acquired from said timer, and in which data is acquired from said AD converter and recorded in said data storage unit as a value SO1; a second procedure in which a control signal to said power supply circuit is switched to an ON signal for supplying power to said heat source, and, after a predetermined time has elapsed, the control signal is switched to an OFF signal M for supplying no power to said heat source; a third procedure in which the current time is acquired from said timer and in which it is determined whether or not the thus acquired current time exceeds a time t1+t2 which is the sum of said time t1 and an elapsed time t2; a fourth procedure in which, if it is determined that the current time exceeds the time t1+t2 in the third procedure, data is acquired from said AD converter and recorded in said data storage unit as a value SO2; a fifth procedure in which the difference SO2−SO1 between said values SO1 and SO2 is calculated and compared with a predetermined threshold value; and a sixth procedure in which said alert signal is outputted from said notification signal generating circuit depending on the result of comparison between the difference SO2−SO1 and the threshold value. 3. The apparatus for determining the type of liquid in a container according to claim 1, wherein said control determination circuit comprises: a lamp circuit for producing a lamp voltage in response to a signal indicating the start of measurement; a first latch circuit for latching the value of an output of said temperature sensor when the absolute value of an output of said lamp circuit is |V1|; a power supply circuit that starts the supply of power to said heat source when the absolute value of the output of said lamp circuit is |V2| which is larger than said |V1| and terminating said supply of power after a predetermined time has elapsed; a second latch circuit for latching the value of an output of said temperature sensor when the voltage of said lamp circuit reaches |V3| which is larger than said |V2|; a differential amplification circuit to which the outputs of said first latch circuit and said second latch circuit are inputted; and a notification signal generating circuit for comparing an output of said differential amplification circuit with a predetermined threshold value and outputting said alert signal to said notification means. 4. The apparatus for determining the type of liquid in a container according to claim 1, wherein said heat source and said temperature sensor are disposed away from the wall of said container. 5. The apparatus for determining the type of liquid in a container according to claim 4, wherein said heat source is a halogen heater and said temperature sensor is an infrared thermopile. 6. The apparatus for determining the type of liquid in a container according to claim 5, wherein a light-absorbing heat shield member is disposed between said heat source and said temperature sensor. 7. The apparatus for determining the type of liquid in a container according to claim 1, further comprising a container sensor for detecting the placement of said container, wherein a signal from said container sensor is used as a trigger for initiating determination. 8. A method for controlling an apparatus for determining the type of liquid in a container, said apparatus comprising: a heat source disposed outside said container; a temperature sensor disposed near said heat source for converting the temperature of an outer wall of said container into a voltage or a current; a notification means capable of issuing an alert indicating that the content of said container is dangerous; and a control determination circuit, said method comprising the steps of: storing or holding the value of an output of said temperature sensor at time t1; starting the supply of power to said heat source at time t3 which is later than said time t1; terminating the supply of power to said heat source at time t4 which is after said time t3; storing or holding the value of an output of said temperature sensor at time t5 which is later than said time t3; finding the difference between the value of an output of said temperature sensor at time t1 and the value of an output of said temperature sensor at time t5; comparing the difference with a predetermined threshold value; and issuing an alert to said notification means depending on the result of comparison between the difference and the threshold value. 9. The control method according to claim 8, wherein said time t5 is later than said time t4. 10. The control method according to claim 8, wherein said apparatus for determining the type of liquid in a container further comprises a container sensor for detecting the placement of said container, wherein the processes after said time t1 are started using a signal from said container sensor as a trigger. 11. The control method according to claim 8, wherein said heat source and said temperature sensor are disposed away from the wall of said container. 12. The control method according to claim 11, wherein said heat source is a halogen heater and said temperature sensor is an infrared thermopile. 13. The control method according to claim 12, wherein a light-absorbing heat shield member is disposed between said heat source and said temperature sensor. 14. An apparatus for determining the type of liquid in a container comprising: one or a plurality of flexible films in contact with a container; a temperature sensor provided to the single film or one of said plurality of films; a heat source provided either to the same film as or a different film from the single film or one of said plurality of films to which said temperature sensor is provided; a notification means capable of issuing an alert indicating that the content of said container is dangerous; a power supply means for supplying power to said heat source; an arithmetic comparison means whereby a comparison value is calculated by acquiring an output of said temperature sensor and compared with said threshold value; an alert signal output means for outputting an alert signal to said notification means depending on the result of comparison by said arithmetic comparison means; and a control means for controlling said power supply means, said arithmetic comparison means, and said alert signal output means. 15. The apparatus for determining the type of liquid in a container according to claim 14, wherein said film is curved and disposed such that the peak of the curvature is facing toward a plane on which said container is placed, wherein as said container is placed, said heat source and said temperature sensor are pressed against the outer wall of said container due to the flexibility of said film. 16. The apparatus for determining the type of liquid in a container according to claim 15, comprising either a first configuration in which the curved surface of said film is in contact with said container along a line in the direction of the height of said container, or a second configuration in which said curved surface is in contact with said container along a line in the circumferential direction of said container. 17. The apparatus for determining the type of liquid in a container according to claim 14, wherein said film is disposed along the outer wall of said container. 18. The apparatus for determining the type of liquid in a container according to claim 14, wherein said temperature sensor is smaller than said heat source. 19. The apparatus for determining the type of liquid in a container according to claim 14, comprising a plurality of heat sources, wherein said temperature sensor is disposed between said plurality of heat sources. 20. The apparatus for determining the type of liquid in a container according to claim 14, wherein said heat source and said temperature sensor are comprised of electric resistor elements patterned on said film. 21. The apparatus for determining the type of liquid in a container according to claim 14, wherein said control means: controls said power supply means such that it supplies power to said heat source at time t1 and terminates the power supply at time t2 which is later than said time t1; measures an output value O1 of said temperature sensor at time t3 and an output value O2 of said temperature sensor at time t4 which is later than said time t3 and t1; and calculates said comparison value from said output value O2 and said output value O1. 22. The apparatus for determining the type of liquid in a container according to claim 14, wherein said control means: controls said power supply means such that it supplies power to said heat source at time t1 and terminates the power supply at time t2 which is later than t1; measures an output value O3 of said temperature sensor at time t6 which is earlier than time t5 at which said container is placed, an output value O4 of said temperature sensor at time t7 which is later than said time t5 and earlier than said time t1, an output value O1 of said temperature sensor at time t3, and an output value O2 of said temperature sensor at time t4 which is later than said time t3 and t1; determines a correction value from said output values O4 ad O3; and calculates said comparison value from said output values O2 and O1 and said correction value. 23. The apparatus for determining the type of liquid in a container according to claim 14, wherein said control means: controls said power supply means such that it supplies power to said heat source at time t1 and terminates the power supply at time t2 which is later than said time t1; measures an output value O3 of said temperature sensor at time t6 which is earlier than time t5 at which said container is placed, an output value O1 of said temperature sensor at time t3, and an output value O2 of said temperature sensor at time t4 which is later than said time t3 and t1; and calculates said comparison value from said output values O2, O1, and O3. 24. The apparatus for determining the type of liquid in a container according to claim 14, further comprising a second temperature sensor disposed such that it is in contact with said container away from said heat source by a distance greater than the distance between said heat source and said temperature sensor, wherein said control means: controls said power supply means such that it supplies power to said heat source at time t1 and terminates the power supply at time t2 which is later than said time t1; measures an output value O1 of said temperature sensor at time t3, an output value O2 of said temperature sensor at time t4 which is later than said time t3 and time t1, and an output value O5 of said second temperature sensor at time t8 which is earlier than said time t4; and calculates said comparison value from said output values O2, O1, and O5. 25. The apparatus for determining the type of liquid in a container according to claim 24, wherein said second temperature sensor is an electric resistor element patterned on said film. 26. The apparatus for determining the type of liquid in a container according to claim 24, wherein said second temperature sensor is disposed at a position circumferentially displaced from the position where said temperature sensor and said heat source are disposed. 27. The apparatus for determining the type of liquid in a container according to claim 14, further comprising a container sensor for detecting the placement of said container, wherein determination is started using a signal from said container sensor as a trigger. 28. A method for controlling an apparatus for determining the type of liquid in a container comprising: one or a plurality of flexible films in contact with a container; a temperature sensor provided to the single film or one of said plurality of films; a heat source provided either to the same film as or a different film from the single film or one of said plurality of films to which said temperature sensor is provided; a notification means capable of issuing an alert indicating that the content of said container is dangerous; a power supply means for supplying power to said heat source; an arithmetic comparison means whereby a comparison value is calculated by acquiring an output of said temperature sensor and compared with said threshold value; an alert signal output means for outputting an alert signal to said notification means depending on the result of comparison by said arithmetic comparison means; and a control means for controlling said power supply means, said arithmetic comparison means, and said alert signal output means, said method comprising the steps of: storing or holding an output value O1 of said temperature sensor at time t3; starting the supply of power to said heat source at time t1; terminating the power supply to said heat source at time t2 which is later than said t1; storing or holding an output value O2 of said temperature sensor at time t4 which is later than said time t3 and time t1; determining said comparison value from said output values O1 and O2; comparing said comparison value and said threshold value; and generating said alert signal depending on the result of comparison. 29. A method for controlling an apparatus for determining the type of liquid in a container comprising: one or a plurality of flexible films in contact with a container; a temperature sensor provided to the single film or one of said plurality of films; a heat source provided to the same film as or a different film from the single film or one of said plurality of films to which said temperature sensor is provided; a notification means capable of issuing an alert indicating that the content of said container is dangerous; a power supply means for supplying power to said heat source; an arithmetic comparison means whereby a comparison value is calculated by acquiring an output of said temperature sensor and compared with said threshold value; an alert signal output means for outputting an alert signal to said notification means depending on the result of comparison by said arithmetic comparison means; and a control means for controlling said power supply means, said arithmetic comparison means, and said alert signal output means, said method comprising the steps of: storing or holding an output value O3 of said temperature sensor at time t6 which is earlier than time t5 at which said container is placed; storing or holding an output value O4 of said temperature sensor at time t7 which is later than said time t5; storing or holding an output value O1 of said temperature sensor at time t3 which is later than said time t7; starting the supply of power to said heat source at time t1 which is later than said time t7; terminating the power supply to said heat source at time t2 which is later than said time t1; storing or holding an output value O2 of said temperature sensor at time t4 which is later than said time t3 and time t1; determining a correction value from said output values O3 and O4; determining said comparison value from said output values O1 and O2 and said correction value; comparing said comparison value and said threshold value; and producing said alert signal depending on the result of comparison. 30. A method for controlling an apparatus for determining the type of liquid in a container comprising: one or a plurality of flexible films in contact with a container; a temperature sensor provided to the single film or one of said plurality of films; a heat source provided either to the same film as or a different film from the single film or one of said plurality of films to which said temperature sensor is provided; a notification means capable of issuing an alert indicating that the content of said container is dangerous; a power supply means for supplying power to said heat source; an arithmetic comparison means whereby a comparison value is calculated by acquiring an output of said temperature sensor and compared with said threshold value; an alert signal output means for outputting an alert signal to said notification means depending on the result of comparison by said arithmetic comparison means; and a control means for controlling said power supply means, said arithmetic comparison means, and said alert signal output means, said method comprising the steps of: storing or holding an output value O3 of said temperature sensor at time t6 which is earlier than time t5 at which said container is placed; storing or holding an output value O1 of said temperature sensor at time t3 which is later than said time t6; starting the supply of power to said heat source at time t1 which is later than said time t6; terminating the power supply to said heat source at time t2 which is later than said time t1; storing or holding an output value O2 of said temperature sensor at time t4 which is later than said time t3 and time t1; determining said comparison value from said output values O1, O2, and O3; comparing said comparison value and said threshold value; and producing said alert signal depending on the result of comparison. 31. A method for controlling an apparatus for determining the type of liquid in a container comprising: one or a plurality of flexible films in contact with a container; a temperature sensor provided to the single film or one of said plurality of films; a heat source provided to the same film as or a different film from the single film or one of said plurality of films to which said temperature sensor is provided; a notification means capable of issuing an alert indicating that the content of said container is dangerous; a power supply means for supplying power to said heat source; an arithmetic comparison means whereby a comparison value is calculated by acquiring an output of said temperature sensor and compared with said threshold value; an alert signal output means for outputting an alert signal to said notification means depending on the result of comparison by said arithmetic comparison means; a control means for controlling said power supply means, said arithmetic comparison means, and said alert signal output means; and a second temperature sensor disposed in contact with said container away from said heat source by a distance larger than the distance between said heat source and said temperature sensor, said method comprising the steps of: storing or holding an output value O1 of said temperature sensor at time t3; staring the supply of power to said heat source at time t1; terminating the power supply to said heat source at time t2 which is later than time t1; storing or holding an output value O2 of said temperature sensor at time t4 which is later than said time t3 and t1; storing or holding an output value O5 of said second temperature sensor at time t8 which is later than said time t4; determining said comparison value from said output values O1, O2, and O5; comparing said comparison value and said threshold value; and producing said alert signal depending on the result of comparison. 32. The method for controlling the apparatus for determining the type of liquid in a container according to claim 28, wherein said heat source and said temperature sensor are electric resistor elements patterned on said film. 33. The method for controlling the apparatus for determining the type of liquid in a container according to claim 31, wherein said heat source, said temperature sensor, and said second temperature sensor are electric resistor elements patterned on said film. 34. The method for controlling the apparatus for determining the type of liquid in a container according to claim 28, wherein said apparatus for determining the type of liquid in a container comprises a container sensor for detecting the placement of said container, wherein processes are started using a signal from said container sensor as a trigger.

