NOVEL BENZOTHIOPHENE DERIVATIVES, THEIR PREPARATION AND USE AS UROKINASE INHIBITORS

Abstract: A compound of formula (I) in which R<1> is hydrogen, optionally substituted lower alkylcarbamoyl(lower)alkylidene, lower alkylidene, lower alkyl, optionally substituted ar(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, protected carboxy(lower)alkyl, carboxy(lower)alkyl, hydroxy(lower)alkyl, optionally substituted lower alkylcarbamoyl(lower)alkyl, lower alkylthio(lower)alkyl, carboxy(lower)alkanoyl, protected carboxy(lower)alkanoyl, aroyl, lower alkanoyl, or optionally substituted arylcarbymoyl(lower)alkyl; R<2> is hydrogen, carboxy, protected carboxy, formyl or N-(lower)alkyl-N-(lower)alkoxycarbamoyl; R<3> is hydrogen or amidino-protective group; A is lower alkylene or carbonyl; X is (1), (2) or (3); Y is lower alkylene, -S- or -SO2-; Z is -S- or -O-; and the line: <u>-----</u> is a single bond or a double bond, or pharmaceutically acceptable salts thereof, which is useful as a medicament.

Description: NOVEL BENZOTHIOPHENE DERIVATIVES, THEIR PREPARATION AND USE AS UROKINASE INHIBITORS Tethnical Field : The present invention relates to novel compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to novel amidino derivatives and pharmaceutically acceptable salts thereof, which are useful as urokmase inhibitors, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, to a use of the same as a medicament and to a method of the therapeutic treatment of diseases in a human being or an animal. Accordingly, one object of the present invention is to provide novel amidino derivatives and pharmaceutically acceptable salts thereof, which are useful as urokmase inhibitors . Another object of the present invention is to provide processes for the preparation of novel amidino derivatives and salts thereof. A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said amidino derivatives and pharmaceutically acceptable salts thereof. Urokinase (urokinase-type Plasminogen Activator, uPA) is a multi-domain serine protease which is able to convert the inactive precursor plasminogen to active piasmine. Among the family of plasminogen activators, tissue type plasminogen activator (tPA) is present both in normal and in malignant tissue, whereas uPA has been shown to be produced abundantly by several common malignancies such as melanoma and colon, breast and prostate cancers. Cellular mvasiveness initiated oy urokmase causes many physiological processes such as angiogenesis, neovascularization, bone restructuring, embryo implantaion the uterus (embryonic development), infiltration of immune cells into inflammatory sites, ovulation, trophoblast implantation, breast, uterine, and prostatm involution, spermatogenesis, tissue remodeling during wound repair (wounα healing) and organ differentiation, fibrosis, local invasion of tumors into ad acent areas (tumor invasion), metastatic spread of tumor cells from primary to secondary sites (tumor metastasis), and tissue destruction in arthritis. Inhibitors of urokmase therefore have mechanism-based anti-ang ogenic, anti-arthritic, anti- flam atory, anti- mvasive, anti-metastatic, anti-osteoporotic, anti- retinopathic (for angiogenesis-dependent ret opathies) , contraceptive, and tumoristatic activities. Disclosure of Invention : The object amidino αerivatives are novel and can oe represented by the following general formula : in which R 1 is hydrogen, optionally substituted lower alkylcarbamoyl (lower) alkylidene, lower alkylidene, lower alkyl, optionally substituted ar (lower ) alkyl , cyclo (lower) alkyl (lower) alkyl, protected carboxy (lower) alkyl, carboxy (lower) alkyl, hydroxy ( lower ) alkyl , optionally substituted lower alkylcarbamoyl (lower) alkyl, lower alkylthio (lower) alkyl, carboxy (lower) alkanoyl, protected carboxy (lower ) alkanoyl, aroyl, lower alkanoyl, or optionally substituted arylcarba oyl (lower) alkyl, R is hydrogen, carboxy, protected carboxy, for yl or N- ( lower) alkyl-N- (lower) al oxycarbamoyl, R is hydrogen or amid o-protective group, A is lower alkylene or carbonyl, Y is lower alkylene, -S- or -SC^-, the line: ' -^^^ is a single bond or double bond, or pharmaceutically acceptable salts thereof. Suitable salts of tne object compound (I) are pharmaceutically acceptable, conventional non-toxic salts ana may include; a salt with a base such as an inorganic base salt, fcr example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic am e salt (e.g. triethylamme salt, pyπdme salt, picoline salt, ethanoiamme salt, triethanolamine salt, dicyclohexylamme salt, N, N' -dibenzylethylenedia me salt, etc.); a salt with an acid such as inorganic acid addition salt (e.g. hydrochloπde, hydrobro ide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.) ; a salt with a basic or acidic am o acid (e.g. argmme, aspartic acid, glutamic acid, etc.); and the like. The object compound (I) and pharmaceutically acceptable salt thereof may include a solvate [e.g. enclosure compound (e.g., hydrate, etc.)]. It is to be noted that the compoαnα (I) and the otner compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention. According to the present invention, the object compounα (I) or pharmaceutically acceptable salts tnereof can be prepared by the processes as illustrated by the following reaction schemes. Process I Conversion of ester moiety to amidme moiety (ID (ϊ-a) or a salt thereof or a salt thereof Process 2 Reduction 3 - (I-b) (I-c) or a salt thereof or a salt thereof Process 3 till) (I-a) or a salt thereof salt thereof Process 4 - (I-d) (I-e) or a salt thereof or a salt thereof Process 5 (I-f) (l-g) or a salt thereof or a salt thereof Process 6 (I-a) (I-h) or salt thereof or a salt thereof Process 7 (I-g) (I-i or its reactive derivative or a sale thereof at cne carboxy group, or a salt thereof Process 8 (I-h) (I-a) or a salt thereof or a salt thereof Process 9 (I-J) (i-k) or a sa. thereof or a salt thereof in which R * , R < R- A, X, Y, Z and the line: ^^ are each as defined above, R a is optionally substituted lower alkylcarbamoyl- (lower) alkylidene or lower alkylidene, R^ is optionally substituted lower alkylcarbamoyl- (lower) alkyl or lower alkyl, R x ~ i1sc rprotected carboxy (lower) alkyl or protected carboxy (lower) alkanoyl, 1 R Q is carboxy (lower) alkyl or carboxy ( lower) alkanoyl, p R g is protected carboxy, p R£ i s N- ( lower ) al kyl -N- ( lower ) a l koxycarbamoyl , R g is amidmo-protect ive group , R^ i s ester res idue , X a is —c,H or N— The object compounds thus obtained can be converted to its salt by a conventional method. The compound (II) used in the Process 1 may be new and can be prepared, for example, according to the following Preparations or by a conventional manner. In the descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows. The term "lower" is intended to mean 1 to 6 carbon atom(s), preferably 1 to 4 carbon atom(s), unless otherwise indicated. Suitable "lower alkoxy" may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-outoxy, pentyloxy, hexyloxy, and the like, and the most preferable example may be methoxy. Suitable "lower alkyl" may include straight or brancneα one such as methyl, ethyl, propyl, isopropyl, butyl, t-outyl, pentyl, hexyl, and the like, and the most preferable example may be ethyl and butyl for R 1 . Suitable "ester residue" means a group substituteα with the hydrogen atom m the "esterified carboxy" as mentioned below. Suitable "optionally substituted arylcarbamoyl ( lower ) alkyl" means aforementioned lower alkyl substituted by arylcarbamoyl group such as phenylcarbamoyi, tolylcarbamoyl, xylylcarba oyl , cumenylcarbamoyl, mesitylcarbamoyl, naphthylcarba oyl, and the like, and said arylcarbamoyl group is optionally substituted by the group consisting of lower alkyl as mentioned above, lower alkoxy as mentioned aoove, and lower alkylenedioxy as mentioned below, in which more preferable example may be phenylcarbamoyl (lower ) alkyl optionally substituted by lower alkylenedioxy, and the most preferable one may be 3,4- methylenedioxyphenylcarbamoylmethyl . Suitable "halogen" may include fluorine, bromine, chlorine ard iodine, m which more preferable example may be fluorine . Suitable "cyclo (lower) alkyl ( lower) alkyl" means aforementioned lower alkyl substituted by cyclo ( lower ) alkyl as mentioned below, in which the most preferable example may be cyclohexylmethyl . Suitable "optionally substituted ar ( lower ) alkyl " means aforementioned lower alkyl substituted by aryl as mentioned below, in which said aryl group is optionally substituted by the group consisting of lower alkyl as mentioned above, lower alkoxy as mentioned above, and lower alkylenedioxy as mentioned below, wherein more preferable example may be Cg-C-] Q ar (lower) alkyl optionally substituted by one or two suitable suostituents selected from the group consisting of lower alkoxy and lower alkylenedioxy, and the most preferable one may be benzyl, phenethyl, 3, 4-dιmethoxyphenethyl and 3, -methylenedιoxyphenethyl . Suitable "lower alkylenedioxy" may include straight or branched one such as methylenedioxy, ethyienedioxy, trimethylenedioxy, tetramethylenedioxy, penramethyienedioxy, nexamethylenedioxy, methylmethylenedioxy, ethylethylenedioxy, propylenedioxy, and the like, in which the most preferable one may be methylenedioxy. Suitable "cyclo ( lower ) alkyl" may include cyclo (C 3 -Cg) - alkyl such as cyclopropyi, cyclobutyl, cyclopentyl, cyclohexyl, and the like, in which the most preferable example may be cyclohexyl . Preferable "aryl" may include C Q -C -^ Q aryl such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, etc., in which the most preferable one may be phenyl. Suitable "lower alkylidene" may include straight or branched one such as methylene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene, methyl ethylidene, ethylethylidene, propylidene, and the like, in which the most preferred one may be butylidene for R 1 . Suitable "optionally substituted lower alkylcarbamoyl (lower ) alkylidene" means aforementioned lower alkylidene substituted by optionally substituted lower alkylcarbamoyl as mentioned below, wherein the most preferable example may be n-butylcarbamoylmethylidene . Suitable "optionally substituted lower alkylcarbamoyl- ( lower) alkyl" means aforementioned lower alkyl substituted by "optionally substituted lower alkylcarbamoyl" as mentioned below, wherein the most preferable example may be n- butylcarbamoylmethyl and 2, 2, 2-trιfluoroethylcarbamoylmethyl . Suitable "optionally substituted lower alkylcarbamoyl" may include carbamoyl substituted by aforementioned lower alkyl, in which the lower alkyl group is optionally substituted by halogen as mentioned above, the most preferable one may be n-butylcarbamoyl and 2,2, 2-trιfluoroethy1carbamoyl . Suitable "hydroxy (lower) alkyl" may include straignt or branched one such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, ana the like, in which the most preferable one may be 2-hydroxyethyl . Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methyl ethylene, ethylethylene, propylene, and the like, m which the most preferable one may be methylene for A and Y, and ethylene for Y. Suitable "protected carboxy" may include esterified carboxy as mentioned below. "Esterified carboxy" can be referred to the ones as mentioned below. Suitable examples of the ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent (s) for example, lower alkanoyloxy (lower) alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l-(or 2-) acetoxyethyl ester, I- (or 2- or 3- ) acetoxypropyl ester, l-(or 2- or 3- or 4-) acetoxybutyl ester, 1- (or 2-)- propionyloxyethyl ester, l-(or 2- or 3-) propionyloxypropyl ester, l-(or 2-) butyryloxyethyl ester, l-(or 2-)- sobutyryloxyethyl ester, 1- (or 2-) pivaloyloxyethyl ester, l-(or 2-) hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3, 3-dimethylbutyryloxymethyl ester, 1- (or 2- ) pentanoyloxyethyl ester, etc.], aroyl ( lower ) alkyl ester such as benzoyl (lower ) alkyl ester (e.g. phenacyl ester, etc.), lower alkanesulfonyl (lower ) alkyl ester (e.g. 2-mesylethyl ester, etc.), mono(or di or tri) halo (lower) alkyl ester (e.g. 2-ιodoethyl ester, 2, 2, 2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy ( lower ) alkyl ester [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxy- methyl ester, l-(or 2-) methoxycarbonyloxyethyl ester, l-(or 2-) ethoxycarbonyloxyethyl ester, l-(or 2-)- lsopropoxycarbonyloxyethyl ester, etc.], phthalidylidene- (lower) alkyl ester, or (5-lower alkyl-2-oxo-l , 3-dioxoI-4- yl) (lower)alkyl ester [e.g. ( 5-methyl-2-oxo-l, 3-dιoxol-4- yDmethyl ester, ( 5-ethyl-2-oxo-l, 3-dioxol-4-yl) methyl ester, (5-ρropyl-2-oxo-l, 3-dioxol-4-yl) ethyl ester, etc.]; lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); ar (lower ) alkyl ester which may have at least one suitable substituent (s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nιtrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-t-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent (s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like. Preferable examples of the protected carboxy thus defined may be lower alkoxycarbonyl . Suitable "carboxy (lower) alkyl" means aforementioned lower alkyl which is substituted by carboxy, wherein the preferable examples may be carboxymethyl . Suitable "protected carboxy (lower) alkyl" means aforementioned lower alkyl which is substituted by above- mentioned "protected carboxy", wherein more preferable example may be lower alkoxycarbonyl (lowe ) alkyl, phenyl (lower) alkoxycarbonyl (lower) alkyl and benzoyl ( lower ) alkoxycarbonyl (lower ) alkyl, and the most preferable one may oe ethoxycarbonylmethy_ and ethoxycarbonylpropyl . Suitable "N- ( lower) alkyl-N- (lower) alkoxycarbamoyl" means carbamoyl group N-substituted by lower alkyl as mentioned above and also N-substituted by lower alkoxy as mentioned above, in which more preferable example may be N-fC^-C^)- alkyl-N- (d -C Δ ) alkoxycarbamoyl, and the most preferable one may be N-methyl-N-methoxycarbamoyl . Suitable "amidmo-protective group may include acyl. Suitable "acyl" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl. Suitable example of said acyl may be illustrated as follows : Carbamoyl; Thiocarbamoyl ; Sulfamoyl; Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2 , 2-dιmethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanovl, octadecanoyl, nonadecanoyl, icosanoyl, etc.) lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); mono (or di or tri ) halo ( lower) alkylsulfonyl [e.g. fluoromethylsulfonyl, dichloromethylsulfonyl, t ifluoromethylsulfonyl, chloromethylsulfonyl , dichloromethylsulfonyl, trichloromethylsulfonyl, 1 or 2- fluoroethvlsulfonyl, 1 or 2-chloroethylsulfonyl, etc.); or the like; -Aromatic acyl such as aroyl (e.g., benzyl, toluoyl, naphthoyl, etc.); ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl ( lower ) alkanoyl (e.g., naphthylacetyl, na hthylpropanoyl, naphthylbutanoyl , etc.), etc.]; ar (lower) alkenoyl [e.g., phenyl (lower ) alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl (lower ) alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]; ar ( lowe ) alkoxycarbonyl [e.g., phenyl (lower ) alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc. ) ; aryloxy (lower) alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.); arylglyoxyioyl (e.g., phenylglyoxyloyl, naphthylglyoxylσyl, etc . ) ; arylsulfonyl (e.g., phenylsulfonyl , p-tolylsulfonyl, etc.); or the like; Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic (lower) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic (lower) alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like. in which suitable "heterocyclic moiety" in the terms "heterocycliccarbonyl", "heterocyclic (lower) alkyl", heterocyclic (lower) alkenoyl" and "heterocyclicglyoxyloyl" as mentioned above means, in more detail, saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And, especially preferable heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 or 6- me bered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrol yl, lmidazolyl, pyrazolyl, pyπdyl, dihydropyridyl, pyrimidmyl, pyrazmyl, pyridaz yl, triazolyl (e.g., 4H-1 , 2, 4-trιazolyl , 1H-1,2,3- triazolyl, 2H-1, 2, 3-trιazolyl, etc.), tetrazolyl (e.g., 1H- tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidmyl, lmidazolidmyl, piperidyl, piperazmyl, etc.; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, mdolyl, isomdolyl, mdol yl, dolizmyl, benzimidazolyl, qu olyl, isoquinolyl, dazolyl, benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) ana 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 , 2, 4-oxadιazolyl , 1,3,4- oxadiazolyl, 1, 2 , 5-oxadiazolyl , etc.), etc. ; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) ana 1 to 3 nitrogen atom(s), for example, oxazcliαmyl, morpholinyl, sydnonyi, etc.; unsaturated condensed heterocyclic group containing I to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) ana I to 3 nitrogen atom(s), for example, triazolyl, isothiazolyl, thiadiazolyl (e.g., 1 , 2 , 3-thiadιazolyl, 1,2,4- thiadiazolyl, 1, 3, 4-thιadiazolyl, 1 , 2, 5-thιadιazolyl , etc.), dihydrothiazinyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyi, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) for example, thienyl, dihydrodithiinyl, dihydrcdith onyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dinydrooxathi yl , etc . ; unsaturated condensed heterocyclic group containing 1 tc 2 sulfur atom(s), for example, benzothienyl, benzodithimyl, etc. ; unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathimyl, etc.; and the like. The acyl moiety as stated above may have one to ten, same or different, suitaole substituen (s) sucn as lower alkyl as exemplified above; lower alkoxy as exemplified above; lower alkylthio wherein lower alkyl moieties as exemplified above; lower alkylammo wherein lower alkyl moiety s as exemplified above; cyclo (lower) lkyl as exemplified above; cyclo (lower) alkenyl as exemplified above; halogen; amino, protected ammo as exemplified above; hydroxy; protected hydroxy; cyano; nitro; carooxy; protected carboxy; sulfo; sulfamoyl; imino; oxo; amino (lower) alkyl wherein lower alkyl moiety is as exemplified above; carbamoyloxv; hydroxy (lower) alkyl wherein lower alkyl moiety is as exemplified above; diammo (lower) alkylidene (e.g., diammomethyiene, etc.); di ( lower ) alkylammo wherein lower alkyl moiety is as exemplified above; di ( lower) alkylammo ( lower) alκyl wherein lower alkyl moiety is as exemplified above; heterocyclic (lower) alkyl wherein heterocyclic moiety and lower alkyl moiety are each as exemplified above, or the like . Preferable example of amid o-protective group thus defined may be lower alkoxycarbonyl, and tne most preferable one may be t-butoxycarbonyl . Suitable "lower alkanoyl" may include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl, and the like, m which more preferable example may be C^-C^ alkanoyl and the most preferable one may be acetyl . Suitable "carboxy (lower) alkanoyl" means lower alkanoyl 5 as mentioned above substituted by carboxy, in which more preferable example may be carboxy {C j _ -C Δ _ ) alkanoyl and the mosi preferable one may be carboxyacetyl . Suitable "protected carboxy ( lower) alkanoyl" means lower 10 alkanoyl as mentioned above substituted by protected carboxy as mentioned above, in which more preferable example may be ) alkanoyl and the most preferable one may be ethoxycarbonylacetyl . i Suitable "aroyl" may include Cg-Cm aroyl such as benzoyl, toluovl, naphthoyl, and the like, in which the mos" preferable one mav be benzovl. One preferable embodiments of R ~ , R , R , A, X, Y, Z anc 0 the line: ' -^^ are as follows : R 1 is hydrogen, lower alkylcarbamoyl (lower ) alkylidene optionally substituted by halogen, lower alkylidene, lower alkyl, ar (lower) alkyl optionally substituted by 5 the group consisting of lower alkyl, lower alkoxy and lower alkylenedioxy, cyclo (lower ) alkyl (lower ) alkyl, lower alkoxycarbonyl (lower) alkyl, carooxy (lower ) alkyl, hydroxy (lower ) alkyl, lower alkylcarbamoyl (lower ) alkyl optionally substituted by halogen, or 0 arylcarbamoyl (lower) alkyl optionally substituted by the group consisting of lower alkyl, lower alkoxy and lower alkylenedioxy, R- is nydrogen, R is hydrogen, 5 A is lower alkylene or carbonyl, X i s — C — — CH — or — N — i Y is lower alkylene, -S- or -Sθ2~, Z is -S- or -0-, and the line: ^^ is single bond or double bond. The processes for the preparation of the object compound (I) of the present invention are explained m detail m the following. (1) Process 1 : The compound (I-a) or a salt thereof can be prepared oy converting the ester moiety of the compound (II) or a salt thereof to the amidino moiety. Suitable salts of the compounds (I-a) and (II) may be the same as those for the compound (I) . This reaction can be carried out by a conventional method which can convert the ester moiety to the amidine moiety such as reacting with a combination of ammonium halide (e.g. ammonium chloride, etc.) and tri ( lower) alkylalm um (e.g. tπmethylalmmum, etc.). This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridme, N,N-dιmethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, toluene, etc., or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under from warming to heating. (2) Process 2 : The compound (I-c) or a salt thereof can be prepared by reducing the compound (I-b) or a salt thereof. Suitable salts of the compounds (I-b) and (I-c) may be the same as those for the compound (I). The reduction method applicable for this removal reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric aciα, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), a a the like. This reaction is usually carried out m a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanoyl, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof.. The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming. (3) Process 3 : The compound (I-a) or a salt thereof can be prepared by reacting the compound (III) or a salt thereof with ammonia or a salt thereof. Suitable salts of the compound (III) may be the same as those for the compound (I) . Suitable salts of ammonia may include acid addition salts as mentioned for the compound (I). The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction sucn as water, acetone, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, pyridme, N, -dimethylformamide, etc., or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating. (4) Process 4 : The compound (I-e) or a salt thereof can be prepared oy subjecting the compound (I-d) or a salt thereof to a removal reaction of the carboxy-protective group in R .. Suitable salts of the compounds (I-d) and (I-e) may be the same as those for the compound (I) . The present reaction is usually carried out by a conventional method such as hydrolysis, reduction, and the like. (l) Hydrolysis : The hydrolysis is preferably carried out m the presence of a base or an acid. Preferable base may include an alkalimetal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hyαride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium ethoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), and alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), and tne like. Preferable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, tπfluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). The acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g. pnenol, anisole, etc.). This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture tnereof. A liquid base or acid can be also used as the solvent . The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating . (n) Reduction : The reduction method applicable for this removal reaction may include, for example, reduction by using a combination of a metal (e.g. z c, zmc amalgam, etc.) or a slat of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); conventional catalytic reduction m the presence of a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloiαal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxiαe, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.); sodium boro hydride; lithium aluminum hydride; and the like. In case that the catalytic reduction is applied, tne reaction is preferably carried out around neutral condition. This reaction is usuallv carried out a conventional solvent which does not adversely influence the reaction sucn as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), ana the like, or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming . (5) Process 5 : The compound (I-g) or a salt thereor can be prepared by subjecting the compound (I-f) or a salt thereof to a removal reaction of the carboxy-protective group m R^. Suitable salts of the compounds (I-f) and (I-g) may oe the same as those for the compound (I) . The present reaction is usually carried out m substantially the same manner as that of Process 4, therefore, the reaction conditions (e.g. temperature, solvents, etc.) can be referred to the explanation of Process 4. ( 6) Process 6 : The compound (I-h) or a salt tnereof can be prepared by introducing an amidmo-protective group into the compcunα (I-a) or a salt thereof. Suitable salts of the compound (I-hi may be the same as those for the compound (I) . Suitable introducing agent of the amidmo-protective group used this reaction may be a conventional agent which is capable of introducing the amidmo-protective group as mentioned before such as carboxylic acid, carbonic acid, sulfonic acid and their reactive derivative, for example, an acid halide, an acid anhydride, an activated amide, ar. activated ester, and the like. Preferable example of such reactive αerivative may include acid chloride, acid bromide, a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphospho ic acid, phenylpnosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylpnosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g. methyl carbonate, ethyl carbonate, propyl carbonate, etc.), aliphatic carboxylm aciα (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyrιc acid, trichloroacetic acid, etc.), aromatic carooxylic acid (e.g., benzoic acid, etc.), a symmetrical acid anhydride, an activated acid amide with a heterocyclic compound containing imino function such as imidazole, 4-sαbstιtuted imidazole, di ethylpyrazole , triazole ana tetrazole, an activated ester (e.g. p-mtrophenyl ester, 2, 4-dmιtrophenyl ester, tnchlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, pnenyl thioester, p-mtrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyridyl ester, piperidinyl ester, 8-quιnolyl thioester, or an ester with a N-hydroxy compound such as N, N-dimethylhydroxylamine, l-hydroxy-2- ( 1H) -pyπdone, N-hydroxysuccmimide, N-hyαroxypbthalimide, 1-hydroxybenzotrιazole, l-hydroxy-6- cMorooenzotriazoie, etc.;, and the like. This reaction can be carried out m the presence of an organic or inorganic base such as alkali metal (e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hyαride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. soαium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alka_ι metal alkoxide (e.g. sodium methoxide, sodium 2 d ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamme (e.g. triethylamme, etc.), pyridme compound (e.g. pyπdme, lutidme, picolme, 4-dιmethylammopyrιdme, etc.), qu olme, and the like. In case that the introducing agent is used in a free form or its salt in this reaction, the reaction is preferably carried out m the presence of a condensing agent such as a carbodiimide compound [e.g. N, N' -dicyclohexylcarbodnmiαe, N-cyclohexyl-N' - ( 4-dιethylammocyclohexyl ) carboonmide, N, N' -diethylcarbodiimide, N, N' -diisopropylcarbodiimide, N-ethyl-N' - ( 3-dιmethylammopropyl ) carbodiimide, etc . ] , a ketenimme compound (e.g. N, N' -carbonylbis (2-methyl- imidazole) , pentamethyleneketene-N-cyclohexylimme, diphenylketene-N-cyclohexylimme, etc. ) ; an olefmic or acetylenic ether compounds (e.g. ethoxyacetylene, β-chlorovinylethyl ether) , a sulfonic acid ester of N-hydroxybenzotriazole derivative [e.g. l-(4- chlorobenzenesulfonvloxy) -6-chloro-lH-benzotrιazole, etc.], a combination of trialkylphosphite or triphenylphosphme ana carbon tetrachloride, disulfide or diazenedicarboxylate (e.g. diethyl diazenedicarboxylate, etc.), a phosphorus compound (e.g. ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, etc.), thionyl chloride, oxalyl chloride, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylιsoxazolιum-3-sulfonate, a reagent (referred to a so-called "Vilsmeier reagent") formed by the reaction of an amide compound such as N, -di ( lower ) alkyl for amide (e.g. di ethylformamide, etc.), N-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, pnosgene or the like. The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, pyridme, N,N- dimethylformamide, etc., or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating. (7) Process 7 : The compound (I-i) or a salt tnereof can be prepared by reacting tne compound (I-g) or its reactive αeπvative at tne carboxy group, with N- (lower) alkyl-N- (lower) alkoxya ine or a salt thereof. Suitable salts of the compound (I-i) may be the same as those for the compound (I) . Suitable salts of N- (lower ) alkyl-N- (lower ) alkoxyamine may be the same acid addition salts as mentioned for the compound (I) . Suitable reactive derivative at the carboxy group of the compound (I-g) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an aciα chloride; an acid azide; a mixed acid anhydride with acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, αioenzylphosohonc acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, tniosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyrιc acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amiαe witr l idazole, 4-substιtuted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g. cyanomethyl ester, metnoxymethyl ester, dimethyliminiometnyl + [ (CH3) 2 N=CH-] ester, vinyl ester, propargyl ester, p-mtrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-mtrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N, N-dimethylhydroxylamine, I-hydroxy-2- ( 1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-lH- benzotπazole, etc.], and the like. These reactive derivatives can optionally be selecteα from them according to the kind of the compound (I-g) to be used. The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water . In this reaction, when the compound (II) is used m a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N ' -dicyclohexylcarbodiimide; N-cyclohexyl-N ' -morpholmoethylcarbodiimide; N-cyclohexyl-N'- ( 4-diethylaminocyclohexyl ) carbo iimide; N, N ' -diethylcarbodiimide, N, N ' -diisopropylcarbodiimide ; N-ethyl-N'- ( 3-dιmethylaminopropyl ) carbodiimide; N, N ' -carbonylbis (2-methylimιdazole) ; pentamethyleneketene-N-cyclohexylimine ; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; O-benzotrιazol-1-yl-N, N, ' , N ' -tetramethylure ium hexafluorophosphate; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride) ; phosphorus trichloride; diphenyl phosphorylazxde; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chlorofor ate, isopropyl chloroformate, etc.j; triphenylphosphme; 2-ethyl-7-hydroxybenzιsoxazolιum salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide intramolecular salt; N-hydroxybenzotriazole; I- (p-chlorobenzenesulfonyloxy) -6-chloro-lH-benzotrιazole; so-calleα Vilsmeier reagent prepared by tne reaction of N, -dimethylformamide with tnionyl chloride, pnosgene, trichloromethyi ch±orofor ate, phosphorus oxychloride, etc.; or the like. The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri ( lower ) alkylamme (e.g. triethylamme, etc.), pyridme, N- (lower) aikylmorpholme, N, N-di (lower ) alkylbenzyl- amme, or the like. The reaction temperature is not critical and the reaction is usually carrieα out under cooling to warming. (8) Process 8 : The compound (I-a) or a salt thereof can be prepared by subjecting the compound (I-h) or a salt thereof to a removal reaction of the amidmo-protective αroup of R^ . The present reaction is usually carried out m substantially the same manner as that of Process 4, therefore, the reaction conditions (e.g. temperature, solvents, etc.) can be referred to the explanation of Process 4. (9) Process 9 : The compound (I-k) or a salt thereof can be prepared by reducing the compound (I- ) or a salt thereof. Suitable salts of the compounds (I-j) and ( I-k) may oe the same as those for the compound (I) . The present reaction is usually carried out in substantially the same reduction reaction as that of Process 4, therefore, the reaction conditions (e.g. temperature, solvents, etc.) can be referred to the explanation of Process 4. [Urokinase Inhibiting Effect] Now in order to show the utility of the object compound (I) and pharmaceutically acceptable salts, the test datum on urokinase inhibiting effect of the representative compound of the compound (I) of this invention is shown in the following. Test Compound : Compound A [The product of Example 2-1 Test Method : Test Compound was incubated at desired concentrations with 25 International Units (IU)/ml human high molecular weight urokinase (Fujisawa Pharmaceutical Co., Ltd.) and urokinase substrate (S-2288, H-D-Isoleucyl-L-prolyl-L- arginine-p-nitroaniline dihvdrochloride; Chromagenix, Sweden; Japan distributors Daiichikagakuyakuhin Co., Ltd.) in a 100 μl final volume of 50 mM Tris, 100 mM NaCl, 1 mM NapΞDTA, 0.01 r c (v/v) polyoxyethylenesorbitan monooleate (Tween 80), pH 7.5 (Buffer Z) . Incubations were carried out at 37°C for 30 minutes. Color was σuantitated by measuring absorbance at 405 nm using EL312 Automated Microplate Reader. Test Result : For therapeutic administration, the object compound (I and the pharmaceutically acceptable salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, m admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration. The pharmaceutical preparations may be m solid form such as tablet, granule, powder, capsule, cr liquid form such as solution, suspension, syrup, emulsion, lemonade, and the like. 0 If needed, there may be included m the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, steaπc acid, magnesium stearate, terra aloa, 5 sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like. While the dosage of the compound (I) may vary from and 0 also depend upon the age, condition of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general, amount between about 0.001 g and about 300 mg, preferably about 0.1 mg to about 50 mg per day may be administered to a patient. -An average single dose of about 5 0.001 mg, 0.01 mg, 0.03 mg, 0.1 mg, 0.3 mg, C.