TECHNICAL FIELD The present invention relates to an apparatus and method for determining the type of liquid in a container, and particularly to a technique for determining whether a liquid in a container is a liquid consisting primarily of water and is not dangerous. BACKGROUND ART Passenger transporting institutions, such as airlines, railroads, and bus companies, have the duty to transport passengers safely. In particular, accidents involving aircraft can lead to disasters and a very high level of safety is required. Thus, airplane passengers are subjected to various tests, such as baggage inspection using X-ray imaging devices, body check through frisking or using metal detectors, and, if necessary, interrogation, so as to pick out passengers with malicious intent and prevent them from boarding the airplane. However, in view of the large number of passengers and the convenience for them, it is difficult to subject all the passengers to strict inspections over a long time or to interrogations. Meanwhile, passengers with malicious intent (such as terrorists) try to slip through these inspections and bring dangerous objects on board. While there would be no problem as long as such dangerous objects can be detected by the current baggage inspection and the like, there are some objects that are difficult to detect using metal detectors or X-ray imaging devices, such as gasoline and other combustible liquids. Gasoline and other dangerous liquids are easy to obtain on the market. If such a dangerous liquid is contained in a commercially available beverage container (such as a PET bottle), for example, it becomes more difficult to distinguish it from authentic beverages, and someone with sinister intent could readily adopt such technique. Thus, it is necessary to devise and prepare countermeasures against such dangerous acts. In order to distinguish a dangerous liquid such as gasoline from a beverage that typically consists primarily of water, the liquid could be subjected to a sensory test, such as smelling, or other various methods. However, in the baggage inspection before boarding an airplane, time is of utmost concern and the inspection should be completed as quickly as possible. In response to such needs, the inventors had developed a method for determining the type of liquid in containers made of insulating (dielectric) material, such as PET bottles, based on the difference in dielectric constant that depends on the type of the liquid. The inventions associated with such technique are described in the specification attached to JP Patent Application No. 2003-198046 or 2003-385627 filed by the same applicants as the present application. Besides the aforementioned method for determining the type of a liquid based on the difference in dielectric constant that depends on the type of liquid, a method is conceivable that takes advantage of the difference in thermal characteristics that depend on the type of liquid. For example, Patent Document 1 discloses a technique involving a heat supply means and a temperature-change measuring means that are disposed inside the fuel tank such as the gas tank of an automobile. In this technique, the nature of the fuel (such as its boiling point and T50 value) inside the tank is detected based on the behavior of heat transmitted to heat conducting members on the side of the wall surface of the tank and on the side of the fuel. Patent Document 2 discloses a technique whereby, in order to detect the introduction of water and the like into a petroleum tank or oil delivery channels, an indirectly heated flow detector is used as a fluid distinguishing device. It is well-known that an indirectly heated flowmeter is a current meter comprised of a heating element and a flow rate detecting element (temperature sensor) that are disposed within the fluid, and that it utilizes the property that the temperature of the flow rate detecting element varies depending on the rate of the fluid. In the technique disclosed in Patent Document 2, the fact that the initial output at rate zero of the indirectly heated flowmeter varies depending on the thermal characteristics of the fluid that is in contact therewith is used for the identification of the fluid. Furthermore, Patent Document 3 discloses a technique involving a level measuring device that utilizes a measurement module equipped with a heating means for heating the outer surface of a container and a temperature sensor disposed in the vicinity of the heating means. In this level measuring device, a plurality of measurement modules are arranged outside the container in a row in a biased manner, and the device aims to detect between which measurement modules the fluid level is at based on the difference in behavior of the heat in the container outer wall when there is liquid in the container and when there is not. These techniques disclosed by Patent Documents 1 to 3 all attempt to distinguish the type of liquid (or the presence or absence thereof) based on the thermal characteristics of the liquid (including when there is no liquid). Patent Document 1: JP Patent Publication (Kokai) No. 10-325815 A (1998) Patent Document 2: JP Patent Publication (Kokai) No. 2000-186815 A Patent Document 3: JP Patent Publication (Kokai) No. 2002-214020 A DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention As mentioned above, the inventors had developed an apparatus and method for distinguishing the type of a liquid in a container based on the difference in dielectric constant depending on the type of the liquid, as an inspection apparatus suitable for the determination of whether or not a liquid about to be brought on board an airplane or the like is dangerous. However, as will be seen from the principle of measurement, the technique is only applicable when the container is made of insulating (dielectric) material. Beverage containers that can be brought on board are not limited to PET and glass bottles and other insulators, but there are conductive metal containers such as aluminum cans. Therefore, there is a need for a quick and contactless inspection method capable of handling these conductive metal containers as well as PET bottles and the like. For distinguishing the type of liquid in a conductive container, the techniques according to Patent Documents 1 to 3 can be used. However, the sensors disclosed in Patent Documents 1 and 2 are both disposed within the container and are not suitable when speed is of concern, such as during the baggage inspection prior to boarding an airplane as mentioned above. In addition, the techniques of Patent Documents 1 and 2 require that the sensor be in contact with the liquid inside the container, which requires a sealed beverage to be opened in a kind of destructive inspection. Having the sensor come into contact with the beverage is not preferable from the hygienic point of view as well. Thus, the aforementioned techniques cannot be adopted for baggage inspection and the like. In view of the application to airplane baggage inspection, a technique is indispensable that allows the type of liquid inside a container to be distinguished from the outside. The technique according to Patent Document 3 is actually capable of measuring the nature of liquid (whether or not there is liquid) from the outside of the container. However, it is only capable of detecting the presence or absence of liquid and not the type of liquid. In a method capable of quickly determining the type of liquid in a container made of a conductive material, such as aluminum, without opening it, an infrared heat source such as a halogen lamp is used for contactless measurement. The inventors, however, are aware of several points to be improved upon when this technique is adopted. Namely, the heating of the container outer wall with the infrared heat source such as a halogen lamp is associated with the problem of different heated conditions depending on the nature of the outer wall of the container, such as the shape of the container outer wall or the type of paint applied thereto. Thus, in the system whereby the temperature near a heated site is measured in a contactless manner, errors in the measured value may increase due to the influence of the shape or the like of the container outer wall. Further, when a halogen lamp is used, the life of the apparatus is limited by the life of the halogen lamp in contradiction to the need to extend the life of the apparatus. In addition, there are other needs, such as to reduce the size of the heating and temperature measuring means and to design such means adapted for mass production. It is an object of the invention to provide a technique for quickly distinguishing the type of liquid in a container regardless of the material of the container and from the outside the container, preferably in a contactless manner. It is another object of the invention to provide a liquid determination technique for quickly determining the type of liquid in a container regardless of the material of the container and from the outside thereof, whereby the container outer wall are heated stably and the temperature near a heated site can be stably measured. Yet another object of the invention is to extend the life of a relevant apparatus. Still another object of the invention is to achieve a reduction in size of a heating unit and a temperature measuring unit, and to provide an apparatus suitable for mass production. MEANS FOR SOLVING THE PROBLEM The inventions disclosed in the present specification are as follows, which are referred to as invention 1, invention 2, and so on in order to distinguish one from another. The numbering is provided only for indexing purposes and for the sake of convenience, and it does not indicate the relative scopes of the inventions or their orders. An apparatus for determining the type of liquid in a container according to invention 1 includes a heat source disposed outside a container, a temperature sensor disposed near the heat source for converting the temperature of the outer wall of the container into a voltage or current, a notification means capable of issuing an alert indicating that the content of the container is dangerous, and a control determination circuit whereby the supply of power to the heat source is controlled, and whereby a difference between the value of an output of the temperature sensor at time t1 which is before or when power is supplied to the heat source, and the value of an output of the temperature sensor at time t1+t2 which is when a predetermined time t2 has passed since the time t1, is compared with a predetermined threshold value, and whereby an alert signal is outputted to the notification means. In the apparatus for determining the type of liquid in a container according to invention 1, heat is supplied to a localized portion of the container wall for a certain time, and then the temperature change in the container wall near where heat was supplied is measured. A model of how the heat supplied to the container wall is diffused consists of two paths, namely, one in which the heat is conducted in the container (container material) and the other in which the heat is conducted to the liquid in the container. Assuming that the area of the portion where heat is supplied is sufficiently small relative to the total area of the container wall, and that a region of concern (the site where temperature is measured) is sufficiently close to the heat-supplied portion, the container wall to which heat is supplied can be considered to be a flat plate extending to infinity. Thus, the heat supplied at a spot can be considered to diffuse radially inside the flat plate from the center of the heat-supplied point. Therefore, by assuming a one-dimensional model of heat conduction from the heat-supplied point, the thermal profile at the point of measurement can be qualitatively understood. Namely, a thermal profile at the point of measurement in invention 1 can be considered by assuming one-dimensional fins radially disposed about the heat-supplied point. Assuming now that a quantity Q of heat is being supplied to a point x0 (x=0), the temperature at point x0 is Ts, and the temperature at infinity x∞ is T∞, the temperature T at point x is expressed by the following equation 1 according to the one-dimensional finned thermal conduction model: T−T∞=(Ts−T∞)exp(−SQRT(hp/kA)x) (Equation 1) where exp is natural logarithm, SQRT is square root, h is heat transfer coefficient, p is the boundary length of the fin, k is the thermal conductivity of a metal, and A is the cross-sectional area of the fin. When it is assumed that the liquid is in contact with one side of the one-dimensional fin and that the other side thereof is thermally insulated, the boundary length p is roughly expressed by the sum of the width 1 of the fin and the thickness t thereof. Since 1 is a sufficiently small value relative to t, equation 1 can be expressed by equation 2: T−T∞=(Ts−T∞)exp(−SQRT(h/kt)x) (Equation 2) Since heat transfer coefficient h is not a physical property value, it is expressed by a function of an approximate physical value. As the average heat transfer coefficient (Nusselt number) N when a horizontal column is surrounded by a liquid is expressed by equation 3, heat transfer coefficient h can be expressed by equation 4: (hl/λ)=N=0.1(l3gν−2Cpμλ−1)1/3 (Equation 3) h=0.1(λ2gCpρ2μ−1)1/3 (Equation 4) where g is gravitational acceleration, ν is the kinematic viscosity (=μ/ρ: ρis the density of liquid) of the liquid, Cp is the specific heat at constant temperature of the liquid, μ is the viscosity of the liquid, and λ is the thermal conductivity of the liquid. When equation 2 is written as T−T∞=(Ts−T∞)exp(−x/τ), attenuation of temperature with respect to the distance x of the one-dimensional fin is characterized by an attenuation coefficient τ and, when equation 4 is applied, τ is expressed by equation 5: τ=(ktμ1/3λ−2/3g−1/3Cp−1/3ρ−2/3)1/2 (Equation 5) Namely, it can be seen that as the heat conduction coefficient k of the fin material (container) or the fin thickness (container thickness) t increases, τ increases such that the temperature increase can be observed even at positions relatively far from the heat-supplied point. This shows that the temperature at a location distanced from the heat-supplied point may be observed with good results if the material of the container to which invention 1 is applied is selected such that the heat conduction coefficient k of the material is sufficiently larger than the heat conduction coefficient λ of the liquid (which is assumed to be water or a combustible liquid such as alcohol or gasoline), or if the thickness t of the container is sufficiently large. Examples of the material of the container suitable for invention 1 include metals such as aluminum and iron. These metals have sufficiently greater heat conduction coefficients than that of the liquid in the container. In invention 1, the distance between the heat-supplied point and the point of observation by the temperature sensor is assumed to be in the range of several millimeters to several centimeters. From equation 5, it can be seen that the greater the heat conduction coefficient λ and density ρ of the liquid, the larger the influence on τ will be. Namely, as the heat conduction coefficient λ and density ρ of the liquid increase, τ decreases, such that the rate of cooling at the observation point increases when the quantity of heat supplied (Q) is constant. This indicates that, when there are various types of liquid with which the container may be filled, and when their thermal characteristics are different (particularly heat conduction coefficient λ and density ρ), the differences of the liquids can be detected based on their thermal characteristics. As discussed above, it is possible to observe temperature changes reflecting the thermal characteristics (particularly, heat conduction coefficient λ and density ρ) of the liquid in a container even at an observation point that is relatively far from the heat-supplied point on the outer wall of the container where heat is supplied locally. In invention 1, the type of the liquid in the container is determined by comparing the temperature prior to heat supply and the temperature after a certain time following heat supply. The heat conduction coefficient of water is 0.63(W/mk) while those of ethanol and petroleum are 0.18(W/mk) and 0.15(W/mk), respectively, indicating that the heat conduction coefficient of water is more than 3.5 times as large as that of ethanol or petroleum. Thus, when there is water in the container, the observation point is readily cooled, while when there is a dangerous liquid, such as ethanol or petroleum, in the container, the observation point is not readily cooled. Therefore, by setting a threshold value in advance regarding the temperature difference before and after heat supply, it can be determined that the liquid in the container is safe if the threshold is exceeded and is dangerous if the threshold is not exceeded, with an alert being issued in the latter case. In invention 1, heat is supplied externally, and the type of liquid in the container can be determined based on the measurement of the temperature of the container outer wall. Therefore, there is no need to open the container and the determination procedure is simplified, making it very suitable for baggage inspections prior to boarding an airplane and the like. Furthermore, because the temperature measurement of the outer wall of the container can be completed by making two measurements, the type of liquid in the container can be determined very simply and quickly. For the determination of the type of liquid based on the result of temperature measurement, the measurement result (output of the temperature sensor) can be handled as digital data and processed in software terms, using an information processing device, such as a CPU. In this case, the control determination circuit may have the following configuration. Namely, the constant current circuit may include a timer, a power supply circuit capable of supplying power to the heat source, a notification signal generating circuit for outputting the alert signal to the notification means, an AD converter for converting the output of the temperature sensor into digital data, a data storage unit for recording a program and data, and an arithmetic processing unit for carrying out processes according to the program stored in the data storage unit. The program causes the arithmetic processing unit to carry out the following procedures: a first procedure in which, on the condition that no power is being supplied form the power supply circuit to the heat source, the current time is acquired from the timer and designated as t1, while data is acquired from the AD converter, designated as a value SO1, and recorded in the data storage unit; a second procedure in which the control signal to the power supply circuit is switched to an ON signal for supplying power to the heat source and, after a predetermined period of time has elapsed, the control signal to the power supply circuit is switched to an OFF signal M for not supplying power to the heat source; a third procedure in which the current time is acquired from the timer and it is determined if the acquired current time exceeds the sum of time t1 and the elapsed time t2, namely, t1+t2; a fourth procedure in which, if it is determined that the current time has exceeded time t1+t2 in the third procedure, data is acquired from the AD converter and recorded in the data storage unit as a value SO2; a fifth procedure in which a difference SO2−SO1 between value SO1 and value SO2 is calculated and compared with a predetermined threshold value, and a sixth procedure in which, depending on the result of comparison between difference SO2−SO1 and the threshold value in the fifth procedure, the alert signal is outputted from the notification signal generating circuit. Alternatively, the output of the temperature sensor may be handled as analog data, and a determination as to whether or not the threshold value is exceeded can be made in an analog circuit. In this case, the constant current circuit includes: a lamp circuit for producing a lamp voltage upon reception of a signal indicating the start of measurement; a first latch circuit for latching the value of the temperature sensor when the absolute value of the output of the analog circuit is |V1|; a power supply circuit that starts the supply of power to the heat source when the absolute value of the output of the lamp circuit is |V2| which is greater than |V1| and that terminates the power supply when a predetermined time elapses; a second latch circuit for latching the value of the output of the temperature sensor when the voltage of the lamp circuit reaches |V3| which is larger than |V2|; a differential amplification circuit to which the outputs of the first latch circuit and the second latch circuit are inputted; and a notification signal generating circuit that compares the output of the differential amplification circuit with a predetermined threshold value and outputs the alert signal to the notification means. The heat source and the temperature sensor may be disposed away from the wall of the container. An example of the heat source is a halogen heater, and an example of the temperature sensor is an infrared thermopile. By disposing the heat source and the temperature sensor away from the outer wall of the container, a quicker determination can be made and the problem of thermal resistance, which depends on the manner of contact in the case where contact is required, can be avoided. Namely, in the case where contact is required, thermal resistance develops or varies depending on the pressure of contact, the presence of dirt on the contact surface, and so on, making it impossible to carry out proper measurement or resulting in poor reproducibility of measurement. These possible problems can be avoided in invention 1 in which measurement can be made contactlessly. A light-absorbing heat shield member may be disposed between the heat source and the temperature sensor. Such heat shield member enhances measurement sensitivity. When the heat source is a halogen heater and the temperature sensor is an infrared thermopile, such heat shield member may also be expected to provide the effect of shielding infrared ray. Furthermore, a container sensor for detecting the placement of the container may be provided, and a signal from the container sensor may be used as a trigger for starting the determination process. In this way, operations can be simplified. Invention 1 directed to the apparatus for determining the type of liquid in a container can also be grasped as invention 2 directed to a method for controlling such apparatus. Specifically, invention 2 is directed to a method for controlling an apparatus for determining the type of liquid in a container including: a heat source disposed outside a container; a temperature sensor disposed near the heat source for converting the temperature of the outer wall of the container into a voltage or current; a notification means capable of issuing an alert indicating that the content of the container is dangerous; and a constant current circuit. The method includes the steps of: storing or holding the value of an output of the temperature sensor at time t1; starting the supply of power to the heat source at time t3 which is later than time t1; terminating the power supply to the heat source at time t4 which is later than t3; storing or holding the value of an output of the temperature sensor at time t5 which is later than t3; calculating a difference between the value of the output of the temperature sensor at time t1 and the value of the output of the temperature sensor at time t5; comparing the difference with a predetermined threshold value; and issuing an alert to the notification means depending on the result of comparison between the difference and the threshold value. In invention 2 of the control method, time t5 may be later than time t4. Namely, after a first temperature measurement is made, heat supply is started and then terminated, followed by a second temperature measurement. When the heat source is comprised of a halogen heater and the temperature sensor of an infrared thermopile, the influence of infrared scattered light associated with heat supply can be eliminated. Other inventions are disclosed in the present specification. Invention 3 is directed to an apparatus for determining the type of liquid in a container that includes: one or a plurality of flexible films that is in contact with a container; a temperature sensor provided to the single film or one of the plurality of films; a heat source provided to the same film as or a different film from the single film or one of the plurality of films to which the temperature sensor is provided; a notification means capable of issuing an alert indicating that the content of the container is dangerous; a power supply means for supply power to the heat source; an arithmetic comparison means that acquires the output of the temperature sensor, calculates a comparison value, and compares the comparison value with a predetermined threshold value; and an alert signal output means that outputs an alert signal to the notification means depending on the result of comparison made by the arithmetic comparison means; and a control means for controlling the power supply means, the arithmetic comparison means, and the alert signal output means. In such invention 3 of the apparatus for determining the type of liquid in a container, the heat source is provided to the flexible film which comes into contact with the container outer wall. Thus, the conduction of heat from the heat source to the container outer wall is realized via intra-solid conduction using contact, so that the container outer wall can be stably heated. Furthermore, because the temperature sensor is provided to the flexible film which is in contact with the container outer wall, the heat from the container outer wall can be conducted to the temperature sensor via intra-solid conduction using contact, so that stable temperature measurement can be achieved. The heat source does not need to be a halogen lamp and instead may be comprised of an electric resistor element, which is longer-life, whereby the life of the apparatus can be extended. Furthermore, the heat source and the temperature sensor that are provided to the flexible film can be selected from a wide variety, and they can be easily reduced in size and better adapted for mass production. Examples of the heat source provided to the flexible film include semiconductor elements such as an electric resistor element and a Peltier element, and optical elements such as an induction heating element and a semiconductor infrared laser. The heat source, however, is not particularly limited as long as it is an element that can be mounted on the flexible film. Pattering an electric resistor element on a flexible film is advantageous from the viewpoint of mass producibility, operating life, size, stability, and so on. Examples of the temperature sensor that can be provided to the flexible film include an electric resistor element, a thermocouple, a semiconductor element having a PN junction (bipolar semiconductor element), and other temperature-sensitive elements. However, the temperature sensor is not particularly limited as long as it is an element that can be mounted on the flexible film. Pattering an electric resistor element on the flexible film is advantageous from the viewpoint of mass producibility, operating life, size, stability, and so on. An example of the flexible film is a polyimide film. The polyimide film is thermally and chemically stable and can be advantageously used for hermetically sealing the heat source and the temperature sensor when these are formed by patterning on the film, whereby improved oxidation resistance can be obtained. The material of the flexible film, however, is not limited to polyimide and other examples include polyamide, polyethylene terephthalate (PET), polyethylene, acrylic resin, polytetrafluoroethylene, and other organic resins. In invention 3 of the apparatus for determining the type of liquid in a container, the film is curved when it is disposed such that the peak of the curvature is facing toward a plane on which the container is placed. Thus, when the container is placed, the heat source and the temperature sensor can be pressed against the outer wall of the container due to the flexibility of the film. As a result, a sufficient contract area can be ensured when the heat source and the temperature sensor are pressed against the outer wall of the container and thermal resistance can be reduced. The apparatus may have either a first configuration in which the curved surface of the film is in contact with the container along a line extending in the height direction of the container, or a second configuration in which it is in contact along a line extending in the circumferential direction of the container. In the first configuration, the heat source and the temperature sensor can be disposed with a greater degree of freedom so that they can be disposed on separate films. When the heat source and the temperature sensor are disposed on separate films, thermal conduction from the heat source to the temperature sensor that is not via the container can be reduced and measurement accuracy can be improved. In the second configuration, the chances of the film being damaged when the container is placed can be reduced. Namely, when a container (such as a beverage aluminum bottle or a PET bottle) is mounted on the apparatus, the container would normally be lowered from where it is held. If the U-shaped cross-sectional plane of the curved surface is disposed opposite the bottom surface of the container (the first configuration), the bottom of the container might be caught by the U-shaped cross-sectional plane of the film and thereby damage it. However, in the case of the second configuration, it is the curved plane that the bottom surface of the container faces, so that the possible dragging of the film by the bottom of the container when the container is lowered would be absorbed by the flexibility of the film, and no damage of the film would result. Alternatively, the film may be disposed along the outer wall of the container. Namely, although the film is disposed in the U-shape as in the previous example, the container does not come into contact with the protruding portion of the curved film but is rather held snugly in the concave portion of the U-shape. In this case, too, the heat source and the temperature sensor provided to the film can become closely attached to the outer wall of the container, and it is even possible to further press the film by using the weight of the container. Because the film is flexible, it can deform in conformity with the outer wall of the container such that the heat source and the temperature sensor can be accurately and closely attached to the outer wall of the container. The temperature sensor may be smaller in size than the heat source. By reducing the size of the temperature sensor, the thermal capacity of the temperature sensor can be reduced, measurement time can be reduced, and accuracy of measurement can be improved. A plurality of the heat sources may be provided, and the temperature sensor may be disposed between the multiple heat sources. By providing a plurality of heat sources around the temperature sensor, sufficient amounts of heat can be delivered to the outer wall of the container, whereby measurement time can be reduced. Preferably, the heat source and the temperature sensor are comprised of electric resistor elements formed by patterning on the film, as mentioned above. Examples of the material of the elements include copper foil film, tungsten thin film, doped silicon, and other semiconductor materials. The resistance value of the elements may be appropriately determined as a design variation by selecting the material and hence the specific resistivity of the material, the film thickness, and sizes such as that of the line width of the pattern, for example. In invention 3 of the apparatus for determining the type of liquid in a container, the control means controls the power supply means such that it supplies power to the heat source at time t1 and terminates the power supply at time t2 which is later than t1. The control means measures an output value O1 of the temperature sensor at time t3 and an output value O2 of the temperature sensor at time t4 which is later than t3 and t1, and calculates the comparison value from the output values O2 and O1. Namely, the type of liquid in the container is determined based on the temperature change in the container outer wall before and after the application of heat from the heat source. In the case of invention 3, too, the thermal profile can be interpreted by applying the result of analysis of the thermal profile discussed in invention 1. Namely, in a one-dimensional finned thermal conduction model, when the temperature T at point x is expressed by equations 1 and 2, the average heat conduction coefficient (Nusselt number) N when a horizontal cylinder is surrounded by a liquid is expressed by equation 3, and when the heat conduction coefficient h is expressed by equation 4, attenuation constant τ that characterizes the attenuation of temperature with respect to the distance x of the one-dimensional fin (thermal profile) can be expressed by equation 5. Namely, as the heat conduction coefficient k of the fin material (container), or the fin thickness (container thickness) t increases, τ increases, indicating that the rise in temperature can be observed at a position relatively far from the heat-supplied point. This shows that the temperature at a location distanced from the heat-supplied point can be observed with good results by selecting the material of the container to which invention 3 is applied such that the heat conduction coefficient λ of the material is sufficiently greater than the heat conduction coefficient k of the liquid in the container (which is assumed to be water or a combustible liquid such as alcohol or gasoline), or by adopting a container having sufficient thickness t. Examples of the container material suitable for invention 3 include metals such as aluminum and iron. The heat conduction coefficient of such metals is sufficiently larger than that of the liquid in the container. In invention 3, the distance between the heat-supplied point and the temperature sensor is assumed to be in the range of several millimeters to several centimeters. It can also be seen from equation 5 that the larger the heat conduction coefficient λ and the density ρ of the liquid, the greater the influence they have on ρ. Namely, as the heat conduction coefficient λ and density ρ of the liquid increase, τ becomes smaller, indicating that the rate of cooling at the observation point becomes greater if the quantity of heat supplied (Q) is constant. Thus, differences among liquids can be detected if the type of the liquid with which the container is filled varies and hence its thermal characteristics (particularly heat conduction coefficient λ and density ρ) vary. As discussed above, the temperature change that reflects the thermal characteristics of the liquid in the container (particularly heat conduction coefficient λ and density ρ) can be observed at an observation point that is relatively far from the heat-supplied point where heat is locally applied to the container. In invention 3, by comparing the temperature before heat supply with the temperature a certain time after heat supply, the type of the liquid in the container is determined. The heat conduction coefficient of water is 0.63(W/mk) while those of ethanol and petroleum are 0.18(W/mk) and 0.15(W/mk), respectively, indicating that the heat conduction coefficient of water is more than 3.5 times greater. Thus, when there is water in the container, the observation point is readily cooled, while when there is ethanol, petroleum, or other dangerous liquid in the container, the observation point is not readily cooled. Therefore, by setting a threshold value regarding the temperature difference before and after heat supply, the liquid in the container can be determined to be safe if the threshold value is exceeded and to be dangerous if the threshold value is not exceeded, with an alert being issued in the latter case. Furthermore, in invention 3, because heat is supplied externally and the type of liquid in the container can be determined based on the temperature measurement of the outer wall of the container, there is no need to open the container and determination can be made simply, making the apparatus very suitable for baggage inspections prior to boarding an airplane and the like. Furthermore, because the temperature measurement of the outer wall of the container can be completed by making two measurements, the type of liquid in the container can be determined very simply and quickly. The control means in invention 3 may control the power supply means such that it supplies power to the heat source at time t1 and terminates the power supply at time t2 which is later than t1, measure an output value O3 of the temperature sensor at time t6 which is earlier than time t5 when the container is placed, an output value O4 of the temperature sensor at time t7 which is later than time t5 and earlier than time t1, an output value O1 of the temperature sensor at time t3, and an output value O2 of the temperature sensor at time t4 which is later than time t3 and t1, determine a correction value from the output values O4 and O3, and calculate the comparison value from the output values O2 and O1 and the correction value. In reality, the temperature of the container or the liquid therein is often very different from the measurement ambient temperature (i.e., the temperature of the temperature sensor prior to the placement of the container). For example, when the beverage is tea or coffee, the beverage is often sold or carried as heated. In such cases, the temperature reading of the temperature sensor may drift due to the influence of the temperature of the liquid in the container (temperature of the outer wall of the container). Such drift values can be predicted and corrected by measuring the sensor output values O3 and O4 before making a measurement. Namely, in accordance with the above-described invention, drifts in container temperature from the ambient temperature can be corrected and an accurate determination of the type of the liquid in the container can be made. The prediction of drift in the sensor output due to the difference between the container temperature and the ambient temperature can be made as follows as well. Namely, the control means controls the power supply means such that it supplies power to the heat source at time t1 and terminates the power supply at time t2 which is later than t1. The control means also measures an output value O3 of the temperature sensor at time t6 which is earlier than t5 when the container is placed, an output value O1 of the temperature sensor at time t3, and an output value O2 of the temperature sensor at time t4 which is later than time t3 and t1, and then calculates the comparison value based on the output values O2, O1, and O3. Namely, the correction value is determined from the output value O3 and the output value O1 or O2, and the comparison value is calculated from the output values O1 and O2 and the correction value. This means that the measurement of the sensor output value O4 can be replaced by the measurement of O1 or O2 when determining the correction value. Alternatively, in invention 3, a second temperature sensor is further provided that is in contact with the container away from the heat source by a distance greater than the distance between the heat source and the temperature sensor. The control means controls the power supply means such that it supplies power to the heat source at time t1 and terminates the power supply at time t2 which is later than time t1. The control means also measures an output value O1 of the temperature sensor at time t3, an output value O2 of the temperature sensor at time t4 which is later than time t3 and t1, and an output value O5 of the second temperature sensor at time t8 which is earlier than time t4, and then calculates the comparison value from the output values O2, O1, and O5. Namely, the correction value is determined from the output value O5 and the output value O1 or O2, and the comparison value is calculated from the output values O1 and O2 and the correction value. Thus, the temperature of the container itself is measured by the second temperature sensor, and corrections are made using the thus measured temperature value. The second temperature sensor may be comprised of an electric resistor element patterned on the film, as in the case of the temperature sensor. The second temperature sensor may be disposed at a position displaced from where the temperature sensor and the heat source are disposed in the circumference direction of the container. In invention 3, a container sensor for detecting the placement of the container may be provided, whereby determination can be started by using a signal from the container sensor as a trigger. In this way, operations can be simplified. Invention 3 of the apparatus for determining the type of liquid in a container as described above can also be grasped as invention 4 of a method for controlling such apparatus. Namely, invention 4 is directed to a method for controlling an apparatus for determining the type of liquid in a container, the apparatus including: one or a plurality of flexible films in contact with a container; a temperature sensor provided to the single film or one of the plurality of films, a heat source provided to the same film as or a different film from the single film or one of the plurality of films to which the temperature sensor is provided; a notification means capable of issuing an alert indicating that the content of the container is dangerous; a power supply means for supplying power to the heat source; an arithmetic comparison means that acquires an output of the temperature sensor, calculates a comparison value, and compares the comparison value with a predetermined threshold value; an alert signal output means for outputting an alert signal to the notification means depending on the result of comparison made by the arithmetic comparison means; and a control means for controlling the power supply means, the arithmetic comparison means, and the alert signal output means. The method includes the steps of: storing or holding an output value O1 of the temperature sensor at time t3; starting the supply of power to the heat source at time t1; terminating the power supply to the heat source at time t2 which is later than time t1; storing or holding an output value O2 of the temperature sensor at time t4 which is later than time t3 and t1; determining the comparison value from the output values O1 and O2; comparing the comparison value with the threshold value; and producing the alert signal depending on the result of comparison. Alternatively, the invention is directed to a method for controlling an apparatus having the same structure as mentioned above for determining the type of liquid in a container, the method including the steps of: storing or holding an output value O3 of the temperature sensor at time t6 which is earlier than time t5 when the container is placed; storing or holding an output value O4 of the temperature sensor at time t7 which is later than time t5; storing or holding an output value O1 of the temperature sensor at time t3 which is later than time t7; starting the supply of power to the heat source at time t1 which is later than time t7; terminating the power supply to the heat source at time t2 which is later than time t1; storing or holding an output value O2 of the temperature sensor at time t4 which is later than time t3 and t1; determining a correction value from the output values O3 and O4; determining the comparison value from the output values O1 and O2 and the correction value; comparing the comparison value with the threshold value; and producing the alert signal depending on the result of comparison. Alternatively, the invention is directed to a method for controlling an apparatus having the same structure as mentioned above for determining the type of liquid in a container, the method including the steps of: storing or holding an output value O3 of the temperature sensor at time t6 which is earlier than time t5 when the container is placed; storing or holding an output value O1 of the temperature sensor at time t3 which is later than time t6; starting the supply of power to the heat source at time t1 which is later than time t6; terminating the power supply to the heat source at time t2 which is later than time t1; storing or holding an output value O2 of the temperature sensor at time t4 which is later than time t3 and t1; determining the comparison value from the output values O1, O2 and O3; comparing the comparison value with the threshold value; and producing the alert signal depending on the result of comparison. Alternatively, the invention is directed to a method for determining the type of liquid in a container, the apparatus having the same structure as mentioned above and additionally including a second temperature sensor disposed such that it is in contact with the container away from the heat source by a distance greater than the distance between the heat source and the foregoing sensor, the method including the steps of: storing or holding an output value O1 of the temperature sensor at time t3; starting the supply of power to the heat source at time t1; terminating the power supply to the heat source at time t2 which is later than time t1; storing or holding an output value O2 of the temperature sensor at time t4 which is later than time t3 and t1; storing or holding an output value O5 of the second temperature sensor at time t8 which is earlier than time t4; determining the comparison value from the output values O1, O2, and O5; comparing the comparison value with the threshold value; and producing the alert signal depending on the result of comparison. These control methods according to invention 4 can be applied to the aforementioned apparatuses according to invention 3. EFFECTS OF THE INVENTION Invention 1 and 2 provide techniques for quickly determining the type of liquid in a container from the outside regardless of the material of the container and preferably in a contactless manner. Inventions 3 and 4 provide methods for quickly determining the type of liquid in a container from the outside thereof regardless of the material thereof, whereby the outer wall of the can be stably heated and the temperature near the heated portion can be stably measured. The inventions also extend the life of the apparatus and achieve reductions in size of the heated portion and the temperature measured portion. The apparatuses according to the inventions are well-adapted to mass production. BEST MODES FOR CARRYING OUT THE INVENTION Embodiment 1 Embodiments of the invention will be hereafter described with reference to the drawings. FIG. 1 shows a block diagram of an example of the structure of an apparatus for determining the type of liquid in a container according to an embodiment of the invention. The apparatus for determining the type of liquid in a container according to the present embodiment includes a halogen heater 102, an infrared thermopile 103, a slit 104, a heat shield plate 105, a control circuit 106, LED display devices 107a, 107b, and 107c, and a container sensor 108, all of which are disposed outside the container. The container 101 is an electrically conductive container made of aluminum, for example. The halogen heater 102 is a heat source for irradiating the surface of the container 101 with an infrared ray via the opening provided by the slit 104. Thus, the halogen heater 102 supplies heat energy to the surface of the container 101, A plurality of thermocouples are connected in series to the infrared thermopile 103 so as to form a contactless temperature sensor, with the cold junction in contact with the case and the hot junction in contact with an infrared absorbing member. The infrared thermopile 103 is disposed at a distance of approximately 2 cm from the halogen heater 102. The slit 104 is an optical member for limiting the irradiation light from the halogen heater 102 such that a specific region on the surface of the container 101 is irradiated therewith. It may be comprised of a member having a circular or rectangular opening of several millimeters. The heat shield plate 105 blocks the transmission of heat from the halogen heater 102 to the infrared thermopile 103. The control circuit 106 controls the supply of power to the halogen heater 102, measures the output of the infrared thermopile 103, and determines the type of liquid in a container. The control circuit 106 is also connected to the LED display devices 107a, 107b, and 107c, by which the result of determination is displayed. The control circuit 106 includes a CPU (central processing unit) 109, a heat-source drive circuit 110, an AD converter 111, a ROM (read-only memory), a RAM (random access memory), a timer 114, a container detection circuit 115, and a display control circuit 117. The CPU 109 is comprised of a general-purpose arithmetic processing device and can execute processes in accordance with a predetermined program. The heat-source drive circuit 110, which is controlled by the CPU 109, supplies power to the halogen heater 102. The AD converter 111 converts the output of the infrared thermopile 103 into digital data, which is fed to the CPU 109. The container detection circuit 115 controls the container sensor 108 so as to detect the presence or absence of the container 101 on a container support member (not shown). The timer 114 is controlled by the CPU 109 and is used for measuring the passage of time. The RAM 113 is a temporary data storage device. It stores programs or data loaded from the ROM 112 and ensures a work area for the execution of the programs. The ROM 112 records programs or data used in the apparatus. The ROM 112 may be replaced with other forms of memory, such as a hard disc drive. The operation of a control program recorded in the ROM 112 will be described later. While the control program recorded in the ROM 112 is intangible by itself, it makes up the apparatus organically together with other hardware resources and provides the function of determining the type of liquid, as will be described later. Thus, the control program is a constituent requirement necessary for specifying the apparatus according to the invention. The display control circuit 117 controls the display on the LED display devices 107a, 107b, and 107c. The LED display devices 107a, 107b, and 107c display the condition of the apparatus and the result of measurement of the type of liquid in the container 101 obtained by the apparatus. The LED display device 107a displays in green, the LED display device 107b displays in blue, and the LED display device 107c displays in red, for example. While the following description is directed to an example in which the condition of the apparatus and the result of measurement are indicated (displayed) by the LED display devices 107a, 107b, and 107c, other notification means may be adopted as needed. For example, messages may be displayed on an LCD, or a buzzer may be used for emitting sound upon detection of abnormality. The container sensor 108 is a sensor for detecting the placement of the container 101 on the container support member. It may be comprised of an optical sensor having a light-emitting portion and a light-receiving portion. It may also be comprised of other forms of sensor, such as a proximity sensor. FIG. 2 shows a chart illustrating how the temperature on the surface of the container changes in the apparatus according to the present embodiment. The horizontal axis shows the time and the vertical axis shows the sensor output. The chart shows the temperature change (changes in the sensor output) over time in a graph. At time t2, the halogen heater 102 is turned on (i.e., supply of power from the heat-source drive circuit 110 is initiated). At time t3, the halogen heater 102 is turned off (i.e., supply of power from the heat-source drive circuit 110 is stopped). As the halogen heater 102 is turned off, the temperature on the surface of the container 101 gradually decreases. A line 118 shows the thermal profile on the surface of the container 101 when the liquid therein is ethanol. As discussed above, the higher the heat conductivity of the liquid, the higher the rate of cooling on the surface of the container 101. Thus, the water, even though heat is fed thereto, is cooled swiftly such that the temperature on the surface of the container 101 does not increase much (line 119). On the other hand, ethanol has a heat conductivity smaller than that of water, so that the temperature on the surface of the container becomes somewhat higher with the same quantity of heat applied. The rate at which the liquid is cooled upon turning off the halogen heater 102 is also somewhat higher for water. As a result, a difference of ΔV is produced as the sensor output in terms of the surface temperature of the container 101 at time t4. Thus, in the apparatus according to the present embodiment, the type of liquid in a container is determined based on the temperature change on the surface of the container 101 before and after the application of heat. The temperature on the container surface is measured at time t1 and t4, a temperature difference is calculated, and a predetermined threshold value is set. If the difference exceeds the threshold value, the liquid is determined to be not water (and rather a dangerous material such as alcohol, petroleum, or gasoline). If the difference is below the threshold value, the liquid is determined to be safe water (or beverage consisting primarily of water). The threshold value may be determined by actually measuring the value of the aforementioned difference Δ and adding ΔV/2 to the expected value of difference of water. When the halogen heater 102 is actually turned on, much noise is caused in the infrared thermopile 103 due to the reflection of infrared ray from the surface of the container 101. This noise, however, is not shown in FIG. 2 for the sake of simplicity of description. FIG. 3 shows a flowchart of an example of a method for determining the type of liquid in a container using the apparatus for determining the type of liquid in a container according to Embodiment 1. The procedure including the processes described below can be described by a computer program that is recorded in the ROM 112. In the present specification, programs are considered part of the apparatus of the invention as long as they are recorded in the ROM 112 or other storage devices. While the following description involves an example in which the following processes are executed by a computer program, it goes without saying that similar processes can be realized through other control means, such as sequence control and automatic control based on hardware. At step 120, it is determined whether or not the container 101 is detected. If not, a green lamp is activated indicating that the apparatus is in a standby mode (step 121). The step 120 is repeated until no container is detected. When a container is detected, the routine proceeds to step 122. At step 122, the output of the temperature sensor (infrared thermopile 103) is measured. The output value (analog value) is converted into a digital value by the AD converter 111, and the digital value is recorded in the RAM 113, for example, as a measured value A. A standby period of 0.5 seconds, for example, is allowed to elapse (step 123), and then a control signal (ON signal) to be sent to the heat-source drive circuit 110 for turning on the halogen heater 102 is produced (step 124). Then, at step 125, it is determined whether or not two seconds, for example, has elapsed. If two seconds has elapsed, the halogen heater 102 is turned off at step 126 (i.e., an OFF signal is sent to the heat-source drive circuit as a control signal). Thereafter, a standby period of 0.5 second is allowed to elapse (step 127), and the output of the temperature sensor (infrared thermopile 103) is measured (step 128). The output value (analog value) is converted into a digital value by the AD converter 111, and the digital value is recorded in the RAM 113, for example, as a measured value B. The difference between the variables A and B is then calculated, and it is determined whether this value is greater than a predetermined threshold value (step 129). If B−A is determined to be smaller than the threshold value at step 129, it can be determined that the liquid in the container is a safe liquid consisting primarily of water, and therefore a blue lamp is activated (step 131). Conversely, if it is determined at step 129 that B−A is greater than the threshold value, the liquid in the container cannot be determined to be a safe liquid consisting primarily of water. Therefore, a red lamp is activated indicating the presence of abnormality (step 130). At steps 130 and 131, a standby period of approximately two seconds is provided so as to ensure the time for the operator to recognize the nature of each indication. In this way, the type of liquid in the container can be determined. In the apparatus for determining the type of liquid in a container according to the present embodiment, the type of the liquid content can be easily determined even when the container is made of metal such as aluminum. The determination process is started upon placing the container 101 on the apparatus, and whether or not the content is a safe liquid consisting primarily of water can be easily determined in view of the blue and red lamps. Because a single measurement can be completed in several seconds, the apparatus can be advantageously utilized for inspections that must be carried out quickly, such as the baggage inspection before boarding an airplane. The foregoing descriptions of the duration of time for halogen lamp irradiation and the standby periods are for exemplary purposes only and may be changed as needed. While the invention has been described above with reference to Embodiment 1, obviously the invention is not limited to the foregoing embodiment and may be changed or modified within the spirit of the invention. For example, while in the foregoing Embodiment 1 an example of control was described in which software was employed by the control circuit 106 including the CPU 109, the output of the temperature sensor (infrared thermopile 103) may be used as analog data, and a control circuit 130 may be comprised of an electronic circuit that carries out analog calculations, as shown in FIG. 4. In the control circuit 130 shown in FIG. 4, upon detecting the placement of the container 101 by the container surface 108, a lamp voltage is generated by a lamp circuit 131 and is fed to a comparator 132. The comparator 132, with reference to reference voltages V1, V2, and V3 (V1<V2<V3), turns on a latch control signal to a first latch circuit 134 when the input reaches V1. In response to the turning-on of the latch control signal, the first latch circuit 134 latches the instantaneous sensor output. The output of the first latch circuit 134 is fed to the—input of a differential amplifier 136. When the input to the comparator 132 reaches V2, the comparator 132 turns on the control signal to the heat-source drive circuit 133. In response to the turning-on of the control signal, the heat-source drive circuit 133 turns on the halogen heater 102 and then turns it off two seconds later, for example. When the input to the comparator 132 reaches V3, the comparator 132 turns on the latch control signal to a second latch circuit 135. In response to the turning-on of the latch control signal, the second latch circuit 135 latches the instantaneous sensor output. The output of the second latch circuit 135 is fed to the+input of a differential amplifier 136, which amplifies the difference in input voltages and produces an output. The input of the differential amplifier 136 is fed to a comparator 137, which, with reference to a threshold voltage Vth, turns on the red LED display device 107c if the input is greater than Vth and turns on the blue LED display device 107b if it is below Vth. The comparator 137 is adapted such that, in the absence of the control signal (latch control signal to the second latch circuit 135), which is outputted when the voltage (lamp voltage) inputted to the comparator 132 becomes V3, no display (in red or blue) is made by the LED display device 107b or 107c, and that in other cases a green display (by the LED display device 107a) is made indicating that a standby mode is present. Thus, the time when the lamp voltage reached V3 can be indicated with the red and the blue lamps. While in the foregoing Embodiment 1 an infrared thermopile has been described as an example of the temperature sensor, this is merely for illustrative purposes only and other temperature sensors, such as a thermocouple, a temperature-sensitive resistor element, or the like, can be used as desired. The heat source is also not limited to the halogen heater but may be realized with a heat-generating resistor, a Peltier device, an infrared laser, or the like as desired. Furthermore, in the foregoing Embodiment 1, the temperature sensor and the heat source were spaced apart from each other. However, this is merely an example and, while the temperature sensor and the heat source are preferably spaced apart from the container from the viewpoint of increased speed of determination process and determination reproducibility, as mentioned above, the present invention does not necessarily require that the temperature sensor and the heat source be disposed away from the container. Namely, the temperature sensor and/or the heat source may be in contact with the container. While in the foregoing Embodiment 1 the container 101 was comprised of a metal container of, e.g., aluminum. The material of the container, however, is not limited to metals as long as the heat conductivity of the container is sufficiently larger than the heat conductivity of the liquid therein, or as long as the container is sufficiently thick. For example, the container may be comprised of a nonmetallic container such as a PET bottle and still the liquid determining apparatus and method of controlling the same according to the invention can be employed. The requirements regarding the heat conductivity of the container and its thickness depend on how far the temperature observation point on the container outer wall is distanced from the heated region. If the temperature observed point is sufficiently close to the heated region, the heat conductivity of the container may be on the same order as that of the liquid in the container, and also the thickness of the container may be on the order of the thickness of practical PET bottles. Embodiment 2 In the following, a second embodiment of the invention will be described with reference to the drawings. FIG. 5 shows a block diagram of an example of the structure of an apparatus for determining the type of liquid in a container (to be hereafter referred to as a liquid determining apparatus) according to Embodiment 2. The liquid determining apparatus according to Embodiment 2 includes a flexible film 202 that is in contact with the outer wall of a container 201, a heat source 203 provided to the film 202, a temperature sensor 204 provided to the film 202, a control circuit 206, LED display devices 207a, 207b, and 207c, and a container sensor 208. The container 201 is an electrically conductive container made of aluminum, for example. The liquid determining apparatus according to Embodiment 2 is suitable for use with conductive containers; however, the container 201 is not limited to conductive containers. For example, an insulating container such as a PET bottle may be subjected to the liquid determining apparatus of Embodiment 2. The size and shape of the container 201 are not particularly limited. As will be described later, the shape and size of the container 201 may be random as long as they are such that the heat source 203 and temperature sensor 204 provided to the film 202 will come into contact with its outer wall. It is noted, however, that the liquid needs to be in the container such that it is at least in contact with the portion thereof corresponding to where the heat source 203 and temperature sensor 204 provided to the film 202 are in contact with the outer wall of the container. The film 202 is a flexible plastic film, for example, such as a film of polyimide. Polyimide has a proper flexibility and resilience and is thermally and chemically stable, making it suitable as the film 202 for the present invention. The material of the film 202, however, is not limited to polyimide and other plastic materials may be used, such as polyamide, polyethylene, polyethylene terephthalate, acrylic resin, polytetrafluoroethylene, and ABS resin, for example, as desired. The material of the film is not limited to plastics either, and any insulating material may be used as desired as long as it has flexibility, such as paper, thin-film glass, and so on. The film 202 is disposed in physical contact with the container 201 as will be described later. The heat source 203 is comprised of an electric resistor patterned on the film 202, as will be described later in detail. The functional requirements of the heat source 203 include that it can be installed on the film 202 and that it can generate proper amounts of heat under proper control. Thus, any means can be selected as the heat source 203 as long as it satisfies these requirements. Examples include a Peltier device, a semiconductor laser, and an inductive heating element (consisting of a heated member and an inductive element). The temperature sensor 204 is comprised of an electric resistor element patterned on the film 202, as will be described later. The functional requirements of the temperature sensor 204 are that it can be installed on the film 202 and that it is sensitive to temperature (i.e., it can produce sufficient output signal in response to temperature change). Thus, any means can be selected as the temperature sensor 204 for Embodiment 2 as long as it satisfies these conditions. Examples include a thermocouple and a PN junction of a semiconductor device. The control circuit 206 controls the supply of power to the heat source 203 and measures the output of the temperature sensor 204 to determine the type of liquid in the container. The control circuit 206 is connected to the LED display devices 207a, 207b, and 207c, on which the result of determination is displayed. The control circuit 206 includes a CPU (central processing unit) 209, a heat-source drive circuit 210, an AD converter 211, a ROM (read-only memory) 212, a RAM (random-access memory) 213, a timer 214, a container detection circuit 215, a constant current circuit 216, and a display control circuit 217. The CPU 209 is comprised of a general-purpose arithmetic processing device capable of executing processes according to a predetermined program. The heat-source drive circuit 210 is controlled by the CPU 209 and supplies power to the heat source 203. The AD converter 211 converts the output of the temperature sensor 204 into digital data, which is outputted to the CPU 209. The container detection circuit 215 controls the container sensor 208 and detects the presence or absence of the container 201 disposed on the container supporting member (not shown). The timer 214, which is controlled by the CPU 209, is used for measuring the passage of time. The RAM 213 is a temporary data storage device, where programs or data loaded form the ROM 212 are retained and where a work area for the execution of a program is ensured. The ROM 212 records programs or data used by the apparatus. The ROM 212 may be replaced with other memory devices, such as a hard disc drive. The operation of the control program recorded in the ROM 212 will be described later. While the control program recorded in the ROM 212 is intangible by itself, it is recorded in the ROM 212, constitutes an organic part of the apparatus together with its hardware resources, and plays a role in the liquid type determination function of the apparatus, as will be described later. Thus, the control program is a constituent requirement for specifying the apparatus according to the invention. The constant current circuit 216 supplies a constant current to the temperature sensor 204 of Embodiment 2. The electric resistor element illustrated as an example of the temperature sensor 204 of Embodiment 2 is a passive element and it does not output any signal by itself. Rather, a constant current is supplied to the temperature sensor 204 (electric resistor element) from the constant current circuit 216 and its resistance value is detected in the form of voltage. When the temperature sensor is comprised of an active element that produces an output voltage (signal) by itself, the constant current circuit 216 would not be necessary. The display control circuit 217 controls the display on the LED display devices 207a, 207b, and 207c. The LED display devices 207a, 207b, and 207c display the result of determination of the type of liquid in the container 201 made by the apparatus as well as the condition thereof, as will be described later. The LED display device 207a emits green light, the LED display device 207b emits blue light, and the LED display device 207c emits red light, for example. While the following example describes the LED display devices 207a, 207b, and 207c giving notification (displaying) of the condition of the apparatus or the result of measurement, any other notifying means may be used. For example, messages may be displayed on an LCD, or a buzzer may emit sound upon detection of abnormality. The container sensor 208 is a sensor for detecting the presence of the container 201 disposed on the container supporting member. An example is an optical sensor consisting of a light-emitting portion and a light-receiving portion. Other sensors, such as a proximity sensor, may be used. FIG. 6 shows a schematic perspective view of an example of a container disposed portion of the liquid determining apparatus according to Embodiment 2. A container disposed portion 218 includes a stage 218a on which the container 201 is to be disposed. At the center of the stage 218a, a slit 218b is provided for the alignment of the position of the container 201. Inside the slit 218b is disposed a film 202 curved in the U-shape, with the bottom of the U facing upward. The container 201 is disposed such that it is partly buried in the slit 218b, with the upper part of the container placed in the back. As the container 201 is aligned with respect to the slit 218b, the container 201 can be easily aligned such that its outer wall come into contact with the film 202 without fail. Because the stage 218a is disposed at an angle, as shown, the container 201 can be stably disposed with the bottom thereof abutting against a front face plate 218c. A stopper may be provided to the front face plate 218c so that the bottom of the container 201 can be reliably abutted against the front face plate 218c. That the stage 218a is disposed at an angle means that the container 201 is also disposed at an angle, which provides the advantage that the liquid when there is only a little of it therein can be collected at the bottom of the container. In such cases, the probability of the liquid when there is only a little of it remaining at a portion of the container where the heat source 203 and temperature sensor 204 of the film 202 are in contact can be increased by disposing the film 202 at near the bottom of the container 201. Thus, the type of liquid can be reliably determined even when there is only a little of the liquid in the container 201 or when the size of the container 201 varies. FIG. 7 shows a perspective view of the film 202 that is curved in the U-shape and disposed with the bottom of the U facing upward. At the convex portion of the curvature (where the container 201 is in contact) are disposed the heat source 203 and the temperature sensor 204. FIG. 8 shows a cross section of the film 202 when the container 201 is disposed at the container disposed portion 218 shown in FIG. 6. The state of the film 202 prior to the placement of the container 201 is indicated by the broken line. As shown, because the film 202 is flexible, the convex portion of the film 202 is pushed down when the container 201 is disposed, such that the convex portion becomes deformed in conformity of the profile of the outer wall of the container 201. As a result, the heat source 203 and the temperature sensor 204 come into contact with the outer wall of the container 202 without fail, thus ensuring contact between them. Furthermore, because the film 202 is flexible, the heat source 203 and the temperature sensor 204 are pressed against the container 201, so that the heat resistance at the contact portion can be reduced and a stable supply of heat and temperature measurement can be ensured. FIG. 9(a) shows a plan view of an example of the heat source 203 and the temperature sensor 204 provided to the film 202. The heat source 203 and the temperature sensor 204 are comprised of electric resistor elements patterned on the film 202. The heat source 203 and the temperature sensor 204 are connected to individual terminals 203a and 204a via wiring lines 203b and 204b, respectively. It goes without saying that the terminals and wiring lines are all patterned as well. It is also obvious that after the heat source 203 and the temperature sensor 204, the individual terminals 203a and 204a, and the wiring lines 203b and 204b have been patterned, they are shielded with the same or a different material from the film 202. Pattern production methods are well-known and their detailed description is omitted herein. Examples of the material of the heat source 203, temperature sensor 204, terminals 203a and 204a, and wiring lines 203b and 204b include metals such as copper and tungsten, and semiconductors such as doped silicon. FIG. 9(b) shows a partly enlarged plan view of a portion B of FIG. 9(a). The heat source 203 can be produced by forming a fine zigzag pattern, as shown. The line width of such pattern is a matter of design variation and may be determined as appropriate depending on the quantity of heat required and the specific resistivity of the material. The same goes for the temperature sensor 204. In the example shown in FIG. 9, there is one each of the heat source 203 and the temperature sensor 204, both having substantially the same size. However, other suitable variations are possible. FIGS. 10 to 12 show plan views of variations of the heat source 203 and the temperature sensor 204 provided to the film 202. In the variation shown in FIG. 10, the temperature sensor 204 is patterned to be larger than the heat source 203, whereby the heat capacity of the temperature sensor can be reduced and the rate of response during temperature measurement can be improved. In the variation shown in FIG. 11, a plurality of heat sources 203 are provided where they are disposed such that the temperature sensor 204 is sandwiched thereby. In this case, sufficient heat amounts can be supplied, so that determination can be made at high speed and with accuracy. In the variation shown in FIG. 12, the film 202 for the heat source 203 and that for the temperature sensor 204 are separately provided. In this case, the path of heat that is not via the container 201, i.e., the path of thermal flow through the film 202, can be blocked, whereby the accuracy of reliability of measurement can be improved. While in the foregoing examples the film 202 is curved in the U-shape with the bottom of the U facing upward, the film 202 may be disposed in other manners. For example, the film 202 may be curved in the U-shape and the bottom of the U may be facing downward, namely, the convex portion facing upward. In this case, the film can be deformed in conformity to the profile of the outer wall of the container using the weight of the container 201 itself. Alternatively, the film 202 may be disposed as shown in FIG. 13 where it is rotated by 90° with respect to the example of FIG. 6, such that the film 202 is in contact with the container 201 along the circumference thereof. In this case, the chances of the film 202 being damaged upon placement can be reduced. Namely, if the container 201 is disposed as shown, the bottom of the container 201 could hit the film 202. If that happens in the example of FIG. 6, the bottom of the container 201 could drag on the curved film cross-sectionally, which would damage the film 202. However, when the film 202 is disposed as shown in FIG. 13, even if the bottom of the container 201 hits the film 202, the contact would be on the curved surface of the film 202, so that the curved surface would merely deform and not be damaged. An example of the patterning of the heat source 203 and the temperature sensor 204 for the case of FIG. 13 is shown in FIG. 14. FIG. 15 is a graph showing how the temperature on the surface of the container changes in the liquid determining apparatus according to Embodiment 2. The graph shows the change in temperature (namely, change in sensor output) over time in which time is shown on the horizontal axis and sensor output on the vertical axis. At time t1, the heat source 203 is turned on (by starting the supply of power from the heat-source drive circuit 210). At time t2, the heat source 203 is turned off (by terminating the supply of power from the heat-source drive circuit 210). When the heat source 203 is turned on, the surface temperature of the container 201 increases (i.e., the sensor output increases); when the heat source 203 is turned off, the surface temperature of the container 201 gradually drops. A line 219a shows the thermal profile on the surface of the container 201 when the liquid in the container 201 is ethanol. A line 219b shows the thermal profile on the surface of the container 201 when the liquid is water. As discussed earlier, the higher the heat conduction coefficient of the liquid, the higher the rate of cooling on the surface of the container 201. Thus, the water is rapidly cooled even though it is fed with heat, such that the surface temperature of the container 201 does not rise much (line 219b). On the other hand, in the case of ethanol, because ethanol's heat conduction coefficient is smaller than that of water, the surface temperature of the container becomes higher with the same quantity of heat applied. The cooling rate upon turning off the heat source 203 is also slightly higher for water. As a result, the difference ΔV is caused in the sensor output indicating the surface temperature of the container 201 at time t4. Thus, in accordance with the liquid determining apparatus of Embodiment 2, the type of liquid in the container is determined based on the temperature change on the surface of the container 201 before and after the application of heat. The container surface temperatures are measured at time t3 and time t4, the difference between them is calculated as a comparison value, and a predetermined threshold value is set. If the comparison value is greater than the threshold value, the liquid is determined to be not water (i.e., alcohol, petroleum, gasoline, or other dangerous substance). If the comparison value is smaller than the threshold value, the liquid is determined to be safe water (or a beverage consisting primarily of water). The threshold value may be determined by actually measuring the value of the aforementioned difference ΔV and adding ΔV/2 to the expected value of the difference for water. Noise could be produced upon actually turning on the heat source 203; in FIG. 15, however, such noise is not shown for the sake of simplicity of explanation. In the example shown in FIG. 15, the initial measurement time for obtaining the comparison value is earlier than time t1 (namely, t3), and the second measurement time is later than time t2 (namely, t4). These are merely examples and the times of measurement are not limited to t3 or t4 as long as the times are such that the comparison value obtained reflects the thermal characteristics of the liquid in the container. For example, the initial measurement time may be at the same time as, or later than, t1. And the second measurement time may be at any time later than the first measurement time (it is noted, however, that the second measurement time must be later than time t1 if the first measurement time is earlier than time t1). Thus, any time in the period stretching over t1 or between t1 and t2 when the container surface temperature is rising, the period stretching over t2 when the container surface temperature is changing, or the period after t2 when the container surface temperature is dropping (i.e., period between the first measurement and the second measurement) may be selected. FIG. 16 shows a flowchart of an example of the method for determining a liquid in a container using the liquid determining apparatus according to Embodiment 2. A procedure involving the processes described below can be implemented as a computer program that is recorded in the aforementioned ROM 212. In the present specification, such program, as long as it is recorded in the ROM 212 or other storage device, constitutes a part of the apparatus of the invention. While an example will be described below in which the processes are executed using a computer program, it goes without saying that the same processes can be realized using other control means, such as sequence control, and hardware-based automatic control, for example. At step 220, it is determined whether or not the container 201 is detected. If no container is detected, the green lamp is turned on, indicating that the apparatus is in a standby state (step 221), and step 220 is repeated until no container is detected. If a container is detected, the routine proceeds to step 222. At step 222, the output of the temperature sensor 204 is measured. The output value (O1) from the temperature sensor 204, which is an analog value, is converted into a digital value by the AD converter 211, and a resultant value A is recorded in the RAM 213, for example. Then, a standby period of 0.5 second, for example, is allowed to elapse (step 223), followed by the production of a control signal (ON signal) to the heat-source drive circuit 210 for turning on the heat source 203 (step 224). Then, it is determined at step 225 whether or not two seconds, for example, has elapsed, and if the time has elapsed, the heat source 203 is turned off at step 226 (i.e., the control signal to the heat-source drive circuit is rendered into an OFF signal). After the apparatus stands by for 0.5 second (step 227), the output of the temperature sensor 204 is measured (step 228). The output value (O2) of the temperature sensor 204 is an analog value, which is converted into a digital value by the AD converter 211 and a resultant value B is recorded in the RAM 213, for example. Then, the difference between the values A and B is calculated, and it is determined whether the difference value (comparison value) is greater or smaller than a predetermined threshold value (step 229). If B−A is smaller than the threshold value at step 229, the liquid in the container can be considered to be a safe liquid consisting primarily of water, and the blue lamp is turned on (step 231). Conversely, if B−A is determined to be greater than the threshold value at step 229, the liquid in the container cannot be considered to be a safe liquid consisting primarily of water, and therefore the red lamp is turned on (step 230), indicating abnormality. At steps 230 and 231, a standby period of 2 seconds, for example, is allocated for the operator to recognize the nature of notification. Thereafter, the routine returns to step 220 and the above-described routine is repeated. In this way, the type of liquid in the container can be determined. As mentioned earlier, the first sensor output measurement (of value A) and the second sensor output measurement (of value B) may be carried out at any time as long as the comparison value obtained reflects the thermal characteristics of the liquid in the container. Namely, the measurement of value A at step 222 may be performed after power is turned on at step 224. The measurement of value B at step 228 may be performed before power is turned off at step 226. The measurement of values A and B at step 222 and step 228, respectively, may be performed after power is turned off at step 226. However, a proper time must be provided between the measurement of value A and the measurement of value B. When a measurement is performed in the period in which the container surface temperature is decreasing, the comparison value B−A becomes a negative number. In this case, therefore, the absolute value of B−A must be used for the determination at step 229. In accordance with the apparatus for determining the type of liquid in a container according to Embodiment 2, the type of liquid can be easily determined even if the liquid is in a metal container, such as that of aluminum. The determination procedure begins upon placing of the container 201 on the apparatus. Whether or not the liquid in the container consists primarily of water and is safe can be easily determined based on the illumination of the blue or red lamp. A single measurement can be completed within several seconds, making the apparatus suitable for applications where expeditious processing is required, such as during baggage inspection prior to boarding an airplane. In accordance with the liquid-type determination apparatus according to Embodiment 2, the heat source 203 and the temperature sensor 204 are patterned on the film 202, which is bent in the U-shape and disposed such that the heat source 203 and the temperature sensor 204 can be in contact with the container 201. Thus, direct contact between the container 201 and the heat source or temperature sensor is ensured, whereby stable supply of heat and temperature measurement can be realized. Because the heat source and the temperature sensor are formed on the film by patterning, the apparatus can be reduced in size and mass-produced easily. Furthermore, stable elements can be employed for the heat source and the temperature sensor, so that the life of the apparatus can be extended. The on/off times and the standby time of the heat source described above are merely examples and may be changed as needed. While the invention has been described above with reference to Embodiment 2, obviously the invention is not limited to the foregoing embodiment, and various changes or modifications may be made within the spirit of the invention. For example, Embodiment 2 was described with reference to a control method in the case where the container temperature is substantially equal to the ambient temperature. The container temperature, however, is in practice often different from the ambient temperature. In such cases, the following improvements may be added. With reference to FIG. 17, the sensor output when the container temperature is different from the ambient temperature is described. When the time at which the container 201 is placed is t5, the sensor output prior to t5 corresponds to the ambient temperature. As the container 201 is placed at t5, the sensor output increases as shown by the broken line. A broken line 240a corresponds to a case where the container temperature is e.g. 50° C. A broken line 240b corresponds to a case where the container temperature is e.g. 40° C. And a broken line 240c corresponds to a case where the container temperature is e.g. 30° C. The higher the container temperature, the higher the asymptotic value toward which the sensor output increases. If there are such fluctuations in sensor output, an accurate determination based on measurement through the above-described control may be hindered. Thus, the determination control is preferably carried out after the sensor output fluctuations due to the container temperature are eliminated. However, the determination must be made quickly and as soon as the container 201 is placed. In the following, thermal profiles upon heating of the container surface when there are sensor output fluctuations due to the container temperature are considered. The solid line shown in the graph of FIG. 18 plots the sensor output upon heating of the container surface for a certain period of time when there is a sensor output fluctuation. The broken line shows the sensor output fluctuations due to the container temperature. The heat source 203 is turned on at time t1 and turned off at time t2. The sensor output is measured at time t3 (sensor output O1 in Embodiment 2 (measured value A)) and at time t4 (sensor output O2 in Embodiment 2 (measured value B)). The measurement times t3 and t4 may be changed, as mentioned above. In this case, the sensor output fluctuation (baseline fluctuation) ΔVb due to the container temperature is included in the difference ΔV in measurement values between times t4 and t3. If ΔVb cannot be ignored with respect to the margin from the threshold value, the validity of determination is called into question. Thus, ΔVb needs to be corrected before determination by measuring or predicting ΔVb in one way or another. FIG. 19 shows a flowchart of an example of determination control when there is baseline fluctuation. At the beginning of the program, the value T0 is initialized to zero (step 250), and then the output of the temperature sensor is measured before detecting a container (step 251). A measurement value (O3) of the sensor output is recorded in the RAM 213, for example, as a value T1, as at step 222 of FIG. 16. It is then determined whether or not the difference between a previously measured value and the value TO is below a predetermined value so as to make sure the sensor output is stable (steps 252 and 253). Once the sensor output is stable, the presence or absence of a container is detected, and, if no container is detected, the green lamp is turned on indicating that measurement can be made (steps 254 to 256). When the sensor output is measured for the stability confirmation purpose, the value T1 is recorded in a buffer and the like as a previous value T0 for the subsequent measurement (steps 253 and 255). If a container is detected, the sensor output is measured (step 258) after a standby period of 0.5 second, for example (step 257). A resultant measurement value (O4) of the sensor output is recorded in the RAM 213 as a value T2 as previously. A correction value C corresponding to the baseline fluctuation ΔVb is determined from the difference between the values T2 and T1 (step 259). During the determination of the correction value C, a pre-recorded correction table 260 can be referred to. The correction method, however, is not limited to the one involving the correction table 260 and the correction value may be determined by calculations using an appropriate model function based on the values T1 and T2. After the correction value C is determined, the value A (sensor output value O1) and the value B (sensor output value O2) are measured as in the case of FIG. 16 (steps 261 to 266). However, in this case, since a proper time has elapsed since the container was placed, the standby period in step 223 in FIG. 16 is not needed. After the values A and B are measured, the correction value C is added and the resultant value is compared with the threshold value (step 267). Steps 268 and 269 are similar to steps 230 and 231 of FIG. 16. These controls allow an accurate determination to be made even if there was a baseline fluctuation. The times at which the values A and B are measured are not particularly limited as long as a comparison value that reflects the thermal characteristics of the liquid in the container can be obtained, as in the previous embodiment. During the controls shown in FIG. 19, the measurement of the value T2 (sensor output value O4) is not necessarily required. Namely, the correction value C may be determined using value A or B instead of value T2. More specifically, the correction value C can be determined based on value T1 and value A, or value T1 and value B, and then the comparison value can be determined based on the correction value C and values A and B. During the determination of the correction value C, a correction table may be employed, or the correction value may be determined by calculations using an appropriate model function, as in the previous case. Alternatively, a second temperature sensor 270 can be disposed at a sufficient distance from the heat source 203 as shown in FIG. 20, separately from the temperature sensor in Embodiment 2. For the measurement of the output of the temperature sensor 270, an AD converter 271 and a constant current circuit 272 are provided. In this case, the container temperature is measured by the second temperature sensor at the same times of measurement for the values A and B so as to measure the baseline fluctuation. The measurement timing for the second temperature sensor 270, however, is not limited to the above example and may be determined as desired. In this case, a correction table or corrective calculations for the correction value C in accordance with the measurement timing must be provided. In the previous example, a software-based control by the control circuit 206 including the CPU 209 was described. It is possible, however, to handle the output of the temperature sensor as analog data and to construct the control circuit 280 with an electronic circuit performing analog calculations, as shown in FIG. 21. In a control circuit 280 shown in FIG. 21, as the placement of the container 201 is detected by the container sensor 208, a lamp voltage is generated by the lamp circuit 281 and fed to a comparator 282. The comparator 282, with reference to reference voltages V1, V2, and V3 (V1<V2<V3), turns on a latch control signal to a first latch circuit 284 if the input reaches V1. The first latch circuit 284, in response to the turning-on of the latch control signal, latches the instantaneous sensor output. The output of the first latch circuit 284 is inputted to the—input of a differential amplifier 286. If the input to the comparator 282 reaches V2, the comparator 282 turns on a control signal to a heat-source drive circuit 283. In response to the turning-on of the control signal, the heat-source drive circuit 283 turns on the heat source 203, and then turns it off two seconds later, for example. If the input to the comparator 282 reaches V3, the comparator 282 turns on a latch control signal to a second latch circuit 285. In response to the turning-on of the latch control signal, the second latch circuit 285 latches the instantaneous sensor output. The output of the second latch circuit 285 is fed to the +input to a differential amplifier 286, which amplifies the difference in input voltages. The input to the differential amplifier 286 is inputted to a comparator 287. The comparator 287, with reference to the threshold voltage Vth, turns on the red LED display device 207c if the input is greater than Vth and turns on the blue LED display device 207b if the input is not greater than Vth. The comparator 287 is adapted such that, in the absence of the control signal (latch control signal to the second latch circuit 285) that is outputted upon the voltage (lamp voltage) inputted to the comparator 282 reaching V3, neither the LED display devices 207b nor 207c (red or blue) are turned on and instead the green display (LED display device 207a) is turned on, indicating a standby. Thus, the determination upon the lamp voltage reaching V3 can be indicated by the illumination of the red or blue lamp. There is also provided a constant current circuit 288 for producing a sensor output. INDUSTRIAL APPLICABILITY The invention relates to an apparatus and method for determining the safety of the content of a beverage container brought aboard transportation means such as aircraft simply and reliably without opening the container. The invention can be applied in industries relating to inspection equipment for inspecting the content of containers. The apparatus for determining the type of liquid in a container according to the invention can also be used by transportation facilities in airline industries, for example. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a block diagram of an example of the structure of an apparatus for determining the type of liquid in a container according to Embodiment 1 of the invention. FIG. 2 shows a chart illustrating how the surface temperature of a container changes in the apparatus according to Embodiment 1. FIG. 3 shows a flowchart of an example of a method for determining the type of liquid in a container in the liquid-type determination apparatus according to Embodiment 1. FIG. 4 shows a block diagram of another example of the structure of an apparatus for determining the type of liquid in a container according to the invention. FIG. 5 shows a block diagram of an example of the structure of an apparatus for determining the type of liquid in a container according to Embodiment 2. FIG. 6 shows a schematic perspective view of an example of a container disposed portion of the liquid determining apparatus according to Embodiment 2. FIG. 7 shows a perspective view of a film 202 curved in the U-shape and disposed with the convex portion thereof facing upward. FIG. 8 shows a cross-sectional view of the film 202 when a container 201 is placed on the container disposed portion 218. FIG. 9(a) shows a plan view of an example of a heat source 203 and a temperature sensor 204 provided to the film 202. FIG. 9(b) shows a partly enlarged plan view of a portion B of FIG. 9(a). FIG. 10 shows a plan view of a variation of the heat source 203 and temperature sensor 204 provided to the film 202. FIG. 11 shows a plan view of a variation of the heat source 203 and temperature sensor 204 provided to the film 202. FIG. 12 show a plan view of a variation of the heat source 203 and temperature sensor 204 provided to the film 202. FIG. 13 shows a schematic perspective view of another example of the container disposed portion of the liquid determining apparatus according to Embodiment 2 of the invention. FIG. 14 shows a plan view of an example of the patterning of the heat source 203 and temperature sensor 204 in the example of FIG. 13. FIG. 15 shows a chart illustrating how the container surface temperature changes in the liquid determining apparatus according to Embodiment 2. FIG. 16 shows a flowchart of an example of a method for determining the type of liquid in a container in the liquid determining apparatus according to Embodiment 2. FIG. 17 shows a graph illustrating an example of the sensor output when the container temperature is different from the ambient temperature. FIG. 18 shows a graph illustrating an example of the sensor output when the container temperature is different from the ambient temperature. FIG. 19 shows a flowchart of an example of determination control when there is a baseline fluctuation. FIG. 20 shows a block diagram of another example of the structure of a liquid-type determination apparatus according to an embodiment of the invention. FIG. 21 shows a block diagram of another example of the structure of a liquid-type determination apparatus according to an embodiment of the invention. EXPLANATION OF THE NUMERALS 101 . . . container, 102 . . . halogen heater, 103 . . . infrared thermopile, 104 . . . slit, 105 . . . heat shield plate, 106 . . . control circuit, 107a . . . LED display device, 107b. . . LED display device, 107c . . . LED display device, 108 . . . container sensor, 109 . . . CPU, 110 . . . heat-source drive circuit, 111 . . . AD converter, 112 . . . ROM, 113 . . . RAM, 114 . . . timer, 115 . . . container detection circuit, 117 . . . display control circuit, 130 . . . control circuit, 131 . . . lamp circuit, 132 . . . comparator, 133 . . . heat-source drive circuit, 134, 135 . . . latch circuit, 136 . . . differential amplifier, 137 . . . comparator, 201 . . . container, 202 . . . film, 203 . . . heat source, 204 . . . temperature sensor, 203a, 204a . . . terminals, 203b, 204b . . . wiring lines, 206 . . . control circuit, 207a, 207b, 207c . . . LED display device, 208 . . . container sensor, 209 . . . CPU, 210 . . . heat-source drive circuit, 211 . . . AD converter, 212 . . . ROM 213 . . . RAM, 214 . . . timer, 215 . . . container detection circuit, 216 . . . constant current circuit, 217 . . . display control circuit, 218 . . . container disposed portion, 218a . . . stage, 218b . . . slit, 218c . . . front plate, 260 . . . correction table, 270 . . . second temperature sensor, 271 . . . AD converter, 272 . . . constant current circuit, 280 . . . control circuit, 281 . . . lamp circuit, 282 . . . comparator, 283 . . . heat-source drive circuit, 284 . . . first latch circuit, 285 . . . second latch circuit, 286 . . . differential amplifier, 287 . . . comparator, 288 . . . constant current circuit

<SOH> BACKGROUND ART <EOH>Passenger transporting institutions, such as airlines, railroads, and bus companies, have the duty to transport passengers safely. In particular, accidents involving aircraft can lead to disasters and a very high level of safety is required. Thus, airplane passengers are subjected to various tests, such as baggage inspection using X-ray imaging devices, body check through frisking or using metal detectors, and, if necessary, interrogation, so as to pick out passengers with malicious intent and prevent them from boarding the airplane. However, in view of the large number of passengers and the convenience for them, it is difficult to subject all the passengers to strict inspections over a long time or to interrogations. Meanwhile, passengers with malicious intent (such as terrorists) try to slip through these inspections and bring dangerous objects on board. While there would be no problem as long as such dangerous objects can be detected by the current baggage inspection and the like, there are some objects that are difficult to detect using metal detectors or X-ray imaging devices, such as gasoline and other combustible liquids. Gasoline and other dangerous liquids are easy to obtain on the market. If such a dangerous liquid is contained in a commercially available beverage container (such as a PET bottle), for example, it becomes more difficult to distinguish it from authentic beverages, and someone with sinister intent could readily adopt such technique. Thus, it is necessary to devise and prepare countermeasures against such dangerous acts. In order to distinguish a dangerous liquid such as gasoline from a beverage that typically consists primarily of water, the liquid could be subjected to a sensory test, such as smelling, or other various methods. However, in the baggage inspection before boarding an airplane, time is of utmost concern and the inspection should be completed as quickly as possible. In response to such needs, the inventors had developed a method for determining the type of liquid in containers made of insulating (dielectric) material, such as PET bottles, based on the difference in dielectric constant that depends on the type of the liquid. The inventions associated with such technique are described in the specification attached to JP Patent Application No. 2003-198046 or 2003-385627 filed by the same applicants as the present application. Besides the aforementioned method for determining the type of a liquid based on the difference in dielectric constant that depends on the type of liquid, a method is conceivable that takes advantage of the difference in thermal characteristics that depend on the type of liquid. For example, Patent Document 1 discloses a technique involving a heat supply means and a temperature-change measuring means that are disposed inside the fuel tank such as the gas tank of an automobile. In this technique, the nature of the fuel (such as its boiling point and T50 value) inside the tank is detected based on the behavior of heat transmitted to heat conducting members on the side of the wall surface of the tank and on the side of the fuel. Patent Document 2 discloses a technique whereby, in order to detect the introduction of water and the like into a petroleum tank or oil delivery channels, an indirectly heated flow detector is used as a fluid distinguishing device. It is well-known that an indirectly heated flowmeter is a current meter comprised of a heating element and a flow rate detecting element (temperature sensor) that are disposed within the fluid, and that it utilizes the property that the temperature of the flow rate detecting element varies depending on the rate of the fluid. In the technique disclosed in Patent Document 2, the fact that the initial output at rate zero of the indirectly heated flowmeter varies depending on the thermal characteristics of the fluid that is in contact therewith is used for the identification of the fluid. Furthermore, Patent Document 3 discloses a technique involving a level measuring device that utilizes a measurement module equipped with a heating means for heating the outer surface of a container and a temperature sensor disposed in the vicinity of the heating means. In this level measuring device, a plurality of measurement modules are arranged outside the container in a row in a biased manner, and the device aims to detect between which measurement modules the fluid level is at based on the difference in behavior of the heat in the container outer wall when there is liquid in the container and when there is not. These techniques disclosed by Patent Documents 1 to 3 all attempt to distinguish the type of liquid (or the presence or absence thereof) based on the thermal characteristics of the liquid (including when there is no liquid). Patent Document 1: JP Patent Publication (Kokai) No. 10-325815 A (1998) Patent Document 2: JP Patent Publication (Kokai) No. 2000-186815 A Patent Document 3: JP Patent Publication (Kokai) No. 2002-214020 A

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows a block diagram of an example of the structure of an apparatus for determining the type of liquid in a container according to Embodiment 1 of the invention. FIG. 2 shows a chart illustrating how the surface temperature of a container changes in the apparatus according to Embodiment 1. FIG. 3 shows a flowchart of an example of a method for determining the type of liquid in a container in the liquid-type determination apparatus according to Embodiment 1. FIG. 4 shows a block diagram of another example of the structure of an apparatus for determining the type of liquid in a container according to the invention. FIG. 5 shows a block diagram of an example of the structure of an apparatus for determining the type of liquid in a container according to Embodiment 2. FIG. 6 shows a schematic perspective view of an example of a container disposed portion of the liquid determining apparatus according to Embodiment 2. FIG. 7 shows a perspective view of a film 202 curved in the U-shape and disposed with the convex portion thereof facing upward. FIG. 8 shows a cross-sectional view of the film 202 when a container 201 is placed on the container disposed portion 218 . FIG. 9 ( a ) shows a plan view of an example of a heat source 203 and a temperature sensor 204 provided to the film 202 . FIG. 9 ( b ) shows a partly enlarged plan view of a portion B of FIG. 9 ( a ). FIG. 10 shows a plan view of a variation of the heat source 203 and temperature sensor 204 provided to the film 202 . FIG. 11 shows a plan view of a variation of the heat source 203 and temperature sensor 204 provided to the film 202 . FIG. 12 show a plan view of a variation of the heat source 203 and temperature sensor 204 provided to the film 202 . FIG. 13 shows a schematic perspective view of another example of the container disposed portion of the liquid determining apparatus according to Embodiment 2 of the invention. FIG. 14 shows a plan view of an example of the patterning of the heat source 203 and temperature sensor 204 in the example of FIG. 13 . FIG. 15 shows a chart illustrating how the container surface temperature changes in the liquid determining apparatus according to Embodiment 2. FIG. 16 shows a flowchart of an example of a method for determining the type of liquid in a container in the liquid determining apparatus according to Embodiment 2. FIG. 17 shows a graph illustrating an example of the sensor output when the container temperature is different from the ambient temperature. FIG. 18 shows a graph illustrating an example of the sensor output when the container temperature is different from the ambient temperature. FIG. 19 shows a flowchart of an example of determination control when there is a baseline fluctuation. FIG. 20 shows a block diagram of another example of the structure of a liquid-type determination apparatus according to an embodiment of the invention. FIG. 21 shows a block diagram of another example of the structure of a liquid-type determination apparatus according to an embodiment of the invention. detailed-description description="Detailed Description" end="lead"?

20060626

20080729

20070628

92594.0

G08B2100

FAN, HONGMIN

APPARATUS FOR DETERMINING TYPE OF LIQUID IN A CONTAINER AND METHOD FOR CONTROLLING THE APPARATUS

UNDISCOUNTED

ACCEPTED

G08B

ACCEPTED

Azetidine ring compounds and drugs comprising the same

It is intended to provide compounds having EDG-5 antagonism. Because of having EDG-5 antagonism, compounds of the formula (I): wherein each symbol is as defined in the description; salts thereof, N-oxides thereof, solvates thereof or prodrugs thereof are useful as preventive and/or therapeutic agent for EDG-5 mediated diseases, for example, diseases caused by blood vessel contraction (e.g. cerebrovascular spasms disease, cardiovascular spasms diseases, coronary artery spasms disease, hypertension, pulmonary hypertension, renal diseases, myocardial infarction, angina pectoris, arrhythmia, portal hypertension, varicosity and the like), arteriosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, respiratory diseases (e.g. bronchial asthma, chronic obstructive pulmonary diseases and the like), nephropathy, diabetes, hyperlipemia and the like.

1. A compound of the formula (I): wherein ring A is an azetidine ring which may have further substituent(s), X is oxygen, sulfur or nitrogen which may have substituent(s), R1, R2, R3 and R4 are each independently, hydrogen, a hydrocarbon group which may have substituent(s), —SO2R5 or a heterocyclic ring which may have substituent(s), R5 is a hydrocarbon group which may have substituent(s), R1 and R2, and R3 and R4 may be taken together to form an N-containing heterocyclic ring group which may have further substituent(s), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. 2. The compound according to claim 1, wherein X is oxygen. 3. The compound according to claim 1, wherein R1, R2, R3 and R4 are each independently, hydrogen, a hydrocarbon group which may have substituent(s), or a heterocyclic ring group which may have substituent(s). 4. The compound according to claim 1, which is a compound of the formula (I-1): wherein R1 and R2 are each independently hydrogen, a hydrocarbon group which may have substituent(s), —SO2R5 or a heterocyclic ring group which may have substituent(s), R5 is a hydrocarbon group which may have substituent(s), R1 and R2 are taken together with the adjacent nitrogen atom to form an N-containing heterocyclic ring group which may have substituent(s), R11 is any arbitrary substituent(s), and n is 0 or an integer of 1-5, with the proviso that when n is 2 or more, the plural R11s may be the same or different. 5. The compound according to claim 1 wherein R1 and R2 are taken together with the adjacent nitrogen atom to form an N-containing heterocyclic ring group which may further have substituent(s). 6. The compound according to claim 1, wherein the N-containing heterocyclic ring group is a piperidine, piperazine, or indoline ring. 7. The compound according to claim 1, wherein R1 is a benzene ring which may have substituent(s). 8. The compound according to claim 1, which is selected from the group consisting of N-(3,5-dichlorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide, 3-(2,3-dihydro-1H-indol-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide, N-(3,5-dichlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide, N-[3,5-bis(trifluoromethyl)phenyl]-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide, 3-(2,3-dihydro-1H-indol-1-yl)-N-(3-phenoxyphenyl)azetidine-1-carboxamide, N-[3,5-bis(trifluoromethyl)phenyl]-3-[methyl(phenyl)amino]azetidine-1-carboxamide and N-[3,5-bis(trifluoromethyl)phenyl]-3-[ethyl(phenyl)amino]azetidine-1-carboxamide. 9. A pharmaceutical composition comprising the compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof described in claim 1, together with a pharmaceutically acceptable carrier. 10. The pharmaceutical composition according to claim 9, which is an S1P receptor antagonist. 11. The pharmaceutical composition according to claim 10, which is an EDG-5 antagonist. 12. The pharmaceutical composition according to claim 9, which is a preventive and/or therapeutic agent for the diseases induced by blood vessel contraction. 13. The pharmaceutical composition according to claim 12, wherein the diseases induced by blood vessel contraction include cerebrovascular spasms disease, hypertension, pulmonary hypertension, myocardial infarction, angina pectoris and portal hypertension. 14. The pharmaceutical composition according to claim 9, which is a preventive and/or therapeutic agent for respiratory diseases. 15. The pharmaceutical composition according to claim 14, wherein the respiratory diseases include bronchial asthma and chronic obstructive pulmonary disease. 16. A medicament comprising a combination of the compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof described in claim 1, and one or more member(s) selected from the group consisting of a calcium antagonist, a thrombolytic agent, a thromboxane synthase inhibitor, an endothelin antagonist, an antioxidant agent, a radical scavenger, a poly-ADP ribose polymerase inhibitor, an astrocyte-function improvement agent, a vasodilating agent and an Rho kinase inhibitor. 17. A method for the prevention and/or treatment of an EDG-5 mediated disease in a mammal, characterized by administering to a mammal an effective dose of the compound of the formula (I), a salt thereof, an N-oxide thereof or a solvate thereof or a prodrug thereof. 18. A method for the manufacture of the preventive and/or therapeutic agent for EDG-5 mediated diseases, which comprises mixing the compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof as described in claim 1 with a pharmaceutically acceptable carrier. 19. A method for the preparation of the compound of the formula (I), a salt thereof, an N-oxide thereof or a prodrug thereof described in claim 1.