β mg, 1.0 mg, 3.0 mg, 10.0 mg, 50.0 mg, 100.0 mg of tne object compound ( I , of the present invention may be used. The following Preparations and Examples are given for C tne purpose of illustrating this invention more detail. P eparation 1-1 ) Diethyl ethoxycarbonyimethylphosphonate (8.47 ml) was dropwise added to a mixture of sodium hydride ( 60^ , 1.71 g) and tetrahydrofuran (THF) (50 ml) at room temperature (r.t.) under nitrogen atmosphere, and the mixture was stirred under the same condition for 30 minutes. To the reaction mixture was added 4-oxo-4, 5, 6, 7-tetrahydrobenzo [b] thiophene (5.00 g) in a portion, and the whole mixture was stirred at r.t. for 3 hours. The reaction mixture was poured into a mixture of water and ethyl acetate (AcOEt) . The separated organic layer was washed with water and brine, and dried over magnesium sulfate (MgS0 4 ), and dried m vacuo to precipitate. The resulting precipitate was washed with isopropyl ether (iPE) to give 4-ethoxycarbonylmethylιdene-4 , 5, 6, 7- tetranydrobenzo [b] thiophene (5.91 g) . IR (Nujol) : 1700, 1605 cm "1 MASS (z/e) : 223 (M-rH) + NMR (DMS0-d 6 , δ) : 1.31 (3H, t, J=7.1Hz), 2.01 (2H, m) , 2.89 (2H, t, J=7.1Hz), 3.15 (2H, m) , 4.19 (2H, t, J=7.1Hz), 5.67 and 6.11 (1H, each s) , 7.06 (1H, d, J=5.4Hz), 7.20 (1H, d, J=5.4Hz) Preparation 1-2) The following compound was obtained according to a similar manner to that of Preparation 3-3). 4-Carooxymethylιdene-4, 5, 6, 7-tetrahycrobenzo [b] tniophene NMR (DMS0-d 6 , δ) : 1.84 (2H, tt, J=5.7, 6.1Hz), 2.85 (2H, t, J=6.1Hz), 3.03 (2H, t, J=5.7Hz), 6.14 (1H, s), 7.33 (1H, d, J=S.4Hz), 7.39 (1H, d, J=5.4Hz), 11.99 (1H, br s) Preparation j-3) To a mixture of 4-carboxymethylιdene-4, 5, 6, 7- tetrahydrobenzo [b] thiophene (0.50 g) , n-butylamme (0.28 ml), 1-hydroxybenzotrιazole (0.43 g) and dimethyl formamide (DMF) (5 ml) was added 1- ( 3-dιmethylammopropyl ) -3- ethylcarbodnmide hydrochloride (0.54 g) . The reaction mixture was stirred at r.t. for 5 hours and poured into a mixture of AcOEt and a saturated aqueous solution of sodium hydrogen carbonate (NaHC03) . The separated organic layer was washed with water and brine, and dried over MgSO^, and evaporated to give 4- (N-butylcarbamoyl ) methylιdene-4, 5, 6, 7- tetrahydrobenzo [b] thiophene (0.60 g) . MASS (z/e) : 250 (M+H) + NMR (DMSO-d 6 , δ) : 0.88 (3H, t, J=7.2Hz), 1.2-1.4 (4R, m) , 1.7-1.9 (2H, m) , 2.82 (2H, d, J=6.0Hz), 3.0-3.2 (4H, m) , 6.21 (1H, s), 7.18 (1H, d, J=5.4Hz), 7.33 (1H, d, J=5.4Hz), 7.84 (1H, br s) Preparation 1-4) To a mixture of 4- (N-butylcarbamoyl ) methylιdene-4, 5, 6, " "- tetrahydrobenzo [b] thiophene (0.49 g) and TKF (8 l) was dropwise added 1.64 M n-butyl lithium (π-BαLi) in n-hexane (2.88 ml) at -70 - -60°C under nitrogen atmosphere and the mixture was stirred under the same condition for 2.5 hours. The reaction mixture was poured into a mixture of dry ice and diethyl ether (Et2θ) . To the mixture were added EtpO and water. The separated aqueous layer was washed with EtpO, and acidified oy 6 N hydrochloric acid (HCl) and was extracted with AcOEt. The organic layer was washed with water ano brme, and dried over MgSO^, and evaporated in vacuo to give 4- (N-butylcarbamoyl) etnylidene-4, 5,6, 7-tetrahydrobenzo [b] - thιophene-2-carboxylιc acid (0.38 g) . This product was used in the following reaction without isolation . Preparation 1-5) A mixture of 4- (N-butylcarbamoyl) methylιdene-4 , 5, 6, 7- tetrahydrobenzo [b] thιophene-2-carboxylιc acid (0.57 g) , cone, sulfuric acid (H 2 S0 4 ) (3 ml), and methanol (MeOH) (15 ml) was stirred at reflux for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt and water. The organic layer was washed with saturated aqueous solution of aHCθ3, water and brine, and dried over MgSO^, and evaporated m vacuo. After evaporation, the resulting oil was purified by cnromatography on silica gel (AcOEt-n-hexane as an eluent) . The fractions including the object compound v/ere collected and evaporated to give 4- (N-butylcarbamoyl ) methylιdene-2- metnoxycarbonyl-4, 5,6, 7-tetrahydrobenzo [b] thiophene (115.3 mg) . NMR (DMSO-d 6 , δ) : 0.89 (3H, t, J=6.9Hz), 1.2-1.6 (4H, m) , 1.7-2.0 (2H, m) , 2.78 (2H, t, J=6.0Hz), 3.0-3.2 (4H, m) , 3.82 (3H, s), 6.39 (IK, s), 7.78 (1H, t, J=5.5Hz) , 7.89 (1H, s) Preparation 2-1) The following compound was obtained according to a similar manner to that of Preparation 4-1) . 4-n-Butylιdene-4, 5, 6, 7-tetrahydrobenzo [b] thiophene MASS (z/e) : 193 (M+H) x NMR (CDC1 3 , δ) : C.9-1.0 (3H, m) , 1.3-1.6 (2H, m) , 1.7-2.9 (8H, m) , 5.5 and 5.8 1F, t, J=7.4Hz), 6.9-7.2 (2H, m) Preparation 2-2) The following compound was obtained according to a similar manner to that of Preparation 1-4) . 4-n-Butylιdene-2-carboxy-4, 5, 6, 7-tetranydrobenzo [b] - thiophene MASS (z/e) : 237 (M^H) + NMR (CDCI3, δ) : 0.85 (3H, t, J=6.5Hz), 0.9-2.0 (8H, m) , 2.6-3.0 (2H, m) , 4.83 (1H, s), 7.61 (1H, s), 12.83 (1H, br s) Pre ara ion 2-3 ) The following compound was obtained according to a similar manner to that of Preparation 4-3) . 4-n-Butylιdene-2-methoxycarbonyl-4, 5, 6, 7- tetrahydrobenzo [b] thiophene IR (Neat) : 2954, 2866, 1713, 1543 cm -1 NMR (DMSO-d 6 , δ) : 0.8-1.0 (3H, ) , 1.2-3.0 (10H, m) , 3.80 (3K, s), 5.62 and 5.97 (1H, each t, J=7.2Kz), 7.64 and 7.93 (1H, each s) Preparation 3-1) The following compound was obtained according to a similar manner to that of Preparation 1-1). Ethyl 5- (2-thιenyl) -2, 4-pentadιenoate NMR (CDC1 3 , δ) : 1.30 (3H, t, J=7.1Hz), 4.23 (2H, q, J=7.1Hz), 5.94 (1H, d, J=15.2Hz), 6.66 (1H, dd, J=15.2, 11.1Hz), 7.0-7.6 (5H, m) Preparation 3-2) A mixture of ethyl 5- (2-thιenyl ) -2, 4-pentdιenoate (20.20 g) , 1CT palladium hydroxide (Pd(OH) 2 ) (2.04 g) , THF (200 ml), MeOH (100 ml) and 1 N HCl (10 ml) was stirred at r.t. under nitrogen atmosphere for 3.5 hours. After removal of insoluble solids, the filtrate was evaporated m vacuo, and the residue was dissolved with a mixture of AcOEt and water. The organic layer was washed with saturated aqueous solution of aHCθ3, water and brme, and dried over MgSO^ , and evaporated in vacuo to give ethyl 5- (2-thιenyl) pentanoate (15.70 g) . MASS (z/e) : 211 (M-H) NMR (DMSO-d 6 , δ) : 1.25 (3H, ) , 1.4-3.0 (8H, m) , 4.2 (2H, m) , 6.8-7.2 (3H, m) Preparation 3-3) A mixture of ethyl 5- (2-thιenyl) pentanoate (15.40 g) , sodium hydroxide (NaOH) (2.90 g) , water (H 2 0) (18 ml), and tetrahydrofuran (THF) (100 ml) was stirred at reflux for 2.5 hours. The reaction mixture was poured into a mixture of water and diethvl ether (Et 0) . The aσueous laver was separated, and acidified with 6 N hydrochloric acid (HCl), and extracted with ethyl acetate (AcOEt) . The organic layer was washed with water and brme, and dried over magnesium sulfate (MgSO /j ), and evaporated to give 5- (2-thιenyl ) - pentanoic acid (12.07 g) as an oil. NMR (CDC1 3 , δ) : 1.6-3.0 (8H, m) , 6.9-7.2 (3H, m) Preparation 3-4) To a mixture of 5- (2-thιenyl) pentanoic acid (5.04 g) and toluene (50 ml) was dropwise added trifluoroacetic anhydride (6.95 ml) over 1 minute with ice-water cooling. The reaction mixture was stirred at room temperature (r.t.) overnight, and was poured into a mixture of a saturated aqueous solution of sodium hydrogen carbonate (NaHC0 3 ) and AcOEt. The organic layer was washed with water and brme, and dried over MgSO^, and evaporated. The resulting oil was purified by chromatography on silica gel (SiOp) (20 ' AcOEt m n-hexane as eluent) . The fractions including the object compound were combined and evaporated to give 4-oxo-5, 6, 7 , 8-tetrahydro-4H- cyclohepta[b] thiophene (1.57 g) as an oil. MASS (z/e) : 167 (M+H) " NMR (CDCI3, δ) : 1.90 (2H, m) , 2.70 (2H, m) , 3.10 (2H, m) , 6.98 (1H, d, J=5.3Hz), 7.41 (1H, d, J=5.3Hz) Preparation 3-5) A mixture of sodium hydride (NaH) (60 m Nu ol, 0.69 g) and dimethyl sulfoxide (DMSO) (9 ml) was stirred at 70°C for 2 hours. After cooling to r.t., THF (6 ml) and n-butyl- tπphenylphosphonium bromide (7.26 g) were added thereto. The reaction mixture was stirred at r.t. for 1 hour, and then 4- OXO -5, 6, 7, 8-tetrahydro-4H-cyclohepta[b] thiophene (1.44 g) was added. The mixture was stirred at r.t. overnight and poured into a mixture of a saturated aqueous solution of ammonium chloride (NH4CD and AcOEt. The separated organic layer was washed with water and brme, and dried over MgSO^, and evaporated. The resulting o_l was purified by chromatography on Sι0 (l c AcOEt in n-hexane as eluent) . The fractions containing the object compound were combined and evaporated to give 4-n-butylιdene-5, 6, 7, 8-tetrahydro-4K- cyclohepta [b] thiophene (1.15 g) as an oil. MASS (z/e) : 251 (M-rH) 4" NMR (CHCI3, δ) : 0.7-3.0 (15H, m) , 5.44 and 5.59 (1H, each t, J=7.4Hz each), 6.8-7.0 (2K, πυ Preparation 3-6) The following compound was obtained according to a similar manner to that of Preparation 4-2) . 4-n-Butylιdene-5, 6, 7, 8-tetrahydro-4H-cycloheρta [b] - thιophene-2-carboxylιc acid MASS (z/e) : 251 (M+H) " " " NMR (DMS0-d β , δ) : 0.8-3.0 (15H, m) , 5.51 and 5.62 (1H, each t, J=7.3 and 7.4Hz), 7.59 and 7.68 (1H, each s) Preparation 3-7) N-Methylmorpholine (0.69 ml) was added to a mixture of 4-n-butylιdene-5, 6, 7, 8-tetrahydro-4H-cyclonepta [b] thiophene- 2-carboxylιc acid (1.05 g) and THF (10 ml) at -15 - -20°C under nitrogen atmosphere, and isobutyl chloroformate (0.82 ml) was added thereto over 2 minutes. The mixture was stirred under the same condition for 30 minutes, and cone, ammonia (C.NH3) was added thereto. The mixture was stirred at r.t. for 2 hours. The reaction mixture was poured into a mixture of water and AcOEt to precipitate. The precipitate was collected by filtration, washed with water and Et 2 0, and dried m vacuo to σive ^-n-butylιdene-5, 6, 7, 8-tetrahyαro-4F- cyclohepta [b] thιophene-2-carboxamιde (0.59 g; . NMR (CDC1 3 , δ) : 0.8-3.0 (15H, m) , 5.48 and 5.59 (IH, each t, J=7.3 and 7.3Hz), 5.77 (2H, br s), 7.2^ a_~d 7.35 (IH, each s) Preparation 3-8) Phosphorus oxycnloride (0.30 ml) was added to a mixture of 4-n-butylιdene-5, 6, 7, 8-tetranydro-4H-cvcloneota [b] - tnιophene-2-carboxamιde (0.55 gj and dimetnylformamiαe (6 ml) with ice-water cooling under nitrogen atmosphere, arc the mixture was stirred under the same condition for _ hour. The reaction mixture was poured into an ice-cooleα mixture of an aqueous solution of NaHC0 3 and AcOEt to precipitate. Tne precipitate was collected by filtration, washed with water, and dried m vacuo to give 4-n-butylιdene-5, 6, " ', 8-tetrahydro- 2-cyano-4H-cyclohepta [b] thiophene (0.42 q t l whicn was immediately used in the next reaction. IR (KBr) : 2929, 2863, 2213, 1710, 1679, 1616 cm-- Preparation 3-9) The following compound was cotamed according to a similar manner to that of Preparation 5-2 . 4-n-Bαtylιdene-2- ( 1-ethoxy-I-ιmmometnyl ) -5, 6, 7, 8- tetrahydro-4K-cyclohepta [b] thiophene, whicn was used in the following reaction without isolation. Preparation 4-1) To a mixture of 4-oxo-4 , 5, 6, " ^-tetrahydrobenzo [b] furan '20.06 gj and THF (200 ml) was added droowise 2M n-butylmagnesium bromide with ice-water cool g over 15 minutes. Tne mixture was stirred at r.t. overnight. The reaction mixture was poured into a mixture of a saturated aqueous solution of NH4CI and AcOEt. The separated organic layer was washed with water and brme, and dried over MgSO^, and evaporated. The resulting oil was purified by chromatography on Sι0 2 (CHCI3 as eluent) to give 4-n- outylιdene-4, 5, 6, 7-tetrahyαrobenzo [b] furan as a yellow oil (12.06 g) . NMR (CDCI3, δ) : 0.85 (3H, m) , 1.2-2.8 (10H, ) , 5.28 and 5.51 (IH, t, J=7.4Hz), 6.2-6.4 (IH, m) , 7.2-7.3 (IH, m) Preparation 4-2) To a mixture of 1.66 N n-butyl lithium (nBuLi) (328 ml in n-hexane solution) and Et p O (100 ml) was added a mixture of 4-n-butylιdene-4, 5, 6, 7-tetrahydrobenzo [b] furan (9.60 g) and EtpO (50 ml) dropwise over 5 minutes while maintaining -30 ~ -20°C by dry ice - carbon tetrachloride (CCl 4 ) cooling. The reaction mixture was stirred at r.t. for 1 hour, and was bubbled by carbon dioxide (C0 2 ) gas for 1 hour. The whole mixture was stirred at r.t. overnight and poured into a mixture of water and Et 2 0. The separated aqueous layer was adjusted to pH 1.4 with 10 " = HCl, and extracted by AcOEt. The orgaic layer was washed with brine, dried over MgSO^, and evaporated to give 4-n-butylιdene-4, 5, 6, 7-tetrahydrobenzo [o] - furan-2-carboxyiιc acid (3.91 g) as a reddish oil, which was used in the next reaction without further purification. Preparation 4-3) A mixture of 4-n-butylιdene-4, 5, 6, -tetrahydrobenzo [oj - furan-2-carboxylιc acid (3.91 g) obtained in Preparation 4- 2), cone, sulfuric acid (H 2 S0 4 ) (10 ml), and methanol (MeOH) (100 ml) was stirred at reflux for 1.5 hours. After being concentrated in vacuo to remove MeOH, the resulting mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed w th water and brme, dried over MgS0 4 , and evaporated. The resulting oil was purified by chromatography on SiOp (7 AcOEt in n-hexane as eluent) to give 4-n-butylιdene-2-methoxycarbonyl-4 ,5,6,7- tetrahydrobenzo [b] furan (1.72 g) as an oil. MASS (z/e) : 235 (M+H) + NMR (CDC1 3 , δ) : 0.93 (3H, t, J= 7 .4Hz), 1.40 (2H, ) , 1.85 (2H, m), 2.15 (2H, q, J=7.4Hz), 2.40 (2H, m' , 2.74 (2H, t, J=7.4Hz), 3.88 and 3.90 (3H, each s), 5.25 and 5.61 (IH, each t, J=7.5Hz), 7.26 (IH, s) Preparation 5-1) To a solution of l-n-butyl-6-cyano-2-oxo-2, 3-dιhydro-lH- thieno [2, 3-b] [1, 4] thiazme (0.43 g) m chloroform (15 ml) was added m-chloroperbenzoic acid (0.88 g) under ice cooling. -After stirring for 22 hours at room temperature, the reaction mixture was poured into a mixture of ethyl acetate and saturated aqueous sodium thiosulfate. The organic layer was successively washed with 20 ' ^ aqueous potassium carbonate, water and brine and dried over magnesium sulfate. The solvent was evaporated m vacuo and the residue was purified by column chromatography on silica gel elutmg with chloroform. The fractions containing the object compound were collected and evaporated in vacuo to give l-n-butyl-6- cyano-2-oxo-2, 3-dihydro-lH-thιeno [2, 3-b] [ 1, ] thiazme 1,1- dioxide (0.32 g) . IR (Nujol) : 2220, 1685, 1540 cm "1 NMR (DMSO-d 6 , δ) : 0.88 (3H, t, J=7.2Hz), 1.1-1.6 (4H, m) , 3.9-4.1 (2H, m) , 5.04 (2H, s), 8.38 (IK, s) Preparation. 5-2) A mixture of l-n-butyl-6-cyano-2-oxo-2 , 3-dιhydro-lH- thieno [2, 3-b] [1, 4] thiazine 1,1-dιoxide (0.30 g) and ethanol (EtOH) (15 ml) was bubbled with hydrogen chloride under ice-water cooling for 15 minutes. After being saturated with hydrogen chloride, the mixture was stood at r.t. for 3 hours. The reaction mixture was evaporated to give precipitate. The resulting precipitate was washed with IPE to give 1-n-butyl- 2-OXO-2, 3-dιhydro-6- ( 1-ethoxy-l-ιmmomethyl ) -lH-thieno- [2,3-b] [l,4]thιazme hydrochloride (0.32 g) . IR (Nujol) : 1685, 1630 cm "1 (-r) APCI MASS : 331 (M+H) NMR (DMSO-d 6 , δ) : 0.8-1.0 (3H, m) , 1.2-1.7 (7H, m) , 3.8-4.1 (2H, m) , 4.53 (2H, q, J=7.0Hz), 5.04 (2H, s) , 8.80 (IH, s) Preparation 6-1) The following compound was obtained according to a similar manner to that of Preparation 15-6) . l-n-Butyl-2, 3-dιhydro-6-methoxycarbonyl-2-oxo-lH- thιeno[2,3-b] [ 1, 4 ] thiazme NMR (DMSO-d 6 , δ) : 0.87 (3H, t, J=7.2Hz), 1.2-1.6 (4K, m) , 3.69 (2H, s), 3.83 (3H, s), 3.9-4.0 (2H, m) , 7.78 (IH, s) Preparation 6-2) To a solution of l-n-butyl-2, 3-dιhydro-6- methoxycarbonyl-2-oxo-lH-thιeno [2, 3-b] [1, 4] thiazme (31.9 g 1 m tetrahydrofuran (300 ml) was added dropwise boran- tetrahydrofuran complex (1.0 M solution m tetrahydrofuran^ (294 ml) . After stirring for 3 hours at room temperature, tne solvent was evaporated in vacuo and the residue was poured into water. The solution was adjusted to pH 8 witn 20" aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed witn water and brme, ana dried over magnesium sulfate. The solvent was evaporated m vacuo and the residue was purified by column chromatography on silica gel elutmg with toluene. The fractions containing tne object compound were collected and evaporated in vacuo to give l-n-butyl-2, 3-dιhydro-6-methoxycarbonyl-lH-thιeno- [2, 3-b] r 1 , 4] thiazme (30.85 g) . IR (Film) : 2950, 2850, 1700, 1550 cm "1 (+) APCI MASS : 272 (M+H) + NMR (DMSO-d 6 , δ) : 0.90 (3H, t, J=7.1Hz), 1.2-1.6 (4K, m) , 3.1-3.3 (4H, m) , 3.4-3.5 (2H, m) , 3.77 (3k, s) 7.37 (IH, s) 5 preparation 7-1) The following compound was obtained according to a similar manner to that of Preparation 15-6) . 10 l-Benzyl-2, 3-dιhydro-6-methoxycarbonyl-2-oxo-lH-fhieno- [2,3-b] [1, 4] thiazme IR (Nu ol) : 1720, 1660 cm "1 NMR (DMSO-d 6 , δ) : 3.77 (3H, s), 3.85 (2H, s), 5.18 (2H, s), 7.2-7.4 (5H, m) , 7.65 (IH, s) i o Preparation 7-2) The following compound was obtained according to a similar manner to that of Preparation 6-2). 0 l-Benzyl-2, 3-dιhydro-6-methoxycarbonyl-lH-thιeno [ 2 , 3-b] - [1,4] thiazme IR (Nujol) : 1690, 1540 cm -1 (+ ) APCI MASS : 306 (M+H) '1' NMR (DMSO-d 6 , δ) : 3.1-3.2 (2H, m) , 3.^-3.6 (2H, ) , 5 3.74 (3H, s), 4.47 (2H, s), 7.2-7.5 (6H, m) Preparation 8-1) The following compound was obtained according to a similar manner to that of Preparation 15-6) by using 3,4- 0 dimethoxyphenethyl p-toluenesulfonate . 2, 3-Dιhydro-6-methoxycarbonyI-l- (3, 4- di ethoxyphenethyl) -2-oxo-lH-thieno [2, 3-b] [1,4] thiazme ( + ) APCI MASS : 394 (M-^H) + 5 NMR (DMSO-d 6 , δ) : 2.6-2.8 (2H, m) , 3.6-3.7 (8H, m) , ! 2H , ) , 6 . 6- 6 . 9 ( 3H, rc ^ , Preparation 8-2) 5 The following compound was obtained according to a similar manner to that of Preparation 15-6) by using cyclohexylmethyl bromide. l-Cyclonexylmethyl-2, 3-dιhydro-6-methoxycarbonyl-2-oxo- 0 lH-thιeno[2, 3-b] [ 1, 4 ] thiazme IR (Nujol) : 1710, 1655, 1550 cm "1 (-r) APCI MASS : 326 (M+H) τ NMR (DMSO-d 6 , δ) : 0.8-1.2 (5H, m) , 1.4-1.8 (6H, m) , 3.69 (2H, s), 3.7-3.9 (5H, m) , 7.83 (IK, s) Preparation 8-3) The following compound was obtained according to a similar manner to that of Preparation 15-6) by using phenethyl bromide. 0 2, 3-Dihydro- 6-methoxycarbonyl-2-oxo-1-phenethyl-1H- thieno [2, 3-b] [ 1, 4 ] tr.iazme (-) APCI MASS : 334 (M+H) ÷ NMR (DMS0-d 6 , δ) : 2.7-2.9 (2H, ) , 3.67 (2H, s), 3.82 5 (3H, s), 4.0-4.2 (2H, ) , 7.1-7.3 (5H, m) , 7.68 (IH, s) Preparation 8-4) Tne following compound was obtained according to a C similar manner to that of Preparation 15-6) by using 3 , 4- ethylenedioxyphenethyl p-toluenesulfonate . 2, 3-Dιhydro-6-methoxycarbonyl-l- (3, 4- methylenedioxyphenethyl) -2-oxo-lH-thieno [2, 3-b] [1,4] thiazme (-O APCI MASS : 378 (M+H) + NMR (DMSO-d 6 , δ) : 2.6-2.8 (2H, m) , 3.67 (2K, s), 3.82 (3H, s) , 4.0-4.2 (2H, m) , 6.5-6.6 (IH, m) , 6.75 (IH, d, J=7.9Hz) , 6.79 (IH, d, J=1.4Hz) , 7.64 (IH, s) Preparation 8-5) The following compound was obtained according to a similar manner to that of Preparation 15-6) by using benzyl bromide . l-Benzyl-6-ethoxycarbonyl-2, 3-dιhydro-2-oxo-lK- trιieno[2, 3-b] [1,4] thiazme IR (Nujol) : 1705, 1645, 1550 cm "1 (+) APCI MASS : 334 (M+H) + NMR (DMSO-d 6 , δ) : 1.24 (3H, t, J=7.1Hz), 3.85 (2H, s), 4.23 (2H, q, J=7.1Hz), 5.18 (2H, s), 7.1-7.4 (5H, ) , 7.65 (IH, s) The following compounds were obtained according to a similar manner to that of Preparation 3-3) . Preparation 9-1) 6-Carboxy-2, 3-dihydro-l- (3, -dιmethoxyphenethyl) -2-oxo- lH-thιeno[2, 3-b] [1, 4] thiazme IR (Nujol) : 1690, 1615, 1515 cm -1 (+) APCI MASS : 380 (M+H) NMR (DMS0-d 6 , δ) : 2.6-2.8 (2H, m) , 3.6-3.8 (8H, n) , 4.0-4.2 (2H, m) , 6.6-6.9 (3H, m) , 7.56 (IH, s) Preparation 9-2) 6-Carboxy-l-cyclohexylmethyl-2, 3-dιhydro-2-oxo-lH- thieno [2, 3-b] [ 1 , 4 ] thiazme IR (Nujol) : 1690, 1605, 1545 cm -1 APCI MASS : 312 (M+H) + NMR (DMS0-d 6 , δ) : 0.8-1.3 (5H, ) , 1.4-1.8 ( 6H, m) , 3.67 (2H, s) , 3.79 (2H, d, J=6.9Hz) , 7.73 (IK, s, Preparation 9-3) 6-Carboxy-2, 3-dιhyαro-2-oxo-l-phenethyl-lH-thieno- [2, 3-b] [1, 4] thiazme IR (Nujol) : 1690, 1615 cm "1 (-i APCI MASS : 320 (M+H) + NMR (DMSO-d 6 , δ) : 2.7-2.9 (2H, ra) , 3.66 (2H, s), 4.0-4.2 (2H, ) , 7.1-7.3 (5H, m) , 7.61 (IH, s) 10 Reparation 9-4) 6-Carboxy-2, 3-dιhydro-l- (3, 4-methylenedιoxyphenethyl) -2- oxo-lH-thieno [2, 3-b] [1,4] thiazme IR (Nujol) : 1685, 1605 cm "1 15 (-M APCI MASS : 364 (M+H) " " NMR (DMSO-dg, δ) : 2.6-2.8 (2H, m) , 3.66 (2H, s) , 4.0- .2 (2H, m) , 5.93 (2H, s) , 6.59 (IH, dd, J=1.5, 7.9Hz) , 6.75 (IH, d, J=7.9Hz), 6.79 (IH, d, J=1.5Hz) , 7.56 (IH, s) , 13.27 (IK, br s) 20 Preparation 9-5) l-3enzyl-6-carboxy-2, 3-dιhydro-2-oxo-lH-thιeno [2, 3-b] - [1,4] thiazme IR (Nujol) : 1690, 1615 cm "1 25 (T) APCI MASS : 306 (M+H) NMR (DMSO-dg, δ) : 3.84 (2H, s , 5.16 (2H, s), 7.2-7.4 (5H, m) , 7.54 (IH, s), 13.27 (IK, br s) Preparation 10-1) 30 The following compound was obtained according to a similar manner to tnat of Preparation 3-7). 6-Carbamoyl-2, 3-dιhydro-l- (3, 4-dιmethoxyphenethyl ) -2- oxo-lH-thιeno[2,3-b] [1, 4] thiazme T c IR (Nujol) 1635, 1510 cm -1 (+) APCI MASS : 379 (M+H) + NMR (DMSO-dg, δ) : 2.7-2.9 (2H, m) , 3.6-3.8 (8H, m) , 3.9-4.1 (2H, m) , 6.7-6.9 (3H, m) , 7.51 (IH, br s,, 7.78 (IH, s) , 7.97 (IH, br s) The following compounds were obtained according to a similar manner to that of Preparation 10-1). Preparation 10-2) 6-Carbamoyl-l-cyclohexylmethyl-2, 3-dιnydro-2-oxo-lH- thιeno[2, 3-b] [1,4] thiazme IR (Nujol) : 3300, 3170, 1655, 1600 cm "1 (-" • ) APCI MASS : 311 (M+H) + NMR (DMSO-dg, δ) : 0.8-1.3 (5H, m) , 1.5-1.8 (6H, m) , 3.6-3.8 (4H, m) , 7.52 (IH, br s), 7.77 (IH, s), 8.00 (IH, br s) Preparation 10-3) 6-Carbamoyl-2, 3-dιhydro-2-oxo-l-phenethyl-lH-thieno- [2, 3-b] [1, 4]thιazme IR (Nujol) : 3330, 3150, 1675, 1640, 1610, 1545 cm "1 ( + ) APCI MASS : 319 (M+H) " " NMR (DMSO-d 6 , δ) : 2.7-2.9 (2H, m) , 3.64 (2H, s), 3.9- 4.1 (2H, ) , 7.2-7.3 (5K, ) , 7.54 (IH, br s 1 , 7.8C (IH, s) , 8.04 (IH, br s) Preparation 10-4) 6-Carbamoyl-2, 3-dιhydro-l- (3, 4-methylenedιoxyphenethyl ) - 2-oxo-lH-thieno [2, 3-b] [ 1 , 4 ] thiazme IR (Nujol) : 1650 cm "1 (-) APCI MASS : 363 (M+H) + NMR (DMSO-dg, δ) : 2.7-2.8 (2H, m) , 3.64 (2H, s), 3.9- 4.1 (2H, m) , 5.96 (2H, s), 6.6-6.9 (3H, s), 7.52 (IH, br s), 7.77 (IH, s), 8.00 (IH, br s) Preparation 10-5) l-Benzyl-6-carbamoyl-2, 3-dιhydro-2-oxo-lH-tnιeno [2, 3-b 1 ■ [1,4] thiazme IR (Nujol) : 1650, 1600 cm "1 (+) APCI MASS : 305 (M+H) NMR (DMSO-dg, δ) : 3.78 (2H, s), 5.04 (2H, s), 7.2-7.6 (6H, ) , 7.71 (IK, s), 7.89 {IH, br s) The following compounds were obtained according to a similar manner to that of Preparation 11-5) . Preparation 11-1) 6-Cyano-2, 3-dιhydro-l- (3, 4-dιmethoxyphenethyl) -2-oxo-lK- thιeno[2, 3-b] [ 1, 4 ] thiazme IR (Nujol) : 2220, 1670 cm "1 APCI MASS : 361 (M+H) " NMR (DMSO-d 6 , δ) : 2.6-2.8 (2H, m) , 3.6-3.8 (8H, ) , 4.0-4.2 (2H, m), 6.6-6.9 (3H, m) , 7.94 (IH, s) Preparation 11-2) 6-Cyano-l-cyclohexylmethyl-2, 3-dιhydro-2-oxo-lH- thιeno[2, 3-b] [ 1 , 4 ] thiazme IR (Nujol) : 2210, 1660 cm "1 (-) APCI MASS : 293 (M^H) τ NMR (DMSO-dg, δ) : 0.8-1.3 (5H, m) , 1.5-1.7 (6H, m) , 3.7-3.8 (4H, m) , 8.11 (IH, s) Preparation 11-3) c-Cyano-2, 3-dιhydro-2-oxo-l-phenethyl-lH-thιeno [2, 3-b] - [1, 4] thiazme IR (Nujol) : 2200, 1660 cm "1 (*) APCI MASS : 301 (M+H) + NMR (DMSO-dg, δ) : 2.7-2.9 (2H, ) , 3.70 (2H, s), 4.0-4.2 (2H, m) , 7.1-7.3 (5H, m) , 7.98 (IH, s) Preparation 11-4) 6-Cyano-2, 3-dιhydro-l- (3, -methylenedιoxyphenethyl) -2- oxo-lH-thieno [2, 3-b] [1,4] thiazme IR (Nujol) : 2210, 