TECHNICAL FIELD The present invention relates to an azetidine ring compound, which is useful as a pharmaceutical. BACKGROUND ART It has been proposed that sphingosine-1-phosphate [(2S,3R,4E)-2-amino-3-hydroxyoctadec-4-enyl-1-phosphate; hereinafter optionally referred to as S1P], which is a lipid synthesized through intracellular metabolic turnover of sphingolipids and with the activity of an extracellular secretory sphingosine kinase, acts as an intracellular messenger and as an intradellular second messenger. Recently, cloning of S1P receptor has made remarkable progresses, and as a result, it has been reported that the G-protein coupled receptors of EDG-1 (S1P1), EDG-3 (S1P3), EDG-5 (AGR16/H218/S1P2), EDG-6 (S1P4) and EDG-8 (S1P5) are the specific S1P receptors. With particular reference to EDG-5, it has been reported that the mRNA expression is strongly recognized in the tissues of the heart, lungs, stomach, and small intestine, and that in the arterial sclerosis model of coronary artery, or the mice carotid balloon injury model, the mRNA expression level in the intima cells significantly decreases as compared with the normal ones [see the specification of JP-A 6-234797]. It is also reported that the S1P receptor (especially EDG-5) is involved in the increased portal vein pressure, asthma and the like (see Biochem. Biophys. Res. Commun., 2004, 320(3), 754-759, Mol. Immunol., 2002, 38(16-18), 1239-1245 and FASEB J., 2003, 17(13), 1789-1799). It is disclosed that the pyrazopyridine compound of the formula (a): wherein R1a, R2a and R3a each represent C1-8 alkyl and the like; R4a represents hydrogen and the like; R5a and R6a, being the same or different, individually represent hydrogen, C1-8 alkyl, C1-6 alkoxy, halogen and the like; Xa represents —NH—, —O—, —CH2— and the like; Ya is —NH— and the like; Za represents —CO— and the like; Wa represents —NH— and the like; ring Aa is aryl, heteroaryl and the like; (essence was quoted) or a pharmaceutically acceptable salt thereof acts on EDG-5 specifically, and is useful as a treating agent for fibrosis (see WO 01/98301 pamphlet). And it is also disclosed that the N-containing compound of the formula (b): wherein R1b is an optionally substituted —CnbH(2nb-2mb)CH3 or optionally substituted aryl; R2b is hydrogen, alkyl or alkylcarbonyl (essence was quoted) or a pharmaceutically acceptable salt antagonizes the EDG receptor (see WO 03/040097 pamphlet). DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The EDG-5 antagonist is useful for the prevention and/or treatment of EDG-5-mediated diseases, such as diseases caused by blood vessel contraction (e.g. cerebrovascular spasmodic disease, cardiovascular spasmodic disease, coronary artery spasm, hypertension, pulmonary hypertension, renal disease, cardiac infarction, angina pectoris, arrhythmia, portal hypertension, varicosity and the like), arteriosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, respiratory diseases (e.g. bronchial asthma, chronic obstructive pulmonary disease and the like), nephropathy, diabetes, hyperlipidemia and the like, and the development of an excellent EDG-5 antagonist has therefore been strongly demanded. Means for Solving the Problems The present inventors have conducted extensive investigation in order to find out a compound which antagonizes EDG-5 and is useful as a pharmaceutical drug, and as a result, have found that the compound of the formula (I) has an excellent antagonistic effect against EDG-5, thereby leading to completion of the present invention. The compound of the formula (I) has an antagonistic effect against EDG-5 and is therefore useful as a preventive and/or therapeutic agent for the diseases induced by EDG-5. DETAILED DESCRIPTION OF THE PRESENT INVENTION Namely, the present invention relates to: [1] a compound of the formula (I): wherein ring A is an azetidine ring which may have further substituent(s); X is oxygen, sulfur or nitrogen which may have substituent(s); R1, R2, R3 and R4 are each independently hydrogen, a hydrocarbon group which may have substituent(s), —SO2R5 or a heterocyclic ring which may have substituent(s); R5 is a hydrocarbon group which may have substituent(s); R1 and R2, and R3 and R4 may be taken together to form an N-containing heterocyclic ring group which may have further substituent(s), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, [2] the compound according to the above item [1], wherein X is oxygen, [3] the compound according to the above item [1], wherein R1, R2, R3 and R4 are each independently hydrogen, a hydrocarbon group which may have substituent(s), or a heterocyclic ring group which may have substituent(s), [4] the compound according to the above item [1], which is a compound of the formula (I-1): wherein R1 and R2 are each independently hydrogen, a hydrocarbon group which may have substituent(s), —SO2R5 or a heterocyclic ring group which may have substituent(s); R5 is a hydrocarbon group which may have substituent(s); R1 and R2 are taken together with the adjacent nitrogen atom to form an N-containing heterocyclic ring group which may have substituent(s); R11 is any arbitrary substituent(s); and n is 0 or an integer of 1-5, with the proviso that when n is 2 or more, the plural R11s may be the same or different, [5] the compound of the above item [1] or [4] wherein R1 and R2 are taken together with the adjacent nitrogen atom to form an N-containing heterocyclic ring group which may further have substituent(s), [6] the compound according to the above item [1] or [5] wherein the N-containing heterocyclic ring group is a piperidine, piperazine or indoline ring, [7] the compound according to the above item [1] or [4], wherein R1 is a benzene ring which may have substituent(s), [8] the compound according to the above item [1], which is selected from the group consisting of N-(3,5-dichlorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide, 3-(2,3-dihydro-1H-indol-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide, N-(3,5-dichlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide, N-[3,5-bis(trifluoromethyl)phenyl]-3-(2,3-dihydro-1H-indol-1-yl)-azetidine-1-carboxamide, 3-(2,3-dihydro-1H-indol-1-yl)-N-(3-phenoxyphenyl)-azetidine-1-carboxamide, N-[3,5-bis(trifluoromethyl)phenyl]-3-[methyl(phenyl)-amino]azetidine-1-carboxamide and N-[3,5-bis(trifluoromethyl)phenyl]-3-[ethyl-(phenyl)amino]azetidine-1-carboxamide, [9] a pharmaceutical composition comprising the compound of the formula (I), a salt thereof, an N-oxide, a solvate thereof or a prodrug thereof described in the above item [1], [10] the pharmaceutical composition according to the above item [9], which is an S1P receptor antagonist, [11] the pharmaceutical composition according to the above item [10], which is an EDG-5 antagonist, [12] the pharmaceutical composition according to the above item [9], which is a preventive and/or therapeutic agent for the diseases induced by blood vessel contraction, [13] the pharmaceutical composition according to the above item [12], wherein the diseases induced by blood vessel contraction include cerebrovascular spasms disease, hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, and portal hypertension, [14] the pharmaceutical composition according to the above item [9], which is a preventive and/or therapeutic agent for respiratory diseases, [15] the pharmaceutical composition according to the above item [14] wherein the respiratory diseases include bronchial asthma and chronic obstructive pulmonary disease, [16] a medicament comprising a combination of the compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof described in the above item [1], and one or more member(s) selected from the group consisting of a calcium antagonist, a thrombolytic agent, a thromboxane synthase inhibitor, an endothelin antagonist, an antioxidant agent, a radical scavenger, a poly-ADP ribose polymerase inhibitor, an astrocyte-function improvement agent, a vasodilating agent and an Rho kinase inhibitor, [17] a method for the prevention and/or treatment of an EDG-5 mediated disease in a mammal, characterized by administering to a mammal an effective dose of the compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, [18] use of the compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof described in the above item [1] for the manufacture of the preventive and/or therapeutic agent for EDG-5-mediated diseases, and [19] a method for the preparation of the compound of the formula (I), a salt thereof, an N-oxide thereof or a prodrug thereof described in the above item [1]. Effect of the Invention The compound of the present invention has an excellent EDG-5 antagonistic effect. It is therefore useful for the prevention and/or treatment of the diseases caused by, for example, blood vessel contraction (e.g. cerebrovascular spasmodic disease, cardiovascular spasmodic disease, coronary artery spasm, hypertension, pulmonary hypertension, renal disease, cardiac infarction, angina pectoris, arrhythmia, portal hypertension, varicosity and the like), arteriosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, respiratory diseases (e.g. bronchial asthma, chronic obstructive pulmonary disease and the like), nephropathy, diabetes, hyperlipidemia and the like. BEST MODE FOR CARRYING OUT THE INVENTION Referring now to the formula (I), the ring A may have optional substituent(s). Such optional substituents in a number of 1 to 5, preferably 1 to 3, may occupy any positions susceptible to substitution. Examples of such substituents on the ring A include (1) a hydrocarbon group which may have substituent(s), (2) a heterocyclic ring which may have substituent(s), (3) a C1-4 alkylsulfonyl group (e.g. methylsulfonyl, ethylsulfonyl and the like), (4) a phenylsulfonyl group which may have substituent(s) (e.g. phenylsulfonyl and 4-methylbenzenesulfonyl and the like), (5) a halogen atom (e.g. fluorine, chlorine, bromine and iodine), (6) a carboxyl group, (7) a cyano group, (8) a nitro group, (9) a carbamoyl group which may have substituent(s), (10) a sulfamoyl group which may have substituent(s), (11) an alkoxycarbonyl group (e.g. C1-6 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl) and the like), (12) a sulfo group (—SO3H), (13) a sulfino group, (14) a phosphono group, (15) an amidino group, (16) —B(OH)2, (17) a C1-6 acyl group (e.g. formyl, acetyl, propionyl, butyryl and the like), (18) a benzoyl group which may have substituent(s), and the like. Examples of the “hydrocarbon group” in the “hydrocarbon group which may have substituent(s)” on the ring A include a straight-chain or branched aliphatic hydrocarbon group, a cyclic hydrocarbon group, a cyclic hydrocarbon-aliphatic hydrocarbon group, a cyclic hydrocarbon-cyclic hydrocarbon group and the like. Examples of the “straight-chain or branched aliphatic hydrocarbon group” include a “C1-8 aliphatic hydrocarbon group” and the like, and as the “C1-8 aliphatic hydrocarbon group”, there are mentioned, for example, C1-8 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like), C2-8 alkenyl (e.g. vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl and the like), C2-8 alkynyl (e.g. ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl, octadiynyl, hexatriynyl, heptatriynyl, octatriynyl and the like), and the like. Examples of the “cyclic hydrocarbon group” include the above-mentioned “saturated cyclic hydrocarbon group” and “unsaturated cyclic hydrocarbon group”. The “saturated cyclic hydrocarbon group” is exemplified by cycloalkanes, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane and the like, as well as fruthermore “3-15 membered saturated hydrocarbon group”, such as perhydropentalene, perhydroazulene, perhydroindene, perhydronaphthalene, perhydroheptalene, spiro[4.4]nonane, spiro[4.5]decane, spiro-[5.5]undecane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, adamantane or noradamantane ring and the like. Examples of the “unsaturated cyclic hydrocarbon group” include cycloalkene, such as cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene and the like, aromatic hydrocarbon, such as benzene, azulene, naphthalene, phenanthrene, anthracene and the like, and “a 3-15 membered unsaturated cyclic hydrocarbon group”, such as pentalene, indene, indan, dihydro-naphthalene, tetrahydronaphthalene, heptalene, biphenylene, as-indacene, s-indacene, acenaphthene, acenaphthyrene, fluorene, phenalene, bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]hept-2-ene or bicyclo[2.2.2]oct-2-ene and the like. As the “cyclic hydrocarbon-aliphatic hydrocarbon group”, there are mentioned, for example, a group in which the above-mentioned “cyclic hydrocarbon group” and “straight-chain or branched aliphatic hydrocarbon group” are linked mutually, such as C7-16 aralkyl (e.g. benzyl, phenylethyl, phenylpropyl, naphthalen-1-ylmethyl and the like), C8-16 aralkenyl (e.g. 3-phenyl-2-propenyl and 2-(2-naphthylvinyl)), (C3-8 cycloalkyl)-(C1-4alkyl) (e.g. cyclopropylmethyl, cyclohexylmethyl, cyclohexyl-ethyl, cyclohexylpropyl and 1-methyl-1-cyclohexylmethyl) or (C3-8 cycloalkenyl)-(C1-4 alkyl) (e.g. 3-cyclohexenylmethyl) and the like. Examples of the “cyclic hydrocarbon-cyclic hydrocarbon group” include a group in which the above “cyclic hydrocarbon group” and “cyclic hydrocarbon group” are linked mutually, such as 2-biphenyl, 3-biphenyl, 4-biphenyl, 2-cyclohexylphenyl, 3-cyclohexylphenyl, 4-cyclohexylphenyl and the like. In the “heterocyclic ring group which may have substituent(s)”, which is a substituent on the ring A, the “heterocyclic ring” is mono-cyclic or multi-cyclic heterocyclic ring group which may have 1-7 of heteroatoms selected from nitrogen, oxygen and sulfur. Examples of the “heterocyclic ring” include “3-15 membered unsaturated mono-cyclic or multi-cyclic heterocyclic ring”, “3-15 membered saturated mono-cyclic or multi-cyclic heterocyclic ring” and the like. As the “3-15 membered unsaturated mono-cyclic or multi-cyclic heterocyclic ring”, there are mentioned, for example, an aromatic mono-cyclic heterocyclic ring, (e.g. pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, thiadiazole ring and the like), an aromatic multi-cyclic heterocyclic ring (e.g. indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, benzofurazane, benzothiadiazole, benzotriazole, carbazole, β-carboline, acridine, phenazine, dibenzofuran, dibenzothiophene, phenanthridine, phenanthroline, perimidine ring and the like), a non-aromatic unsaturated heterocyclic ring (e.g. azepine, diazepine, pyran, oxepin, thiopyran, thiepin, oxazine, oxadiazine, oxazepine, oxadiazepine, thiazine, thiadiazine, thiazepine, thiadiazepine, indolizine, dithianaphthalene, quinolidine, chromene, benzoxepin, benzoxazepine, benzoxadiazepine, benzothiepin, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, xanthene, phenothiazine, phenoxazine, phenoxathiin, thianthrene, pyrroline, imidazoline, 2,3-dihydro-1H-pyrazole, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine, tetrahydropyridazine, tetrahydrotriazine, dihydroazepine, tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrofuran, dihydropyran, dihydrooxepin, tetrahydrooxepin, dihydrothiophene, dihydrothiopyran, dihydrothiepin, tetrahydrothiepin, dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrofurazane, dihydrooxadiazole, dihydrooxazine, dihydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothiophene, dihydroindazole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, benzoxathian, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepan, dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, dihydro-β-carboline, tetrahydro-β-carboline, dihydroacridine, tetrahydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, dioxaindan, benzodioxane, chromane, benzodithiolan and benzodithian ring) and the like. And the “3-15 membered saturated mono-cyclic or multi-cyclic heterocyclic ring” includes, for example, aziridine, azetidine, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, perhydroazepine, perhydrodiazepine, perhydroazocine, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, perhydrooxepin, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, perhydrothiepine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isooxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazane, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, perhydrobenzofuran, perhydroisobenzofuran, perhydrobenzothiophene, perhydroisobenzothiophene, perhydroindazole, perhydroquinoline, perhydroisoquinoline, perhydrophthalazine, perhydronaphthyridine, perhydroquinoxaline, perhydroquinazoline, perhydrocinnoline, perhydrobenzoxazole, perhydrobenzothiazole, perhydrobenzimidazole, perhydrocarbazole, perhydro-β-carboline, perhydroacridine, perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane, the ring of the formula: and the like. The above-mentioned “hydrocarbon group” or “heterocyclic ring group” may have 1-5 of substituents selected from the groups mentioned under the following items (1)-(39), and when they have more than one substituent, such substituents may be the same or different. Examples of the “substituents” include (1) a hydrocarbon group which may have substituent(s) [e.g. a C1-8 aliphatic hydrocarbon group (the “hydrocarbon group” has the same meaning as described hereinbefore, e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, propenyland hexenyl and the like), amino, sulfo, halogen, carboxy, cyano, nitro, oxo, thioxo, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, allyloxy, benzyloxy and the like] (the “hydrocarbon group” has the same meaning as the “hydrocarbon group” described hereinbefore), (2) a heterocyclic ring which may have substituent(s) [e.g. a hydrocarbon group (the “hydrocarbon group” has the same meaning as the “hydrocarbon group” described hereinbefore) which may have substituent(s) (e.g. halogen, hydroxy, trifluoromethyl, trifluoromethoxy, acetyloxy and the like), amino, sulfo, halogen, carboxy, cyano, nitro, oxo, thioxo, hydroxy, methoxy, methoxycarbonyl, trifluoromethyl, trifluoromethoxy, acetyl and the like], (3) amino, (4) C1-6 acylamino (e.g. acetylamino, propionylamino and the like), (5) mono- or di-substituted amino substituted with a hydrocarbon group (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, cyclohexylamino, 1-carbamoyl-2-cyclohexylethylamino, N-butyl-N-cyclohexylmethylamino, phenylamino and the like) (the “hydrocarbon group” has the same meaning as the “hydrocarbon group” described hereinbefore, and the group may be substituted with oxo, amino, carbamoyl and the like), (6) C1-4 alkylsulfonylamino (e.g. methylsulfonylamino, ethylsulfonylamino and the like), (7) phenylsulfonylamino, (8) C1-4 alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl and the like), (9) phenylsulfonyl, (10) halogen (e.g. fluorine, chlorine, bromine, iodine), (11) carboxy, (12) cyano, (13) nitro, (14) oxo, (15) thioxo, (16) hydroxy, (17) C1-8 alkoxy which may have substituent(s) (e.g. mono- or di-substituted amino, carboxy, halogen and the like) (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, hexyloxy, octyloxy, cyclohexylmethyloxy, benzyloxy, 2-propenyloxy, trifluoromethoxy, carboxymethoxy, dimethylaminopropoxy, diethylaminoethoxy and the like), (18) C3-8 cycloalkoxy (e.g. cyclohexyloxy and the like), (19) phenoxy which may have substituent(s) (e.g. halogen and the like), (20) mercapto, (21) C1-4 alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio and the like), (22) phenylthio (e.g. 4-chlorophenylthio and the like) which may have substituent(s) (e.g. halogen and the like), (23) carbamoyl, (24) aminocarbonyl which may be substituted with hydrocarbon group(s) (e.g. N-butylaminocarbonyl, N-cyclohexylmethylaminocarbonyl, N-butyl-N-cyclohexylmethylaminocarbonyl, N-cyclohexylaminocarbonyl, phenylaminocarbonyl and the like) (the “hydrocarbon group” has the same meaning as the “hydrocarbon group” described hereinbefore), (25) sulfamoyl, (26) aminosulfonyl substituted with hydrocarbon group(s) (e.g. methylaminosulfonyl and the like) (the “hydrocarbon group” has the same meaning as the “hydrocarbon group” described hereinbefore), (27) aminosulfonyl (e.g. dimethylaminoethylaminosulfonyl, dimethylaminopropyl-aminosulfonyl and the like) substituted with hydrocarbon group(s) which is/are substituted with amino (the “hydrocarbon group” has the same meaning as the “hydrocarbon group” described hereinbefore), (28) C1-6 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like), (29) sulfo(—SO3H), (30) sulfino, (31) phosphono, (32) amidino, (33) imino, (34) —B(OH)2, (35) C1-4 alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl and the like), (36) C1-6 acyl (e.g. formyl, acetyl, propionyl, butyryl and the like), (37) benzoyl, (38) hydroxyimino or (39) C1-4 alkyloxyimino (e.g. methyloxyimino, ethyloxyimino and the like), etc. In the definitions of the terms “phenylsulfonyl which may have substituent(s)”, “carbamoyl which may have substituent(s)”, “sulfamoyl which may have substituent(s)” and “benzoyl which may have substituent(s)”, which are described hereinbefore for defining a substituent on the ring A, the term “substituent” has the same meaning as the “substituent” appearing in the term “hydrocarbon group which may have substituent(s)” mentioned for the substituent on the ring A described hereinbefore. Examples of the “nitrogen atom which may have a substituent” represented by X include =NR101 wherein R101 includes, for example, hydrogen, cyano, hydroxy, C1-4 alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy and the like), a hydrocarbon group which may have substituent(s) (the “hydrocarbon group” has the same meaning as the “hydrocarbon group which may substituent(s)”), sulfo, C1-8 alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl and the like), phenylsulfonyl and the like. X is preferably oxygen. The “hydrocarbon group which may have substituent(s)” represented by R1, R2, R3, R4 or R5 has the same meaning as the “hydrocarbon group” mentioned as the substituent on the ring A described hereinbefore. The “heterocyclic ring group which may have substituent(s)” represented by R1, R2, R3 or R4 has the same meaning as the “heterocyclic ring group which may have substituent(s)” mentioned as the substituent on the ring A described hereinbefore. R1 and R2 as well as R3 and R4 each independently may be taken together with the adjacent nitrogen atom(s) to form an N-containing heterocyclic ring which may have substituent(s). The “N-containing heterocyclic ring” includes, for example, a mono-cyclic or multi-cyclic heterocyclic ring which may contain 1-6 of heteroatom(s) selected from nitrogen, oxygen and sulfur in addition to the above nitrogen atom. Examples of the “N-containing heterocyclic ring” include a “3-15 membered N-containing unsaturated mono-cyclic or multi-cyclic heterocyclic ring”, “3-15 membered N-containing saturated mono-cyclic or multi-cyclic heterocyclic ring” and the like. As examples of the “3-15 membered N-containing unsaturated mono-cyclic or multi-cyclic heterocyclic ring”, there are mentioned pyrrole, imidazole, triazole, tetrazole, pyrazole, azepine, diazepine, indole, isoindole, indazole, purine, benzimidazole, benzazepine, benzodiazepine, benzotriazole, carbazole, β-carboline, phenothiazine, phenoxazine, perimidine, pyrroline, imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine, tetrahydropyridazine, dihydroazepine, tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrofurazane, dihydrooxadiazole, dihydrooxazine, dihydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine, dihydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, indoline, isoindoline, dihydroindazole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, dihydroacridine, tetrahydroacridine, hexahydroazocine, hexahydroazonine, hexahydrodiazocine, hexahydrodiazonine, octahydroazecine, octahydrodiazecine ring and the like. Examples of the “3-15 membered N-containing saturated mono-cyclic or multi-cyclic heterocyclic ring” include aziridine, azetidine, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, perhydroazepine, perhydrodiazepine, perhydroazocine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isooxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazane, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, tetrahydrothiazepine, perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, perhydroindazole, perhydroquinoline, perhydroisoquinoline, perhydrophthalazine, perhydronaphthyridine, perhydroquinoxaline, perhydroquinazoline, perhydrocinnoline, perhydrobenzoxazole, perhydrobenzothiazole, perhydrobenzimidazole, perhydrocarbazole, perhydroacridine, perhydroazonine, perhydroazecine, azaundecane, azadodecane, azatridecane, azatetradecane, azapentadecane, perhydrodiazocine, perhydrodiazonine, perhydrodiazecine, diazaundecane, diazadodecane, diazatridecane, diazatetradecane, diazapentadecane, perhydroindole, perhydroisoindole, perhydro-β-carboline, perhydrophenazine, perhydrophenothiazine, perhydrophenoxazine, perhydrophenanthridine, perhydrophenanthroline, perhydroperimidine, azabicyclo[3.2.2]nonane, azabicyclo[3.3.2]decane, azabicyclo[2.2.2]octane, azabicyclo[3.3.3]undecane, azabicyclo[4.3.3]dodecane, azabicyclo[4.4.3]tridecane, azabicyclo[4.4.4]tetradecane, 1,4-dioxa-8-azaspiro[4.5]decane, etc. The said “N-containing heterocyclic ring” may be substituted with 1-5 of arbitrary substituents, and examples of the “substituents” include the same as the substituents on the ring A described hereinbefore. The “substituent” represented by R11 has the same meaning as the “substituent(s)” on the “carbocyclic group which may have substituent(s)” mentioned as the substituent of the above ring A. R1 is preferably a hydrocarbon group which may have substituent(s), and more preferably, C1-8 alkyl which may have substituent(s) or a benzene ring which may have substituent(s). R2 is preferably a hydrocarbon group which may have substituent(s) or a heterocyclic ring which may have substituent(s), etc., more preferably C1-8 alkyl which may have substituent(s) or a benzene ring which may have substituent(s), and most preferably methyl or ethyl. And R1 and R2 may prefereably be taken together with the adjacent nitrogen atom to form an N-containing heterocyclic ring group, and the said N-containing heterocyclic ring group includes preferably, for example, piperidine, pyrrolidine, morpholine, piperazine, indoline, tetrahydroquinoline and tetrahydroisoquinoline rings, and more preferably, piperidine, piperazine or indoline ring. R3 is preferably hydrogen, a hydrocarbon group which may have substituent(s) or a heterocyclic ring group which may have substituent(s) and the like, and more preferably, a benzene ring which may have substituent(s) or a pyridine ring which may have substituent(s), and most preferably, a benzene ring which is substituted with 1-2 of trifluoromethyl or halogen. R4 is preferably hydrogen, a hydrocarbon group which may have substituent(s) or a heterocyclic ring group which may have substituent(s), and more preferably, hydrogen. R5 is preferably a benzene ring which may have substituent(s) or a methyl group, etc. R11 is preferably halogen or C1-8 alkyl which may have substituent(s), and more preferably, chlorine, trifluoromethyl, etc. n is preferably 0 or an integer of 1 to 2, and more preferably 2. Referring specifically to the compound of the present invention of the formula (I), preferred are the compounds represented by the formula (I-1): wherein all the symbols have the same meanings as described hereinbefore; the formula (I-2): wherein R12 has the same meaning as R11, n1 is 0 or an integer of 1-4, and when n1 is 2 or more, the plural R12s may be the same or different, while other symbols have the same meanings as described hereinbefore; the formula (I-3): wherein R13 has the same meaning as R11, n2 is 0 or an integer of 1-5, and when n2 is 2 or more, the plural R13s may be the same or different, while other symbols have the same meanings as described hereinbefore; the formula (I-4): wherein R14 has the same meaning as R11, n3 is 0 or an integer of 1-5, and when n3 is 2 or more, the plural R14s may be the same or different, while other symbols have the same meanings as described hereinbefore; the formula (I-5): wherein R15 and R16 have each independently the same meanings as R11, n4 is 0 or an integer of 1-4, and when n4 is 2 or more, the plural R6s may be the same or different, while other symbols have the same meanings as described hereinbefore; the formula (I-6): wherein R17 has the same meaning as R11, n5 is 0 or an integer of 1-6, and when n5 is 2 or more, the plural R17s may be the same or different, while the other symbols have the same meanings as described hereinbefore; and the formula (I-7): wherein R18 has the same meaning as R11, n6 is 0 or an integer of 1-7, and when n6 is 2 or more, the plural R18s may be the same or different, while the other symbols have the same meanings as described hereinbefore, a salt thereof, an N-oxide thereof, a solvate thereof, a prodrug thereof and the like. In particular, more preferred are the compounds represented by the formula (I-1-1): wherein all the symbols have the same meanings as described hereinbefore; the formula (I-1-2): wherein all the symbols have the same meanings as described hereinbefore; and the formula (I-1-3): wherein all the symbols have the same meanings as described hereinbefore, a salt thereof, an N-oxide, a solvate thereof or a prodrug thereof and the like. The specific examples of the compound according to the present invention include N-[3,5-bis(trifluoromethyl)phenyl]-3-[isobutyl(3-methoxyphenyl)amino]-N,2,2-trimethylazetidine-1-carboxamide, methyl 4-[[2-(hydroxymethyl)-1-({[3-(2-methylphenoxy)phenyl]amino}carbonothioyl)azetidin-3-yl](2-phenoxyethyl)amino]-benzoate, N-[1-[[butyl(3,4-difluorophenyl)amino](imino)methyl]-3-(4-chlorophenyl)-azetidin-3-yl]-N-[4-(methylsulfonyl)phenyl]-β-alanine, 3-[(2-chlorophenyl)-(phenylsulfonyl)amino]-1-[[(2-cyano-4-nitrophenyl)amino](methoxyimino)methyl]-azetidin-2-carboxylic acid, N-{l-[(benzylimino)(morpholine-4-yl)methyl]-3-fluoroazetidin-3-yl}-N-[3-(trifluoromethyl)phenyl]ethanesulfonamide, 3-methyl-N-(1-{([4-(methylsulfonyl)piperazin-1-yl]carbonyl}-2-pyridin-2-ylazetidin-3-yl)-N-phenylbutanamide, N-benzyl-3-{[(benzylamino)carbonyl]amino}-N-(2,6-dichloropyridin-4-yl)-3-(3,6-dihydro-2H-pyran-4-yl)azetidine-1-carboxamide, isopropyl {1-[(cyanoimino)(4-methylpiperazin-1-yl)methyl]azetidin-3-yl}(2-cyanophenyl)carbamate, N,N-dimethyl-N′-(3-nitrophenyl)-N′-[1-(2,3,4,7-tetrahydro-1H-azepin-1-ylcarbonyl)-azetidin-3-yl]sulfamide, (4-{[[1-(2,3-dihydro-1H-indol-1-ylcarbonyl)azetidin-3-yl](morpholin-4-ylcarbonyl)amino]methyl}phenyl)boronic acid, 3-[{{2-isobutyl-3-[(4-methyl-1,3-thiazol-2-yl)(2-morpholin-4-ylethyl)amino]azetidin-1-yl}[(phenyl-sulfonyl)-imino]methyl}(tetrahydro-2H-pyran-4-ylmethyl)amino]benzoic acid, N-[3-(cyclopentylmethyl)-1-(pyrrolidin-1-ylcarbonyl)azetidin-3-yl]-N′,N′-dimethyl-N-(1-phenylazepan-3-yl)propan-1,3-diamine, methyl 4-[(3-{benzyl[3-(methylamino)-3-oxopropyl]amino}azetidin-1-yl)carbonyl]piperazin-1-carboxylate, 2-[(3-biphenyl-3-yl-1-{[4-(3-chlorobenzoyl)piperazin-1-yl]carbonyl}azetidin-3-yl)(cyclohexyl)-amino]ethanol, 3-[[1-[(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]-2-(3-thienyl)azetidin-3-yl](1-naphthyl)amino]propanenitrile, {1-({[2-(1-naphthyl)ethyl]-amino}carbonyl)-3-[(2-phenylethyl)(4-pyridin-2-ylphenyl)amino]azetidin-3-yl}-phosphonic acid, 2-[amino(imino)methyl]-3-[1H-indol-5-yl(phenyl)amino]-N-(tetrahydro-2H-pyran-4-yl)azetidine-1-carboxamide, N-[2-chloro-6-(pentyloxy)-pyridin-4-yl]-3-[isopropyl(pyridin-2-yl)amino]azetidine-1-carboxamide, N-(3,5-difluorophenyl)-3-(2,6-dimethylmorpholin-4-yl)azetidine-1-carboxamide, 3-(3,5-dimethylthiomorpholin-4-yl)-N-(4-methyl-1,3-thiazole-2-yl)azetidine-1-carboxamide, N-(6-methylpyrazin-2-yl)-3-{2-[3-(methylthio)phenyl]-1,3-thiazolidin-3-yl}-azetidine-1-carboxamide, N3′,N3′-diethyl-N1′-[3-fluoro-5-(trifluoromethyl)phenyl]-3-hydroxy-1,3′-biazetidin-1′,3′-dicarboxamide, N-[2-(cyclohexyloxy)pyrimidin-4-yl]-3-(3,4-dihydro-1,6-naphthyridine-1(2H)-yl)azetidine-1-carboxamide, N-(3-butoxy-5-chlorophenyl)-3-[(1,3-dimethyl-1H-pyrazole-5-yl)(propyl)amino]azetidine-1-carboxamide, 3-[(5-cyanopyridin-2-yl)(cyclopropyl)amino]-N-[3-(tetrahydro-2H-pyran-4-yloxy)-5-(trifluoromethyl)phenyl]azetidine-1-carboxamide, 3-(5-acetyl-2,3-dihydro-1H-indol-1-yl)-N-[3-chloro-5-(methylthio)phenyl]azetidine-1-carboxamide, methyl 2-[(1-{[(6-chloropyridazine-4-yl)amino]carbonyl}azetidin-3-yl)(isobutyl)-amino]-1-methyl-1H-imidazole-4-carboxylate, 3-[(5-chloro-2-methoxypyrimidin-4-yl)(isopropyl)amino]-N′-cyano-N-(3,5-dimethylphenyl)azetidine-1-carboximidamide, 3-{cyclopentyl[3-(trifluoromethyl)phenyl]amino}-N-[6-(phenylthio)pyridin-2-yl]-azetidine-1-carboxamide, or N-(3-chloro-5-fluorophenyl)-3-cyano-3-(5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide and the like. Those compounds described in the below-mentioned Examples are all preferred. As the more preferable compounds, there are mentioned, for example, N-(3,5-dichlorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide, 3-(2,3-dihydro-1H-indol-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide, N-(3,5-dichlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide, N-[3,5-bis(trifluoromethyl)phenyl]-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide, 3-(2,3-dihydro-1H-indol-1-yl)-N-(3-phenoxyphenyl)azetidine-1-carboxamide, N-[3,5-bis(trifluoromethyl)phenyl]-3-[methyl(phenyl)amino]azetidine-1-carboxamide and N-[3,5-bis(trifluoromethyl)phenyl]-3-[ethyl(phenyl)amino]azetidine-1-carboxamide, and the like. In the present invention, as may be easily understood by those skilled in the art and unless otherwise specified particularly, the symbol: is understood to indicate that the substituent is linked in such an orientation as may go into the sheet of paper (α-configuration); the symbol: is understood to indicate that the substituent is linked in such an orientation as may come out of the sheet of paper (β-configuration); the symbol: is understood to indicate that the substituent is linked either in the α-configuration, β-configuration or any combined configurations thereof at arbitrary ratios; and the symbol: is understood to indicate that the substituent is linked in any combined configurations of the α-configuation and β-configuration at arbitrary ratios. The present invention is understood to emcompass and include all of the isomers, unless otherwise specified particularly. Whenever reference is made to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene, for example, such terms should be understood to include both of the straight-chain and branched ones. Moreover, the present invention is intended to encompass any isomers existing with respect to the presence of a double bond, ring or fused ring (namely, E, Z, and cis- and trans-isomers), any isomers existing with respect to the presence of the asymmetric carbon atom, etc. (namely, R-and S-isomers, α- and β-configurations, enantiomers and diastereomers), any optically active compounds having optical rotation (namely, D-, L-, d-, and l-isomers), any polar compounds by chromatographic separation (namely, highly polar or weakly polar), any equilibrium compounds, any rotational isomers, and any mixtures thereof in arbitrary ratios and racemic mixtures thereof. [Salts] The salts of the compound of the formula (I) include non-toxic salts, pharmacologically acceptable salts and any other salts. Such pharmacologically acceptable salts are preferably non-toxic and water-soluble ones. Appropriate salts of the compound of the formula (I) include, for example, salts with alkali metals (e.g. potassium, sodium and lithium salts), salts with alkaline-earth metals (e.g. calcium, magnesium and the like), ammonium salts (e.g. tetramethylammonium salt, tetrabutyl-ammonium salt and the like), organic-amine salts (e.g. salts with triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arguinine, N-methyl-D-glucamine and the like), or acid-addition salts [inorganic acid salts (e.g. hydrochloride, hydrobromate, hydroiodate, sulfate, phosphate, nitrate and the like), organic acid salts (e.g. acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate and the like) and the like]. The salts of the compound of the present invention include solvates, or solvates of the above-mentioned alkali metal salts, alkaline-earth metal salts, ammonium salts, organic-amine salts or acid-addition salts and the like. The solvates are preferably non-toxic and water-soluble ones. Appropriate solvates include, for example, solvates with water or alcoholic solvents (e.g. ethanol and the like). The compound of the present invention may be converted to non-toxic salts or pharmacologically acceptable salts by the known methods. And the salts include quaternary ammonium salts. The quaternary ammonium salts refer to any compounds of the formula (I) wherein the nitrogen atom is quaternized by R0 group (wherein R0 is C1-8 alkyl or C1-8 alkyl substituted with a phenyl group). The compound of the present invention may be converted to an N-oxide by arbitrary methods. An N-oxide means a compound whose nitrogen atom is oxidized in the compound of the formula (I). The prodrugs of the compound of the formula (I) refer to the compounds being convertible in vivo into the compound of the formula (I) by the reactions with the enzymes, gastric acid and the like. As the prodrugs of the compound of the formula (I), for example, there are mentioned the compounds of the formula (I) wherein when the compound of the formula (I) has an amino group, such amino group is acylated, alkylated or phosphorylated (e.g. the compounds having the amino group of the compound of the formula (I) which are eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofuranylated,. pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated or tert-butylated); the compounds of the formula (I) wherein when the compound of the formula (I) has a hydroxy group, such hydroxy group is acylated, alkylated, phosphorylated or borated (e.g. the compounds having the hydroxy group of the compound of the formula (I) which are acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethyl or carbonylated); the compounds of the formula (I) wherein when the compound of the formula (I) has an carboxyl group, such carboxyl group is esterified or amidated (e.g. the compounds having the carboxyl group of the compound of the formula (I) which are ethylesterified, phenylesterified, carboxymethylesterified, dimethylaminomethyl-esterified, pivaloyloxymethylesterified, ethoxycarbonyloxyethylesterified, phthalidylesterified, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methylesterified, cyclohexyloxycarbonylethylesterified or methylamidated); and the like. These compounds can be manufactured by the conventional methods. In addition, the prodrugs of the compounds of the formula (I) may be either of solvates and non-solvates. The prodrugs of the compound of the formula (I) may be the ones which are converted to the compound of the formula (I) under physiological conditions as described in Development of Pharmaceutical Products, Vol. 7 “Molecular Design”, 163-198, 1990, published by Hirokawa Shoten of Japan. And the compound of the formula (I) may be labeled with isotopes (e.g. 3H, 14C, 35S, 125I and the like), etc. [The Method for Preparation of the Compound of the Present Invention] The compound of the formula (I) of the present invention may be prepared by the below-described processes, the processes as delineated in Examples or the known processes, such as the processes described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999), after being suitably modified and combined. It is to be added that the starting compound may be used as a salt in each of the below-mentioned production processes, wherein use can be made of salts mentioned in the above as the salts of the formula (I). The compounds of the formula (I) wherein X is oxygen or sulfur and R4 is hydrogen may be prepared by the below-described two processes: wherein the rings AP, R1P, R2P and R3P have each the same meanings as the rings A , R1, R2 and R3 respectively, with the proviso that the carboxy, hydroxy, amino and mercapto groups included in the group represented by A, R1, R2 or R3 are protected if necessary, and other symbols have the same meanings as described hereinbefore. These urea- and thiourea-formation reactions are known and, for example, can be carried out in an organic solvent (e.g. toluene, benzene, xylene, tetrahydrofuran, dichloromethane, diethyl ether, 1,2-dichloroethane, N,N-dimethylformamide and the like), in the presence or absence of a base (e.g. triethylamine, pyridine, diisopropylethyl-amine and the like), at a temperature of about 0° C. to the the refluxing temperature. These reactions may preferably be carried out under the atmosphere of an inert gas and under anhydrous conditions. The deprotection reaction of protective groups is conducted according to the known procedures, for example, those described in Protective Groups in Organic Synthesis (T. W. Greene, Wiley, New York, 1999) or those similar thereto. For example, the deprotection reaction of a protective group for carboxy, hydroxy, amino or mercapto is well known, and as the deprotection reaction, for example, there are mentioned (1) a deprotection reaction by alkaline hydrolysis, (2) a deprotection reaction under acidic conditions, (3) a deprotection reaction by hydrogenolysis, (4) a deprotection reaction by use of a silyl group, (5) a deprotection reaction using metals, (6) a deprotection reaction using metal complexes, and the like. These procedures are to be explained more particularly in the following: (1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g. methanol, tetrahydrofuran, or dioxane and the like) using an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, or lithium hydroxide and the like), an alkaline-earth metal hydroxide (e.g. barium hydroxide, or calcium hydroxide and the like), their carbonate (e.g. sodium carbonate or potassium carbonate and the like), an aqueous solution thereof, or a mixture thereof at a temperature of about 0 to 40° C. (2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (e.g. dichloromethane, chloroform, 1,4-dioxane, ethyl acetate, anisole and the like) in the presence of an organic acid (e.g. acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like), an inorganic acid (e.g. hydrochloric acid, sulfuric acid and the like) or a mixture thereof (e.g. hydrogen bromide/acetic acid and the like) at a temperature of about 0 to 100° C. (3) The deprotection reaction by hydrogenolysis is carried out, for example, in. a solvent (e.g. ethers (e.g. tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether and the like), alcohols (e.g. methanol, ethanol and the like), benzenes (e.g. benzene, toluene and the like), ketones (e.g. acetone, methyl ethyl ketone and the like), nitrites (e.g. actetonitrile and the like), amides (e.g. dimethylformamide and the like), water, ethyl acetate, acetic acid, or solvent mixtures of at least two thereof and the like) in the presence of a catalyst (e.g. palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel and the like) under the atmosphere of hydrogen at atmospheric or suitably applied pressure or in the presence of ammonium formate at a temperature of about 0 to 200° C. (4) The deprotection reaction for a silyl group is carried out, for example, in a water-miscible organic solvent (e.g. tetrahydrofuran, acetonitrile and the like) using a fluoride (e.g. tetrabutylammonium fluoride, potassium fluoride, hydrogen fluoride and the like) at a temperature of about 0 to 40° C. (5) The deprotection reaction using metals is carried out, for example, in an acidic solvent (e.g. acetic acid, buffer solution at a pH value of about 4.2-7.2, or a mixture of such solutions with an organic solvent, e.g. tetrahydrofuran, and the like) in the presence of zinc powder, with sonication if necessary, at a temperature of about 0 to 40° C. (6) The deprotection reaction using metal complexes is carried out, for example, in an organic solvent (e.g. dichloromethane, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, 1,4-dioxane, ethanol and the like), water, or mixtures thereof, in the presence of a trap reagent (e.g. tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine and the like), an organic acid (e.g. acetic acid, formic acid, 2-ethylhexanoic acid and the like) and/or organic acid salts (e.g. sodium 2-ethylhexanoate, potassium 2-ethylhexanoate and the like), in the presence or absence of a phosphine reagent (e.g. triphenylphosphine and the like), using metal complexes [e.g. tetrakistriphenylphosphinepalladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium acetate(II), tris(triphenylphosphine)rhodium(II) chloride and the like) at a temperature of about 0 to 40° C. As may easily be understood by those skilled in the art, properly selected use can be made of these deprotection reactions to produce easily the objective compounds of the present invention. The protective groups for carboxy include, for example, methyl, ethyl, allyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl and the like, while the protective groups for hydroxy may be exemplified by methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), or 2,2,2-trichloroethoxycarbonyl (Troc) and the like. As the protective groups for amino, there is mentioned, for example, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenyl-methoxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM), or 2-(trimethylsilyl)-ethoxymethyl (SEM). The protective groups for mercapto include, for example, benzyl, methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP), diphenylmethyl, or acetyl (Ac). The protective groups for carboxy, hydroxy, amino or mercapto are not limited particularly to the above-mentioned ones, only if they can be easily and selectively eliminated. For example, those described in Protective Groups in Organic Synthesis, (T. W. Greene, Wiley, New York, 1999) are usable. The compound of the formula (I) wherein X is oxygen and R4 is any atoms or groups other than hydrogen, i.e. the compound of the formula (I-c): wherein R4-1 is a hydrocarbon group which may have substituent(s), —SO2R5 or a heterocyclic ring group which may have substituent(s) and the other symbols have the same meanings as described hereinbefore, may be prepared by subjecting the compound of the formula (I-a) and the compound of the formula (V): T—R4-1P (V), wherein R4-1P has the same meaning as R4-1 and T is a leaving group (e.g. halogen, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy and the like), with the proviso that the carboxy, hydroxy, amino and mercapto groups contained in the group represented by R4-1 are protected if necessary, to a reaction, optionally followed by a deprotection reaction. The reaction is known and can be carried out, for example, in an organic solvent (e.g. tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane and the like) in the presence or absence of a phosphine reagent [e.g. triphenylphosphine, tri(o-tolyl)phosphine, tri-tert-butylphosphine, di-tert-butylphosphino-2-biphenyl and the like] and in the presence or absence of a metal complex [e.g. tetrakistriphenylphosphine palladium (0), dichlorobis(triphenyl-phosphine)palladium (II), palladium acetate (II), chlorotris(triphenylphosphine)rhodium (I) and the like] at a temperature of about 0° C. to the refluxing temperature, using a base (e.g. sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide and the like). The deprotection reaction may be carried out by the same method as described hereinbefore. And the compound of the formula (I-c) may be prepared by subjecting the compound of the formula (VI) wherein all the symbols have the same meanings as described hereinbefore, which is prepared by reacting the compound of the formula (II) with phosgene or triphosgene in the presence of a base (e.g. pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate and the like), and the compound of the formula (VII): wherein all the symbols have the same meanings as described hereinbefore, to a reaction, optionally followed by a deprotection reaction. The compound of the formula (I-c) may be prepared by subjecting the compound of the formula (VI): wherein all the symbols have the same meanings as described hereinbefore, which is prepared by reacting the compound of the formula (II) with phosgene or triphosgene in the presence of a base (e.g. pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate and the like), and the compound of the formula (VII): wherein all the symbols have the same meanings as described hereinbefore, to a reaction, optionally followed by a deprotection reaction. This reaction is known and is carried out, for example, in an organic solvent (e.g. dichloromethane, tetrahydrofuran, N,N-dimethylformamide and the like) in the presence of a base (e.g. pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate and the like) at a temperature of about −78° C. to the refluxing temperature. The compound of the formula (I) wherein R4 is hydrogen and X is nitrogen which may be substituted, i.e. the compound of the formula (I-d): wherein all symbols have the same meanings as described hereinbefore, is prepared by subjecting the isothiourea compound, which is given by reacting the compound of the formula (I-b) with a halogenated alkyl (e.g. methyl iodide and the like), and the compound of the formula (VIII) H2N—R101P (VIII), wherein R101P has the same meaning as R101, with the proviso that the carboxy, hydroxy, amino or mercapto group contained in the group represented by R101 is protected if necessary, to a reaction, optionally followed by a deprotection reaction. This reaction is known and is carried out, for example, in an organic solvent (e.g. methanol, ethanol, isopropanol, N,N-dimethylformamide and the like) at a temperature ranging from room temperature to the refluxing temperature, using a base (e.g. triethylamine and the like). The deprotection reaction is carried out by the same method as described hereinbefore. The compound of the formula (I) in which R1 and R2 are taken together with the adjacent nitrogen atom to form a piperazine ring, i.e. the compound of the formula (I-e): wherein R201 is a hydrocarbon group which may have substituent(s) or arbitrary substituents and the other symbols have the same meanings as described hereinbefore, may be prepared by subjecting the compound of the formula (I-f): wherein XP has the same meaning as X, with the proviso that the carboxy, hydroxy, amino or mercapto in X is protected if necessary and the other symbols have the same meanings as described hereinbefore, which is prepared by the method described hereinbefore and the compound of the formula (IX): R201P—CHO (IX), wherein R201P has the same meaning as R201, with the proviso that the carboxy, hydroxy, amino or mercapto in R201 is protected if necessary, to a reductive amination reaction, optionally followed by a deprotection reaction. This reductive amination reaction is known and is carried out, for example, in an organic solvent (e.g. dichloroethane, dichloromethane, N,N-dimethylformamide and the like) in the presence of a reducing agent (e.g. sodium triacetoxyborohydride, sodium cyanoborohydride and the like) at a temperature of about 0 to 40° C., with or without use of a tertiary amine (e.g. triethylamine, diisopropylethylamine and the like) and/or an acid (e.g. acetic acid and the like). The deprotection reaction may be carried out by the same method as described hereinbefore. The compound of the formula (I) wherein. R1 is a hydrocarbon group which may be substituted, i.e. the compound of the formula (I-g): wherein R1-1 is a hydrocarbon group which may be substituted, and the other symbols have the same meanings as described hereinbefore, may be prepared by subjecting the compound of the formula (I-h): wherein all the symbols have the same meanings as described hereinbefore, which is prepared by the method described hereinbefore, and the compound of the formula (X): R1-1P—T (X), wherein R1-1P has the same meaning as R1-1, with the proviso that the carboxy, hydroxy, amino or mercapto in R1-1 is protected if necessary, and the other symbols have the same meanings as described hereinbefore, to an alkylation reaction, optionally followed by a deprotection reaction. This alkylation reaction is known and is carried out, for example, in an organic solvent (e.g. N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran and the like) in the presence or absence of a base (e.g. triethylamine, diisopropylamine, cesium carbonate, sodium carbonate, potassium carbonate and the like) at a temperature of about 0 to 40° C., using halogenated (C1-6)alkyl or halogenated benzyl. The deprotection reaction for the protective groups may be carried out by the same method as described hereinbefore. The compound of the formula (I) wherein R1 is —SO2R5, i.e. the compound of the formula (I-i): wherein all the symbols have the same meanings as described hereinbefore, may be prepared by subjecting the compound of the formula (I-h) as described hereinbefore and the compound of the formula (XI): wherein R55P has the same meaning as R5, with the proviso that the carboxy, hydroxy, amino or mercapto group contained in the group represented by R5 is protected if necessary, to a sulfonamidation reaction, optionally followed by a deprotection reaction. This sulfonamidation reaction is known and is carried out, for example, by reacting a sulfonic acid with an acid halide (e.g. oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous trichloride and the like) in an organic solvent (e.g. chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, tert-butyl methyl ether and the like) or without a solvent at a temperature of about −20° C. to the refluxing temperature, and the resultant sulfonyl halide is subjected to a reaction with an amine in an organic solvent (e.g. chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran and the like) in the presence of a base [e.g. diisopropylethylamine, pyridine, triethylamine, N,N-dimethylaniline, 4-(dimethylamino)pyridine and the like] at a temperature of about 0 to 40° C. The deprotection reaction of the protective groups may be carried out as described hereinbefore. The compound of the formula (I) wherein R1 is the compound of the formula (I-j): wherein R201 has the same meaning as described hereinbefore, i.e. the compound of the formula (I-j): wherein all the symbols have the same meanings as described hereinbefore, may be prepared by subjecting the above-mentioned compound of the formula (I-h) and the compound of the formula (XII): wherein R201P has the same meaning as R201, with the proviso that the carboxy, hydroxy, amino or mercapto group in the group represented by R201 is protected if necessary and the other symbols have the same meanings as described hereinbefore, to an acylation reaction, optionally followed by a deprotection reaction. This acylation reaction is known and is carried out, for example, in an organic solvent (e.g. dichloromethane, dichloroethane, tetrahydrofuran, N,N-dimethylformamide and the like) in the presence of a base (e.g. pyridine, triethylamine, diisopropylethylamine and the like) at a temperature of about −78° C. to the refluxing temperature. The deprotection reaction of the protective groups may be carried out by the same procedure as described hereinbefore. The compound of the formula (I) wherein R1 is the compound of the formula: wherein R202 is hydrogen or a hydrocarbon group which may have substituent(s), i.e. the compound of the formula (I-k): wherein all the symbols have the same meanings as described hereinbefore, may be prepared by subjecting the above-mentioned compound of the formula (I-h) and the compound of the formula (XIII): R202P—N═C═O (XIII), wherein R202P has the same meaning as R202, with the proviso that the carboxy, hydroxy, amino or mercapto group contained in the group represented by R202 is protected if necessary and the other symbols have the same meanings as described hereinbefore, to a urea-formation reaction, optionally followed by a deprotection reaction. This urea-formation reaction and the deprotection reaction for the protective group may be carried out by the method as described hereinbefore. The compounds of the formulae (II) to (XIII) which are used as starting materials or reagents may be known per se or may be prepared easily by suitably modifying or combining the known methods, e.g. the methods as described in Comprehensive Organic Transformations : A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) or in the specification of U.S. Pat. No. 5,968,923. For example, the compound of the formula (II) may be prepared by the following reaction scheme: In the reaction steps, all the symbols have the same meanings as described hereinbefore. In each of the reactions described in the present specification, the heating-involving reaction can be conducted using a water bath, an oil bath, a sand bath or microwave radiation, as is evident to those skilled in the art. In each of the reactions described in the present specification, solid-phase supported reagents on high molecular polymers (e.g. polystyrene, polyacrylamide, polypropylene, polyethyleneglycol and the like) may be appropriately used. In each of the reactions described in the present specification, the reaction products may be purified by the ordinarily employed purification techniques, e.g. atmospheric or vacuum distillation, high performance liquid chromatography on silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin or column chromatography, washing, recrystallization and the like. Purification may be carried out at each reaction or after completion of several reactions. [Toxicity] The compound of the formula (I), a salt thereof, an N-oxide thereof, a solvate therof or a prodrug thereof (hereafter from time to time referred to briefly as Compound of the Present Invention) exhibits extremely lowered toxicity, and is therefore safe enough to allow the use as pharmaceuticals. [Application to Pharmaceuticals] The Compound of the Present Invention exerts an antagonistic effect against EDG-5, and is useful for the prevention and/or treatment of the EDG-5-mediated diseases, for example, the diseases caused by blood vessel contraction (e.g. cerebrovascular spasmodic diseases, cardiovascular spasmodic diseases, coronary artery spasm, hypertension, pulmonary hypertension, renal diseases, cardiac infarction, angina pectoris, arrhythmia, portal hypertension, varicosity and the like), arteriosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, respiratory diseases (e.g. bronchial asthma, chronic obstructive pulmonary disease and the like), nephropathy, diabetes, hyperlipidemia and the like. The Compound of the Present Invention may be administered as a concomitant drug preparation in combination with other drugs for the purpose of; (1) supplementation and/or enhancement of the preventive and/or therapeutic effect of the said Compound of the Present Invention, (2) improvement of the dynamic and absorption of, and lowering of the dose of, the said Compound of the Present Invention, and/or (3) alleviation of side effects of the said Compound of the Present Invention. The concomitant drug preparations of the Compound of the Present Invention with other drugs may be administered either in the form of a combination drug having a plurality of the drug substances formulated in one pharmaceutical preparation or in the form of separate pharmaceutical preparations individually comprising a plurality of drug substances. Administration in the form of such separate pharmaceutical preparations is understood to include both the simultaneous administration and the intermittent time-lag administration. On the occasion of the intermittent time-lag administration, the Compound of the Present Invention may be administered firstly, followed by other drugs, and vice versa, whereby the individual methods of administration may be the same or different. Said other drugs may be low-molecular compounds, high-molecular proteins, polypeptides, polynucleotides (DNA, RNA, genes), anti-senses, decoys, antibodies, or vaccines and the like. The other drugs include, for example, a calcium antagonist, endothelin antagonist, a vasodilating agent, an Rho kinase inhibitor, a nitrate drug, a xanthine derivative, prostaglandins, an angiotensin II antagonist, a diuretic, an angiotensin converting enzyme inhibitor, a prostacyclin preparation, a β-blocker, a β-adrenergic agent, an anticholinergic agent, a thrombolytic agent, a thromboxane synthase inhibitor, a thromboxane A2 receptor antagonist, an antioxidant, a radical scavenger, a poly-ADP ribose polymerase (PARP) inhibitor, an astrocyte-function improvement agent, a phosphodiesterase 4 inhibitor, a steroidal agent, an aldsterone antagonist, a leukotriene receptor antagonist, a mediator liberation inhibitor, an anti-histamine agent, a cytokine inhibitor, a Forskolin prepration, an elastase inhibitor, a metalloprotease inhibitor, an expectorant drug, an antibiotic agent and the like, but are not limited thereto. And these other drugs may preferably be suitably selected according to the disease to which the compound of the present invention is applied. The dose of the other drugs may be suitably selected in relation to the clinically used doses as a reference. The ratio of the Compound of the Present Invention to the other drugs may be suitably selected depending upon the age and weight of an subject to be administered, route of administration, time of administration, targeted disease, symptom or drug combination and the like. For example, approximately 0.01 to 100 parts by weight of the other drugs may be used against 1 part of the Compound of the Present Invention. The other drugs may be administered in combination of one or not less than two being arbitrarily selected from the above-indicated groups of the similar and different types. The diseases, against which the above-mentioned concomitant drug preparations can produce the preventive and/or therapeutic effects, are not particularly limited and may be any diseases so long as they can attain the supplementation and/or enhancement of the preventive and/or therapeutic effects of the Compound of the Present Invention. Examples of the other drugs for supplementation and/or enhancement of the preventive and/or therapeutic effects on cerebrovascular spasm diseases and cardiovascular spasm diseases include a calcium antagonist, a thrombolytic agent, a thromboxane synthase inhibitor, an endothelin antagonist, an antioxidant agent, a radical scavenger, a PARP inhibitor, an astrocyte-function improvement agent, a vasodilating agent, an Rho kinase inhibitor and the like. Examples of the other drugs for supplementation and/or enhancement of the preventive and/or therapeutic effects on hypertension include a calcium antagonist, an angiotensin II antagonist, an angiotensin converting enzyme inhibitor, a diuretic, a phosphodiesterase 4 inhibitor, prostaglandins (hereinafter from time to time referred to briefly as PG or PGs), an aldosterone antagonist and the like. Examples of the other drugs for supplementation and/or enhancement of the preventive and/or therapeutic effects on pulmonary hypertension include an endothelin antagonist, a prostacyclin prearation and the like. Examples of the other drugs for supplementation and/or enhancement of the preventive and/or therapeutic effects on angina pectoris include a nitrate drug, a β-blocker, a calcium antagonist and a vasodialator and the like. Examples of the other drugs for supplementation and/or enhancement of the preventive and/or therapeutic effects on bronchial asthma or chronic obstructive pulmonary disease include a phosphodiesterase 4 inhibitor, a steroidal drug, a β-adrenergic agent, a leukotriene receptor antagonist, a thromboxane synthase inhibitor, a thromboxane A2 receptor antagonist, a mediator liberation inhibitor, an anti-histamine drug, a xanthine derivative, an anti-cholinergic agent, a cytokine inhibitor, prostaglandins, a Forskolin preparation, an elastase inhibitor, a metalloprotease inhibitor, an expectorant drug and an antibiotic agent and the like. Examples of the calcium antagonists include nifedipine, benidipine hydrochloride, diltiazem hydrochloride, verapamil hydrochloride, nisoldipine, nitrendipine, bepridil hydrochloride, amlodipine besilate, lomerizine hydrochloride and efonidipine hydrochloride and the like. Examples of the thrombolytic drugs include alteprase, urokinase, tisokinase, nasaruplase, nateplase, tissue plasminogen activator, pamiteplase and monteplase and the like. Examples of the thromboxane synthase inhibitors include ozagrel hydrochloride, and imitrodast sodium and the like. Examples of the radical scavengers include radicut and the like. Examples of the PARP inhibitors include, 3-aminobenzamide or 1,3,7-trimethylxanthine (caffeine), PD-141076 and PD-141703 and the like. Examples of the astrocyte-function improvement agents include ONO-2506 and the like. Examples of the Rho kinase inhibitors include fasudil hydrochloride and the like. Examples of the angiotensin II antagonists include losartan, candesartan, valsartan, irbesartan, olmesartan and telmesartan and the like. Examples of the angiotensin converting enzyme inhibitors include alacepril, imidapril hydrochloride, quinapril hydrochloride, temocapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, captopril, trandolapril, perindopril erubumine, enalapril maleate and lisinopril and the like. Examples of the diuretics include mannitol, furosemide, acetazolamide, diclofenamide, methazolamide, trichlormethiazide, mefruside, spironolactone and aminophylline and the like. Examples of the phospodiesterase 4 inhibitor include rolipram, cilomilast, Bay19-8004, NIK-616, roflumilast (BY-217), cipamfylline (BRL-61063), atizoram (CP-80633), SCH-351591, YM-976, V-11294A, PD-168787, D-4396 and IC-485 and the like. Examples of the PGs include a PG receptor agonist and PG receptor antagonist and the like. Examples of the PG receptors include PGE receptors (EP1, EP2, EP3, EP4), a PGD receptor (DP, CRTH2), PGF receptor (FP), PGI recptor (IP) and TX receptor (TP) and the like. Examples of the aldosterone antagonists include drospirenon, metyrapone, potassium canrenoate, canrenone, eplerenone and ZK-91857 and the like. Examples of the prostacyclin preparations include treprostinil sodium, epoprestenol sodium and beraprost sodium and the like. Examples of the nitrate drugs include amyl nitrite, nitroglycerine, isosorbide dinitrate and the like. Examples of the β-blockers include, bupranolol hydrochloride, bufetolol hydrochloride, oxprenolol hydrochloride, atenolol, bisoprolol fumarate, betaxolol hydrochloride, bevantolol hydrochloride, metoprolol tartrate, acebutolol hydrochloride, celiprolol hydrochloride, nipradilol, tilisolol hydrochloride, nadolol, propranolol hydrochloride, indenolol hydrochloride, carteolol hydrochloride, pindolol, bunitrolol hydrochloride, arotinolol hydrochloride and carvedilol hydrochloride and the like. Examples of the vasodilating agents include diltiazem hydrochloride, trimetazidine hydrochloride,. dipyridamole, ethanofen hydrochloride, dilazep hydrochloride, trapidil, nicorandil and the like. Examples of the steroidal drugs include, in the form of a preparation for internal use or an injectable solution, cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butylacetate, prednisolone sodium phosphate, halopredone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, betamethasone and the like. Examples of the steroidal drugs include, in the form of an inhalant, beclomethasone propionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone palomitionate, mometasone furancarbonate, prasterone sulfonate, deflazacort, methyl prednisolone sreptanate, methyl prednisolone sodium succinate and the like. Examples of the β-adrenergic agonists include fenoterol hydrobromide, salbutamol sulfate, terbutaline sulfate, formoterol fumarate, salmeterol xinafoate, isoproterenol sulfate, orciprenalin sulfate, chloroprenalin sulfate, epinephrine, trimetoquinol hydrochloride, hexoprenalinmesyl sulfate, procaterol hydrochloride, tulobuterol hydrochloride, tulobuterol, pirbuterol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, ritodrine hydrochloride, bambuterol, dopexamin hydrochloride, meradrin tartrate, AR-C68397, levosalbutamol, R,R-formoterol, KUR-1246, KUL-7211, AR-C89855, S-1319 and the like. Examples of the leukotriene receptor antagonists include pranlukast hydrate, montelukast, zafirlukast, seratrodast, MCC-847, KCA-757, CS-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284, ONO-4057 and the like. Examples of the thromboxane A2 receptor antagonists include seratrodast, ramatroban, domitroban calcium hydrate, KT-2-962 and the like. Examples of the mediator liberation inhibitors include tranilast, sodium cromoglycate, amlexanox, repirinast, ibudilast, dazanolast, potassium pemirolast and the like. Examples of the anti-histamine drugs include ketotifen fumarate, mequitazine, azelastine hydrochloride, oxatomide terfenadine, emedastine difumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, bepotastine, fexofenadine, loratadine, desloratadine, olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294, auranofin, acrivastin and the like. Examples of the xanthine derivatives include aminophylline, theophylline, doxofyllin, cipamphylline, diprophylline and the like. Examples of the anticholinergic agents include ipratropium bromide, oxitropium bromide, futropium bromide, simetropium bromide, temiverine, thiotropium bromide, revatropate (UK-112166) and the like. Examples of the cytokine inhibitors include suplatast tosylate (Brand Name: IPD) and the like. Examples of the elastase inhibitors include ONO-5046, ONO-6818, MR-889, PBI-1101, EPI-HNE-4, R-665 and the like. Examples of the expectorant drugs include carbocysteine, ambroxol hydrochloride, controlled release preparation of ambroxol hydrochloride, methylcysteine hydrochloride, acetyl cysteine, L-ethylcysteine hydrochloride, tyloxapol and the like. Examples of the endothelin antagonists include BE-18257B, BQ-123, FR139317, bosentan, SB209670 and the like. Examples of the metalloprotease inhibitors include KB-R7785, S-3536 and the like. Examples of the antibiotic drugs include cefuroxime sodium, meropenem trihydrate, netilmicin sulfate, sisomicin sulfate, ceftibuten, PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromicin sulfate, cefetamet pivoxil hydrochloride and the like. Examples of the inhalant antibiotic drugs include PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromicin sulfate, cefetamet pivoxil hydrochloride and the like. Other drugs which act to supplement and/or enhance the preventive and/or therapeutic effects of the Compound of the Present Invention include the drugs which not only have already been found out in the past, but also are to be found out in the future, to exhibit such activities on the basis of the above-described mechanism. The Compound of the Present Invention or the concomitant drug preparation thereof with other drugs, when used for the above-described purposes, is ordinarily administered systemically or topically in the form of oral or parenteral preparation. The Compound of the Present Invention, whose dosage may vary depending upon the age, body weight and symptom of a patient to be treated, the intended therapeutic effect, administration route and duration of the treatment, etc., preferably is generally administered to a human adult orally in a dose ranging from about 100 μg to about 1000 mg once to several times a day, to a human adult parenterally in a dose of ranging from 50 μg to about 500 mg once to several times a day, or to a human adult through sustained intraveneous infusion over the period of time ranging from about 1 hour to 24 hours a day. As has been described in the above, naturally, the dosage may change with a variety of conditions. Consequently, the Compound of the Present Invention in some instances can produce the intended effect satisfactorily even in doses lower than the above-mentioned doses and is in other instaces required to be administered in doses in excess of the above dose ranges. The Compound of the Present Invention or the concomitant drug preparation thereof with other drugs is administered as used in the dosage forms of solid pharmaceutical preparation or liquid solution for internal use for the purpose of oral administration, or in the dosage forms of an injectable solution, a topical preparation, a suppository, an ophthalmic solution, an inhalant, etc. for the purpose of parenteral administration. The solid pharmaceutical preparation for internal use for the purpose of oral administration includes, for example, a tablet, a pill, a capsule, powders, granules, etc. As the capsule, there may be mentioned, for example, a hard capsule and a soft capsule. In such a solid pharmaceutical preparation for internal use, one or more of the active substances is/are used as such or by mixing them with, for example, an excipient. (e.g. lactose, mannnitol, glucose, microcrystalline cellulose, starch and the like), a binder (e.g. hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesium metasilicate aluminate and the like), a disintegrating agent (e.g. cellulose calcium glycolate and the like), a lubricating agent (e.g. magnesium stearate and the like), a stabilizer and a dissolving adjuvant (e.g. glutamic acid,asparatic acid and the like), followed by processing into the prearation by the conventional procedures. The solid pharmaceutical preparation, if necessary, may be covered with a coating agent (e.g. sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl cellulose phthalate and the like) or with two or more layers. A capsule consisting of a bioabsorbable material, such as gelatin, is also included. The liquid solution for internal use includes, for example, a pharmaceutically acceptable aqueous solution, a suspension, an emulsion, syrup, elixir and the like. In such a liquid solution, one or more active compound(s) is/are dissolved, suspended or emulsified in an ordinarily used diluent (e.g. purified water, ethanol or a mixture thereof and the like). Furthermore, such liquid solution may also contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a perfuming (aromatic) agent, a buffering agent, a preservative, a buffering agent and the like. The topical preparation for external use for the purpose of parenteral administration includes, for example, an ointment, gel, cream, poultice, patch, liniment, nebula, inhalant, spray, aerosol, an ophthalmic solution or collunarium and the like. These contain one or more active substances and are prepared by the known methods or in accordance with the usually employed formulations. The ointment is prepared by the known methods or in accordance with the usually employed formulations. For example, it is prepared by mixing with, or melting in, a base one or more active substances. The ointment base is selected from the bases which are known or are normally used: it is used by mixing one or not less than two of the bases being selected from higher fatty acids or higher fatty acid esters (e.g. adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipates, myristates, palmitates, stearares, oleates and the like), waxes (e.g. beeswax, whale wax, ceresin and the like), sufactants (e.g. polyoxyethylenealkylether phosphate and the like), higher alcohols (e.g. cetyl alcohol, stearyl alcohol, cetostearyl alcohol and the like), silicon oils (e.g. dimethylpolysiloxane and the like), hydrocarbons (e.g. hydrophilic vaseline, white vaseline, purified lanolin, liquid petrolatum and the like), glycols (e.g. ethyleneglycol, diethyleneglycol, propyleneglycol, polyethyleneglycol, macrogol and the like), vegetable oils (e.g. castor oil, oliveoil, sesame oil, turpentine and the like), animal oils (e.g. mink oil, yolk oil, squalane, squalene and the like), water, absorption promoters, protectives for skin eruption and the like. Furthermore, it may contain ahumectant and emollient, preservative, stabilizer, antioxidant, flavoring agentand the like. The gel is prepared by the known methods or in accordance with the usually employed formulations. For example, the gel is prepared by melting one or more of the active substance(s) in the base. The gel base is selected from those which are known or are ordinarily used, such as lower alcohols (e.g. ethanol, isopropyl alcohol and the like), gelling agents (e.g. carboxymethyl-cellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose and the like), acid-neutralizing agents (e.g. triethanolamine, diisopropanolamine and the like), surfactants (e.g. polyoxyethylene glycol stearate and the like), gums, water, absorption promoters, protectives against skin eruption and the like. and is used alone or as an admixture of two or more thereof. Furthermore, such gel base may include a preservative, an antioxidant, a flavoring agent and the like. The cream is prepared by the known methods or in accordance with the usually employed formulations, and is prepared, for example, by melting or emulsifying one or more active substances in a base. The cream base is selected from those which are known or are ordinarily used, such as higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (e.g. propylene glycol, 1,3-butylene glycol and the like), higher alcohols (e.g. 2-hexyldecanol, cetyl alcohol and the like), emulsifying agents (e.g. polyoxyethylenated alkylethers, fatty acid esters and the like), water, absorption promoters, protectives against skin eruption and the like, and is used alone or as an admixture of two or more thereof. Furthermore, such cream base may include a preservative, an antioxidant, a flavoring agent and the like. The poultice is prepared by the known methods or in accordance with the usually employed formulations, and is prepared, for example, by melting one or more active substances in a base and spreading for application the mixture on a supporting material. The poultice base is selected from those which are known or are ordinarily used, such as thickeners (e.g. polyacrylic acid, polyvinyl pyrrolidone, gum arabic, starch, gelatin, methylcellulose and the like), humectants and emollients (e.g. urea, glycerin, propylene grycol and the like), filler S (e.g. kaolin, zinc oxide, talc, calcium carbonate, magnesium carbonate and the like), water, solubilizing agents, tackifiers, protective for skin eruption and the like, and is used alone or as an admixture of two or more thereof. Furthermore, such poultice base may include a preservative, an antioxidant, a flavoring agent and the like. The patch is prepared by the known methods or in accordance with the usually employed formulations, and is prepared by melting one or more of the active substance(s) in a base and spreading for application the mixture on a supporting material. The patch base is selected from those which are known or are normally used, such as polymer bases, oils and fats, higher fatty acids, tackifiers, protectives for skin eruption and the like, and is used alone or an admixture of two or more thereof. Furthermore, such patch base may include a preservative agent, an antioxidant, a flavoring agent and the like. The liniment is prepared by the known methods or in accordance with the usually employed formulations, and is prepared, for example, by dissolving, suspending or emulsifying one or more of active substances in a base consisting of one or more member(s) selected from water, alcohols (e.g. ethanol, polyethylene glycol and the like), higher fatty acids, glycerin, soaps, emulsifiers, suspending agents and the like. The nebula, inhalant or spray preparation may contain, in addition to the generally used diluents, a stabilizer such as sodium bisulfite, an isotonizing buffer and an isotonic agent such as sodium chloride, sodium citrate or citric acid. The manufacturing process for spray preparations is described in detail, for example, in U.S. Patent Nos. 2,868,691 and 3,095,355. Examples of the injectable solution for the purpose of parenteral administration include solutions, suspensions, emulsions and solid injections to be applied by dissolving or suspending in a solvent on the occasion of use. The injectable solutions are used by dissolving, suspending or emulsifying one or more of the active substances in a solvent. Examples of the solvent include distilled water for injection, saline solution, vegetable oils, propylene glycol, polyethylene glycol, alcohols (e.g. ethanol and the like) and combinations thereof. Such injectable solutions may additionally contain a stabilizer, a solubilizer (e.g. glutamic acid, aspartic acid, Polysorbate 80 (the registered trademark) and the like), a suspending agent, emulsifyer, pain-soothing agent, a buffering agent, a preservative and the like. These are prepared by sterilization in the final processing step or by the aseptic manipulation. Alternatively, such injectable solutions can be utilized by preparing a sterile solid, such as freeze-dried product and dissolving, prior to use, the same in sterilized or sterile distilled water for injection. The ophthalmic solution for the purpose of parenteral administration include, for example, ophthalmic solution, suspension-type ophthalmic solution, emulsion-type ophthalmic solution, ophthalmic solution for dissolution on the occasion of use or ophthalmic ointment and the like. These ophthalmic solutions are prepared by following the known procedures. For example, use is made by dissolving, suspending or emulsifying one or more of the active substances in the solvent. The solvent for ophthalmic solution includes, for example, sterile purified water, saline solution, other aqueous solvents or non-aqueous solvents for injection (e.g. vegetable oils and the like), and combinations thereof. The ophthalmic solutions may contain an isotonic agent (e.g. sodium chloride, concentrated glycerin and the like), buffering agent (e.g. sodium phosphate, sodium acetate and the like), sufactant (e.g. Polysorbate 80 (the registered trademark), polyoxyl stearate 40, polyoxyethylenated hardened castor oil and the like), stabilizer (e.g. sodium citrate, edentate sodium and the like), preservative (e.g. benzalkonium chloride, paraben and the like) and the like, which are suitably selected as the case may be. These are prepared by sterilization in the final processing step or by the aseptic manipulation. And, such ophthalmic solutions may be utilized by preparing a sterile solid, such as freeze-dried or lyophilized product and dissolving, prior to use, the same in sterilized or sterile purified water or other solvents. The inhalant for the purpose of parenteral administration includes an aerosol agent, powder for inhalation or liquid for inhalation, and such liquid for inhalation may be formulated into such a dosage form as may be used by dissolving or suspending, on the occasion of use, the same in water or other suitable media. These inhalants are prepared by the known methods. The liquid for inhalation is prepared for example by suitably selecting, as the case may be, a preservative (e.g. benzalkonium chloride, parabens and the like), coloring agent, buffering agent (e.g. sodium phosphate, sodium acetate and the like), isotonic agent (e.g. sodium chloride, concentrated glycerin and the like), thickener (e.g. carboxy vinyl polymer and the like), absorption promoter and the like. The dry powder for inhalation is prepared by suitably selecting, as the case may be, a lubricant (e.g. stearic acid and salt thereof and the like), binder (e.g. starch, dextrin and the like), coloring agent, preservative (e.g. benzalkonium chloride, parabens and the like), absorption promoter and the like. On the occasion of administration of the liquid for inhalation, the spraying devices (e.g. atomizer, nebulizer and the like) are usually used, while in the case of administration of the dry powder for inhalation, the inhalation-administering devices for dry powders are generally employed. Other compositons for parenteral administration include a suppository for intrarectal application and pessary for intravaginal administration which comprises one or more of the active substances and may be processed by the conventional methods. The present invention is to be illustrated below in detail by way of Examples, but the present invention shall not be limited thereto. The parenthesized solvents, which are described under the chromatographic separatory and TLC procedures, are understood to designate the eluting or developing solvents, with the ratios being expressed on a volume basis. The NMR data denote the data of 1H-NMR, unless otherwise specified. The parenthesized solvents, which are indicated under NMR measurements, are understood to signify the solvents used for the measurements. MS, unless otherwise specified, was conducted using ESI (electron spray ion) method to detect the positive ions (pos.) alone. The conditions for HPLC are as follows: (A) Condition A (Analysis) Equipment used: Waters LC/MS Column: Xterra (the registered trade mark) MS C18 5 μm, 4.6×50 mm I.D. Flow rate: 3 mL/min Eluting solvent: Solvent A: 0.1% aqueous trifuloroacetic acid solution Solvent B: 0.1% trifuloroacetic acid-acetonitrile solution (A time-course change of the eluting solvent composition in vol. % is shown below) Time (min) solvent A solvent B 0 95 5 0.5 95 5 3 0 100 3.5 0 100 3.51 95 5 5 95 5 (2) Condition B (Analysis) Epuipment used: Waters LC/MS Column: Xterra (the registered trademark) MS C18 5 μm, 4.6×50 mm I.D. Flow rate: 3 mL/min Solvent A: 10 mM aqueous ammonium carbonate solution Solvent B: acetonitrile Time (min) solvent A solvent B 0 95 5 0.5 95 5 3 0 100 3.5 0 100 3.51 95 5 7 95 5 In the HPLC, all the measurements were performed under Condition A, unless the conditions were otherwise specified particularly. The compounds described in the present specification were named by use of ACD/Name or ACD/Name Batch (both are the registered trademarks, manufactured by Advanced Chemistry Development Inc.) or in accordance with the IUPAC nomenclature. For example, the compound of the formula: was named N-[3,5-bis(trifluoromethyl)phenyl]-3-[ethyl(phenyl)amino]azetidine-1-carboxamide. EXAMPLE 1 Tert-butyl 4-[1-(diphenylmethyl)azetidin-3-yl]piperazine-1-carboxylate Potassium carbonate (26 g) was added to a solution of tert-butyl piperazine-1-carboxylate (7.7 g) in acetonitrile (100 ML), to which a suspension of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (12.05 g) in tetrahydrofuran (30 mL) was added at room temperature, and the mixture was stirred for 4 hours at 100° C., and then concentrated. To the resulting residue was added water, and the mixture was extracted with ethyl acetate twice. The extract was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=3:1→1:2), and the product was washed with tert-butyl methyl ether and collected by filtration to give the title compound (10.68 g) having the following