1665 cm "1 (- APCI MASS : 345 (M+H) "L NMR (DMSO-dg, δ) : 2.6-2.8 (2H, m) , 3.69 (2H, s), 3.9- 4.1 (2H, m) , 5.95 (2H, s), 6.63 (IH, dd, J=1.6, 7.9Hz), 6.77 (IH, d, J=7.9Hz), 6.84 (IH, d, J=1.6Hz), 7.99 (IH, s) Preparation 11-5) A mixture of l-benzyl-6-carbamoyl-2 , 3-dmydro-2-oxo-lH- th eno [2, 3-b] [1, 4] thiazme (0.18 g) and p-toluenesulfonyl chloride (0.17 g) m pyridme (5 ml) was stirred for 24 hours at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water, and adjusted to pH 1.5 with concentrated hydrochloric acid. The organic layer was successively washed with water ana brme and dried over magnesium sulfate. Tne solvent was evaporated vacuo and the residue was purified by column cnromatography on silica gel elut g with chloroform. The fractions containing the object compound were collected and evaporated m vacuo to give l-benzyl-6-cyano-2, 3-dιhydro-2-oxo-lH-thιeno [2, 3-b] - [1, 4] thiazme (0.11 g) IR (Film) : 2950, 2220, 1670, 1540 cm "1 NMR (DMSO-dg, δ) : 3.85 (2H, s), 5.12 (2H, s), 7.2-7.4 (5H, ) , 7.95 (IH, s) The following compounds were obtained according to a similar manner to that of Preparation 5-2). Preparation 12-1) 2, 3-Dihydro-l- (3, -dimethoxyphenethy1) -6- (I-ethoxy-1- immomethyl) -2-oxo-lH-thieno [2, 3-b] [1,4] thiazme hydrochloπde IR ( ujol) : 1662, 1600 cm "1 ( ■ >- ) APCI MASS : 407 (M+H) + NMR (DMSO-dg, δ) : 1.3-1.5 (3H, m) , 2.7-2.9 (2H, m) , 3.69 (3H, s), 3.74 (2H, s) , 3.76 (3H, s), 4.0-4.1 (2K, m) , 4.56 (2H, q, J=6.9Hz), 6.7-7.0 (3K, ) , 8.84 (IH, s) Preparation 12-2) l-Cyclohexylmethyl-2, 3-dihydro-6- ( 1-ethoxy-l-imino- methyl) -2-oxo-lH-thieno [2, 3-b] [1, 4] thiazine hydrochloride IR (Nujol) : 1655, 1600 cm "1 (+) APCI MASS : 339 (M+H) + NMR (DMSO-dg, δ) : 0.8-1.3 (5H, m) , 1.41 (3H, t, J=6.9Hz), 1.5-1.8 (6H, m) , 3.7-3.8 (4H, ) , 4.57 (2H, q, J=6.9Hz), 8.81 (IH, s) Preparation 12-3) 2, 3-Dihydro-6- ( 1-ethoxy-l-iminomethyl) -2-oxo-l- phenethyl-lH-thieno [2, 3-b] [ 1, 4 ] thiazine hydrochloride IR (Nujol) : 1665, 1610 cm "1 (+) APCI MASS : 347 (M+H) + NMR (DMSO-dg, δ) : 1.42 (3H, t, J=6.9Hz), 2.8-2.9 (2H, m) , 3.9-4.1 (2H, m) , 4.57 (2H, q, J=6.9Hz), 7.1-7.4 (5K, m) , 8.73 (IH, s) Preparation 12-4) 2, 3-Dihydro-6- ( 1-ethoxy-l-iminomethyl ) -1- (3, 4- ethylenedioxyphenethyl) -2-oxo-lH-thieno [2, 3-b] [1, 4 ] thiazine hydrochloride IR (Nujol) : 1695, 1670 cm "1 (+) APCI MASS : 391 (M+H) + NMR (DMSO-dg, δ) : 1.42 (3H, t, J=7.0Hz), 2.7-2.9 (2H, m) , 3.74 (2H, s), 3.9-4.1 (2H, m) , 4.58 (2H, q, J=7.0Hz), 5.95 (2H, s), 6.6-6.9 (2H, m) , 6.94 (IH, d, J=1.3Hz), 8.77 (IH, s) Preparation 12-5) l-Benzyl-2, 3-dihydro-6- ( 1-ethoxy-l-iminomethyl) -2-oxo- lH-thieno[2, 3-b] [ 1 , 4 ] thiazine hydrochloride (÷) APCI MASS : 333 (M÷H) + NMR (DMSO-dg, δ) : 1.37 (3K, t, J=6.9Hz), 3.89 (2H, s), 4.52 (2H, q, J=6.9Hz), 5.10 (2H, s), 7.2-7.4 (5H, m) , 8.73 (IH, s) Preparation 13-1) The following compound was obtained according to a similar manner to that of Preparation 15-6) by using ethoxycarbonylmethyl bromide. 6-Cyano-l-ethoxycarbonyImethyl-2, 3-dihydro-2-oxc-lH- thieno [2, 3-b] [1, ] thiazine IR (Nujol) : 2210, 1725, 1675 cm "1 MASS (z/e) : 283 (M+H) + NMR (DMSO-dg, δ) : 1.20 (3H, t, J=7.1Hz), 3.79 (2H, s), 4.13 (2H, σ, J=7.1Hz), 4.64 (2H, s), ^.98 (IH, s) Preparation 13-2) The following compound was obtained according to a similar manner to that of Preparation 5-2) . 6- (i-Ethoxy-1-iminomethyl) -l-ethoxycarbonylmethyl-2, 3- dihydro-2-oxo-lH-thieno[2, 3-b] [1,4] thiazme hydrochloride IR (Nujol) : 1760, 1690, 1600 cm "1 (-M APCI MASS : 329 (M+H) " NMR (DMSO-dg, δ) : 1.22 (3H, t, J=7.1Hz), 1.41 (3H, t, J=7.0Hz), 3.84 (2H, s), 4.16 (2H, q, J=7.1Hz), 4.5- 4.7 (4H, m) , 8.58 (IH, s) Preparation 14 The following compound was obtained according to a similar manner to that of Preparation 5-2). 2 , 3-D hydro-2 -oxo- l H- thιeno [ 2 , 3-b ] [ 1 , 4 ] thia z me nydro chloride ( + ) APC I MASS : 24 3 (M+H) + 5 Preparation 15-1) The following compound was obtained according to a similar manner to that of Preparation 15-6) by using 2-oxo- 1 , 3-dιoxolane . IC 6-Cyano-2, 3-dιhydro-l- (2-hydroxyethyl ) -2-oxo-lH- thιeno[2,3-b] [1 , 4 ] thiazme (-) APCI MASS : 241 (M+H) + NMR (DMSO-d 6 , δ) : 3.4-3.6 (2H, m) , 3.71 (2H, s), 3.8- 4.0 (2H, m) , 4.83 (IH, t, J=5.5Hz), 8.01 (IH, s) Preparation 15-2) Tne following compound was obtained according to a similar manner to that of Preparation 15-6) by using n-butylcarbamoylmethyl bromide. 0 1- m-Butylcarbamoylmethyl) -6-cyano-2, 3-dιhydro-2-oxo-lH- thιeno[2, 3-o] [1, 4] thiazine (-) APCI MASS : 310 (M-'-Hi τ NMR (DMSO-dg, δ) : 0.8-1.0 (3H, ) , 1.1-1.5 (4K, m , 5 3.0-3.2 (2H, ) , 3.76 (2H, s), 4.44 (2H, s), 7.78 (IH, s), 8.06 (IH, t, J=5.4Hz) Preparation 15-3) The following compound was obtained according to a 0 similar manner to that of Preparation 15-6) by using 2,2,2- trifluoroethylcarbamoylmethyl bromide . 6-Cyano-l- (2,2, 2-trιfluoroethylcarbamoylmethyl ) -2,3- dihydro-2-oxo-lH-thieno [2, 3-b] [1,4] thiazme 3 IR (Nujol) : 3300, 3100, 2220, 1670, 1580 cm "1 NMR (DMSO-dg, δ) : 3.77 (2H, s) , 3.8-4.1 (2H, m) , 4.56 (2H, s) , 7.80 (IH, s) , 8.84 (IH, t, J=6.2Hz) Preparation 15-4) The following compound was obtained according to a similar manner to that of Preparation 15-6) by using 3- ethoxycarbonylpropyl bromide. 6-Cyano-l- ( 3-ethoxycarbonylpropyl ) -2, 3-dιhydro-2-oxo-lH- thιeno[2, 3-bl [1, 4] thiazine (-) APCI MASS : 311 (M^-H) NMR (DMSO-dg, δ) : 1.18 (3H, t, J=7.1Hz), 1.6-1.9 (2h\ ) , 2.32 (2H, t, J=7.3Hz), 3.72 (2H, s), 3.8-3.9 (2H, m) , 4.05 (2H, q, J=7.1Hz), 8.06 (IH, s) Preparation 15-5) The following compound was obtained according to a similar manner to that of Preparation 15-6) by using 3,4- methylenedioxyphenylcarbamoylmethyl bromide . 6-Cyano-2, 3-dιhydro-l- (3, 4-methylenedιoxyphenyl- carbamoylmethyl) -2-oxo-lH-thιeno [2, 3-b] [1,4] thiazme IR (Nujol) : 2210, 1670, 1540 cm "1 (-) APCI MASS : 374 (M+H) + NMR (DMS0-d 6 , δ) : 3.79 (2H, s), 4.64 (2H, s), 5.98 (2H, s), 6.86 (IH, d, J=8.4Hz), 6.95 (IH, dd, J=1.9, 8.4Hz), 7.28 (IH, d, J=1.9Hz), " '.95 (IH, s,, 10.18 (IH, s) Preparation 15-6) To a solution of 6-cyano-2 , 3-dιhydro-2-oxo-lH- thieno[2, 3-b] [1, 4] thiazine (13.6 g) in N, -dimethylformamide (270 ml) was added potassium tert-butoxide (9.3 g) under ice cooling. A.fter stirring for 10 minutes under ice cooling, tc the reaction mixture was added 1-ιodobutane (9.5 ml). After stirring for 8 hours at room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel elut g with chloroform. The fractions containing the object compounds were collected and evaporated in vacuo to give l-n-butyl-6-cyano-2, 3-dihydro-2- oxo-lH-thieno[2, 3-b] [1, 4] thiazine (13.78 g) . IR (Nujol) : 2200, 1660, 1540 cm "1 (+) APCI MASS : 253 (M+H) + NMR (DMS0-d 6 , δ) : 0.87 (3H, t, J=7.2Hz), 1.2-1.6 (4H, ) , 3.71 (2H, s), 3.8-3.9 (2H, m) , 8.07 (IH, s) The following compounds were obtained according to a similar manner to that of Preparation 5-2). Preparation 16-1) 2, 3-Dihydro-6- ( 1-ethoxy-l-ιminomethyl ) -1- (2- hydroxyethyl) -2-oxo-lH-thieno [2, 3-b] [ 1, 4 ] hiazine hydrochloride, which was used in the next reaction without further purification. Preparation 16-2) 1- (n-Butylcarbamoylmethyl) -2, 3-dihydro-6- (1-ethoxy-l- iminomethyl) -2-oxo-lH-thieno [2 , 3-b] [1,4] thiazine hydrochloride (+) APCI MASS : 356 (M+H) + NMR (DMS0-d 6 , δ) : 0.8-0.9 (3H, m) , 1.2-1.5 (7H, m) , 3.0- 3.2 (2H, m) , 3.81 (2H, s) , 4.42 (2H, s), 4.57 (2H, q, J=6.9Hz), 8.20 (IH, t, J=5.5Hz) , 8.38 (IH, s) Preparation 16-3) 1- (2, 2, 2-TrifluoroethylcarbamoylmethyI, -2, 3-dιhydro-6- (1-ethoxy-l-ιmmomethyl) -2 -oxo-lH-thieno [2, 3-b] [l,4]thιazme hydrochloride I:RR ((NNUuJjOol! 3250, 1705, 1675, 1590, 1550 cm -1 !-) APCI MASS : 382 (M+H) + NMR ((DDMMSSOO--ddgg,, δδ)) :: 11..4411 ((33H, t, J=7.0Hz), 3.4-4.1 (4H, ) , 4.4-4.7 (4H, m) , 8.40 (IH, s), 8.8-9.1 (IH, m Preparation 16-4) 1- (3-Ethoxycarbonylpropyl) -2, 3-dιhydro-6- (1-ethoxy-l- lmmomethyl) -2-oxo-lH-thieno [2, 3-b] [ 1, 4 ] tniazme hydrochloride (+ ) APCI MASS : 357 (M+H) " " NMR (DMSO-dg, δ) : 1.17 (3H, t, J=7.iHz), 1.41 (3H, t, J=6.9Hz), 1.7-1.9 (2H, m) , 2.37 (2H, t, J=7.5Hz), 3.77 (2H, s) , 3.89 (2H, t, J=7.1Hz), 4.04 (2H, c, J=7.1Hz), 4.57 (2H, q, J=6.9Hz), 8.83 (IH, s) Preparation 16-5) 2, 3-Dιhydro-6- ( 1-ethoxy-l-ιmmomethyl) -1- (3, 4- methylenedioxyphenylcarbamoylmethyl ) -2-oxo-lH-thιeno [2, 3-b] - [1, 4] thiaz e hydrochloride (+) APCI MASS : 420 (M+H) + NMR (DMSO-dg, δ) : 1.41 (3H, t, J=7.1Hz), 3.84 (2H, s), 4.5-4.7 (4H, ) , 5.98 (2H, s), 6.86 (IH, d, J=8.4Hz), 7.00 (IH, dd, J=2.0, 8.4Hz), 7.2-7.4 (IH, m) , 8.50 (IH, s), 10.44 (IH, s) Prep r on 16-6) l-n-Butyl-2, 3-dιhydro-6- ( 1-ethoxy-l-ιmmomethyl ) -2-oxo- lH-thieno [2, 3-b] [ 1, 4] thiazme hydrochloride IR (Nujol) : 1680, 1605 cm "1 ( •■ -) APCI MASS : 299 (M+H) + NMR (DMSO-dg, δ) : 0.89 (3H, t, J=7.2Hz) , 1.2-1.6 (7H, m) , 3.75 (2H, s) , 3.8-3.9 (2H, m) , 4.58 (2H, q, J=7.0Hz) , 8.82 (IH, s) Preparation 17 Under nitrogen atmosphere, potassium hydroxide (147 mg) m dimethyl sulfoxide (10 ml) was stirred at room temperature for 30 minutes. To the solution were added 2, 3-dιhydro-6- methoxycarbonyl-2-oxothιeno[2, 3-b] [1, ] thiazine (0.50 g) , sodium iodide (0.39 g) and 2-chloroethyl methyl sulfide (0.26 ml), and the mixture was stirred at 50°C for 6.5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brme, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent : hexane:ethyl acetate = 3:1) to give 2, 3-dιhydro-6-methoxycarbonyl-i- [2- (methylthio) - ethyl] -2-oxothιeno [2, 3-b] [1, 4] thiazine (465 mg) . NMR (DMSO-d 6 , δ) : 2.08 (3H, s), 2.62 (2H, t, J=7.2Hz), 3.71 (2H, s), 4.10 (2H, t, J=6.9Hz), 7.86 (IH, s) Preparation 18-1) Sodium borohydride (0.17 g) was added into a mixture of 6-ethoxycarbonyl-4, 5, 6-7-tetrahydro-4-oxobenzo [b] thiophene (1.00 g) and methanol (MeOH) (20 ml) in a portion at room temperature (r.t.) under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added into a mixture of ethyl acetate (AcOEt) and water, and was adjusted to pH 1.6 with 6 N hydrochloric acid (HCl). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (sat. NaHC03 ac ϊ ' )' water, and br e, and dried over magnesium sulfate (MgSO^), and then evaporated in vacuo. After evaporation of the filtrate, the resulting oil was purified by chromatography on silica gel (chloroform (CHC^J-MeOH as eluent) to give 6-ethoxycarbonyl-4-hydroxy-4, 5, 6, 7- tetrahydrobenzo [b] thiophene (0.79 g) as an oil. IR (KBr) : 3433, 1730 cm -1 APCI MASS : 225 (M-H) NMR (CDCI3, δ) : 1.27 (3H, t, J=7.1Hz), 1.96 (2H, m) , 2.18 (2H, m) , 2.99 (IH, m) , 4.22 (2H, q, J=7.1Hz), 6.1 (IH, t J=6.1Hz), 7.06 (IH, d, J=5.2Hz), 7.12 (IH, d, J=5.2Hz) Process 18-2) Acetic anhydride (4.1 ml) was added to a mixture of 6- ethoxycarbony1- -hydroxy-4, 5,6, 7 -tetrahydrobenzo [b] thiophene (2.06 g) and pyridme (8 ml) under water cooling, and was stirred at r.t. for 2.5 hours. The reaction mixture was added into a mixture of AcOEt and water, and was adjusted to pH 1.6 with 6N HCl. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (sat. NaHC0 3 aq.), water, and brme, and dried over MgSO^, and then evaporated in vacuo to give 4-acetoxy-6- ethoxycarbonyl-4, 5, 6, 7-tetrahydrobenzo [b] tniophene (2.36 g) as an oil . APCI MASS : 269 (M+H) NMR (CDCI3, δ) : 1.29 (3H, t, J=7.1Hz), 2.09 (3H, s), 1.9-2.6 (2H, m) , 2.95-3.2 (3H, m) , 4.22 (2H, q, J=7.1Hz), 6.05 (IH, m) , 6.82 (IH, d, J=5.2Hz), 7.10 (IH, d, J=5.2Hz) Preparation 18-3) A mixture of 4-acetoxy-6-ethoxycarbonyl-4 , 5, 6, 7- tetrahydrobenzo[b] thiophene (2.34 g) , tosic acid monohydrate (0.13 g) , and toluene (50 ml) was stirred at reflux for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the separated organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and brine, and dried over MgSO^, and then evaporated in vacuo. After evaporation of the filtrate, the resulting oil was purified by chromatography on silica gel (CHCl 3 -MeOH as eluent) to give 6-ethoxycarbonyl-6 , 7-dιhydrobenzo [b] hiophene (1.03 g) APCI MASS : 209 (M+H) NMR (CDC1 3 , δ) : 1.30 (3H, t, J=7.1Hz), 3.10 and 3.13 (2H, each s), 3.4-3.7 (IH, m) , 4.15 (2H, q, J=7.1Hz), 5.90 (IH, dd, J=9.6, 3.4Hz), 6.53 ( IH, dd, J=9.6, 3.4Hz), 6.83 (IH, d, J=5.1Hz), 7.03 (IH, G, J=5.1Hz) Preparation 18-4) A mixture of 6-ethoxycarbonyl-6, 7-dιhydrobenzo [b] - thiophene (1.00 g) , 10% palladium on carbon (2.16 g) , AcOEt (30 ml) and MeOH (10 ml) was stirred at r.t. under hydrogen atmosphere for 4 hours. After removal of insoluble solids, tne filtrate was concentrated in vacuo to give 6-ethoxy- carbonyl-4, 5, 6, 7-tetrahydrobenzo [b] thiophene (0.96 g) as an IR (Neat) : 2935, 1730, 1596 cm "1 APCI MASS : 211 (M+H) NMR (CDCI3, δ) : 1.28 (3H, t, J=7.1Hz), 1.6-2.4 (3H, m) , 2.6-3.3 (4H, m) , 4.14 (2H, q, J=7.1Hz), 6.75 (IH, d, J=5.1Hz), 7.07 (IH, d, J=5.1Hz) Preparation 18-5) A mixture of 6-ethoxycarbonyl- , 5, 6, 7-tetrahycrobenzo- [b]tnιophene (0.80 g) and dichloromethane (CH 2 Cl 2 ) was dropwise added to a mixture of aluminum chloride (AICI3) (1.01 g) and CH 2 C1 2 (5 ml) under ice-water cooling, and was stirred under the same conditions for 15 minutes. A mixture of 1, 1-dιchloromethyl methyl ether (0.52 ml) and CH C1 2 (3 mi) was thereto added, and was stirred under the same conditions for 10 minutes. The reaction mixture was added into a mixture of CHCI3, ice, and water. The separated organic layer was washed with water, and brme, and dried over MgS0 4 . After evaporation of the filtrate, the resulting cil was purified by chromatography on silica gel (n-hexane- AcOEt as eluent) to give 6-ethoxycarbonyl-2-formyl-4 , 5, 6, 7- tetrahydrobenzo [b] thiophene (0.33 g) . IR (Neat) : 2935, 1730, 1596 cm "1 APCI MASS : 239 (M+H) NMR (CDC1 3 , δ) : 1.26 (3H, t, J=7.1Hz), 1.6-2.4 (3H, m) , 2.6-3.3 (4H, m) , 4.16 (2H, q, J=7.1Hz), 7.43 (IH, s), 9.80 (IH, s) Preparation 18-6) A mixture of 6-ethoxycarbonyl-2-formyi-4 , 5, 6, 7- tetrahydrobenzo[b] thiophene (3.23 g) , hydroxylamme hydrochloride (0.92 g) , and ethanol (EtOH) (30 ml) was stirred at reflux for 30 minutes. The reaction mixture was added into a mixture of AcOEt and water. The separated organic layer was washed with water, and brine, and dried over MgS0 4 . After evaporation of the filtrate, the resulting precipitate was washed with a mixture of n-hexane and isopropyl ether to give 6-ethoxycarbonyl-2-hydroxyιmmo- , 5, 6, 7-tetrahydrobenzo [b] thiophene (1.81 g) . APCI MASS : 254 (M+H) NMR (DMSO-dg, δ) : 1.26 (3H, t, J=7.1Hz), 1.6-3.2 (7H, ) , 4.14 (2H, q, J=7.1Hz), 7.11 (IH, s), 7.6^ (IH, s) Preparation 18-7) A mix t ure of 6-ethoxycarbonyl-2-hydroxyιmmo-4 , 5, 6, - tetrahydrobenzo[b] thiophene (1.77 g) and acetic anhydride (0.84 ml) was stirred at reflux for 45 minutes. The reaction mixture was added into a mixture of AcOEt and water. The separated organic layer was washed with water, and brme, and dried over MgS0 . After evaporation of the filtrate, the resulting precipitate was washed with n-hexane to give 6- ethoxycarbonyl-2-cyano- ,5,6,7-tetrahydrobenzo[b] thiopnene (1.28 g) . IR (Neat) : 2937, 2212, 1724 cm "1 APCI MASS : 236 (M+H) NMR (DMSO-dg, δ) : 1.26 (3H, t, J=7.1Hz), 1.6-3.2 ( 7H, m) , 4.14 (2H, q, J=7.1Hz), 7.66 (IH, s) Preparation 18-8) A mix t ure of 6-ethoxycarbonyl-2-cyano-4 , 5, 6, 7- tetrahyorooenzofb] thiopnene (1.26 g), and EtOH (10 ml) was bubbled with hydrogen chloride with ice-water cooling. After being saturated with hydrogen chloride, the mixture was stirred at r.t. for 3 hours. The reaction mixture was evaporated to give precipitate. The resulting precipitate was washed with diethyl ether (Et 2 0) to give 6-ethoxycarbonyl 2- (l-ethoxy-l-ιmιnomethyl)-4, 5,6, 7 -tetrahydrobenzo [b] hiophen e hydrochloride (1.55 g) . NMR (DMSO-d 6 , δ) : 1.16 (3H, t, J=7.1Hz), 1.26 (3H, t , J=7.1Hz), 1.6-3.2 (7H, m) , 4.11 (2H, q, J=7.1Hz), 4.58 (2H, q, J=7.1Hz), 8.22 (IH, s) Preparation 19-1) The following compound was obtained according to a similar manner to that of Preparation 20-1) . 2- (Methoxycarbonylmetnylth o) -5-cyano-3-nιtrothιopnene NMR (DMSO-dg, δ) : 3.75 (3H, s), 4.3 " (2H, s), 8.61 (IH, s) Preparation 19-2) The following compound was ootained according to a similar manner to that of Preparation 20-2) . 6-Cyano-2, 3-dιhydro-2-oxothιeno [2 , 3-b] [1,4] thiazme NMR (DMSO-d β , δ) : 3.64 (2H, s), 7.45 (IH, s) , 10.85 (IH, s) Preparation 20-1; To a mixture of 2-bromo-5-methoxycarbonyl-3- mtrothiophene (110.7 g) and methyl mercaptoacetate (37.2 ml) in tetrahydrofuran (1 0 was added triethylamme (63.8 ml). After stirring for 4 hours at room temperature, the reaction 5 mixture was poured into water. The resulting precipitate was collected by filtration and washed with water to give 2- methoxycarbonylmethylthιo-5-methoxycarbonyl-3-nιtrothiophene (118.15 g) . NMR (DMSO-dg, δ) : 3.74 (3H, s), 3.86 (3H, s), 4.37 10 (2H, s), 8.16 (IH, s) Preparation 20-2) To a solution of 2-methoxycarbonyimethylthιo-5- methoxycarbonyl-3-nιtrothιophene (26.1 g) _n acetic aciα 15 ml) and water (36 ml) was added portionwise iron (36.5 g) at 80°C. After stirring for 3 hours at 80°C, the hot reaction mixture was filtered and the filtrate was poured into ice- water. The resulting precipitate was collected by filtration and washed with water to give 2 , 3-dιhydro-6-methoxycarbonyI- 20 2-oxothιeno[2, 3-b] [1, 4] thiazme (11.12 g) . NMR (DMSO-dg, δ) : 3.63 (2H, s), 3.80 (3H, s), 7.31 (IH, s) Preparation 21-1) 25 The following compounα was obtained according to a similar manner to that of Preparation 6-2) . 6-Cyano-2, 3-dihydrothieno [2, 3-b] ri, 4 ι thiazme NMR (DMSO-dg, δ) : 3.0-3.1 (2H, ) , 3.4-3.6 (2H, m) , 30 6.0-6.2 (IH, m) , 7.23 (IK, S Pre ar ion 21-2) The following compound was obtained according to a similar manner to that of Preparation 23-1;. o 5 6-Cyano-2, 3-d hydro-l- (ethoxycarbonyiacetyl) thieno- [2, 3-b] [1, 4] thiazme IR (Nujol) : 2220, 1740, 1660 cm "1 (+) APCI MASS : 297 (M+H) + NMR (DMSO-dg, δ) : 1.0-1.3 (3H, m) , 3.2-3.5 (2H, m) , 3.80 (2H, s), 3.9-4.2 (4H, ) , 8.19 (IH, s) Pre ra ion 23,-3 ) The following compound was obtained according to a similar manner to that of Preparation 5-2) . Ethyl 2, 3-dιhydro-l- (ethoxycarbonyiace yl) -6- ( 1-ethoxy- 1-ιmmomethyl ) thieno [2, 3-b] [1, 4] thiazme nyαrochlo iαe ( ■ > ■ ) APCI MASS : 343 (M+H)" NMR (DMSO-dg, δ) : 1.1-1.5 (6K, ) , 3.3-4.2 (8K, m) , 4.58 (2H, q, J=7.0Hz), 8.80 (IH, s) Preparation 22-1) Tne following compound was obtained according to a similar manner to that of Preparation 6-2) . 2, 3-Dιhydro-6-methoxycarbonylthieno [2, 3-b] f 1, 4] thiazme IR (Nujol- : 3350, 1680, 1565 cm "1 (-) APCI MASS : 216 (M+H)" NMR (DMSO-dg, δ) : 3.0-3.1 (2H, m) , 3.4-3.5 (2h, m) , 3.75 (3H, s), 5.9-6.0 (IH, m) , 7.13 (IH, s) Preparation 22-2) The following compound was obtained according to a similar manner to that of Preparation 23-1). l-Benzoyl-2, 3-dιhydro-6-methoxycarbonyithιeno [2, 3-b] - [1,4] thiazme IR (Nujol) : 1690, 1640 cm "1 ( + ι APCI MASS : 320 (M*H) " NMR (DMSO-d 6 , δ) : 3.3-3.4 (2H, m) , 3.^6 (3H, s, , 3.9- 4.1 (2H, m) , 7.4-7.8 (6H, m) Preparation 22-3) The following compound was obtained according to a similar manner to that of Preparation 3-3) . I-Benzoyl-6-carboxy-2, 3-dihydrothieno [2, 3-b] [1,4]- thiazine IR ( ujol) : 1635 cm "1 (+) APCI MASS : 306 (M+H) + NMR (DMSO-dg, δ) : 3.2-3.4 (2H, m) , 3.9-4.1 (2H, m) , 7.4-7.6 (6H, m) , 13.05 (IH, s) Preparation 22-4) The following compound was obtained according to a similar manner to that of Preparation 3-7). l-Benzoyl-6-carbamoyl-2, 3-dihydrothieno [2, 3-b] [1,4]- thiazine IR (Nujol) : 1660, 1620 cm "1 ( + ) APCI MASS : 305 (M+H) 4" NMR (DMSO-d 6 , δ) : 3.3-3.4 (2H, m) , 3.9-4.0 (2H, m) , 7.28 (IH, br s), 7.4-7.6 (5H, m) , 7.7-8.0 (2K, m) Preparation 22-5) The following compound was obtained according to a similar manner to that of Preparation 11-5) . 1-Benzoyl- 6-cyano-2, 3-dihydrothieno [2, 3-b] [1,4] thiazine IR (Nujol) : 2220, 1640 cm "1 ( ■ > ■ ) APCI MASS : 287 (M+H) + NMR (DMSO-dg, δ) : 3.3-3.4 (2H, m) , 3.9-4.1 (2H, m) , 7.4-7.6 (5H, m) , 7.80 (IH, s) Preparation 22-6) The following compound was obtained according to a similar manner to that of Preparation 5-2) . 5 1-Benzoyl-6- ( 1-ethoxy-l-ιmmomethyl) -2, 3-dihydrothieno- [2, 3-D] [ 1, 4] thiaz e hydrochloride (- • -) APCI MASS : 333 (M+H) "1" NMR (DMSO-dg, δ) : 1.3-1.5 (3H, ) , 3.3-3.5 (2H, m) , 3.9-4.0 (2K, m) , 4.56 (2H, q, J=7.0Hz), 7.4-". 0 (5K, ) , 8.53 (IH, s) Preparation 23-1) To a mixture of 6-cyano-2, 3-dιhydrotmeno [2, 3-b] [ 1 , 4 ] - thiazme (0.3 g) and triethylamme (0.46 ml) m 5 dichloromethane (10 ml) was dropwise added acetyl chloriαe (0.23 ml) . After stirring for 5 hours at room temperature, tne reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brme and dried over magnesium sulfate. The solvent was 0 evaporated m vacuo and the residue was pulverized from dusopropyl ether to give l-acetyl-6-cyano-2, 3-dιhydrothιeno- [2, 3-b] [1,4] thiazme (0.33 g) . IR (Nujol) : 2200, 1660 cm "1 NMR (DMSO-dg, δ) : 2.21 (3H, s), 3.2-3.4 (2H, m) , 3.9- 5 4.0 (2H, ) , 8.18 (IH, s) Preparation 23-2) Tne following compound was obtained according to a similar manner to that of Preparation 5-2) . C l-A.cetyl-6- ( 1-ethoxy-l-ιmmomethyl ) -2, 3-dmydrothιeno- [2, 3-b] [1, 4 ] thiazme hydrochloride IR (Nujol) : 1665, 1595 cm "1 (+) APCI MASS : 271 (M+H) + NMR (DMSO-d 6 , δ) : 1.3-1.5 (3H, m) , 2.26 (3H, s), 3.2- 3.5 (2H, m) , 3.9-4.1 (2H, m) , 4.5-4.7 ' 2H, m, , 8.81 (IH, s) Preparation 24-1 ) The following compound was obtained according to a similar manner to that of Preparation 15-6). 2, -Dihydro- 1-ethyl-6-methoxycarbonyI-2-oxothieno- [2, 3-b] [1, ] thiazine IR (Nujol) : 1700, 1650 cm "1 NMR (DMSO-dg, δ) : 1.08 (3H, t, J=7.1Hz), 3.69 2H, ε), 3.83 (3H, s), 3.92 (2H, σ, J=7.1Hz), 7.7^ (IH, s- Preparation 24-2) The following compound was obtained according to a similar manner to that of Preparation 6-2). 2, 3-Dιhydro-l-ethyl-6-methoxycarbcnyltmeno [2, 3-b] - [1,4] thiazine IR (Nujol) : 2950, 1700, 1550 cm "1 (+) APCI MASS : 244 (M+H) + NMR (DMSO-dg, δ) : 1.02 (3H, t, J=7.0Hz), 3.1-3.5 (6K, m) , 3.76 (3H, s), 7.41 ;1H, s, Example 1 To a mixture of ammonium chloride (NK^Ci) (66.5 g) and toluene (3 ml) was dropwise added 2 M trimethylalmmuir (AlMe 3 ) (0.62 ml) under nitrogen atmosphere at r.t., and the mixture was stirred at r.t. for 1 hour. To the reaction mixture was added a mixture of 4-(N- butylcarbamoylmethylidene) -2-methoxycarbonyl-4, 5, 6, 7- tetrahydrobenzo [bl thiophene (95.6 mg) and toluene (2 r_j. The reaction mixture was stirred at reflux for 8 hours. A-fter bemg allowed to cool at room temperature, the reaction mixture was poured into a mixture of chloroform (CHCl^) ana MeOH. After removal of insoluble solids, the filtrate was evaporated m vacuo. The resulting residue was purified by chromatography on silica gel (CHCl 3 -MeOH as an eiuent) . The fractions including the object compound were collected and evaporated in vacuo. The resulting precipitate was washed with Et 9 0 to give 4- (N-butylcarbamoylmethylidene) -2-amιdmo- 4 , 5, 6, 7- etranydrobenzo [b] thiophene (39.8 mg) . mp : 114-117°C IR (KBr) : 3274, 1648, 1558, 1540, 1508 cm "1 MASS (z/e) : 292 (M+H) + of free NMR (DMSO-dg, δ) : 0.88 (2H, t, J=6.9Hz), 1.2-1.6 (4H, m) , 1.87 (2H, m) , 2.94 (2H, t, J=5.6Hz), 3.0-3.2 '4H, m) , 6.30 (IH, s), 8.05 (IK, t, J=7.5Hz), 8.3 " ilH, s), 9.31 (4H, s) Example 2-1) The following compound was obtained according to a similar manner to that of Example 1. 