physical data. TLC:Rf 0.55 (hexane:ethyl acetate=l:l). EXAMPLE 2 Tert-butyl 4-azetidin-3-ylpiperazine-1-carboxylate Under atmosphere of argon, a solution of the compound, prepared in Example 1 (8.68 g), in methanol (50 ml)/acetic acid (8.5 mL) was added to a suspension of 20% palladium hydroxide (1.74 g, wet) in methanol (5 mL). The mixture was stirred for 5 hours under atmosphere of hydrogen at 5 atm. The reaction solution was filtered and concentrated. To the residue was added tert-butyl methyl ether, and the mixture was extracted with water. To the aqueous layer was added 5N aqueous solution of sodium hydroxide, and the solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (5.1 g) having the following physical data. TLC:Rf 0.41 (ethyl acetate:acetic acid:water=3:1:1). EXAMPLE 3 Tert-butyl 4-[1-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)azetidin-3-yl]piperazine-1-carboxylate To a solution of the compound prepared in Example 2 (986 mg) in tetrahydrofuran (12 mL) was dropwise added 1-isocyanato-3,5-bis(trifluoromethyl)benzene (0.85 mL), and the mixture was stirred for 30 minutes. The reaction solution was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (1.413 g) having the following physical data. TLC:Rf 0.21 (hexane:ethyl acetate=1:1); NMR(CDCl3):δ 1.47 (s, 9H), 2.34 (m, 4H), 3.24 (m, 1H), 3.47 (m, 4H), 3.98 (dd, J=8.00, 5.50 Hz, 2H), 4.11 (t, J=8.00 Hz, 2H), 6.26 (s, 1H), 7.51 (s, 1H), 7.91 (s, 2H). EXAMPLES 3(1) to 3(809) Each of the following compounds of the present invention was prepared from an azetidine derivative corresponding to the compound prepared in Example 2 and an isocyanate derivative corresponding to 1-isocyanato-3,5-bis(trifluoromethyl)benzene using a procedure analogous to that described for Example 3. EXAMPLE 3(1) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide TLC:Rf 0.30 (hexane:ethyl acetate=1:1); NMR(CDCl3):δ 2.58 (m, 4H), 3.24 (m, 4H), 3.33 (m, 1H), 4.04 (dd, J=8.00, 5.00 Hz, 2H), 4.15 (t, J=8.00 Hz, 2H), 6.25 (s, 1H), 6.93 (m, 3H), 7.28 (m, 2H), 7.51 (s, 1H), 7.92 (s, 2H). EXAMPLE 3(2) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2- methoxyphenyl)piperazin-1-yl]azetidine-1-carboxamide TLC:Rf 0.22 (hexane:ethyl acetate=1:1); NMR(CDCl3):δ 2.62 (m, 4H), 3.14 (m, 4H), 3.36 (m, 1H), 3.87 (s, 3H), 4.04 (dd, J=8.00, 5.00 Hz, 2H), 4.14 (t, J=8.00 Hz, 2H), 6.32 (s, 1H), 6.88 (d, J=7.50 Hz, 1H), 6.94 (m, 2H), 7.03 (m, 1H), 7.51 (s, 1H), 7.93 (s, 2H). EXAMPLE 3(3) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-methoxyphenyl)piperazin-1-yl]azetidine-1-carboxamide TLC:Rf 0.29 (hexane:ethyl acetate=1:1); NMR(CDCl3): δ 2.55 (m, 4H), 3.23 (m, 4H), 3.30 (m, 1H), 3.80 (s, 3H), 4.02 (dd, J=8.00, 5.00 Hz, 2H), 4.13 (t, J=8.00 Hz, 2H), 6.45 (m, 3H), 6.55 (m, 1H), 7.19 (t, J=8.00 Hz, 1H), 7.51 (s, 1H), 7.92 (s, 2H). EXAMPLE 3(4) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(4-methoxyphenyl)piperazin-1-yl]azetidine-1-carboxamide TLC:Rf 0.17 (hexane:ethyl acetate=1:1); NMR(CDCl3): δ 2.58 (m, 4H), 3.13 (m, 4H), 3.32 (m, 1H), 3.77 (s, 3H), 4.03 (dd, J=8.00, 5.00 Hz, 2H), 4.14 (t, J=8.00 Hz, 2H), 6.28 (s, 1H), 6.85 (d, J=9.00 Hz, 2H), 6.91 (d, J=9.00 Hz, 2H), 7.51 (s, 1H), 7.92 (s, 2H). EXAMPLE 3(5) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[3-(trifluoromethoxy)phenyl]piperazine-1-yl}azetidine-1-carboxamide TLC:Rf 0.39 (hexane:ethyl acetate=1:1); NMR(CDCl3): δ 2.56 (m, 4H), 3.25 (m, 4H), 3.32 (m, 1H), 4.03 (dd, J=8.00, 5.00 Hz, 2H), 4.15 (t, J=8.00 Hz, 2H), 6.22 (s, 1H), 6.71 (m, 2H), 6.82 (m, 1H), 7.26 (m, 1H), 7.51 (s, 1H), 7.92 (s, 2H). EXAMPLE 3(6) N-(2-Ethylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide TLC:Rf 0.26 (ethyl acetate:methanol:triethylamine=10:1:2); NMR(CDCl3): δ 1.24 (t, J=7.50 Hz, 3H), 2.33 (s, 3H), 2.56 (m, 10H), 3.21 (m, 1H), 3.89 (dd, J=8.00, 5.50 Hz, 2H), 4.00 (t, J=8.00 Hz, 2H), 5.84 (s, 1H), 7.06 (m, 1H), 7.19 (m, 2H), 7.69 (d, J=8.00 Hz, 1H). EXAMPLE 3(7) N-(2,4-Dimethylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide TLC:Rf 0.23 (ethyl acetate:methanol:triethylamine=10:1:2); NMR(CDCl3): δ 2.20 (s, 3H), 2.27 (s, 3H), 2.31 (s, 3H), 2.43 (m, 8H), 3.18 (m, 1H), 3.87 (dd, J=8.00, 5.50 Hz, 2H), 3.97 (t, J=8.00 Hz, 2H), 5.69 (s, 1H), 6.97 (m, 2H), 7.47 (d, J=8.00 Hz, 1H). EXAMPLE 3(8) 3-(4-Methylpiperazin-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide TLC:Rf 0.21 (ethyl acetate:methanol:triethylamine=10:1:2); NMR(CDCl3): δ 2.32 (s, 3H), 2.47 (m, 8H), 3.25 (m, 1H), 3.96 (dd, J=8.00, 5.50 Hz, 2H), 4.08 (t, J=8.00 Hz, 2H), 6.07 (s, 1H), 7.26 (m, 1H), 7.39 (t, J=8.00 Hz, 1H), 7.64 (m, 2H). EXAMPLE 3(9) N-(3,5-Dimethylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide TLC:Rf 0.21 (ethyl acetate:methanol:triethylamine=10:1:2); NMR(CDCl3): δ 2.27 (s, 6H), 2.32 (s, 3H), 2.46 (m, 8H), 3.22 (m, 1H), 3.92 (dd, J=8.00, 5.50 Hz, 2H), 4.03 (t, J=8.00 Hz, 2H), 5.85 (s, 1H), 6.68 (s, 1H), 7.00 (s, 2H). EXAMPLE 3(10) Methyl 3-({[3-(4-methylpiperazin-1-yl)azetidin-1-yl]carbonyl}amino)benzoate TLC:Rf 0.16 (ethyl acetate:methanol:triethylamine=10:1:2); NMR(CDl3): δ 2.35 (s, 3H), 2.51 (m, 8H), 3.26 (m, 1H), 3.90 (s, 3H), 3.96 (dd, J=8.00, 5.00 Hz, 2H), 4.08 (t, J=8.00 Hz, 2H), 6.05 (s, 1H), 7.36 (t, J=8.00 Hz, 1H), 7.70 (m, 1H), 7.80 (m, 1H), 7.86 (m, 1H). EXAMPLE 3(11) N-(2,4-Dimethylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide TLC:Rf 0.68 (ethyl acetate:methanol:triethylamine=10:1:2); NMR(CDCl3): 6 1.83 (m, 4H), 2.20 (s, 3H), 2.27 (s, 3H), 2.50 (m, 4H), 3.31 (m, 1H), 3.90 (dd, J=8.00, 5.00 Hz, 2H), 4.02 (t, J=8.00 Hz, 2H), 5.69 (s, 1H), 6.98 (m, 2H), 7.49 (d, J=8.00 Hz, 1H). EXAMPLE 3(12) N-(3,5-Dichlorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide TLC:Rf 0.37 (hexane:ethyl acetate=1:1); NMR(CDCl3): δ 1.82 (m, 6H), 2.52 (m, 1H), 2.91 (m, 2H), 3.17 (m, 1H), 3.95 (dd, J=8.24, 7.87 Hz, 2H), 4.06 (t, J=7.87 Hz, 2H), 6.61 (s, 1H), 6.98 (t, J=1.83 Hz, 1H), 7.20 (m, 3H), 7.30 (m, 2H), 7.39 (d, J=1.83 Hz, 2H). EXAMPLE 3(13) 3-(2,3-Dihydro-1H-indol-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide TLC:Rf 0.61 (hexane:ethyl acetate=1:1); NMR(CDl3): δ 3.00 (t, J=8.24 Hz, 2H), 3.43 (t, J=8.24 Hz, 2H), 4.28 (m, 5H), 6.29 (s, 1H), 6.39 (d, J=7.69 Hz, 1H), 6.75 (m, 1H), 7.07 (t, J=7.69 Hz, 1H), 7.12 (d, J=7.87 Hz, 1H), 7.26 (m, 1H), 7.38 (t, J=8.06 Hz, 1H), 7.63 (d, J=8.06 Hz, 1H), 7.68 (s, 1H). EXAMPLE 3(14) N-(3,5-Dichlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide TLC:Rf 0.73 (hexane:ethyl acetate=1:1); NMR(CDCl3): δ 3.01 (t, J=8.24 Hz, 2H), 3.43 (t, J=8.24 Hz, 2H), 4.25 (m, 5H), 6.12 (s, 1H), 6.38 (d, J=7.88 Hz, 1H), 6.75 (m, 1H), 7.01 (t, J=1.83 Hz, 1H), 7.07 (t, J=7.88 Hz, 1H), 7.13 (d, J=7.32 Hz, 1H), 7.38 (d, J=1.83 Hz, 2H). EXAMPLE 3(15) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide TLC:Rf 0.82 (hexane:ethyl acetate=1:1); NMR(CDCl3): δ 3.02 (t, J=8.05 Hz, 2H), 3.45 (t, J=8.05 Hz, 2H), 4.31 (m, 5H), 6.35 (s, 1H), 6.40 (d, J=7.69 Hz, 1H), 6.76 (m, 1H), 7.07 (m, 1H), 7.13 (d, J=7.32 Hz, 1H), 7.52 (s, 1H), 7.93 (s, 2H). EXAMPLE 3(16) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(3-phenoxyphenyl)azetidine-1-carboxamide TLC:Rf 0.59 (hexane:ethyl acetate=1); NMR(CDCl3): δ 2.99 (t, J=8.06 Hz, 2H), 3.42 (t, J=8.06 Hz, 2H), 4.22 (m, 5H), 6.10 (s, 1H), 6.38 (d, J=7.69 Hz, 1H), 6.68 (m, 1H), 6.74 (m, 1H), 7.01 (m, 2H), 7.11 (m, 5H), 7.21 (m, 1H), 7.32 (m, 2H). EXAMPLE 3(17) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[methyl(phenyl)amino]azetidine-1-carboxamide TLC:Rf 0.82 (hexane:ethyl acetate=1:1); NMR(CDCl3): δ 2.91 (s, 3H), 4.09 (m, 2H), 4.31 (t, J=7.50 Hz, 2H), 4.42 (m, 1H), 6.50 (m, 1H), 6.76 (d, J=7.87 Hz, 2H), 6.89 (m, 1H), 7.27 (m, 2H), 7.50 (s, 1H), 7.91 (s, 2H). EXAMPLE 3(18) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[ethyl(phenyl)amino]azetidine-1-carboxamide TLC:Rf 0.86 (hexane:ethyl acetate=1:1); NMR(CDCl3): δ 1.05 (t, J=7.14 Hz, 3H), 3.35 (q, J=7.14 Hz, 2H), 3.98 (m, 2H), 4.29 (t, J=7.69 Hz, 2H), 4.40 (m, 1H), 6.42 (s, 1H), 6.75 (d, J=7.32 Hz, 2H), 6.90 (t, J=7.32 Hz, 1H), 7.26 (m, 2H), 7.49 (s, 1H), 7.90 (s, 2H). EXAMPLE 3(19) 3-{4-[4-(Trifluoromethoxy)phenyl]piperazin-1-yl}-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide TLC:Rf 0.60 (chloroform:methanol=10:1); NMR(CDCl3): δ 2.54 (m, 4H), 3.21 (m, 4H), 3.30 (m, 1H), 4.00 (dd, J=7.69, 5.31 Hz, 2H), 4.12 (t, J=7.69 Hz, 2H), 6.19 (s, 1H), 6.89 (d, J=8.42 Hz, 2H), 7.12 (d, J=8.42 Hz, 2H), 7.29 (d, J=7.87 Hz, 1H), 7.39 (t, J=7.87 Hz, 1H), 7.64 (d, J=7.87 Hz, 1H), 7.66 (s, 1H). EXAMPLE 3(20) N-(3,5-Dimethylphenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide TLC:Rf 0.64 (chloroform:methanol=10:1); NMR(CDCl3): δ 2.27 (s, 6H), 2.55 (m, 4H), 3.21 (m, 4H), 3.27 (m, 1H), 3.96 (dd, J=8.06, 5.31 Hz, 2H), 4.07 (t, J=8.06 Hz, 2H), 5.92 (s, 1H), 6.68 (s, 1H), 6.89 (d, J=8.24 Hz, 2H), 7.02 (s, 2H), 7.12 (d, J=8.24 Hz, 2H). EXAMPLE 3(21) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide TLC:Rf 0.48 (hexane: ethyl acetate=3:7); NMR(CDCl3): δ 2.56 (t, J=4.95 Hz, 4H), 3.21 (t, J=4.95 Hz, 4H), 3.32 (m, 1H), 4.03 (dd, J=8.32, 5.13 Hz, 2H), 4.14 (t, J=8.32 Hz, 2H), 6.37 (s, 1H), 67.89 (d, J=9.15 Hz, 2H), 7.12 (d, J=9.15 Hz, 2H), 7.51 (s, 1H), 7.92 (s, 2H). EXAMPLE 3(22) N-Phenyl-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.36; MS:421 (M+H)+. EXAMPLE 3(23) N-Butyl-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:401 (M+H)+. EXAMPLE 3(24) N-(4-Chlorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.44; MS:457, 455 (M+H)+. EXAMPLE 3(25) N-(3-Chlorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.44; MS:457, 455 (M+H)+. EXAMPLE 3(26) N-Cyclohexyl-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.34; MS:427 (M+H)+. EXAMPLE 3(27) N-(2-Chlorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.38; MS:457, 455 (M+H)+. EXAMPLE 3(28) N-(3,4-Dichlorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.53; MS:491, 489 (M+H)+. EXAMPLE 3(29) 3-{4-[4-(Trifluoromethoxy)phenyl]piperazin-1-yl}-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.51; MS:489 (M+H)+. EXAMPLE 3(30) N-(2-Methoxyphenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.34; MS:451 (M+H)+. EXAMPLE 3(31) N-Hexyl-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.45; MS:429 (M+H)+. EXAMPLE 3(32) N-(3-Methoxyphenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.36; MS:452 (M+H)+. EXAMPLE 3(33) N-(4-Methoxyphenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.34; MS:451 (M+H)+. EXAMPLE 3(34) 3-{4-[4-(Trifluoromethoxy)phenyl]piperazin-1-yl}-N-[2-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.42; MS:489 (M+H)+. EXAMPLE 3(35) N-(2,4-Dichlorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.47; MS:491, 489 (M+H)+. EXAMPLE 3(36) Ethyl N-[(3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-yl)carbonyl]glycinate HPLC retention time (min.):3.22; MS:431 (M+H)+. EXAMPLE 3(37) N-(2-Fluorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.34; MS:439 (M+H)+. EXAMPLE 3(38) N-(3-Fluorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.38; MS:439 (M+H)+. EXAMPLE 3(39) N-Benzyl-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.34; MS:435 (M+H)+. EXAMPLE 3(40) N-(4-Fluorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.38; MS:439 (M+H)+. EXAMPLE 3(41) 3-{4-[4-(Trifluoromethoxy)phenyl]piperazin-1-yl}- N-[4-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.53; MS:489 (M+H)+. EXAMPLE 3(42) N-(3,5-Dichlorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.56; MS:491, 489 (M+H)+. EXAMPLE 3(43) N-(2,5-Dichlorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.47; MS:491, 489 (M+H)+. EXAMPLE 3(44) N-Pentyl-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.38; MS:415 (M+H)+. EXAMPLE 3(45) N-(2,6-Dichlorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.34; MS:491, 489 (M+H)+. EXAMPLE 3(46) N-(2-Phenylethyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.38; MS:449 (M+H)+. EXAMPLE 3(47) N-(2,3-Dichlorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.47; MS:491, 489 (M+H)+. EXAMPLE 3(48) N-(3-Cyanophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.36; MS:446 (M+H)+. EXAMPLE 3(49) Ethyl 4-{[(3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-yl]carbonyllamino}benzoate HPLC retention time (min.):3.44; MS:493 (M+H)+. EXAMPLE 3(50) N-(4-Phenoxyphenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.56; MS:513 (M+H)+. EXAMPLE 3(51) Ethyl 3-{[(3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-yl)carbonyl]amino}benzoate HPLC retention time (min.):3.44; MS:493 (M+H)+. EXAMPLE 3(52) N-Isopropyl-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.23; MS:387 (M+H)+. EXAMPLE 3(53) N-(3-Phenoxyphenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.60; MS:513 (M+H)+. EXAMPLE 3(54) N-(4-Cyanophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.34; MS:446 (M+H)+. EXAMPLE 3(55) N-(3,5-Difluorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.44; MS:457 (M+H)+. EXAMPLE 3(56) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.67; MS:557 (M+H)+. EXAMPLE 3(57) N-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.56; MS:534, 507 (M+H)+. EXAMPLE 3(58) N-(3-Chloro-5-fluorophenyl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.51; MS:475, 473 (M+H)+. EXAMPLE 3(59) N-[3-(Cyclopentyloxy)phenyll-3-{4-]4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.58; MS:505 (M+H)+. EXAMPLE 3(60) N-[3-(Cyclohexyloxy)phenyl]-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.64; MS:519 (M+H)+. EXAMPLE 3(61) N-(2,6-Dichloropyridin-4-yl)-3-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.):3.44; MS:492, 490 (M+H)+. EXAMPLE 3(62) 3-(Dimethylamino)-N-hexylazetidine-1-carboxamide HPLC retention time (min.):2.98; MS:228 (M+H)+. EXAMPLE 3(63) 3-(Dimethylamino)-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):3.05(condition B); MS:238 (M+H)+. EXAMPLE 3(64) 3-(Dimethylamino)-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.84; MS:234 (M+H)+. EXAMPLE 3(65) 3-(Dimethylamino)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.):2.66; MS:254 (M+H)+. EXAMPLE 3(66) 3-(Dimethylamino)-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.13; MS:523 (2M+H)+, 262 (M+H)+. EXAMPLE 3(67) N-(3-Chlorophenyl)-3-(dimethylamino)azetidine-1-carboxamide HPLC retention time (min.):2.96; MS:256, 254 (M+H)+. EXAMPLE 3(68) 3-(Dimethylamino)-N-(2,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.85; MS:248 (M+H)+. EXAMPLE 3(69) N-(4-Chlorophenyl)-3-(dimethylamino)azetidine-1-carboxamide HPLC retention time (min.):2.94; MS:256, 254 (M+H)+. EXAMPLE 3(70) N-Benzyl-3-(dimethylamino)azetidine-1-carboxamide HPLC retention time (min.):3.01(condition B); MS:234 (M+H)+. EXAMPLE 3(71) 3-(Dimethylamino)-N-(l-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):2.91; MS:539 (2M+H)+, 27.0 (M+H)+. EXAMPLE 3(72) 3-(Dimethylamino)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):3.06; MS:539 (2M+H)+, 270 (M+H)+. EXAMPLE 3(73) 3-(Dimethylamino)-N-[1-(l-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.):3.10; MS:595 (2M+H)+, 298 (M+H)+, 144. EXAMPLE 3(74) 3-(Dimethylamino)-N-(3,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.96; MS:495 (2M+H)+, 248 (M+H)+. EXAMPLE 3(75) 3-(Dimethylamino)-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.83; MS:234 (M+H)+. EXAMPLE 3(76) N-Cyclohexyl-3-(dimethylamino)azetidine-1-carboxamide HPLC retention time (min.):2.67; MS:226 (M+H)+. EXAMPLE 3(77) 3-(Dimethylamino)-N-(2,6-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.05(condition B); MS:495 (2M+H)+, 248 (M+H)+. EXAMPLE 3(78) 3-(Dimethylamino)-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.89; MS:264 (M+H)+. EXAMPLE 3(79) 3-(Dimethylamino)-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.86; MS:264 (M+H)+. EXAMPLE 3(80) 3-(Dimethylamino)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.):2.83; MS:248 (M+H)+. EXAMPLE 3(81) 3-(Dimethylamino)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.07; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(82) N-Cyclopentyl-3-(dimethylamino)azetidine-1-carboxamide HPLC retention time (min.):2.93(condition B); MS:212 (M+H)+. EXAMPLE 3(83) 3-(Dimethylamino)-N-(2,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.86; MS:248 (M+H)+. EXAMPLE 3(84) N-(3,5-Dichlorophenyl)-3-(dimethylamino)azetidine-1-carboxamide HPLC retention time (min.):3.15; MS:577, 575 (2M+H)+, 290, 288 (M+H)+. EXAMPLE 3(85) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(dimethylamino)azetidine-1-carboxamide HPLC retention time (min.):3.30; MS:356 (M+H)+. EXAMPLE 3(86) 3-(Dimethylamino)-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.21; MS:623 (2M+H)+, 312 (M+H)+. EXAMPLE 3(87) N-(3,5-Difluorophenyl)-3-(dimethylamino)azetidine-1-carboxamide HPLC retention time (min.):2.93; MS:256 (M+H)+. EXAMPLE 3(88) 3-(Dimethylamino)-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.00(condition B); MS:499 (2M+H)+, 250 (M+H)+. EXAMPLE 3(89) 3-(Dimethylamino)-N-(3,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.00; MS:495 (2M+H)+, 248 (M+H)+. EXAMPLE 3(90) 3-(Dimethylamino)-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):2.72; MS:238 (M+H)+. EXAMPLE 3(91) Methyl 3-({[3-(dimethylamino)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.):2.87; MS:555 (2M+H)+, 278 (M+H)+. EXAMPLE 3(92) 3-(Dimethylamino)-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):2.96; MS:531 (2M+H)+, 266 (M+H)+. EXAMPLE 3(93) 3-(Diethylamino)-N-propylazetidine-1-carboxamide HPLC retention time (min.):3.00(condition B); MS:214 (M+H)+. EXAMPLE 3(94) Ethyl N-([3-(diethylamino)azetidin-1-yl]carbonyl)glycinate HPLC retention time (min.):2.93(condition B); MS:258 (M+H)+. EXAMPLE 3(95) 3-(Diethylamino)-N-hexylazetidine-1-carboxamide HPLC retention time (min.):3.05; MS:256 (M+H)+. EXAMPLE 3(96) 3-(Diethylamino)-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):2.78; MS:266 (M+H)+. EXAMPLE 3(97) 3-(Diethylamino)-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.93; MS:523 (2M+H)+, 262 (M+H)+. EXAMPLE 3(98) 3-(Diethylamino)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.):2.83; MS:282 (M+H)+. EXAMPLE 3(99) 3-(Diethylamino)-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.18; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(100) N-(3-Chlorophenyl)-3-(diethylamino)azetidine-1-carboxamide HPLC retention time (min.):3.01; MS:563 (2M+H)+, 284, 282 (M+H)+. EXAMPLE 3(101) 3-(Diethylamino)-N-(2,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.94; MS:551 (2M+H)+, 276 (M+H)+. EXAMPLE 3(102) N-(4-Chlorophenyl)-3-(diethylamino)azetidine-1-carboxamide HPLC retention time (min.):3.02; MS:284, 282 (M+H)+. EXAMPLE 3(103) N-Benzyl-3-(diethylamino)azetidine-1-carboxamide HPLC retention time (min.):2.73; MS:262 (M+H)+. EXAMPLE 3(104) 3-(Diethylamino)-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):2.98; MS:595 (2M+H)+, 298 (M+H)+. EXAMPLE 3(105) 3-(Diethylamino)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):3.11; MS:595 (2M+H)+, 298 (M+H)+. EXAMPLE 3(106) 3-(Diethylamino)-N-[l-(l-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.):3.15; MS:651 (2M+H)+, 326 (M+H)+, 172. EXAMPLE 3(107) 3-(Diethylamino)-N-(3,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.03; MS:551 (2M+H)+, 276 (M+H)+. EXAMPLE 3(108) 3-(Diethylamino)-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.91; MS:262 (M+H)+. EXAMPLE 3(109) N-Cyclohexyl-3-(diethylamino)azetidine-1-carboxamide HPLC retention time (min.):2.82; MS:254 (M+H)+. EXAMPLE 3(110) 3-(Diethylamino)-N-(2,6-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.78; MS:276 (M+H)+. EXAMPLE 3(111) 3-(Diethylamino)-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.97; MS:583 (2M+H)+, 292 (M+H)+. EXAMPLE 3(112) 3-(Diethylamino)-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.90; MS:551 (2M+H)+, 276 (M+H)+. EXAMPLE 3(113) 3-(Diethylamino)-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.93; MS:583 (2M+H)+, 292 (M+H)+. EXAMPLE 3(114) 3-(Diethylamino)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.):2.92; MS:276 (M+H)+. EXAMPLE 3(115) 3-(Diethylamino)-N-phenylazetidine-1-carboxamide HPLC retention time (min.):3.23(condition B); MS:495 (2M+H)+, 248 (M+H)+. EXAMPLE 3(116) N-(2-Chlorophenyl)- 3-(diethylamino)azetidine-1-carboxamide HPLC retention time (min.):2.81; MS:282 (M+H)+. EXAMPLE 3(117) 3-(Diethylamino)-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):3.24(condition B); MS:266 (M+H)+. EXAMPLE 3(118) 3-(Diethylamino)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.13; MS:316 (M+H)+. EXAMPLE 3(119) N-Cyclopentyl-3-(diethylamino)azetidine-1-carboxamide HPLC retention time (min.):3.14(condition B); MS:240 (M+H)+. EXAMPLE 3(120) 3-(Diethylamino)-N-(2,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.93; MS:551 (2M+H)+, 276 (M+H)+. EXAMPLE 3(121) N-(3,5-Dichlorophenyl)-3-(diethylamino)azetidine-1-carboxamide HPLC retention time (min.):3.21; MS:633, 631 (2M+H)+, 318, 316 (M+H)+. EXAMPLE 3(122) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(diethylamino)azetidine-1-carboxamide HPLC retention time (min.):3.38; MS:384 (M+H)+. EXAMPLE 3(123) 3-(Diethylamino)-N-( 3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.26; MS:679 (2M+H)+, 340 (M+H)+. EXAMPLE 3(124) 3-(Diethylamino)-N-(3,5-difluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):3.00; MS:284 (M+H)+. EXAMPLE 3(125) 3-(Diethylamino)-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.74; MS:278 (M+H)+. EXAMPLE 3(126) 3-(Diethylamino)-N-(3,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.05; MS:551 (2M+H)+, 276 (M+H)+. EXAMPLE 3(127) 3-(Diethylamino)-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):2.87; MS:266 (M+H)+. EXAMPLE 3(128) Methyl 3-({[3-(diethylamino)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.):2.93; MS:611 (2M+H)+, 306 (M+H)+. EXAMPLE 3(129) 3-(Diethylamino)-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.01; MS:587 (2M+H)+, 294 (M+H)+. EXAMPLE 3(130) 3-(Diethylamino)-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.65; MS:262 (M+H)+. EXAMPLE 3(131) 3-(Diisopropylamino)-N-propylazetidine-1-carboxamide HPLC retention time (min.):3.37(condition B); MS:242 (M+H)+. EXAMPLE 3(132) Ethyl N-{[3-(diisopropylamino)azetidin-1-yl]carbonyl}glycinate HPLC retention time (min.):3.31(condition B); MS:286 (M+H)+. EXAMPLE 3(133) 3-(Diisopropylamino)-N-hexylazetidine-1-carboxamide HPLC retention time (min.):3.11; MS:284 (M+H)+. EXAMPLE 3(134) 3-(Diisopropylamino)-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):2.93; MS:294 (M+H)+. EXAMPLE 3(135) 3-(Diisopropylamino)-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.01; MS:290 (M+H)+. EXAMPLE 3(136) 3-(Diisopropylamino)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.):2.95; MS:310 (M+H)+. EXAMPLE 3(137) 3-(Diisopropylamino)-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.24; MS:635 (2M+H)+, 318 (M+H)+. EXAMPLE 3(138) N-(3-Chlorophenyl)-3-(diisopropylamino)azetidine-1-carboxamide HPLC retention time (min.):3.08; MS:312, 310 (M+H)+. EXAMPLE 3(139) 3-(Diisopropylamino)-N-(2,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.02; MS:304 (M+H)+. EXAMPLE 3(140) N-(4-Chlorophenyl)-3-(diisopropylamino)azetidine-1-carboxamide HPLC retention time (min.):3.09; MS:312, 310 (M+H)+. EXAMPLE 3(141) N-Benzyl-3-(diisopropylamino)azetidine-1-carboxamide HPLC retention time (min.):2.89; MS:290 (M+H)+. EXAMPLE 3(142) 3-(Diisopropylamino)-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):3.06; MS:651 (2M+H)+, 326 (M+H)+. EXAMPLE 3(143) 3-(Diisopropylamino)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):3.16; MS:651 (2M+H)+, 326 (M+H)+. EXAMPLE 3(144) 3-(Diisopropylamino) -N- [1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.):3.22; MS:354 (M+H)+. EXAMPLE 3(145) 3-(Diisopropylamino)-N-(3,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.10; MS:607 (2M+H)+, 304 (M+H)+. EXAMPLE 3(146) 3-(Diisopropylamino)-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.02; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(147) N-Cyclohexyl-3-(diisopropylamino)azetidine-1-carboxamide HPLC retention time (min.):2.94; MS:282 (M+H)+. EXAMPLE 3(148) 3-(Diisopropylamino)-N-(2,6-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.91; MS:304 (M+H)+. EXAMPLE 3(149) 3-(Diisopropylamino)-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.04; MS:320 (M+H)+. EXAMPLE 3(150) 3-(Diisopropylamino)-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.98; MS:607 (2M+H)+, 304 (M+H)+. EXAMPLE 3(151) 3-(Diisopropylamino)-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.03; MS:639 (2M+H)+, 320 (M+H)+. EXAMPLE 3(152) 3-(Diisopropylamino)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.):3.01; MS:304 (M+H)+. EXAMPLE 3(153) 3-(Diisopropylamino)-N-phenylazetidine-1-carboxamide HPLC retention time (min.):2.86; MS:276 (M+H)+. EXAMPLE 3(154) N-(2-Chlorophenyl)-3-(diisopropylamino)azetidine-1-carboxamide HPLC retention time (min.):2.94; MS:312, 310 (M+H)+. EXAMPLE 3(155) 3-(Diisopropylamino)-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):2.81; MS:294 (M+H)+. EXAMPLE 3(156) 3-(Diisopropylamino)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.32; MS:344 (M+H)+. EXAMPLE 3(157) N-Cyclopentyl-3-(diisopropylamino)azetidine-1-carboxamide HPLC retention time (min.):2.79; MS:268 (M+H)+. EXAMPLE 3(158) 3-(Diisopropylamino)-N-(2,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.03; MS:607 (2M+H)+, 304 (M+H)+. EXAMPLE 3(159) N-(3,5-Dichlorophenyl)-3-(diisopropylamino)azetidine-1-carboxamide HPLC retention time (min.):3.27; MS:346, 344 (M+H)+. EXAMPLE 3(160) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(diisopropylamino)azetidine-1-carboxamide HPLC retention time (min.):3.43; MS:412 (M+H)+. EXAMPLE 3(161) 3-(Diisopropylamino)-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.32; MS:735 (2M+H)+, 368 (M+H)+. EXAMPLE 3(162) N-(3,5-Difluorophenyl)-3-(diisopropylamino)azetidine-1-carboxamide HPLC retention time (min.):3.07; MS:312 (M+H)+. EXAMPLE 3(163) 3-(Diisopropylamino)-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.88; MS:611 (2M+H)+, 306 (M+H)+. EXAMPLE 3(164) 3-(Diisopropylamino)-N-(3,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.13; MS:607 (2M+H)+, 304 (M+H)+. EXAMPLE 3(165) 3-(Diisopropylamino)-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):2.99; MS:294 (M+H)+. EXAMPLE 3(166) Methyl 3-({[3-(diisopropylamino)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.):3.00; MS:667 (2M+H)+, 334 (M+H)+. EXAMPLE 3(167) 3-(Diisopropylamino)-N-[3 -(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.09; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(168) 3-(Diisopropylamino)-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):2.88; MS:290 (M+H)+. EXAMPLE 3(169) 3-(Dipropylamino)-N-propylazetidine-1-carboxamide HPLC retention time (min.):3.36(condition B); MS:242 (M+H)+. EXAMPLE 3(170) Ethyl N-{[3-(dipropylamino)azetidin-1-yl]carbonyl}glycinate HPLC retention time (min.):3.29(condition B); MS:286 (M+H)+. EXAMPLE 3(171) 3-(Dipropylamino)-N-hexylazetidine-1-carboxamide HPLC retention time (min.):3.17; MS:284 (M+H)+. EXAMPLE 3(172) 3-(Dipropylamino)-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):3.00; MS:294 (M+H)+. EXAMPLE 3(173) 3-(Dipropylamino)-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.07; MS:579 (2M+H)+, 2.90 (M+H)+. EXAMPLE 3(174) 3-(Dipropylamino)-N-(2-thien-2-ylethyl)azetidine-1- carboxamide HPLC retention time (min.):3.01; MS:310 (M+H)+. EXAMPLE 3(175) 3-(Dipropylamino)-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.29; MS:635 (2M+H)+, 318 (M+H)+. EXAMPLE 3(176) N-(3-Chlorophenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:312, 310 (M+H)+. EXAMPLE 3(177) N-(2,5-Dimethylphenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.08; MS:607 (2M+H)+,304 (M+H)+. EXAMPLE 3(178) N-(4-Chlorophenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.14; MS:312, 310 (M+H)+. EXAMPLE 3(179) N-Benzyl-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 2.96; MS:290 (M+H)+. EXAMPLE 3(180) 3-(Dipropylamino)-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.11; MS:651 (2M+H)+,326 (M+H)+. EXAMPLE 3(181) 3-(Dipropylamino)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.21; MS:651 (2M+H)+,326 (M+H)+. EXAMPLE 3(182) 3-(Dipropylamino)-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.): 3.26; MS:707 (2M+H)+,354 (M+H)+. EXAMPLE 3(183) N-(3,4-Dimethylphenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:607 (2M+H)+,304 (M+H)+. EXAMPLE 3(184) 3-(Dipropylamino)-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.07; MS:579 (2M+H)+,290 (M+H)+. EXAMPLE 3(185) N-Cyclohexyl-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.00; MS:282 (M+H)+. EXAMPLE 3(186) N-(2,6-Dimethylphenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 2.98; MS:607 (2M+H)+,304 (M+H)+. EXAMPLE 3(187) 3-(Dipropylamino)-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.11; MS:320 (M+H)+. EXAMPLE 3(188) 3-(Dipropylamino)-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.06; MS:607 (2M+H)+,304 (M+H)+. EXAMPLE 3(189) 3-(Dipropylamino)-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.06; MS:639 (2M+H)+,320 (M+H)+. EXAMPLE 3(190) 3-(Dipropylamino)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.06; MS:304 (M+H)+. EXAMPLE 3(191) 3-(Dipropylamino)-N-phenylazetidine-1-carboxamide HPLC retention time (min.): 2.95; MS:276 (M+H)+. EXAMPLE 3(192) N-(2-Chlorophenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.02; MS:312, 310 (M+H)+. EXAMPLE 3(193) 3-(Dipropylamino)-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.91; MS:294 (M+H)+. EXAMPLE 3(194) 3-(Dipropylamino)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.26; MS:344 (M+H)+. EXAMPLE 3(195) N-Cyclopentyl-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 2.88; MS:268 (M+H)+. EXAMPLE 3(196) N-(2,4-Dimethylphenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.09; MS:607 (2M+H)+,304 (M+H)+. EXAMPLE 3(197) N-(3,5-Dichlorophenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.33; MS:346, 344 (M+H)+. EXAMPLE 3(198) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.47; MS:412 (M+H)+. EXAMPLE 3(199) 3-(Dipropylamino)-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.37; MS:735 (2M+H)+,368 (M+H)+. EXAMPLE 3(200) N-(3,5-Difluorophenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:312 (M+H)+. EXAMPLE 3(201) 3-(Dipropylamino)-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.96; MS:611 (2M+H)+,306 (M+H)+. EXAMPLE 3(202) N-(3,5-Dimethylphenyl)-3-(dipropylamino)azetidine-1-carboxamide HPLC retention time (min.): 3.18; MS:607 (2M+H)+,304 (M+H)+. EXAMPLE 3(203) 3-(Dipropylamino)-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.05; MS:294 (M+H)+. EXAMPLE 3(204) Methyl 3-({[3-(dipropylamino)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.): 3.04; MS:667 (2M+H)+,334 (M+H)+. EXAMPLE 3(205) 3-(Dipropylamino)-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.14; MS:643 (2M+H)+,322 (M+H)+. EXAMPLE 3(206) 3-(Dipropylamino)-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.95; MS:579 (2M+H)+,290 (M+H)+. EXAMPLE 3(207) 3-[Bis(2-hydroxyethyl)amino]-N-hexylazetidine-1-carboxamide HPLC retention time (min.): 2.97; MS:575 (2M+H)+,288 (M+H)+. EXAMPLE 3(208) 3-[Bis(2-hydroxyethyl)amino]-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.91(condition B); MS:595 (2M+H)+,298 (M+H)+. EXAMPLE 3(209) 3-[Bis(2-hydroxyethyl)amino]-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.83; MS:587 (2M+H)+,294 (M+H)+. EXAMPLE 3(210) 3-[Bis(2-hydroxyethyl)amino]-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.10; MS:643 (2M+H)+,322 (M+H)+. EXAMPLE 3(211) 3-[Bis(2-hydroxyethyl)amino]-N-(3-chlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.95; MS:627 (2M+H)+,316, 314 (M+H)+. EXAMPLE 3(212) 3-[Bis(2-hydroxyethyl)amino]-N-(2,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.83; MS:615 (2M+H)+,308 (M+H)+. EXAMPLE 3(213) 3-[Bis(2-hydroxyethyl)amino]-N-(4-chlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.95; MS:316, 314 (M+H)+. EXAMPLE 3(214) 3-[Bis(2-hydroxyethyl)amino]-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 2.90; MS:659 (2M+H)+,330 (M+H)+. EXAMPLE 3(215) 3-[Bis(2-hydroxyethyl)amino]-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.03; MS:659 (2M+H)+,330 (M+H)+. EXAMPLE 3(216) 3-[Bis(2-hydroxyethyl)amino]-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.): 3.07; MS:715 (2M+H)+,358 (M+H)+,204. EXAMPLE 3(217) 3-[Bis(2-hydroxyethyl)amino]-N-(3,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.96; MS:615 (2M+H)+,308 (M+H)+. EXAMPLE 3(218) 3-[Bis(2-hydroxyethyl)amino]-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.81; MS:587 (2M+H)+,294 (M+H)+. EXAMPLE 3(219) 3-[Bis(2-hydroxyethyl)amino]-N-cyclohexylazetidine-1-carboxamide HPLC retention time (min.): 2.92(condition B); MS:571 (2M+H)+,286 (M+H)+. EXAMPLE 3(220) 3-[Bis(2-hydroxyethyl)amino]-N-(2,6-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.90(condition B); MS:615 (2M+H)+,308 (M+H)+. EXAMPLE 3(221) 3-[Bis(2-hydroxyethyl)amino]-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.88; MS:647 (2M+H)+,324 (M+H)+. EXAMPLE 3(222) 3-[Bis(2-hydroxyethyl)amino]-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.78; MS:615 (2M+H)+,308 (M+H)+. EXAMPLE 3(223) 3-[Bis(2-hydroxyethyl)amino]-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.85; MS:647 (2M+H)+,324 (M+H)+. EXAMPLE 3(224) 3-[Bis(2-hydroxyethyl)amino]-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.): 2.83; MS:615 (2M+H)+,308 (M+H)+. EXAMPLE 3(225) 3-[Bis(2-hydroxyethyl)amino]-N-phenylazetidine-1-carboxamide HPLC retention time (min.): 2.87(condition B); MS:559 (2M+H)+,280 (M+H)+. EXAMPLE 3(226) 3-[Bis(2-hydroxyethyl)amino]-N-(2-chlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.97(condition B); MS:627 (2M+H)+,316, 314 (M+H)+. EXAMPLE 3(227) 3-[Bis(2-hydroxyethyl)amino]-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.84(condition B); MS:595 (2M+H)+,298 (M+H)+. EXAMPLE 3(228) 3-[Bis(2-hydroxyethyl)amino]-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.06; MS:348 (M+H)+. EXAMPLE 3(229) 3-[Bis(2-hydroxyethyl)amino]-N-cyclopentylazetidine-1-carboxamide HPLC retention time (min.): 2.80(condition B); MS:543 (2M+H)+,272 (M+H)+. EXAMPLE 3(230) 3-[Bis(2-hydroxyethyl)amino]-N-(2,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.85; MS:308 (M+H)+. EXAMPLE 3(231) 3-[Bis(2-hydroxyethyl)amino]-N-(3,5-dichlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.13; MS:697, 695 (2M+H)+,350, 348 (M+H)+. EXAMPLE 3(232) 3-[Bis(2-hydroxyethyl)amino]-N-[3,5-bis(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.28; MS:831 (2M+H)+,416 (M+H)+. EXAMPLE 3(233) 3-[Bis(2-hydroxyethyl)amino]-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.18; MS:743 (2M+H)+,372 (M+H)+. EXAMPLE 3(234) 3-[Bis(2-hydroxyethyl)amino]-N-(3,5-difluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.92; MS:631 (2M+H)+,316 (M+H)+. EXAMPLE 3(235) 3-[Bis(2-hydroxyethyl)amino]-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.87(condition B); MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(236) 3-[Bis(2-hydroxyethyl)amino]-N-(3,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.98; MS:615 (2M+H)+,308 (M+H)+. EXAMPLE 3(237) 3-[Bis(2-hydroxyethyl)amino]-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.71; MS:595 (2M+H)+,298 (M+H)+. EXAMPLE 3(238) Methyl 3-[({3-[bis(2-hydroxyethyl)amino]azetidin-1-yl}carbonyl)amino]benzoate HPLC retention time (min.): 2.85; MS:675 (2M+H)+,338 (M+H)+. EXAMPLE 3(239) 3-[Bis(2-hydroxyethyl)amino]-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 2.95; MS:651 (2M+H)+,326 (M+H)+. EXAMPLE 3(240) N-Ethyl-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 2.73; MS:234 (M+H)+,146. EXAMPLE 3(241) 3-[Methyl(phenyl)amino]-N-propylazetidine-1-carboxamide HPLC retention time (min.): 2.95; MS:248 (M+H)+. EXAMPLE 3(242) Ethyl N-({3-[methyl(phenyl)amino]azetidin-1-yl}carbonyl)glycinate HPLC retention time (min.): 2.91; MS:292 (M+H)+. EXAMPLE 3(243) N-Hexyl-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.46; MS:290 (M+H)+. EXAMPLE 3(244) N-(4-Fluorophenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.33; MS:300 (M+H)+. EXAMPLE 3(245) N-(3-Methylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.38; MS:591 (2M+H)+,296 (M+H)+. EXAMPLE 3(246) 3-[Methyl(phenyl)amino]-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.27; MS:316 (M+H)+. EXAMPLE 3(247) N-(4-Isopropylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.62; MS:647 (2M+H)+,324 (M+H)+. EXAMPLE 3(248) N-(3-Chlorophenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.52; MS:318, 316 (M+H)+. EXAMPLE 3(249) N-(2,5-Dimethylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.40; MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(250) N-(4-Chlorophenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.49; MS:318, 316 (M+H)+. EXAMPLE 3(251) N-Benzyl-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.22; MS:296 (M+H)+. EXAMPLE 3(252) 3-[Methyl(phenyl)amino]-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.43; MS:663 (2M+H)+,332 (M+H)+. EXAMPLE 3(253) 3-[Methyl(phenyl)amino]-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.55; MS:663 (2M+H)+,332 (M+H)+. EXAMPLE 3(254) 3-[Methyl(phenyl)amino]-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.): 3.56; MS:719 (2M+H)+,360 (M+H)+,206. EXAMPLE 3(255) N-(3,4-Dimethylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.47; MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(256) N-(4-Methylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.38; MS:591 (2M+H)+,296 (M+H)+. EXAMPLE 3(257) N-Cyclohexyl-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.27; MS:288 (M+H)+. EXAMPLE 3(258) N-(2,6-Dimethylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.30; MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(259) N-(2-Ethoxyphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.55; MS:651 (2M+H)+,326 (M+H)+. EXAMPLE 3(260) N-(2-Ethylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.39; MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(261) N-(4-Ethoxyphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.35; MS:651 (2M+H)+,326 (M+H)+. EXAMPLE 3(262) 3-[Methyl(phenyl)amino]-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:310 (M+H)+. EXAMPLE 3(263) 3-[Methyl(phenyl)amino]-N-phenylazetidine-1-carboxamide HPLC retention time (min.): 3.25; MS:563 (2M+H)+,282 (M+H)+. EXAMPLE 3(264) N-(2-Chlorophenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.49; MS:318, 316 (M+H)+. EXAMPLE 3(265) N-(2-Fluorophenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.30; MS:300 (M+H)+. EXAMPLE 3(266) 3-[Methyl(phenyl)amino]- N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.63; MS:350 (M+H)+. EXAMPLE 3(267) N-Cyclopentyl-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:274 (M+H)+. EXAMPLE 3(268) N-(2,4-Dimethylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.39; MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(269) N-(3,5-Dichlorophenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.78; MS:352, 350 (M+H)+. EXAMPLE 3(270) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.94; MS:418 (M+H)+. EXAMPLE 3(271) 3-[Methyl(phenyl)amino]-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.73; MS:747 (2M+H)+,374 (M+H)+. EXAMPLE 3(272) N-(3,5-Difluorophenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.53; MS:318 (M+H)+. EXAMPLE 3(273) N-(4-Methoxyphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.23; MS:623 (2M+H)+,312 (M+H)+. EXAMPLE 3(274) N-(3,5-Dimethylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.49; MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(275) N-(3-Fluorophenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.40; MS:300 (M+H)+. EXAMPLE 3(276) Methyl 3-[({3-[methyl(phenyl)amino]azetidin-1-yl}carbonyl)amino]benzoate HPLC retention time (min.): 3.35; MS:679 (2M+H)+,340 (M+H)+. EXAMPLE 3(277) 3-[Methyl(phenyl)amino]-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.46; MS:655 (2M+H)+,328 (M+H)+. EXAMPLE 3(278) N-(2-Methylphenyl)-3-[methyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.28; MS:591 (2M+H)+,296 (M+H)+. EXAMPLE 3(279) 3-[Ethyl(phenyl)amino]-N-propylazetidine-1-carboxamide HPLC retention time (min.): 2.87; MS:262 (M+H)+. EXAMPLE 3(280) Ethyl N-({3-[ethyl(phenyl)amino]azetidin-1-yl}carbonyl)glycinate HPLC retention time (min.): 2.84; MS:306 (M+H)+. EXAMPLE 3(281) 3-[Ethyl(phenyl)amino]-N-hexylazetidine-1-carboxamide HPLC retention time (min.): 3.32; MS:304 (M+H)+. EXAMPLE 3(282) 3-[Ethyl(phenyl)amino]-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.17; MS:314 (M+H)+. EXAMPLE 3(283) 3-[Ethyl(phenyl)amino]-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.24; MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(284) 3-[Ethyl(phenyl)amino]-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.14; MS:330 (M+H)+. EXAMPLE 3(285) 3-[Ethyl(phenyl)amino]-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.47; MS:675 (2M+H)+,338 (M+H)+. EXAMPLE 3(286) N-(3-Chlorophenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.34; MS:332, 330 (M+H)+. EXAMPLE 3(287) N-(2,5-Dimethylphenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.25; MS:647 (2M+H)+,324 (M+H)+. EXAMPLE 3(288) N-(4-Chlorophenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.32; MS:332, 330 (M+H)+. EXAMPLE 3(289) N-Benzyl-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.13; MS:310 (M+H)+. EXAMPLE 3(290) 3-[Ethyl(phenyl)amino]-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.28; MS:691 (2M+H)+,346 (M+H)+. EXAMPLE 3(291) 3-[Ethyl(phenyl)amino]-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.39; MS:691 (2M+H)+,346 (M+H)+. EXAMPLE 3(292) 3-[Ethyl(phenyl)amino]-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.): 3.41; MS:747 (2M+H)+,374 (M+H)+,220. EXAMPLE 3(293) N-(3,4-Dimethylphenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:647 (2M+H)+,324 (M+H)+. EXAMPLE 3(294) 3-[Ethyl(phenyl)aminol-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.23; MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(295) N-Cyclohexyl-3-[(ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:302 (M+H)+. EXAMPLE 3(296) N-(2,6-Dimethylphenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.16; MS:647 (2M+H)+,324 (M+H)+. EXAMPLE 3(297) N-(2-Ethoxyphenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.36; MS:679 (2M+H)+,340 (M+H)+. EXAMPLE 3(298) N-(2-Ethylphenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.25; MS:647 (2M+H)+,324 (M+H)+. EXAMPLE 3(299) N-(4-Ethoxyphenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.23; MS:679 (2M+H)+,340 (M+H)+. EXAMPLE 3(300) 3-[Ethyl(phenyl)amino]-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.19; MS:324 (M+H)+. EXAMPLE 3(301) 3-[Ethyl(phenyl)amino]-N-phenylazetidine-1-carboxamide HPLC retention time (min.): 3.12; MS:296 (M+H)+. EXAMPLE 3(302) N-(2-Chlorophenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.30; MS:332, 330 (M+H)+. EXAMPLE 3(303) 3-[Ethyl(phenyl)amino]-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.14; MS:314 (M+H)+. EXAMPLE 3(304) 3-[Ethyl(phenyl)amino]-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.46; MS:364 (M+H)+. EXAMPLE 3(305) N-Cyclopentyl-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.06; MS:288 (M+H)+. EXAMPLE 3(306) N-(2,4-Dimethylphenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.24; MS:647 (2M+H)+,324 (M+H)+. EXAMPLE 3(307) N-(3,5-Dichlorophenyl)-3-[ethyl(phenyl)aminolazetidine-1-carboxamide HPLC retention time (min.): 3.58; MS:729, 727 (2M+H)+,366, 364 (M+H)+. EXAMPLE 3(308) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.74; MS:432 (M+H)+. EXAMPLE 3(309) 3-[Ethyl(phenyl)amino]-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.56; MS:775 (2M+H)+,388 (M+H)+. EXAMPLE 3(310) N-(3,5-Difluorophenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.36; MS:332 (M+H)+. EXAMPLE 3(311) 3-[Ethyl(phenyl)amino]-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.11; MS:651 (2M+H)+,326 (M+H)+. EXAMPLE 3(312) N-(3,5-Dimethylphenyl)-3-[ethyl(phenyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.35; MS:647 (2M+H)+,324 (M+H)+. EXAMPLE 3(313) 3-[Ethyl(phenyl)amino]-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.25; MS:314 (M+H)+. EXAMPLE 3(314) Methyl 3-[({3-[ethyl(phenyl)amino]azetidin-1-yl}carbonyl)amino]benzoate HPLC retention time (min.): 3.21; MS:707 (2M+H)+,354 (M+H)+. EXAMPLE 3(315) 3-[Ethyl(phenyl)amino]-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.32; MS:683 (2M+H)+,342 (M+H)+. EXAMPLE 3(316) 3-[Ethyl(phenyl)amino]-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.13; MS:619 (2M+H)+,310 (M+H)+. EXAMPLE 3(317) 3-[Phenyl(propyl)amino]-N-propylazetidine-1-carboxamide HPLC retention time (min.): 3.05; MS:276 (M+H)+. EXAMPLE 3(318) Ethyl N-({3-[phenyl(propyl)amino]azetidin-1-yl}carbonyl)glycinate HPLC retention time (min.): 3.02; MS:320 (M+H)+. EXAMPLE 3(319) N-Hexyl-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.49; MS:318 (M+H)+. EXAMPLE 3(320) N-(4-Fluorophenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.36; MS:328 (M+H)+. EXAMPLE 3(321) N-(3-Methylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.41; MS:324 (M+H)+. EXAMPLE 3(322) 3-[Phenyl(propyl)amino]-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:344 (M+H)+. EXAMPLE 3(323) N-(4-Isopropylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.63; MS:703 (2M+H)+,352 (M+H)+. EXAMPLE 3(324) N-(3-Chlorophenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.54; MS:346, 344 (M+H)+. EXAMPLE 3(325) N-(2,5-Dimethylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.44; MS:675 (2M+H)+, 338 (M+H)+. EXAMPLE 3(326) N-(4-Chlorophenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.52; MS:346, 344 (M+H)+. EXAMPLE 3(327) N-Benzyl-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.27; MS:324 (M+H)+. EXAMPLE 3(328) N-(1-Naphthyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.45; MS:719 (2M+H)+,360 (M+H)+. EXAMPLE 3(329) N-(2-Naphthyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.56; MS:719 (2M+H)+,360 (M+H)+. EXAMPLE 3(330) N-[1-(1-Naphthyl)ethyl]-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.56; MS:775 (2M+H)+,388 (M+H)+,234. EXAMPLE 3(331) N-(3,4-Dimethylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.50; MS:675 (2M+H)+,338 (M+H)+. EXAMPLE 3(332) N-(4-Methylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.41; MS:324 (M+H)+. EXAMPLE 3(333) N-Cyclohexyl-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:316 (M+H)+. EXAMPLE 3(334) N-(2,6-Dimethylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.34; MS:675 (2M+H)+,338 (M+H)+. EXAMPLE 3(335) N-(2-Ethoxyphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.58; MS:707 (2M+H)+,354 (M+H)+. EXAMPLE 3(336) N-(2-Ethylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.42; MS:675 (2M+H)+,338 (M+H)+. EXAMPLE 3(337) N-(4-Ethoxyphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.38; MS:707 (2M+H)+,354 (M+H)+. EXAMPLE 3(338) N-(2-Phenylethyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.36; MS:338 (M+H)+. EXAMPLE 3(339) N-Phenyl-3-[phenyl(propyl)aminolazetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:310 (M+H)+. EXAMPLE 3(340) N-(2-Chlorophenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.53; MS:346, 344 (M+H)+. EXAMPLE 3(341) N-(2-Fluorophenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.34; MS:328 (M+H)+. EXAMPLE 3(342) 3-[Phenyl(propyl)amino]-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.65; MS:378 (M+H)+. EXAMPLE 3(343) N-Cyclopentyl-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.21; MS:302 (M+H)+. EXAMPLE 3(344) N-(2,4-Dimethylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.42; MS:675 (2M+H)+, 338 (M+H)+. EXAMPLE 3(345) N-(3,5-Dichlorophenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.79; MS:380, 378 (M+H)+. EXAMPLE 3(346) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.95; MS:446 (M+H)+. EXAMPLE 3(347) N-(3-Phenoxyphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.73; MS:803 (2M+H)+, 402 (M+H)+. EXAMPLE 3(348) N-(3,5-Difluorophenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.57; MS:346 (M+H)+. EXAMPLE 3(349) N-(4-Methoxyphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.29; MS:679 (2M+H)+, 340 (M+H)+. EXAMPLE 3(350) N-(3,5-Dimethylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.52; MS:675 (2M+H)+, 338 (M+H)+. EXAMPLE 3(351) N-(3-Fluorophenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.43; MS:328 (M+H)+. EXAMPLE 3(352) Methyl 3-[({3-[phenyl(propyl)amino]azetidin-1-yl}carbonyl)amino]benzoate HPLC retention time (min.): 3.41; MS:735 (2M+H)+, 368 (M+H)+. EXAMPLE 3(353) N-[3-(Methylsulfanyl)phenyl]-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.50; MS:711 (2M+H)+, 356 (M+H)+. EXAMPLE 3(354) N-(2-Methylphenyl)-3-[phenyl(propyl)amino]azetidine-1-carboxamide HPLC retention time (min.): 3.34; MS:647 (2M+H)+, 324 (M+H)+. EXAMPLE 3(355) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-propylazetidine-1-carboxamide HPLC retention time (min.): 2.92(condition B); MS:284 (M+H)+. EXAMPLE 3(356) Ethyl N-{[3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidin-1-yl]carbonyl}glycinate HPLC retention time (min.): 2.88(condition B); MS:328 (M+H)+. EXAMPLE 3(357) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-hexylazetidine-1-carboxamide HPLC retention time (min.): 3.08; MS:326 (M+H)+. EXAMPLE 3(358) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.89; MS:671 (2M+H)+, 336 (M+H)+. EXAMPLE 3(359) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.97; MS:663 (2M+H)+, 332 (M+H)+. EXAMPLE 3(360) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 2.89; MS:352 (M+H)+. EXAMPLE 3(361) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.20; MS:719 (2M+H)+, 360 (M+H)+. EXAMPLE 3(362) N-(3-Chlorophenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.05; MS:703 (2M+H)+, 354, 352 (M+H)+. EXAMPLE 3(363) N-(2,5-Dimethylphenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 2.98; MS:691 (2M+H)+, 346 (M+H)+. EXAMPLE 3(364) N-(4-Chlorophenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.06; MS:703 (2M+H)+, 354, 352 (M+H)+. EXAMPLE 3(365) N-Benzyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 2.86; MS:332 (M+H)+. EXAMPLE 3(366) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.01; MS:735 (2M+H)+, 368 (M+H)+. EXAMPLE 3(367) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.12; MS:735 (2M+H)+, 368 (M+H)+. EXAMPLE 3(368) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.): 3.16; MS:791 (2M+H)+, 396 (M+H)+, 242. EXAMPLE 3(369) N-(3,4-Dimethylphenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.06; MS:691 (2M+H)+, 346 (M+H)+. EXAMPLE 3(370) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.97; MS:663 (2M+H)+, 332 (M+H)+. EXAMPLE 3(371) N-Cyclohexyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 2.91; MS:647 (2M+H)+, 324 (M+H)+. EXAMPLE 3(372) N-(2,6-Dimethylphenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 2.90; MS:691 (2M+H)+, 346 (M+H)+. EXAMPLE 3(373) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.00; MS:723 (2M+H)+, 362 (M+H)+. EXAMPLE 3(374) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.96; MS:691 (2M+H)+, 346 (M+H)+. EXAMPLE 3(375) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.98; MS:723 (2M+H)+, 362 (M+H)+. EXAMPLE 3(376) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.): 2.97; MS:346 (M+H)+. EXAMPLE 3(377) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-phenylazetidine-1-carboxamide HPLC retention time (min.): 2.80; MS:635 (2M+H)+, 318 (M+H)+. EXAMPLE 3(378) N-(2-Chlorophenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 2.91; MS:703 (2M+H)+, 354, 352 (M+H)+. EXAMPLE 3(379) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.76; MS:336 (M+H)+. EXAMPLE 3(380) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.16; MS:771 (2M+H)+, 386 (M+H)+. EXAMPLE 3(381) N-Cyclopentyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 2.74; MS:310 (M+H)+. EXAMPLE 3(382) N-(2,4-Dimethylphenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 2.97; MS:691 (2M+H)+, 346 (M+H)+. EXAMPLE 3(383) N-(3,5-Dichlorophenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.23; MS:773, 771 (2M+H)+, 388, 386 (M+H)+. EXAMPLE 3(384) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.39; MS:907 (2M+H)+, 454 (M+H)+. EXAMPLE 3(385) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.27; MS:819 (2M+H)+, 410 (M+H)+. EXAMPLE 3(386) N-(3,5-Difluorophenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.04; MS:707 (2M+H)+, 354 (M+H)+. EXAMPLE 3(387) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.85; MS:695 (2M+H)+, 348 (M+H)+. EXAMPLE 3(388) N-(3,5-Dimethylphenyl)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.08; MS:691 (2M+H)+, 346 (M+H)+. EXAMPLE 3(389) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.94; MS:671 (2M+H)+, 336 (M+H)+. EXAMPLE 3(390) Methyl 3-(([3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.): 2.96; MS:751 (2M+H)+, 376 (M+H)+. EXAMPLE 3(391) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.05; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(392) 3-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.84; MS:663 (2M+H)+, 332 (M+H)+. EXAMPLE 3(393) N-Propyl-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.91(condition B); MS:212 (M+H)+. EXAMPLE 3(394) Ethyl N-[(3-pyrrolidin-1-ylazetidin-1-yl)carbonyl]glycinate HPLC retention time (min.): 2.86(condition B); MS:256 (M+H)+. EXAMPLE 3(395) N-Hexyl-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.03; MS:254 (M+H)+. EXAMPLE 3(396) N-(4-Fluorophenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.69; MS:264 (M+H)+. EXAMPLE 3(397) N-(3-Methylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.90; MS:519 (2M+H)+, 260 (M+H)+. EXAMPLE 3(398) 3-Pyrrolidin-1-yl-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 2.79; MS:280 (M+H)+. EXAMPLE 3(399) N-(4-Isopropylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(400) N-(3-Chlorophenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.00; MS:559 (2M+H)+, 282, 280 (M+H)+. EXAMPLE 3(401) N-(2,5-Dimethylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.91; MS:547 (2M+H)+, 274 (M+H)+. EXAMPLE 3(402) N-(4-Chlorophenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.00; MS:282, 280 (M+H)+. EXAMPLE 3(403) N-Benzyl-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.13(condition B); MS:260 (M+H)+. EXAMPLE 3(404) N-(1-Naphthyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.97; MS:591 (2M+H)+, 296 (M+H)+. EXAMPLE 3(405) N-(2-Naphthyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.09; MS:591 (2M+H)+, 296 (M+H)+. EXAMPLE 3(406) N-[1-(1-Naphthyl)ethyl]-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.12; MS:647 (2M+H)+, 324 (M+H)+, 170. EXAMPLE 3(407) N-(3,4-Dimethylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.01; MS:547 (2M+H)+, 274 (M+H)+. EXAMPLE 3(408) N-(4-Methylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.89; MS:519 (2M+H)+, 260 (M+H)+. EXAMPLE 3(409) N-Cyclohexyl-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.80; MS:252 (M+H)+. EXAMPLE 3(410) N-(2,6-Dimethylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.73; MS:547 (2M+H)+, 274 (M+H)+. EXAMPLE 3(411) N-(2-Ethoxyphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.96; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(412) N-(2-Ethylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.87; MS:547 (2M+H)+, 274 (M+H)+. EXAMPLE 3(413) N-(4-Ethoxyphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.91; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(414) N-(2-Phenylethyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.90; MS:274 (M+H)+. EXAMPLE 3(415) N-Phenyl-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.13(condition B); MS:491 (2M+H)+, 246 (M+H)+. EXAMPLE 3(416) N-(2-Chlorophenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.75; MS:282, 280 (M+H)+. EXAMPLE 3(417) N-(2-Fluorophenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.14(condition B); MS:527 (2M+H)+, 264 (M+H)+. EXAMPLE 3(418) 3-Pyrrolidin-1-yl-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.12; MS:627 (2M+H)+, 314 (M+H)+. EXAMPLE 3(419) N-Cyclopentyl-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.07(condition B); MS:238 (M+H)+. EXAMPLE 3(420) N-(2,4-Dimethylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.92; MS:547 (2M+H)+, 274 (M+H)+. EXAMPLE 3(421) N-(3,5-Dichlorophenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.19; MS:629, 627 (2M+H)+, 316, 314 (M+H)+. EXAMPLE 3(422) N-[3,5-Bis(trifluoromethyl)phenyl]-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.35; MS:763 (2M+H)+, 382 (M+H)+. EXAMPLE 3(423) N-(3-Phenoxyphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.24; MS:675 (2M+H)+, 338 (M+H)+. EXAMPLE 3(424) N-(3,5-Difluorophenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.97; MS:282 (M+H)+. EXAMPLE 3(425) N-(4-Methoxyphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.68; MS:551 (2M+H)+, 276 (M+H)+. EXAMPLE 3(426) N-(3,5-Dimethylphenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.04; MS:547 (2M+H)+, 274 (M+H)+. EXAMPLE 3(427) N-(3-Fluorophenyl)-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.84; MS:264 (M+H)+. EXAMPLE 3(428) Methyl 3-{[(3-pyrrolidin-1-ylazetidin-1-yl)carbonyl]amino}benzoate HPLC retention time (min.): 2.91; MS:607 (2M+H)+, 304 (M+H)+. EXAMPLE 3(429) N-[3-(Methylsulfanyl)phenyl]-3-pyrrolidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.99; MS:583 (2M+H)+, 292 (M+H)+. EXAMPLE 3(430) 3-Piperidin-1-yl-N-propylazetidine-1-carboxamide HPLC retention time (min.): 3.04(condition B); MS:226 (M+H)+. EXAMPLE 3(431) Ethyl N-[(3-piperidin-1-ylazetidin-1-yl)carbonyl]glycinate HPLC retention time (min.): 2.98(condition B); MS:270 (M+H)+. EXAMPLE 3(432) N-Hexyl-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.06; MS:268 (M+H)+. EXAMPLE 3(433) N-(4-Fluorophenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.81; MS:278 (M+H)+. EXAMPLE 3(434) N-(3-Methylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.94; MS:547 (2M+H)+, 274 (M+H)+. EXAMPLE 3(435) 3-Piperidin-1-yl-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 2.85; MS:294 (M+H)+. EXAMPLE 3(436) N-(4-Isopropylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.18; MS:603 (2M+H)+, 302 (M+H)+. EXAMPLE 3(437) N-(3-Chlorophenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.02; MS:587 (2M+H)+, 296, 294 (M+H)+. EXAMPLE 3(438) N-(2,5-Dimethylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.96; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(439) N-(4-Chlorophenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.03; MS:587 (2M+H)+, 296, 294 (M+H)+. EXAMPLE 3(440) N-Benzyl-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.77; MS:274 (M+H)+. EXAMPLE 3(441) N-(1-Naphthyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.99; MS:619 (2M+H)+, 310 (M+H)+. EXAMPLE 3(442) N-(2-Naphthyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.11.; MS:619 (2M+H)+, 310 (M+H)+. EXAMPLE 3(443) N-[1-(1-Naphthyl)ethyl]-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.16; MS:675 (2M+H)+, 338 (M+H)+, 184. EXAMPLE 3(444) N-(3,4-Dimethylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.04; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(445) N-(4-Methylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.93; MS:547 (2M+H)+, 274 (M+H)+. EXAMPLE 3(446) N-Cyclohexyl-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.85; MS:266 (M+H)+. EXAMPLE 3(447) N-(2,6-Dimethylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.82; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(448) N-(2-Ethoxyphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.98; MS:607 (2M+H)+, 304 (M+H)+. EXAMPLE 3(449) N-(2-Ethylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.92; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(450) N-(4-Ethoxyphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.96; MS:607 (2M+H)+, 304 (M+H)+. EXAMPLE 3(451) N-(2-Phenylethyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.94; MS:288 (M+H)+. EXAMPLE 3(452) N-Phenyl-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.66; MS:260 (M+H)+. EXAMPLE 3(453) N-(2-Chlorophenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.85; MS:296, 294 (M+H)+. EXAMPLE 3(454) N-(2-Fluorophenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.28(condition B); MS:555 (2M+H)+, 278 (M+H)+. EXAMPLE 3(455) 3-Piperidin-1-yl-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.14; MS:655 (2M+H)+, 328 (M+H)+. EXAMPLE 3(456) N-Cyclopentyl-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.19(condition B); MS:252 (M+H)+. EXAMPLE 3(457) N-(2,4-Dimethylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.95; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(458) N-(3,5-Dichlorophenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.22; MS:657, 655 (2M+H)+, 330, 328 (M+H)+. EXAMPLE 3(459) N-[3,5-Bis(trifluoromethyl)phenyl]-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.38; MS:791 (2M+H)+, 396 (M+H)+. EXAMPLE 3(460) N-(3-Phenoxyphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.26; MS:703 (2M+H)+, 352 (M+H)+. EXAMPLE 3(461) N-(3,5-Difluorophenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.01; MS:591 (2M+H)+, 296 (M+H)+. EXAMPLE 3(462) N-(4-Methoxyphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.78; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(463) N-(3,5-Dimethylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.05; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(464) N-(3-Fluorophenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.88; MS:555 (2M+H)+, 278 (M+H)+. EXAMPLE 3(465) Methyl 3-{[(3-piperidin-1-ylazetidin-1-yl)carbonyl]amino}benzoate HPLC retention time (min.): 2.94; MS:635 (2M+H)+, 318 (M+H)+. EXAMPLE 3(466) N-[3-(Methylsulfanyl)phenyl]-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 3.02; MS:611 (2M+H)+, 306 (M+H)+. EXAMPLE 3(467) N-(2-Methylphenyl)-3-piperidin-1-ylazetidine-1-carboxamide HPLC retention time (min.): 2.71; MS:274 (M+H)+. EXAMPLE 3(468) 3-Azepan-1-yl-N-propylazetidine-1-carboxamide HPLC retention time (min.): 3.19(condition B); MS:240 (M+H)+. EXAMPLE 3(469) Ethyl N-[(3-azepan-1-ylazetidin-1-yl)carbonyl]glycinate HPLC retention time (min.): 3.12(condition B); MS:284 (M+H)+. EXAMPLE 3(470) 3-Azepan-1-yl-N-hexylazetidine-1-carboxamide HPLC retention time (min.): 3.10; MS:282 (M+H)+. EXAMPLE 3(471) 3-Azepan-1-yl-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.91; MS:292 (M+H)+. EXAMPLE 3(472) 3-Azepan-1-yl-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.01; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(473) 3-Azepan-1-yl-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 2.93; MS:308 (M+H)+. EXAMPLE 3(474) 3-Azepan-1-yl-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.23; MS:631 (2M+H)+, 316 (M+H)+. EXAMPLE 3(475) 3-Azepan-1-yl-N-(3-chlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.09; MS:615 (2M+H)+, 310, 308 (M+H)+. EXAMPLE 3(476) 3-Azepan-1-yl-N-(2,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.02; MS:603 (2M+H)+, 302 (M+H)+. EXAMPLE 3(477) 3-Azepan-1-yl-N-(4-chlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.08; MS:310,.308 (M+H)+. EXAMPLE 3(478) 3-Azepan-1-yl-N-benzylazetidine-1-carboxamide HPLC retention time (min.): 2.89; MS:288 (M+H)+. EXAMPLE 3(479) 3-Azepan-1-yl-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.05; MS:647 (2M+H)+, 324 (M+H)+. EXAMPLE 3(480) 3-Azepan-1-yl-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:647 (2M+H)+, 324 (M+H)+. EXAMPLE 3(481) 3-Azepan-1-yl-N-[l-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.): 3.21; MS:703 (2M+H)+, 352 (M+H)+. EXAMPLE 3(482) 3-Azepan-1-yl-N-(3,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.09; MS:603 (2M+H)+, 302 (M+H)+. EXAMPLE 3(483) 3-Azepan-1-yl-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.00; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(484) 3-Azepan-1-yl-N-cyclohexylazetidine-1-carboxamide HPLC retention time (min.): 2.92; MS:280 (M+H)+. EXAMPLE 3(485) 3-Azepan-1-yl-N-(2,6-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.91; MS:603 (2M+H)+, 302 (M+H)+. EXAMPLE 3(486) 3-Azepan-1-yl-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.04; MS:635 (2M+H)+, 318 (M+H)+. EXAMPLE 3(487) 3-Azepan-1-yl-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.98; MS:603 (2M+H)+, 302 (M+H)+. EXAMPLE 3(488) 3-Azepan-1-yl-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.01; MS:635 (2M+H)+, 318 (M+H)+. EXAMPLE 3(489) 3-Azepan-1-yl-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.00; MS:302 (M+H)+. EXAMPLE 3(490) 3-Azepan-1-yl-N-phenylazetidine-1-carboxamide HPLC retention time (min.): 2.84; MS:274 (M+H)+. EXAMPLE 3(491) 3-Azepan-1-yl-N-(2-chlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.93; MS:310, 308 (M+H)+. EXAMPLE 3(492) 3-Azepan-1-yl-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.79; MS:292 (M+H)+. EXAMPLE 3(493) 3-Azepan-1-yl-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.19; MS:342 (M+H)+. EXAMPLE 3(494) 3-Azepan-1-yl-N-cyclopentylazetidine-1-carboxamide HPLC retention time (min.): 2.78; MS:266 (M+H)+. EXAMPLE 3(495) 3-Azepan-1-yl-N-(2,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.01; MS:603 (2M+H)+, 302 (M+H)+. EXAMPLE 3(496) 3-Azepan-1-yl-N-(3,5-dichlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.26; MS:685, 683 (2M+H)+, 344, 342 (M+H)+. EXAMPLE 3(497) 3-Azepan-1-yl-N-[3,5-bis(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.41; MS:819 (2M+H)+, 410 (M+H)+. EXAMPLE 3(498) 3-Azepan-1-yl-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:731 (2M+H)+, 366 (M+H)+. EXAMPLE 3(499) 3-Azepan-1-yl-N-(3,5-difluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.06; MS:310 (M+H)+. EXAMPLE 3(500) 3-Azepan-1-yl-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.88; MS:607 (2M+H)+, 304 (M+H)+. EXAMPLE 3(501) 3-Azepan-1-yl-N-(3,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.11; MS:603 (2M+H)+, 302 (M+H)+. EXAMPLE 3(502) 3-Azepan-1-yl-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.96; MS:583 (2M+H)+, 292 (M+H)+. EXAMPLE 3(503) Methyl 3-{[(3-azepan-1-ylazetidin-1-yl)carbonyl]amino}benzoate HPLC retention time (min.): 2.99; MS:663 (2M+H)+, 332 (M+H)+. EXAMPLE 3(504) 3-Azepan-1-yl-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.07; MS:639 (2M+H)+, 320 (M+H)+. EXAMPLE 3(505) 3-Azepan-1-yl-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 2.86; MS:575 (2M+H)+, 288 (M+H)+. EXAMPLE 3(506) 3-(Diisobutylamino)-N-ethylazetidine-1-carboxamide HPLC retention time (min.): 2.76; MS:256 (M+H)+. EXAMPLE 3(507) 3-(Diisobutylamino)-N-propylazetidine-1-carboxamide HPLC retention time (min.): 2.89; MS:270 (M+H)+. EXAMPLE 3(508) Ethyl N-{[3-(diisobutylamino)azetidin-1-yl]carbonyl}glycinate HPLC retention time (min.): 2.88; MS:314 (M+H)+. EXAMPLE 3(509) 3-(Diisobutylamino)-N-hexylazetidine-1-carboxamide HPLC retention time (min.): 3.28; MS:312 (M+H)+. EXAMPLE 3(510) 3-(Diisobutylamino)-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.14; MS:322 (M+H)+. EXAMPLE 3(511) 3-(Diisobutylamino)-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.20; MS:318 (M+H)+. EXAMPLE 3(512) 3-(Diisobutylamino)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.):3.13; MS:338 (M+H)+. EXAMPLE 3(513) 3-(Diisobutylamino)-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.40; MS:346 (M+H)+. EXAMPLE 3(514) N-(3-Chlorophenyl)-3-(diisobutylamino)azetidine-1-carboxamide HPLC retention time (min.):3.27; MS:340, 338 (M+H)+. EXAMPLE 3(515) 3-(Diisobutylamino)-N-(2,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.20; MS:332 (M+H)+. EXAMPLE 3(516) N-(4-Chlorophenyl)-3-(diisobutylamino)azetidine-1-carboxamide HPLC retention time (min.):3.27; MS:340, 338 (M+H)+. EXAMPLE 3(517) N-Benzyl-3-(diisobutylamino)azetidine-1-carboxamide HPLC retention time (min.):3.10; MS:318 (M+H)+. EXAMPLE 3(518) 3-(Diisobutylamino)-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):3.22; MS:707 (2M+H)+, 354 (M+H)+. EXAMPLE 3(519) 3-(Diisobutylamino)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):3.33; MS:707 (2M+H)+, 354 (M+H)+. EXAMPLE 3(520) 3-(Diisobutylamino) -N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.):3.36; MS:382 (M+H)+. EXAMPLE 3(521) 3-(Diisobutylamino)-N-(3,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.26; MS:332 (M+H)+. EXAMPLE 3(522) 3-(Diisobutylamino)-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.19; MS:318 (M+H)+. EXAMPLE 3(523) N-Cyclohexyl-3-(diisobutylamino)azetidine-1-carboxamide HPLC retention time (min.):3.13; MS:310 (M+H)+. EXAMPLE 3(524) 3-(Diisobutylamino)-N-(2,6-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.11; MS:663 (2M+H)+, 332 (M+H)+. EXAMPLE 3(525) 3-(Diisobutylamino)-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.25; MS:348 (M+H)+. EXAMPLE 3(526) 3-(diisobutylamino)-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.19; MS:332 (M+H)+. EXAMPLE 3(527) 3-(Diisobutylamino)-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.20; MS:695 (2M+H)+, 348 (M+H)+. EXAMPLE 3(528) 3-(Diisobutylamino)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.):3.17; MS:332 (M+H)+. EXAMPLE 3(529) 3-(Diisobutylamino)-N-phenylazetidine-1-carboxamide HPLC retention time (min.):3.10; MS:304 (M+H)+. EXAMPLE 3(530) N-(2-Chlorophenyl)-3-(diisobutylamino)azetidine-1-carboxamide HPLC retention time (min.):3.16; MS:340, 338 (M+H)+. EXAMPLE 3(531) 3-(Diisobutylamino)-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):3.07; MS:322 (M+H)+. EXAMPLE 3(532) 3-(Diisobutylamino)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.36; MS:372 (M+H)+. EXAMPLE 3(533) N-Cyclopentyl-3-(diisobutylamino)azetidine-1-carboxamide HPLC retention time (min.):3.04; MS:296 (M+H)+. EXAMPLE 3(534) 3-(Diisobutylamino)-N-(2,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.20; MS:332 (M+H)+. EXAMPLE 3(535) N-(3,5-Dichlorophenyl)-3-(diisobutylamino)azetidine-1-carboxamide HPLC retention time (min.):3.44; MS:374, 372 (M+H)+. EXAMPLE 3(536) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(diisobutylamino)azetidine-1-carboxamide HPLC retention time (min.):3.57; MS:440 (M+H)+. EXAMPLE 3(537) 3-(Diisobutylamino)-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.47; MS:791 (2M+H)+, 396 (M+H)+. EXAMPLE 3(538) N-(3,5-Difluorophenyl)-3-(diisobutylamino)azetidine-1-carboxamide HPLC retention time (min.):3.27; MS:340 (M+H)+. EXAMPLE 3(539) 3-(Diisobutylamino)-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.09; MS:334 (M+H)+. EXAMPLE 3(540) 3-(Diisobutylamino)-N-(3,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.29; MS:332 (M+H)+. EXAMPLE 3(541) 3-(Diisobutylamino)-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.):3.18; MS:322 (M+H)+. EXAMPLE 3(542) Methyl 3-({[3-(diisobutylamino)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.):3.16; MS:723 (2M+H)+, 362 (M+H)+. EXAMPLE 3(543) 3-(Diisobutylamino)-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.25; MS:699 (2M+H)+, 350 (M+H)+. Example 3(544) 3-(Diisobutylamino)-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.10; MS:318 (M+H)+. EXAMPLE 3(545) 3-Morpholin-4-yl-N-propylazetidine-1-carboxamide HPLC retention time (min.):2.68(condition B); MS:228 (M+H)+. EXAMPLE 3(546) N-Hexyl-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):3.01; MS:270 (M+H)+. EXAMPLE 3(547) N-(4-Fluorophenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):3.02(condition B); MS:559 (2M+H)+, 280 (M+H)+. EXAMPLE 3(548) N-(3-Methylphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.86; MS:551 (2M+H)+, 276 (M+H)+. EXAMPLE 3(549) 3-Morpholin-4-yl-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.):2.73; MS:296 (M+H)+. EXAMPLE 3(550) N-(4-Isopropylphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):3.14; MS:607 (2M+H)+, 304 (M+H)+. EXAMPLE 3(551) N-(3-Chlorophenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.97; MS:591 (2M+H)+, 298, 296 (M+H)+. EXAMPLE 3(552) N-(2,5-Dimethylphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.88; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(553) N-(4-Chlorophenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.98; MS:298, 296 (M+H)+. EXAMPLE 3(554) N-Benzyl-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.97(condition B); MS:276 (M+H)+. EXAMPLE 3(555) 3-Morpholin-4-yl-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):2.93; MS:623 (2M+H)+, 312 (M+H)+. EXAMPLE 3(556) 3-Morpholin-4-yl-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):3.06; MS:623 (2M+H)+, 312 (M+H)+. EXAMPLE 3(557) 3-Morpholin-4-yl-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.):3.12; MS:679 (2M+H)+, 340 (M+H)+, 186. EXAMPLE 3(558) N-(3,4-Dimethylphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.98; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(559) N-(4-Methylphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.86; MS:551 (2M+H)+, 276 (M+H)+. EXAMPLE 3(560) N-Cyclohexyl-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.73; MS:268 (M+H)+. EXAMPLE 3(561) N-(2,6-Dimethylphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.57; MS:290 (M+H)+. EXAMPLE 3(562) N-(2-Ethoxyphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.91; MS:611 (2M+H)+, 306 (M+H)+. EXAMPLE 3(563) N-(2-Ethylphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.81; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(564) N-(4-Ethoxyphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.88; MS:611 (2M+H)+, 306 (M+H)+. EXAMPLE 3(565) 3-Morpholin-4-yl-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.):2.87; MS:290 (M+H)+. EXAMPLE 3(566) 3-Morpholin-4-yl-N-phenylazetidine-1-carboxamide HPLC retention time (-min.):2.96(condition B); MS:523 (2M+H)+, 262 (M+H)+. EXAMPLE 3(567) N-(2-Chlorophenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):3.10(condition B); MS:591 (2M+H)+, 298, 296 (M+H)+. EXAMPLE 3(568) N-(2-Fluorophenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.96 (condition B); MS:559 (2M+H)+, 280 (M+H)+. EXAMPLE 3(569) 3-Morpholin-4-yl-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.09; MS:330 (M+H)+. EXAMPLE 3(570) N-Cyclopentyl-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.91(condition B); MS:254 (M+H)+. EXAMPLE 3(571) N-(2,4-Dimethylphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.88; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(572) N-(3,5-Dichlorophenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):3.16; MS:661, 659 (2M+H)+, 332, 330 (M+H)+. EXAMPLE 3(573) N-[3,5-Bis(trifluoromethyl)phenyl]-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):3.34; MS:398 (M+H)+. EXAMPLE 3(574) 3-Morpholin-4-yl-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.21; MS:707 (2M+H)+, 354 (M+H)+. EXAMPLE 3(575) N-(3,5-Difluorophenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.95; MS:298 (M+H)+. EXAMPLE 3(576) N-(4-Methoxyphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.97(condition B); MS:583 (2M+H)+, 292 (M+H)+. EXAMPLE 3(577) N-(3,5-Dimethylphenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):3.01; MS:579 (2M+H)+, 290 (M+H)+. EXAMPLE 3(578) N-(3-Fluorophenyl)-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.77; MS:280 (M+H)+. EXAMPLE 3(579) Methyl 3-{[(3-morpholin-4-ylazetidin-1-yl)carbonyl]amino}benzoate HPLC retention time (min.):2.88; MS:639 (2M+H)+, 320 (M+H)+. EXAMPLE 3(580) N-[3-(Methylsulfanyl)phenyl]-3-morpholin-4-ylazetidine-1-carboxamide HPLC retention time (min.):2.97; MS:615 (2M+H)+, 308 (M+H)+. EXAMPLE 3(581) N-Hexyl-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.01; MS:565 (2M+H)+, 283 (M+H)+. EXAMPLE 3(582) N-(4-Fluorophenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.78; MS:585 (2M+H)+, 293 (M+H)+. EXAMPLE 3(583) N-(3-Methylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.89; MS:577 (2M+H)+, 289 (M+H)+. EXAMPLE 3(584) 3-(4-Methylpiperazin-1-yl)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.):2.79; MS:617 (2M+H)+, 309 (M+H)+. EXAMPLE 3(585) N-(4-Isopropylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.13; MS:633 (2M+H)+, 317 (M+H)+. EXAMPLE 3(586) N-(3-Chlorophenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.00; MS:617 (2M+H)+, 309 (M+H)+. EXAMPLE 3(587) N-(2,5-Dimethylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.90; MS:605 (2M+H)+, 303 (M+H)+. EXAMPLE 3(588) N-(4-Chlorophenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.99; MS:617 (2M+H)+, 311, 309 (M+H)+. EXAMPLE 3(589) N-Benzyl-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.68; MS:289 (M+H)+. EXAMPLE 3(590) 3-(4-Methylpiperazin-1-yl)-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):2.94; MS:649 (2M+H)+, 325 (M+H)+. EXAMPLE 3(591) 3-(4-Methylpiperazin-1-yl)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.):3.07; MS:649 (2M+H)+, 325 (M+H)+. EXAMPLE 3(592) 3-(4-Methylpiperazin-1-yl)-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.):3.10; MS:705 (2M+H)+, 353 (M+H)+. EXAMPLE 3(593) N-(3,4-Dimethylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.99; MS:605 (2M+H)+, 303 (M+H)+. EXAMPLE 3(594) N-(4-Methylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.90; MS:577 (2M+H)+, 289 (M+H)+. EXAMPLE 3(595) N-Cyclohexyl-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.81; MS:561 (2M+H)+, 281 (M+H)+. EXAMPLE 3(596) N-(2,6-Dimethylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.75; MS:605 (2M+H)+, 303 (M+H)+. EXAMPLE 3(597) N-(2-Ethoxyphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.95; MS:637 (2M+H)+, 319 (M+H)+. EXAMPLE 3(598) N-(2-Ethylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.86; MS:605 (2M+H)+, 303 (M+H)+. EXAMPLE 3(599) N-(4-Ethoxyphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.91; MS:637 (2M+H)+, 319 (M+H)+. EXAMPLE 3(600) 3-(4-Methylpiperazin-1-yl)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.):2.87; MS:303 (M+H)+. EXAMPLE 3(601) 3-(4-Methylpiperazin-1-yl)-N-phenylazetidine-1-carboxamide HPLC retention time (min.):2.91(condition B); MS:549 (2M+H)+, 275 (M+H)+. EXAMPLE 3(602) N-(2-Chlorophenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.83; MS:617 (2M+H)+, 311, 309 (M+H)+. EXAMPLE 3(603) N-(2-Fluorophenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.91(condition B); MS:585 (2M+H)+, 293 (M+H)+. EXAMPLE 3(604) 3-(4-Methylpiperazin-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.09; MS:685 (2M+H)+, 343 (M+H)+. EXAMPLE 3(605) N-Cyclopentyl-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.84(condition B); MS:267 (M+H)+. EXAMPLE 3(606) N-(2,4-Dimethylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.93; MS:605 (2M+H)+, 303 (M+H)+. EXAMPLE 3(607) N-(3,5-Dichlorophenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.17; MS:687, 685 (2M+H)+, 345, 343 (M+H)+; TLC:Rf 0.83 (chloroform:methanol:ammonia water=80:20:1); NMR(CD3OD):d 2.30 (s, 3H), 2.32-2.67 (m, 8H), 3.16-3.27 (m, 1H), 3.90 (dd, J=9.15, 5.13 Hz, 2H), 4.06-4.14 (m, 2H), 7.02 (t, J=1.83 Hz, 1H), 7.50 (d, J=1.83 Hz, 2H). EXAMPLE 3(608) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.34; MS:821 (2M+H)+, 411 (M+H)+. EXAMPLE 3(609) 3-(4-Methylpiperazin-1-yl)-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):3.21; MS:733 (2M+H)+, 367 (M+H)+. EXAMPLE 3(610) N-(3,5-Difluorophenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.98; MS:621 (2M+H)+, 311 (M+H)+. EXAMPLE 3(611) N-(4-Methoxyphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.92(condition B); MS:609 (2M+H)+, 305 (M+H)+. EXAMPLE 3(612) N-(3,5-Dimethylphenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.02; MS:605 (2M+H)+, 303 (M+H)+. EXAMPLE 3(613) N-(3-Fluorophenyl)-3-(4-methylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.86; MS:585 (2M+H)+, 293 (M+H)+. EXAMPLE 3(614) Methyl 3-({[3-(4-methylpiperazin-1-yl)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.):2.90; MS:665 (2M+H)+, 333 (M+H)+. EXAMPLE 3(615) 3-(4-Methylpiperazin-1-yl)-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):2.98; MS:641 (2M+H)+, 321 (M+H)+. EXAMPLE 3(616) N-Ethyl-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.83; MS:289 (M+H)+. EXAMPLE 3(617) 3-(4-Phenylpiperazin-1-yl)-N-propylazetidine-1-carboxamide HPLC retention time (min.):2.93; MS:303 (M+H)+. EXAMPLE 3(618) Ethyl N-{[3-(4-phenylpiperazin-1-yl)azetidin-1-yl]carbonyl}glycinate HPLC retention time (min.):2.92; MS:347 (M+H)+. EXAMPLE 3(619) N-Hexyl-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.26; MS:345 (M+H)+. EXAMPLE 3(620) N-(4-Fluorophenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.14; MS:355 (M+H)+. EXAMPLE 3(621) N-(3-Methylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.18; MS:701 (2M+H)+, 351 (M+H)+. EXAMPLE 3(622) 3-(4-Phenylpiperazin-1-yl)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.):3.13; MS:371 (M+H)+. EXAMPLE 3(623) N-(4-Isopropylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.36; MS:757 (2M+H)+, 379 (M+H)+. EXAMPLE 3(624) N-(3-Chlorophenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.25; MS:741 (2M+H)+, 373, 371 (M+H)+. EXAMPLE 3(625) N-(2,5-Dimethylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.18; MS:729 (2M+H)+, 365 (M+H)+. EXAMPLE 3(626) N-(4-Chlorophenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.23; MS:741 (2M+H)+, 373, 371 (M+H)+. EXAMPLE 3(627) N-Benzyl-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.10; MS:351 (M+H)+. EXAMPLE 3(628) N-(1-Naphthyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.21; MS:773 (2M+H)+, 387 (M+H)+. EXAMPLE 3(629) N-(2-Naphthyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.29; MS:773 (2M+H)+, 387 (M+H)+. EXAMPLE 3(630) N-[1-(1-Naphthyl)ethyl]-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.33; MS:829 (2M+H)+, 415 (M+H)+. EXAMPLE 3(631) N-(3,4-Dimethylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.25; MS:729 (2M+H)+, 365 (M+H)+. EXAMPLE 3(632) N-(4-Methylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.18; MS:701 (2M+H)+, 351 (M+H)+. EXAMPLE 3(633) N-Cyclohexyl-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.13; MS:343 (M+H)+. EXAMPLE 3(634) N-(2,6-Dimethylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.13; MS:729 (2M+H)+, 365 (M+H)+. EXAMPLE 3(635) N-(2-Ethoxyphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.21; MS:761 (2M+H)+, 381 (M+H)+. EXAMPLE 3(636) N-(2-Ethylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.16; MS:729 (2M+H) +, 365 (M+H)+. EXAMPLE 3(637) N-(4-Ethoxyphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.18; MS:761 (2M+H)+, 381 (M+H)+. EXAMPLE 3(638) N-(2-Phenylethyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.16; MS:365 (M+H)+. EXAMPLE 3(639) N-Phenyl-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.09; MS:673 (2M+H)+, 337 (M+H)+. EXAMPLE 3(640) N-(2-Chlorophenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.14; MS:741 (2M+H)+, 373, 371 (M+H)+. EXAMPLE 3(641) N-(2-Fluorophenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.08; MS:709 (2M+H)+, 355 (M+H)+. EXAMPLE 3(642) 3-(4-Phenylpiperazin-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):3.34; MS:809 (2M+H)+, 405 (M+H)+. EXAMPLE 3(643) N-Cyclopentyl-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.05; MS:329 (M+H)+. EXAMPLE 3(644) N-(2,4-Dimethylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.18; MS:729 (2M+H)+, 365 (M+H)+. EXAMPLE 3(645) N-(3,5-Dichlorophenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.40; MS:811, 809 (2M+H)+, 407, 405 (M+H)+. EXAMPLE 3(646) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.54; MS:945 (2M+H)+, 473 (M+H)+. EXAMPLE 3(647) N-(3-Phenoxyphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.43; MS:857 (2M+H)+, 429 (M+H)+. EXAMPLE 3(648) N-(3,5-Difluorophenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.23; MS:745 (2M+H)+, 373 (M+H)+. EXAMPLE 3(649) N-(4-Methoxyphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.09; MS:733 (2M+H)+, 367 (M+H)+. EXAMPLE 3(650) N-(3,5-Dimethylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.26; MS:729 (2M+H)+, 365 (M+H)+. EXAMPLE 3(651) N-(3-Fluorophenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.17; MS:709 (2M+H)+, 355 (M+H)+. EXAMPLE 3(652) Methyl 3-({[3-(4-phenylpiperazin-1-yl)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.):3.16; MS:789 (2M+H)+, 395 (M+H)+. EXAMPLE 3(653) N-[3-(Methylsulfanyl)phenyl]-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.23; MS:765 (2M+H)+, 383 (M+H)+. EXAMPLE 3(654) N-(2-methylphenyl)-3-(4-phenylpiperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.11; MS:701 (2M+H)+, 351 (M+H)+. EXAMPLE 3(655) N-Ethyl-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):2.99; MS:288 (M+H)+, 279. EXAMPLE 3(656) 3-(4-phenylpiperidin-1-yl)-N-propylazetidine-1-carboxamide HPLC retention time (min.):3.01; MS:302 (M+H)+. EXAMPLE 3(657) Ethyl N-{[3-(4-phenylpiperidin-1-yl)azetidin-1-yl]carbonyl})glycinate HPLC retention time (min.):2.99; MS:346 (M+H)+. EXAMPLE 3(658) N-Hexyl-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.31; MS:687 (2M+H)+, 344 (M+H)+. EXAMPLE 3(659) N-(4-Fluorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.19; MS:707 (2M+H)+, 354 (M+H)+. EXAMPLE 3(660) N-(3-Methylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.23; MS:699 (2M+H)+, 350 (M+H)+. EXAMPLE 3(661) 3-(4-Phenylpiperidin-1-yl)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.):3.18; MS:739 (2M+H)+, 370 (M+H)+. EXAMPLE 3(662) N-(4-Isopropylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.42; MS:755 (2M+H)+, 378 (M+H)+. EXAMPLE 3(663) N-(3-Chlorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.29; MS:739 (2M+H)+, 372, 370 (M+H)+. EXAMPLE 3(664) N-(2,5-Dimethylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.24; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(665) N-(4-Chlorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.29; MS:739 (2M+H)+, 372, 370 (M+H)+. EXAMPLE 3(666) N-Benzyl-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.16; MS:699 (2M+H)+, 350 (M+H)+. EXAMPLE 3(667) N-(1-Naphthyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.27; MS:771 (2M+H)+, 386 (M+H)+. EXAMPLE 3(668) N-(2-Naphthyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.35; MS:771 (2M+H)+, 386 (M+H)+. EXAMPLE 3(669) N-[1-(1-Naphthyl)ethyl]-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.38; MS:827 (2M+H)+, 414 (M+H)+. EXAMPLE 3(670) N-(3,4-Dimethylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.30; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(671) N-(4-Methylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.23; MS:699 (2M+H)+, 350 (M+H)+. EXAMPLE 3(672) N-Cyclohexyl-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.):3.18; MS:683 (2M+H)+, 342 (M+H)+; TLC:Rf 0.71 (chloroform:methanol=9:1); NMR(CD3OD): δ 7.29-7.10 (m, 5H), 3.97 (br t, J=8.4 Hz, 2H), 3.84-3.76 (m, 2H), 3.54-3.38 (m, 1H), 3.22-3.10 (m, 1H), 3.02-2.92 (m, 2H), 2.61-2.48 (m, 1H), 2.08-1.98 (m, 2H), 1.88-1.54 (m, 9H), 1.42-1.10 (m, 5H). EXAMPLE 3(673) N-(2,6-Dimethylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.18; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(674) N-(2-Ethoxyphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.28; MS:759 (2M+H)+, 380 (M+H)+. EXAMPLE 3(675) N-(2-Ethylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.23; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(676) N-(4-Ethoxyphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.23; MS:759 (2M+H)+, 380 (M+H)+. EXAMPLE 3(677) N-(2-Phenylethyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.22; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(678) N-Phenyl-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:671 (2M+H)+, 336 (M+H)+. EXAMPLE 3(679) N-(2-Chlorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.19; MS:739 (2M+H)+, 372, 370 (M+H)+. EXAMPLE 3(680) N-(2-Fluorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:707 (2M+H)+, 354 (M+H)+. EXAMPLE 3(681) 3-(4-Phenylpiperidin-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.37; MS:807 (2M+H)+, 404 (M+H)+. EXAMPLE 3(682) N-Cyclopentyl-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.11; MS:328 (M+H)+. EXAMPLE 3(683) N-(2,4-Dimethylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.24; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(684) N-(3,5-Dichlorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.45; MS:809, 807 (2M+H)+, 406, 404 (M+H)+. EXAMPLE 3(685) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.58; MS:943 (2M+H)+, 472 (M+H)+. EXAMPLE 3(686) N-(3-Phenoxyphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.46; MS:855 (2M+H)+, 428 (M+H)+. EXAMPLE 3(687) N-(3,5-Difluorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.30; MS:743 (2M+H)+, 372 (M+H)+. EXAMPLE 3(688) N-(4-Methoxyphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.15; MS:731 (2M+H)+, 366 (M+H)+. EXAMPLE 3(689) N-(3,5-Dimethylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(690) N-(3-Fluorophenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.22; MS:707 (2M+H)+, 354 (M+H)+. EXAMPLE 3(691) Methyl 3-({[3-(4-phenylpiperidin-1-yl)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.): 3.20; MS:787 (2M+H)+, 394 (M+H)+. EXAMPLE 3(692) N-[3-(Methylsulfanyl)phenyl]-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.28; MS:763 (2M+H)+, 382 (M+H)+. EXAMPLE 3(693) N-(2-Methylphenyl)-3-(4-phenylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.16; MS:699 (2M+H)+, 350 (M+H)+. EXAMPLE 3(694) 3-(4-benzylpiperidin-1-yl)-N-ethylazetidine-1-carboxamide HPLC retention time (min.): 3.04; MS:302 (M+H)+, 293. EXAMPLE 3(695) 3-(4-Benzylpiperidin-1-yl)-N-propylazetidine-1-carboxamide HPLC retention time (min.): 3.09; MS:316 (M+H)+. EXAMPLE 3(696) Ethyl N-{[3-(4-benzylpiperidin-1-yl)azetidin-1-yl]carbonyl}glycinate HPLC retention time (min.): 3.09; MS:360 (M+H)+. EXAMPLE 3(697) 3-(4-Benzylpiperidin-1-yl)-N-hexylazetidine-1-carboxamide HPLC retention time (min.): 3.37; MS:715 (2M+H)+, 358 (M+H)+. EXAMPLE 3(698) 3-(4-Benzylpiperidin-1-yl)-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.27; MS:735 (2M+H)+, 368 (M+H)+. EXAMPLE 3(699) 3-(4-Benzylpiperidin-1-yl)-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.30; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(700) 3-(4-Benzylpiperidin-1-yl)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.26; MS:767 (2M+H)+, 384 (M+H)+. EXAMPLE 3(701) 3-(4-Benzylpiperidin-1-yl)-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.46; MS:783 (2M+H)+, 392 (M+H)+. EXAMPLE 3(702) 3-(4-Benzylpiperidin-1-yl)-N-(3-chlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.38; MS:767 (2M+H)+, 386, 384 (M+H)+. EXAMPLE 3(703) 3-(4-Benzylpiperidin-1-yl)-N-(2,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.32; MS:755 (2M+H)+, 378 (M+H)+. EXAMPLE 3(704) 3-(4-Benzylpiperidin-1-yl)-N-(4-chlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.35; MS:767 (2M+H)+, 386, 384 (M+H)+. EXAMPLE 3(705) N-Benzyl-3-(4-benzylpiperidin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.24; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(706) 3-(4-Benzylpiperidin-1-yl)-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.32; MS:799 (2M+H)+, 400 (M+H)+. EXAMPLE 3(707) 3-(4-Benzylpiperidin-1-yl)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.40; MS:799 (2M+H)+, 400 (M+H)+. EXAMPLE 3(708) 3-(4-Benzylpiperidin-1-yl)-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.): 3.43; MS:855 (2M+H)+, 428 (M+H)+. EXAMPLE 3(709) 3-(4-Benzylpiperidin-1-yl)-N-(3,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.36; MS:755 (2M+H)+, 378 (M+H)+. EXAMPLE 3(710) 3-(4-Benzylpiperidin-1-yl)-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(711) 3-(4-Benzylpiperidin-1-yl)-N-cyclohexylazetidine-1-carboxamide HPLC retention time (min.): 3.25; MS:711 (2M+H)+, 356 (M+H)+. EXAMPLE 3(712) 3-(4-Benzylpiperidin-1-yl)-N-(2,6-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.26; MS:755 (2M+H)+, 378 (M+H)+. EXAMPLE 3(713) 3-(4-Benzylpiperidin-1-yl)-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.34; MS:787 (2M+H)+, 394 (M+H)+. EXAMPLE 3(714) 3-(4-Benzylpiperidin-1-yl)-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:755 (2M+H)+, 378 (M+H)+. EXAMPLE 3(715) 3-(4-Benzylpiperidin-1-yl)-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.30; MS:787 (2M+H)+, 394 (M+H)+. EXAMPLE 3(716) 3-(4-Benzylpiperidin-1-yl)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.30; MS:755 (2M+H)+, 378 (M+H)+. EXAMPLE 3(717) 3-(4-Benzylpiperidin-1-yl)-N-phenylazetidine-1-carboxamide HPLC retention time (min.): 3.23; MS:699 (2M+H)+, 350 (M+H)+. EXAMPLE 3(718) 3-(4-Benzylpiperidin-1-yl)-N-(2-chlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.28; MS:767 (2M+H)+, 386, 384 (M+H)+. EXAMPLE 3(719) 3-(4-Benzylpiperidin-1-yl)-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.24; MS:735 (2M+H), 368 (M+H)+. EXAMPLE 3(720) 3-(4-Benzylpiperidin-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.45; MS:835 (2M+H)+, 418 (M+H)+. EXAMPLE 3(721) 3-(4-Benzylpiperidin-1-yl)-N-cyclopentylazetidine-1-carboxamide HPLC retention time (min.): 3.19; MS:683 (2M+H)+, 342 (M+H)+. EXAMPLE 3(722) 3-(4-Benzylpiperidin-1-yl)-N-(2,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.31; MS:755 (2M+H)+, 378 (M+H)+. EXAMPLE 3(723) 3-(4-Benzylpiperidin-1-yl)-N-(3,5-dichlorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.49; MS:837, 835 (2M+H)+, 420, 418 (M+H)+. EXAMPLE 3(724) 3-(4-Benzylpiperidin-1-yl)-N-[3,5-bis(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.63; MS:971 (2M+H)+, 486 (M+H)+. EXAMPLE 3(725) 3-(4-Benzylpiperidin-1-yl)-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.53; MS:883 (2M+H)+, 442 (M+H)+. EXAMPLE 3(726) 3-(4-Benzylpiperidin-1-yl)-N-(3,5-difluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.35; MS:771 (2M+H)+, 386 (M+H)+. EXAMPLE 3(727) 3-(4-Benzylpiperidin-1-yl)-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.22; MS:759 (2M+H)+, 380 (M+H)+. EXAMPLE 3(728) 3-(4-Benzylpiperidin-1-yl)-N-(3,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.37; MS:755 (2M+H)+, 378 (M+H)+. EXAMPLE 3(729) 3-(4-Benzylpiperidin-1-yl)-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.29; MS:735 (2M+H)+, 368 (M+H)+. EXAMPLE 3(730) Methyl 3-({[3-(4-benzylpiperidin-1-yl)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.): 3.28; MS:815 (2M+H)+, 408 (M+H)+. EXAMPLE 3(731) 3-(4-Benzylpiperidin-1-yl)-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.35; MS:791 (2M+H)+, 396 (M+H)+. EXAMPLE 3(732) 3-(4-Benzylpiperidin-1-yl)-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.23; MS:727 (2M+H)+, 364 (M+H)+. EXAMPLE 3(733) 3-(2,3-Dihydro-1H-indol-1-yl)-N-ethylazetidine-1-carboxamide HPLC retention time (min.): 3.22; MS:246 (M+H)+. EXAMPLE 3(734) 3-(2,3-Dihydro-1H-indol-1-yl)-N-propylazetidine-1-carboxamide HPLC retention time (min.): 3.37; MS:260 (M+H)+. EXAMPLE 3(735) Ethyl N-{[3-(2,3-dihydro-1H-indol-1-yl)azetidin-1-yl]carbonyl}glycinate HPLC retention time (min.): 3.29; MS:304 (M+H)+. EXAMPLE 3(736) 3-(2,3-Dihydro-1H-indol-1-yl)-N-hexylazetidine-1-carboxamide HPLC retention time (min.): 3.82; MS:603 (2M+H)+, 302 (M+H)+. EXAMPLE 3(737) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.66; MS:312 (M+H)+. EXAMPLE 3(738) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.73; MS:615 (2M+H)+, 308 (M+H)+. EXAMPLE 3(739) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.61; MS:655 (2M+H)+, 328 (M+H)+. EXAMPLE 3(740) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.93; MS:671 (2M+H)+, 336 (M+H)+. EXAMPLE 3(741) N-(3-Chlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.82; MS:655 (2M+H)+, 328 (M+H)+. EXAMPLE 3(742) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.76; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(743) N-(4-Chlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.81; MS:655 (2M+H)+, 330, 328 (M+H)+. EXAMPLE 3(744) N-Benzyl-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.58; MS:615 (2M+H)+, 308 (M+H)+. EXAMPLE 3(745) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.76; MS:687 (2M+H)+, 344 (M+H)+. EXAMPLE 3(746) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.86; MS:687 (2M+H)+, 344 (M+H)+. EXAMPLE 3(747) 3-(2,3-Dihydro-1H-indol-1-yl)-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.): 3.87; MS:743 (2M+H)+, 372 (M+H)+, 218. EXAMPLE 3(748) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(3,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.80; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(749) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.73; MS:615 (2M+H)+, 308 (M+H)+. EXAMPLE 3(750) N-Cyclohexyl-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.66; MS:599 (2M+H)+, 300 (M+H)+. EXAMPLE 3(751) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2,6-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.65; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(752) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.90; MS:675 (2M+H)+, 338 (M+H)+. EXAMPLE 3(753) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.74; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(754) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.68; MS:675 (2M+H)+, 338 (M+H)+. EXAMPLE 3(755) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.65; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(756) 3-(2,3-Dihydro-1H-indol-1-yl)-N-phenylazetidine-1-carboxamide HPLC retention time (min.): 3.61; MS:294 (M+H)+. EXAMPLE 3(757) N-(2-Chlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.82; MS:655 (2M+H)+, 330, 328 (M+H)+. EXAMPLE 3(758) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.65; MS:312 (M+H)+. EXAMPLE 3(759) 3-(2,3-Dihydro-1H-indol-1-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.90; MS:723 (2M+H)+, 362 (M+H)+. EXAMPLE 3(760) N-Cyclopentyl-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.55; MS:571 (2M+H)+, 286 (M+H)+. EXAMPLE 3(761) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.73; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(762) N-(3,5-Dichlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide HPLC retention time (min.):4.06; MS:725, 723 (2M+H)+, 364, 362 (M+H)+. EXAMPLE 3(763) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide HPLC retention time (min.):4.16; MS:430 (M+H)+. EXAMPLE 3(764) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):4.00; MS:771 (2M+H)+, 386 (M+H)+. EXAMPLE 3(765) N-(3,5-Difluorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.83; MS:330 (M+H)+. EXAMPLE 3(766) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.59; MS:647 (2M+H)+, 324 (M+H)+. EXAMPLE 3(767) 3-(2,3-dihydro-1H-indol-1-yl)-N-(3,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.84; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(768) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.73; MS:623 (2M+H)+, 312 (M+H)+. EXAMPLE 3(769) Methyl 3-({[3-(2,3-dihydro-1H-indol-1-yl)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.): 3.68; MS:703 (2M+H)+, 352 (M+H)+. EXAMPLE 3(770) 3-(2,3-Dihydro-1H-indol-1-yl)-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.79; MS:679 (2M+H)+, 340 (M+H)+. EXAMPLE 3(771) 3-(2,3-Dihydro-1H-indol-1-yl)-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.64; MS:615 (2M+H)+, 308 (M+H)+. EXAMPLE 3(772) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-propylazetidine-1-carboxamide HPLC retention time (min.): 3.50; MS:274 (M+H)+. EXAMPLE 3(773) Ethyl N-{[3-(3,4-dihydroquinolin-1(2H)-yl)azetidin-1-yl]carbonyl}glycinate HPLC retention time (min.): 3.42; MS:318 (M+H)+. EXAMPLE 3(774) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-hexylazetidine-1-carboxamide HPLC retention time (min.): 3.94; MS:631 (2M+H)+, 316 (M+H)+. EXAMPLE 3(775) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(4-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.78; MS:326 (M+H)+. EXAMPLE 3(776) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(3-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.86; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(777) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2-thien-2-ylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.73; MS:683 (2M+H)+, 342 (M+H)+. EXAMPLE 3(778) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(4-isopropylphenyl)azetidine-1-carboxamide HPLC retention time (min.):4.04; MS:699 (2M+H)+, 350 (M+H)+. EXAMPLE 3(779) N-(3-Chlorophenyl)-3-(3,4-dihydroquinolin-1(2H)-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.95; MS:683 (2M+H)+, 344, 342 (M+H)+. EXAMPLE 3(780) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.86; MS:671 (2M+H)+, 336 (M+H)+. EXAMPLE 3(781) N-(4-Chlorophenyl)-3-(3,4-dihydroquinolin-1(2H)-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.92; MS:683 (2M+H)+, 344, 342 (M+H)+. EXAMPLE 3(782) N-Benzyl-3-(3,4-dihydroquinolin-1(2H)-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.71; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(783) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(1-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.87; MS:715 (2M+H)+, 358 (M+H)+. EXAMPLE 3(784) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2-naphthyl)azetidine-1-carboxamide HPLC retention time (min.): 3.98; MS:715 (2M+H)+, 358 (M+H)+. EXAMPLE 3(785) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-[1-(1-naphthyl)ethyl]azetidine-1-carboxamide HPLC retention time (min.): 3.98; MS:771 (2M+H)+, 386 (M+H)+, 232. EXAMPLE 3(786) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(3,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.92; MS:671 (2M+H) +, 336 (M+H)+. EXAMPLE 3(787) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(4-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.84; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 3(788) N-Cyclohexyl-3-(3,4-dihydroquinolin-1(2H)-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.77; MS:627 (2M+H)+, 314 (M+H)+. EXAMPLE 3(789) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2,6-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.76; MS:671 (2M+H)+, 336 (M+H)+. EXAMPLE 3(790) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):4.02; MS:703 (2M+H)+, 352 (M+H)+. EXAMPLE 3(791) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2-ethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.86; MS:671 (2M+H)+, 336 (M+H)+. EXAMPLE 3(792) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(4-ethoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.81; MS:703 (2M+H)+, 352 (M+H)+. EXAMPLE 3(793) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2-phenylethyl)azetidine-1-carboxamide HPLC retention time (min.): 3.77; MS:671 (2M+H)+, 336 (M+H)+. EXAMPLE 3(794) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-phenylazetidine-1-carboxamide HPLC retention time (min.): 3.75; MS:615 (2M+H)+, 308 (M+H)+. EXAMPLE 3(795) N-(2-Chlorophenyl)-3-(3,4-dihydroquinolin-1(2H)-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.96; MS:344, 342 (M+H)+. EXAMPLE 3(796) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.79; MS:326 (M+H)+. EXAMPLE 3(797) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-[3-(trifluoromethyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.):4.02; MS:751 (2M+H)+, 376 (M+H)+. EXAMPLE 3(798) N-Cyclopentyl-3-(3,4-dihydroquinolin-1(2H)-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.67; MS:599 (2M+H)+, 300 (M+H)+. EXAMPLE 3(799) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2,4-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.86; MS:671 (2M+H)+, 336 (M+H)+. EXAMPLE 3(800) N-(3,5-Dichlorophenyl)-3-(3,4-dihydroquinolin-1(2H)-yl)azetidine-1-carboxamide HPLC retention time (min.):4.17; MS:753, 751 (2M+H)+, 378, 376 (M+H)+. EXAMPLE 3(801) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(3,4-dihydroquinolin-1(2H)-yl)azetidine-1-carboxamide HPLC retention time (min.):4.26; MS:444 (M+H)+. EXAMPLE 3(802) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(3-phenoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.):4.11; MS:799 (2M+H)+, 400 (M+H)+. EXAMPLE 3(803) N-(3,5-Difluorophenyl)-3-(3,4-dihydroquinolin-1(2H)-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.95; MS:344 (M+H)+. EXAMPLE 3(804) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(4-methoxyphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.69; MS:675 (2M+H)+, 338 (M+H)+. EXAMPLE 3(805) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(3,5-dimethylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.95; MS:671 (2M+H)+, 336 (M+H)+ EXAMPLE 3(806) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(3-fluorophenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.85; MS:326 (M+H)+. EXAMPLE 3(807) Methyl 3-({[3-(3,4-dihydroquinolin-1(2H)-yl)azetidin-1-yl]carbonyl}amino)benzoate HPLC retention time (min.): 3.80; MS:731 (2M+H)+, 366 (M+H)+. EXAMPLE 3(808) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-[3-(methylsulfanyl)phenyl]azetidine-1-carboxamide HPLC retention time (min.): 3.90; MS:707 (2M+H)+, 354 (M+H)+. EXAMPLE 3(809) 3-(3,4-Dihydroquinolin-1(2H)-yl)-N-(2-methylphenyl)azetidine-1-carboxamide HPLC retention time (min.): 3.76; MS:643 (2M+H)+, 322 (M+H)+. EXAMPLE 4 N-[3,5-Bis(trifluoromethyl)phenyl]-3-piperazin-1-ylazetidine-1-carboxamide To a solution of the compound, prepared in Example 3 (1.04 g), in dichloromethane (21 mL) was added 2,6-lutidine (0.49 mL) at room temperature. To the mixture was added trimethylsilyl triflate (0.57 mL) dropwise, and the mixture was stirred for 80 minutes. The reaction solution was diluted with dichloromethane and to the mixture were added water and 5N aqueous solution of sodium hydroxide and it was extracted with dichloromethane. To the organic layer was added methanol and the mixture was concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol:triethylamine=10:1:1→3:1:1). The obtained compound was washed with tert-butyl methyl ether and tert-butyl methyl ether/hexane, and dried to give the compound of the present invention (800 mg) having the following physical data. TLC:Rf 0.21 (chloroform:methanol:triethylamine=5:1:1); NMR(CD3OD):δ 2.45 (m, 4H), 2.94 (m, 4H), 3.23 (m, 1H), 3.95 (dd, J=9.00, 5.00 Hz, 2H), 4.13 (t, J=9.00 Hz, 2H), 7.51 (s, 1H), 8.11 (s, 2H). EXAMPLE 5 3-(4-Benzylpiperazin-1-yl)-N-[3,5-bis(trifluoromethyl)phenyl]azetidine-1-carboxamide To a solution of the compound, prepared in Example 4 (20 mg), in tetrahydrofuran (0.25 mL) was added acetic acid (0.004 mL), and to the mixture was added 0.50 mol/L solution of benzaldehyde in dichloroethane (0.15 mL) at room temperature and the mixture was stirred for a while and it was allowed to stand for 30 minutes. To a solution of the compound, prepared in Example 4 (20 mg), in tetrahydrofuran (0.25 mL) was added acetic acid (0.004 mL), and then to the mixture was added a 0.50 mol/L solution of benzaldehyde in dichloroethane at room temperature, and the mixture was allowed to stand for 7.5 hours. To the reaction solution was added MP-triacetoxyborohydride (macroporous triethylammonium methyl polystyrene triacetoxyborohydride) (Argonote Technology Inc.; Cat. #.800415)(2.01 mmol/g, 75 mg) and it was shaken for a while and allowed to stand overnight. Thereto was added polystyrene sulfonylhydrazide (Argonote Technology Inc.; Cat. #.800272) (2.54 mmol/g, 59 mg) and tetrahydrofuran (0.35 mL), and the mixture was allowed to stand for 7.5 hours. The resin was filtered off and washed with tetrahydrofuran and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2→ethyl acetate→ethyl acetate:methanol=20:1) to give the compound of the present invention (13 mg) having the following physical data. TLC:Rf 0.42 (ethyl acetate:methanol=10:1); NMR(CDCl3):δ 2.50 (m, 8H), 3.26 (m, 1H), 3.54 (s, 2H), 3.98 (dd, J=8.00, 5.00 Hz, 2H), 4.09 (t, J=8.00 Hz, 2H), 6.22 (s, 1H), 7.29 (m, 5H), 7.50 (s, 1H), 7.90 (s, 2H). EXAMPLES 5(1) to 5(122) The following compounds of the present invention were prepared from an aldehyde derivative corresponding to benzaldehyde using a procedure analogous to that described for Example 5. EXAMPLE 5(1) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-phenylpropyl)piperazine-1-yl]azetidinyl-1-carboxamide acetate TLC:Rf 0.24 (ethyl acetate:methanol=10:1); NMR(CDCl3): δ 1.85 (m, 2H), 2.06 (s, 3H), 2.56 (m, 12H), 3.28 (m, 1H), 4.00 (dd, J=8.00, 5.50 Hz, 2H), 4.10 (t, J=8.00 Hz, 2H), 6.33 (s, 1H), 7.19 (m, 3H), 7.29 (m, 2H), 7.50 (s, 1H), 7.92 (s, 2H). EXAMPLE 5(2) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(1-methyl-1H-pyrrole-2-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.43; MS: 979 (2M+H)+, 490 (M+H)+. EXAMPLE 5(3) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(1,5-dimethyl-3-oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.38; MS: 597 (M+H)+. EXAMPLE 5(4) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(5-methyl-2-furyl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.45; MS: 981 (2M+H)+, 491 (M+H)+. EXAMPLE 5(5) [5-({4-[1-({[3,5-Bis(trifluoromethyl)phenyl]amino}carbonyl)azetidinyl-3-yl]piperazine-1-yl}methyl)-2-furyl]methyl acetate HPLC retention time (min.): 3.42; MS: 549 (M+H)+. EXAMPLE 5(6) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{[5-(hydroxymethyl)-2-furyl]methyl}piperazine-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.31; MS: 507 (M+H)+. EXAMPLE 5(7) 3-(4-Benzylpiperazin-1-yl)-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.44; MS: 973 (2M+H)+, 487 (M+H)+. EXAMPLE 5(8) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2-methoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.45; MS: 517 (M+H)+. EXAMPLE 5(9) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2,3-dimethoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.48; MS: 547 (M+H)+. EXAMPLE 5(10) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2,4-dimethoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.49; MS: 547 (M+H)+. EXAMPLE 5(11) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2,4,6-trimethoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.53; MS: 577 (M+H)+, 181. EXAMPLE 5(12) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2,5-dimethoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.49; MS: 547 (M+H)+. EXAMPLE 5(13) [2-({4-[1-({[3,5-Bis(trifluoromethyl)phenyl]aamino}carbonyl)azetidinyl-3-yl]piperazine-1-yl}methyl)phenoxy]acetic acid HPLC retention time (min.): 3.42; MS: 561 (M+H)+. EXAMPLE 5(14) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[2-(trifluoromethyl)benzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.58; MS: 555 (M+H)+. EXAMPLE 5(15) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2-methylbenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.48; MS: 501 (M+H)+. EXAMPLE 5(16) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-cyanobenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.45; MS: 512 (M+H)+. EXAMPLE 5(17) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-fluorobenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.46; MS: 505 (M+H)+. EXAMPLE 5(18) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-fluoro-4-methoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.48; MS: 535 (M+H)+. EXAMPLE 5(19) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-phenoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.66; MS: 579 (M+H)+. EXAMPLE 5(20) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-methoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.46; MS: 517 (M+H)+. EXAMPLE 5(21) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3,4-dimethoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.41; MS: 547 (M+H)+. EXAMPLE 5(22) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3,4,5-trimethoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.45; MS: 577 (M+H)+, 181. EXAMPLE 5(23) 3-(4-[4-(Benzyloxy)-3-methoxybenzyl]piperazine-1-yl)-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.63; MS: 623 (M+H)+, 227. EXAMPLE 5(24) 3-{4-[3-(Benzyloxy)benzyl]piperazine-1-yl}-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.68; MS: 593 (M+H)+. EXAMPLE 5(25) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-hydroxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.38; MS: 503 (M+H)+. EXAMPLE 5(26) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-hydroxy-4-methoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.40; MS: 533 (M+H)+. EXAMPLE 5(27) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[3-(trifluoromethyl)benzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.57; MS: 555 (M+H)+. EXAMPLE 5(28) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-methylbenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.51; MS: 501 (M+H)+. EXAMPLE 5(29) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(4-cyanobenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.43; MS: 512 (M+H)+. EXAMPLE 5(30) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(4-fluorobenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.46; MS: 505 (M+H)+. EXAMPLE 5(31) 3-{4-[4-(Acetylamino)benzyl]piperazine-1-yl}-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.35; MS: 544 (M+H)+. EXAMPLE 5(32) N-[3,5-Bis(trifludromethyl)phenyl]-3-{4-[4-(dimethylamino)benzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.29; MS: 530 (M+H)+, 397, 134. EXAMPLE 5(33) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[4-(diethylamino)benzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.25; MS: 558 (M+H)+, 469, 162. EXAMPLE 5(34) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(4-phenoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.65; MS: 579 (M+H)+. EXAMPLE 5(35) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(4-methoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.47; MS: 517 (M+H)+. EXAMPLE 5(36) 3-{4-[4-(Benzyloxy)benzyl]piperazine-1-yl}-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.67; MS: 593 (M+H)+. EXAMPLE 5(37) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(1H-imidazol-2-ylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.18; MS: 953 (2M+H)+, 477 (M+H)+. EXAMPLE 5(38) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(1-naphthylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.55; MS: 537 (M+H)+. EXAMPLE 5(39) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(4-methoxy-1-naphthyl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.59; MS: 567 (M+H)+, 171. EXAMPLE 5(40) 3-{4-[3,4-Bis(benzyloxy)benzyl]piperazine-1-yl}-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.83; MS: 699 (M+H)+. EXAMPLE 5(41) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(1H-pyrrole-2-ylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.38; MS: 951 (2M+H)+, 476 (M+H)+, 397. EXAMPLE 5(42) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(thien-2-ylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.43; MS: 985 (2M+H)+, 493 (M+H)+. EXAMPLE 5(43) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(3-methylthien-2-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.47; MS: 507 (M+H)+. EXAMPLE 5(44) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(4-bromothien-2-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.51; MS: 573, 571 (M+H)+. EXAMPLE 5(45) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(5-bromothien-2-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.53; MS: 573, 571 (M+H)+. EXAMPLE 5(46) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(1H-indol-3-ylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.49; MS: 526 (M+H)+, 397. EXAMPLE 5(47) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(pyridin-4-ylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.18; MS: 975 (2M+H)+, 488 (M+H)+. EXAMPLE 5(48) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(4-hydroxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.38; MS: 503 (M+H)+. EXAMPLE 5(49) 3-[4-(1,1′-Biphenyl-4-ylmethyl)piperazine-1-yl]-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.63; MS: 563 (M+H)+. EXAMPLE 5(50) Methyl 4-({4-[1-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)azetidinyl-3-yl]piperazine-1-yl}methyl)benzoate HPLC retention time (min.): 3.45; MS: 545 (M+H)+. EXAMPLE 5(51) 4-({4-[1-({[3,5-Bis(trifluoromethyl)phenyl]amino}carbonyl)azetidinyl-3-yl]piperazine-1-yl}methyl)benzoate HPLC retention time (min.): 3.38; MS: 531 (M+H)+. EXAMPLE 5(52) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[4-(trifluoromethyl)benzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.57; MS: 555 (M+H)+. EXAMPLE 5(53) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(4-methylbenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.50; MS: 501 (M+H)+. EXAMPLE 5(54) {4-[1-({[3,5-Bis(trifluoromethyl)phenyl]amino}carbonyl)azetidinyl-3-yl]piperazine-1-yl}acetic acid HPLC retention time (min.): 3.28; MS: 909 (2M+H)+, 455 (M+H)+. EXAMPLE 5(55) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(2E)-2-methylbut-2-enyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.42; MS: 929 (2M+H)+, 465 (M+H)+. EXAMPLE 5(56) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-isobutylpiperazin-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.37; MS: 905 (2M+H)+, 453 (M+H)+. EXAMPLE 5(57) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2-ethylhexyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.61; MS: 509 (M+H)+. EXAMPLE 5(58) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{(2E)-3-[4-(dimethylamino)phenyl]prop-2-enyl}piperazine-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.28; MS: 556 (M+H)+, 397, 160. EXAMPLE 5(59) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-isopentylpiperazin-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.43; MS: 933 (2M+H)+, 467 (M+H)+. EXAMPLE 5(60) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-propylpiperazin-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.33; MS: 877 (2M+H)+, 439 (M+H)+. EXAMPLE 5(61) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[3-(methylsulfanyl)propyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.39; MS: 969 (2M+H)+, 485 (M+H)+. EXAMPLE 5(62) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-butylpiperazin-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.40; MS: 905 (2M+H)+, 453 (M+H)+. EXAMPLE 5(63) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(quinolin-2-ylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.33; MS: 538 (M+H)+. EXAMPLE 5(64) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-nitrobenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.48; MS: 532 (M+H)+. EXAMPLE 5(65) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3,5-di-tert-butyl-4-hydroxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.79; MS: 615 (M+H)+. EXAMPLE 5(66) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.46; MS: 545 (M+H)+. EXAMPLE 5(67) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3-furylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.38; MS: 953 (2M+H)+, 477 (M+H)+. EXAMPLE 5(68) 4-{4-[1-({[3,5-Bis(trifluoromethyl)phenyl]amino}carbonyl)azetidinyl-3-yl]piperazine-1-yl}butanoic acid HPLC retention time (min.): 3.26; MS: 483 (M+H)+, 397. EXAMPLE 5(69) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(2,6-dimethoxybenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.51; MS: 547 (M+H)+. EXAMPLE 5(70) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{4-[3-(dimethylamino)propoxy]benzyl}piperazine-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.26; MS: 588 (M+H)+. EXAMPLE 5(71) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(2-methyl-1H-indol-3-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.52; MS: 540 (M+H)+, 397, 144. EXAMPLE 5(72) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(cyclopropylmethyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.36; MS: 901 (2M+H)+, 451 (M+H)+. EXAMPLE 5(73) 3-{4-[4-(Allyloxy)benzyl]piperazine-1-yl}-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.55; MS: 543 (M+H)+. EXAMPLE 5(74) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[4-(octyloxy)benzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 4.01; MS: 615 (M+H)+. EXAMPLE 5(75) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(1-methyl-1H-indol-3-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.54; MS: 540 (M+H)+, 144. EXAMPLE 5(76) 3-[4-(1-Benzofuran-2-ylmethyl)piperazine-1-yl]-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.54; MS: 527 (M+H)+. EXAMPLE 5(77) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(4-pyrrolidin-1-ylbenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.57; MS: 556 (M+H)+, 160. EXAMPLE 5(78) 3-{4-[2-(Benzyloxy)benzyl]piperazine-1-yl}-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.67; MS: 593 (M+H)+. EXAMPLE 5(79) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[4-(heptyloxy)benzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.91; MS: 601 (M+H)+. EXAMPLE 5(80) 3-[4-(1,3-Benzodioxol-4-ylmethyl)piperazine-1-yl]-N-[3,5-bis(trifluoromethyl)phenyl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.46; MS: 531 (M+H)+. EXAMPLE 5(81) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(3,5,6-trimethylcyclohex-3-en-1-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.62; MS: 533 (M+H)+. EXAMPLE 5(82) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[4-(hexyloxy)-3-methoxybenzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.79; MS: 617 (M+H)+, 221. EXAMPLE 5(83) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(6-chloro-1,3-benzodioxol-5-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.51; MS: 567, 565 (M+H)+. EXAMPLE 5(84) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(5-ethyl-2-furyl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.51; MS: 505 (M+H)+. EXAMPLE 5(85) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(4-tert-butylbenzyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.66; MS: 543 (M+H)+. EXAMPLE 5(86) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(3,7-dimethyloct-6-enyl)piperazine-1-yl]azetidinyl-1-carboxamide HPLC retention time (min.): 3.71; MS: 535 (M+H)+. EXAMPLE 5(87) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[2-(tert-butylsulfanyl)benzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.68; MS: 575 (M+H)+. EXAMPLE 5(88) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[4-(trifluoromethoxy)benzyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.59; MS: 571 (M+H)+. EXAMPLE 5(89) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(3,5-dimethyl-1-phenyl-1H-pyrazole-4-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.48; MS: 581 (M+H)+, 185. EXAMPLE 5(90) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{2-[(4-chlorophenyl)sulfanyl]benzyl}piperazine-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.78; MS: 631, 629 (M+H)+. EXAMPLE 5(91) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(3-methyl-1-benzothien-2-yl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.61; MS: 557 (M+H)+. EXAMPLE 5(92) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(4-hydroxy-1-naphthyl)methyl]piperazine-1-yl}azetidinyl-1-carboxamide HPLC retention time (min.): 3.50; MS: 553 (M+H)+, 397. EXAMPLE 5(93) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{4-[2-(diethylamino)ethoxy]benzyl}piperazine-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.26; MS: 602 (M+H)+. EXAMPLE 5(94) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{[(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl}piperazine-1-yl)azetidinyl-1-carboxamide HPLC retention time (min.): 3.61; MS:531 (M+H)+. EXAMPLE 5(95) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(6-methoxy-2-naphthyl)methyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.57; MS:567 (M+H)+, 171. EXAMPLE 5(96) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-({4-[(2E)-4-methylpent-2-enyl]cyclohex-3-en-1-yl}methyl)piperazin-1-yl]azetidine-1-carboxamide HPLC retention time (min.): 3.79; MS:573 (M+H)+. EXAMPLE 5(97) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.54; MS:601 (M+H)+, 205. EXAMPLE 5(98) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(2-chloroquinolin-3-yl)methyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.51; MS:574, 572 (M+H)+. EXAMPLE 5(99) 2-(Acetylamino)-1-{4-[1-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)azetidin-3-yl]piperazin-1-yl}-1,2-dideoxy-D-galactitol HPLC retention time (min.): 3.27; MS:793, 602 (M+H)+, 397. EXAMPLE 5(100) 5-{4-[1-({[3,5-Bis(trifluoromethyl)phenyl]amino}carbonyl)azetidin-3-yl]piperazin-1-yl}-4,5-dideoxy-D-erhthro-pentitol HPLC retention time (min.): 3.24; MS:515 (M+H)+. EXAMPLE 5(101) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{[(3a′S,5′S,6′R,6a′S)-6′-hydroxytetrahydrospiro[cyclohexane-1,2′-furo[2,3-d][1,3]dioxol]-5′-yl]methyl}piperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.48; MS:609 (M+H)+. EXAMPLE 5(102) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]azetidine-1-carboxamide HPLC retention time (min.): 3.34; MS:987 (2M+H)+, 494 (M+H)+. EXAMPLE 5(103) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(5-ethylthien-2-yl)methyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.55; MS:521 (M+H)+. EXAMPLE 5(104) 4-({4-[1-({[3,5-Bis(trifluoromethyl)phenyl]amino}carbonyl)azetidin-3-yl]piperazin-1-yl)methyl}phenylboronic acid HPLC retention time (min.): 3.39; MS:531 (M+H)+, 503. EXAMPLE 5(105) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(8-hydroxyquinolin-2-yl)methyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.42; MS:554 (M+H)+. EXAMPLE 5(106) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(4-methyl-1H -imidazol-5-yl)methyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.26; MS:981 (2M+H)+, 491 (M+H)+, 397. EXAMPLE 5(107) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(2-phenyl-1H -imidazol-4-yl)methyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.28; MS:553 (M+H)+. EXAMPLE 5(108) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-({5-[3,5-bis(trifluoromethyl)phenyl]-2-furyl}methyl)piperazin-1-yl]azetidine-1-carboxamide HPLC retention time (min.): 3.83; MS:689 (M+H)+. EXAMPLE 5(109) Methyl 3-({4-[1-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)azetidin-3-yl]piperazin-1-yl}methyl)benzoate HPLC retention time (min.): 3.46; MS:545 (M+H)+. EXAMPLE 5(110) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.26; MS:521 (M+H)+, 397. EXAMPLE 5(111) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{[5-(4-chlorophenyl)-2-furyl]methyl}piperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.70; MS:589, 587 (M+H)+, 193, 191. EXAMPLE 5(112) Methyl 2-({4-[1-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)azetidin-3-yl]piperazin-1-yl}methyl)benzoate HPLC retention time (min.): 3.46; MS:545 (M+H)+. EXAMPLE 5(113) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[3-(5-methyl-2-furyl)butyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.55; MS:533 (M+H)+. EXAMPLE 5(114) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{[5-(3-chlorophenyl)-2-furyl]methyl}piperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.69; MS:589, 587 (M+H)+, 193, 191. EXAMPLE 5(115) Methyl 3-({4-[1-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)azetidin-3-yl]piperazin-1-yl}methyl)-1-indole-6-carboxylate HPLC retention time (min.): 3.49; MS:584 (M+H)+, 397, 188. EXAMPLE 5(116) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[4-(methylsulfonyl)benzyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.38; MS:565 (M+H)+. EXAMPLE 5(117) N-[3,5-Bis(trifluoromethyl)phenyl]-3-(4-{[5-(2-chlorophenyl)-2-furyl]methyl}piperazin-1-yl)azetidine-1-carboxamide HPLC retention time (min.): 3.67; MS:589, 587 (M+H)+, 193, 191. EXAMPLE 5(118) N-[3,5-Bis(trifluoromethyl)phenyl]-3-{4-[(3-phenyl-1H-pyrazol-4-yl)methyl]piperazin-1-yl}azetidine-1-carboxamide HPLC retention time (min.): 3.43; MS:553 (M+H)+. EXAMPLE 5(119) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-({5-[2-(trifluoromethyl)phenyl]-2-furyl}methyl)piperazin-1-yl]azetidine-1-carboxamide HPLC retention time (min.): 3.70; MS:621 (M+H)+. EXAMPLE 5(120) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-({5-[3-(trifluoromethyl)phenyl]-2-furyl}methyl)piperazin-1-yl]azetidine-1-carboxamide HPLC retention time (min.): 3.72; MS:621 (M+H)+, 225. EXAMPLE 5(121) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-({5-[2-chloro-5-(trifluoromethyl)phenyl]-2-furyl}methyl)piperazin-1-yl]azetidine-1-carboxamide HPLC retention time (min.): 3.78; MS:657, 655 (M+H)+. EXAMPLE 5(122) N-[3,5-Bis(trifluoromethyl)phenyl]-3-[4-({5-[2-(trifluoromethoxy)phenyl]-2-furyl}methyl)piperazin-1-yl]azetidine-1-carboxamide HPLC retention time (min.): 3.74; MS:637 (M+H)+, 241. BIOLOGICAL EXAMPLE Evaluation of Antagonistic Activity for EDG-5 by Monitoring the Concentration Change of Intracellular Calcium Ion. Chinese hamster ovary (CHO) cells in which human EDG-5 gene was overexpressed were cultured in Ham's F12 medium (GIBCO BRL) containing 10% FBS (fetal bovine serum), penicillin/streptomycin. and blasticidin (5 μg/mL). Thus cultured cells were incubated in a Fura2 (5 μM)-AM solution [Ham's F12 medium containing FBS (10%), HEPES buffer (20 mM, pH7.4), and probenecid (2.5 mM)] at 37° C. for 60 minutes. Then the cells were washed once with a Hanks' solution (2.5 mM) containing probenecid and immersed into the Hanks' solution. A plate was set on a fluorescent drug screening system, and the concentration of intracellular calcium ion was measured for 30 seconds with no stimulation. A solution of a compound (dimethyl sulfoxide (DMSO) solution of 1 nM to 10 μM at the final concentration) to be tested was added. After lapse of 5 minutes, S1P (final concentration: 100 nM) was added, the concentration of intracellular calcium ion before and after the addition of SiP was measured every 3 seconds (excitation wave length: 340 nm and 380 nm; fluorescent wave length: 500 nm). The antagonisitc activity for EDG-5 was calculated as an inhibition rate (%) by the following equation, wherein the peak value of S1P (final concentration: 100 nM) in a well into which DMSO was added instead of the test compound was regarded as a control value (A), and in the cells treated with the compound the difference value (B) between the value before addition of the compound and that after the addition was obtained and compared with the control value. Inhibition rate (%)=((A-B)/A)×100 IC50 value was given as the concentration of the compound of the present invention at which it shows an inhibition rate of 50%. As a result, the compound of the present invention showed an antagonisitic activity against EDG-5. For example, the IC50 value of the compound of Example 3(18) was 950 nM. FORMULATION EXAMPLE 1 N-[3,5-bis(trifluoromethyl)phenyl]-3-[ethyl(phenyl)amino]azetidine-1-carboxamide (100 g), carboxymethylcellulose calcium (20.0 g), magnesium stearate (10.0 g) and microcrystalline cellulose (870 g) were admixed in a conventional method and it was punched out to give 10,000 tablets each containing 10 mg of active ingredient. FORMULATION EXAMPLE 2 N-[3,5-bis(trifluoromethyl)phenyl]-3-[ethyl(phenyl)amino]azetidine-1-carboxamide (200 g), mannitol (2 kg) and distilled water (50 L) were admixed in a conventional method, and the mixture was filtrated over a dust removal filter. 5 ml of the solution was filled into each ampoule and the ampoules were heat-sterilized with an autoclave to give 10,000 ampoules each containing 20 mg of active ingredient. INDUSTRIAL APPLICABILITY Because of having EDG-5 antagonism, the compound of the present invention is useful as a preventive and/or therapeutic agent for, for example, diseases caused by blood vessel contraction (e.g. cerebrovascular spasms disease, cardiovascular spasms diseases, coronary artery spasms disease, hypertension, pulmonary hypertension, renal diseases, myocardial infarction, angina pectoris, arrhythmia, portal hypertension, varicosity and the like), arteriosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, respiratory diseases (e.g. bronchial asthma, chronic obstructive pulmonary diseases and the like), nephropathy, diabetes, hyperlipemia and the like. Therefore, the compound of the present invention. is applicable as a pharmaceutical.