2-Amιdmo-4-n-butylιdene-4, 5, 6, 7-tetrahydrobenzo [b] - t iophene hydrochloride mp : 115-118 °C IR (KBr) : 3085, 1660, 1564, 1504 cm "1 MASS (z/e) : 235 (M+H) of free NMR (DMSO-d 6 , δ) : 0.88 (3H, m) , 1.3-3.0 (10H, m) , 5.67 and 5.95 (IH, each t, J=7.2Hz), 8.10 and 8.39 (IH, each s), 9.14 and 9.32 (4H, each s) Example 2-2) The following compound was obtained according to a similar manner to that of Example 4-2) . 2-Amιdmo-4-n-butyl-4, 5, 6, 7-tetrahydrobenzo [b] thiophene tπfluoroacetate mo : 235-238°C IR (KBr) : 3305, 3093, 2937, 1668, 1597, 1512 cm "1 MASS (z/e) : 237 (M+H) + of free NMR (DMSO-dg, δ) : 0.91 (3K, m) , 1.2-3.0 (13K, m) , 7.91 (IH, s), 9.01 and 9.10 (4H, each s) Example 3 A mixture of 4-n-butylιdene-2- ( 1-ethoxy-l-ιmmomethyi ) - 5,6,7, 8-tetrahydro-4H-cyclohepta [b] thiophene nydrochloride (0.34 g) , 2.7 N ethanol solution of ammonia (I.00 ml) and EtOH (20 ml) was stirred at reflux for 6 hours. After evaporation, the resulting oil was purified by chromatography on silica gel (CHCl 3 -MeOH as an eluent) . The fractions including the object compound were collected and evaporateα in vacuo. The resulting syrup was dissolved with a mixture of 0.1 TFA aqueous solution and acetonitrile (CH3CN) , and lyophilized to give 2-amιdmo-4-n-butylιdene-5, 6, 7, 8- tetrahydrc-4H-cyclohepta [b] thiophene trifluoroacetate (84.2 mg) . mp : 91-94°C IR (KBr) : 3087, 1660, 1564, 1504 cm "1 MASS (z/e) : 249 (M+H) τ of free NMR (DMSO-dg, δ) : 0.7-2.4 (13H, m) , 2.89 (2H, t, J=6.1Hz), 5.71 and 5.89 (IH, each t, J= .4Hz (at 5.71) and 5.8 (at 5.89)), 8.00 and 8.12 (IH, each s), 9.11, 9.26, and 9.33 (4H, each s) Example 4-1) Tne following compound was obtained according to a similar manner to that of Example 1. 2-Amιdmo-4-n-butylιdene-4, 5, 6, 7-tetrahydrobenzo [b] furan hydrochloride mp : 156-160°C IR (KBr) : 3336, 3101, 1672, 1612, 1556 cm "1 MASS (z/e) : 219 (M+H) " of free NMR (DMSO-dg, δ) : 0.90 (3H, t, J=7.4Hz), 1.38 (2H, q, =7.4Hz), 1.90 (2H, m) , 2.14 (2H, q, J=7.4Hz), 2.38 (2H, ) , 2.78 (2H, t, J=6.3Hz), 5.36 and 5.63 (IH, each t, J=7.4Hz), 8.06 (IH, s), 9.12 and 9.37 (4K, each br s) Example 4-2) A mixture of 2-amιdιno-4-n-butylιdene- , 5, 6, 7- tetrahyαrobenzo [b] furan hydrochloride (107.3 mq), 10 Pd on carbon, a a MeOH (1 ml) was stirred at r.t. ur.dei hydrogen (K ) atmosphere for 2 nours . After removal of tne catalyst, the filtrate was evaporated, and dissolved in a mixture of acetonitrile (CH3CN) and 0.1 r aqueous trifluoroacetic acid (TFA aq) . The solution was subjected to preparative High Performance Liquid Chromatography (HPLC) under the following condition : Preparative HPLC condition : Column YMC- PACK-0DS - 15 S - 15 120A Oέ x 250 mm Eluent 40 - CH3CN in 0 . 1 1 TFA aq Flow 1 1 8 ml/m utes Fractions including the object compound were combined, concentrated m vacuo, and lyophilized to give 2-amιdιno-4- butyl-4, 5, 6, " '-tetranydrooenzo [b] furan (0.05 g) . mp : 243-245°C IR (KBr) : 3305, 3104, 2937, 1672, 1569 cm "1 MASS (z/e) : 221 (MτH) x of free NMR (DMSO-d 6 , δ) : 0.90 (3H, ) , 1.2-2.2 (11H, m) , 2.80 (2H, m) , 7.65 (IH, s), 8.88 and 9.09 (4H, each s) The following compound was obtained according to a similar manner to that of Example 3. 6-Amιdmo-l-butyl-2, 3-dihydro-2-oxo-lH-thιeno [2, 3-b] - [ 1, 4 ] thiaz e 4,4-dιoxιde hydrochloride IR (Nujol) : 1670, 1550, 1510 cm "1 (-) APCI MASS : 302 (M+H) + NMR (DMSO-dg, δ) : 0.89 (3H, t, J=7.2Hz), ...2-1.7 (4K, ) , 3.9-4.1 (2H, m), 5.05 (2H, s), 8.37 (IK, s), 9.50 (4H, br s) Elemental Analysis for C-, 1 H 16 C1N 3 03S 9 -1.6H 2 0 Calcd. : C 36.03, H 5.28, N 11.46 Found : C 36.01, H 5.07, N 11.3C Example 6 The following compound was obtained according to a similar manner to that of Example I. 6-Amιdmo-l-butyl-2, 3-dιhydro-lH-thιeno ι 2, 3-b] [1,4]- thiazme trifluoroacetate IR (Nujol) : 1655, 1570, 1505 cm "1 (+) APCI MASS : 256 (M+H) + NMR (DMSO-dg, δ) : 0.92 (3H, t, J=7.2Hz), 1.2-1.5 (4H, m) , 3.1-3.3 (4K, m) , 3.4-3.6 (2H, m) , 7.73 (iκ, s i , 9.01 (4K, br 3) Example 7 The following compound was obtained according to a similar manner to that of Example 1. 6-Amιdιno-l-benzyl-2 , 3-dιhydro-lH-tnιeno [ 2 , 3-b] [ 1 , J - thiazme hydrochloride IR (Nujol) : 1650, 1570, 1500 cm "1 (-) APCI MASS : 290 (M+H) + NMR (DMSO-d 6 , δ) : 3.0-3.2 (2H, ) , 3.4-3.6 (2H, m) , 4.4-4.6 (2H, m) , 7.2-7.5 (5H, m) , 8.07 (IH, s,, 9.06 (4H, br s) The following compounds were obtained according to a similar manner to that of Example 3. Example 8-1) 6-Amιdino-2, 3-dihydro-l- (3, 4-dιmethoxyphenethyl ) -2-oxo- lH-thieno [2, 3-b] [ 1 , 4 ] thiazme hydrochloride mp : 133-135 °C IR (Nujol) : 1660, 1565, 1505 cm "1 (+) APCI MASS : 378 (M-H) + NMP (DMSO-dg, δ) : 2.7-2.9 (2H, ) , 3.69 (3H, s,, 3.72 (2H, s), 3.74 (3H, s), 4.0-4.2 (2H, ) , 6.7-6.9 (3H, m) , 8.29 (IH, s;, 9.28 (4K, br s) Elemental Analysis for C 17 H 20 ClN 3 O 3 S 2 -l .2H 2 0 Calcd. : C 46.88, H 5.18, N 9.65 Found : C 46.60, H 4.74, N 9.43 Example 8-2) 6-Amidino-l-cyclohexylmethyl-2, 3-dιhydro-2-oxo-lK- thieno [ 2 , 3-b] [1,4] thiazine hydrochloride mp : >250°C IR (Nujol) : 1665, 1565 cm "1 (+) APCI MASS : 310 (M+H)" NMR (DMSO-dg, δ) : 0.8-1.2 (5H, m) , 1.5-1.8 (6K, m) , 3.7-3.8 (4H, n) , 8.27 (IK, s), 9.30 (4K, br s) Elemental Analysis for C 14 K 0 CIN 3 OS 2 -: .3H 2 0 Calcd. : C 45.53, H 6.17, N 11.38 Found : C 45.51, H 6.14, N 11.14 Example 8-3) 6-Amidino-2, 3-dihydro-2-oxo-l-phenethyl-lH-thιeno- [2, 3-b] [1, ] thiazine hydrochloride mp : >250°C IR (Nujol) : 3350, 1675, 1630, 1570 cm "1 ( J -l APCI MASS : 318 (M+H)" NMR (DMSO-dg, δ) : 2.8-3.0 (2H, m) , 3.73 (2H, s), 4.0-4.2 (2H, m) , 7.1-7.4 (5H, m) , 8.27 (IH, s), 9.33 (4H, br s) Elemental Analysis for C-, 5 H 16 C1N 3 OS 2 -0.2H 2 0 Calcd. : C 50.40, K 4.62, N 11.75 Found : C 50.36, H 4.54, N 11.62 5 Example 8-4) 6-Amιdιno-2, 3-dihydro-1- ( 3, 4-methylenedιoxyphenethyI ) -2- oxo-lH-thieno [2, 3-b] [1,4] thiazme hydrochloride mp : 161-162"C C IR (Nujol) : 1660, 1565, 1500 cm "1 ( A ) APCI MASS : 362 (M+H)" NMR (DMSO-dg, δ) : 2.7-2.9 (2H, m) , 3.72 (2H, s), 3.9-4.2 (2H, m) , 5.96 (2H, s), 6.6-7.0 (3K, m) , 8.25 (IH, s) , 9.30 (4H, br s) 5 Elemental Analysis for C 1 6 E l Cl 3 0 3 S2-l .0H 2 O Calcd. : C 46.21, H 4 . 36 , N 10. IC Found : C 46.03, K 4.02, N 9.69 Example 8-5) 6-Amιdmo-l-benzyl-2, 3-dιhydrc-2-oxo-lH-thιeno [2, 3-b] - [1, 4] thiazme hydrochloride mp : 164-166°C IR (Nujol) : 1665, 1570 cm "1 (+) APCI MASS : 304 (M+H) ~ NMR (DMS0-d 6 , δ) : 3.88 (2H, s), 5.10 (2H, s), 7.2-7.4 (5H, ) , 3.26 (IH, s), 9.25 (4H, or s) Elemental Analysis for C^π^Cl^ϋS^-l .2H 2 0 Calcd. : C 46.52, H 4.57, N 11.62 Found : C 46.52, H 4.18, N 11.58 Example 9-1) Tne following compound was obtained according to a similar manner to that of Example 3. 6-Amιdmo-l-ethoxycarbonylmethyl-2 , 3-dιhydro-2-oxc-lH- thieno [2, 3-b] [ 1, 4 ] tmazme hydrochloride IR (Nujol) : 3380, 1735, 1660, 1570 cm "1 (+) APCI MASS : 300 (M+H) τ NMR (DMSO-dg, δ) : 1.22 (3H, t, J=7.1Hz), 3.82 (2H, s), 4.16 (2H, q, J=7.1Hz), 4.63 (2H, s), 8.11 (IH, s,, 9.24 (4K, br s) Example 9-2) A. mixture of 6-amιdmo-l-ethoxycarbonylmethyl-2, 3- dιhydro-2-oxo-lH-thιeno [2, 3-b] [1, 4 ] thiazme hydrochloride (0.15 g) ano cHCl (1.5 ml) was stirred at 80°C for 7 hours. The reaction mixture was evaporated in vacuo. The resulting oil was dissolved witn water, and lyophilized to give 6- amιdmo-l-carboxymethyl-2, 3-dιhydro-2-oxo-lH-thιeno [2, 3-b - [ 1 , 4 ] thiazme hydrochloride (90.6 mg) . IR (Nujol) : 1715, 1665, 1575 cm "1 (^) APCI MASS : 272 (M+H) + NMR (DMS0-d 6 , δ) : 3.81 (2H, s), 4.54 (2H, s), 8.09 (IH, s), 9.10 and 9.37 (4H, each s) Example 10 The following compound was obtained according to a similar manner to that of Example 3. 6-Am dmo-2, 3-dιhydro-2-oxo-lH-thιeno[2, 3-b] [l,4j- thiaz e nydrochlonde mp : >250°C IR (Nujol) : 3150, 1665 cm "1 (-) APCI MASS : 214 (M-i-H) ~ NMR (DMSO-dg, δ) : 3.66 (2H, s), 7.72 (IH, s), 9.37 (4H, br s) , 11.10 (IH, br s) Tne following compounds were obtained according to a similar manner to that of Example 3. 6-Amidino-2 , 3-dihydro- 1- (2-hydroxyethyl ) -2-oxo-lK- tnieno [2, 3-b] [1,4] thiazme trifluoroacetate IR (Nujol) : 1625 cm "1 (-, APCI MASS : 258 (M+H) " NMR (DMSO-dg, δ) : 3.5-3.7 (2H, m) , 3.74 (2H, s), 5.8-4.0 (2H, m) , 8.09 (IH, s), 9.18 and 9.30 (4K, each s) Example 11-2) 6-Amid o-1- (n-butylcarbamoylmethyl ) -2, 3-dιhydro-2-oxc- lH-thieno [2, 3-D] [ 1 , 4 ] thiazine hydrochloπαe IR (Nujol) : 1650, 1560, 1500 cm "1 NMR (DMSO-dg, δ) : 0.8-0.9 (3H, m) , 1.2-1.5 (4K, m) , 3.0-3.2 (2H, ) , 3.79 (2H, s), 4.42 (2H, s), 8.03 (IH, s), 8.19 (IH, t, J=5.4Hz), 9.23 (4H, br s) Example 11-3) 6-Amιdino-l- (2,2, 2-tr fluoroetnylcarbamoylm.ethvl ) -2,3- dιhydro-2-oxo-lH-thιeno [2, 3-b] [1, ] thiazine hydrochloride IR (Nujol) : 3300, 3100, 1640, 1570, 1510 cm "1 (-) APCI MASS : 353 (M+H) + NMR (DMSO-dg, δ) : 3.80 (2H, s), 3.8-4.1 (2H, m) , 4.53 (2H, s), 8.00 (IH, s), 8.9-9.1 (IH, m) , 9.22 (4H, br s) Example 11- 2-Amιdmo-l- ( 3-ethoxycarbonylpropyl ) -2, 3-dιhyαro-2-cxc- lH-thieno i 2, 3-b] [ 1 , 4 ] thiazme hydrochloride IR (Nujol) : 3350, 1720, 1655, 1630, 1570 cm "1 ( - ) APCI MASS : 328 (M+H) " NMR (DMSO-dg, δ) : 1.17 (3K, t, J=7.1Hz), 1.7-1.9 (2H, ) , 2.35 (2H, t; J=7.5Hz), 3.75 (2H, s), 3.89 (2K, t, J=7.0Hz), 4.04 (2H, q, J=7.1Hz), 8.26 (IH, s}, 9.29 (4H, br s) Example 1 1 -5 ) 6-Aidino-2, 3-dihydro-l- (3, 4-methyIenedιoxyphenyl- carbamoylmethyl) -2-oxo-lH-thieno [2 , 3-b] [1,4] thiazine hydrochloride IR (Nujol) : 1660, 1565 cm "1 NMR (DMSO-dg, δ) : 3.82 (2H, s) , 4.66 (2H, s), 5.98 (2H, s), 6.85 (IH, d, J=8.4Hz), 7.02 (IH, d, J=3.4Hz), 7.32 (IK, s), 8.19 (IK, s), 9.26 { 4K, hi s), 10.43 (IH, s) Example 11-6) 6-Amidino-l-n-butyl-2, 3-dihydro-2-oxo-lH-thienc [2, 3-b] - [1,4-] thiazine hydrochloride mp : 213-21 °C IR (Nujol) : 164C, 1570 cm "2 (÷) APCI MASS : 270 (M+H) ÷ NMR (DMSO-dg, δ) : 0.89 (3H, t, J=7.2Kz), 1.2-1.6 (4K, m) , 3.74 (2H, s), 3.8-4.C (2H, m) , 8.25 (IH, s) , 9.31 ( 4H, br s) Elemental Analysis for C 11 H 16 C1N 3 OS 2 , 0.75H 2 0 Calcd. : C 41.37, H 5.52, N 13.16 Found : C 41.42, H 5.40, N 13.22 The following compound was synthesized according to the similar manner to that of Example I. Example 12 6-Amidino-2, 3-dihydro-i- (2-methylthιoethyl) -2- oxothieno [2, 3-b] [ 1 , 4 ] thiazine hydrochloride IR (KBr) : 1664, 1594 cm "1 NMR (DMSO-d β , δ) : 2.15 (3H, s), 2.71 (2H, t, J= 7 .4), 3.86 (2H, s), 4.13 (2H, t, J=7.4Hz), 7.50 (IH, br s), 7.97 (IH, s), 8.15 (IH, br s), 9.13 (IH, br s) Example 13-1) 6-Ethoxycarbonyl-2- ( 1-ethoxy-l-ιmmomethyl ) -4,5,6,7- tetrahydrobenzo [b] thiophene hydrochloride (1.51 g) , 2.7 N ethanol solution of ammonia (1.41 ml) and EtOH (5 ml) was stirred at reflux for 4 hours. After evaporation, the resulting oil was purified by chromatography on silica gel (CHCl 3 -MeOH as eluent) , and subsequently washed with Et 2 0 to give 2-amιdmo-6-ethoxycarbonyl-4, 5, 6, 7-tetrahydrobenzo [b] - thiophene hydrochloride (1.20 g) . mp : 155-157°C IR (KBr) : 3101 (br), 1726, 1660, 1573, 1513 cm "1 APCI MASS : 253 (M+H of free) NMR (DMSO-d 6 , δ) : 1.20 (3H, t, J=7.1Hz), 1.8 (IH, m) , 2.1 (IH, m) , 2.67 (2H, t, J=5.8Hz), 2.8-3.2 (3H, m) , 4.11 (2H, q, J= " MHz), 7.81 (IH, s), 9.02 and 9.22 (4H, both br s) Example 13-2) A mixture of 2-amιdmo-6-ethoxycarbonyl-4 , 5, 6, 7- tetrahydrobenzo [b] thiophene hydrochloride (1.15 g) , and 6 N HCl (10 ml) was stirred at 70°C for 9 hours. The resulting precipitate was washed with Et-pO to give 2-amιdmo-6-carboxy- 4, 5, 6, 7-tetrahydrobenzo[b] thiophene hydrochloride (0.96 g) . mp : >250°C IR (KBr) : 3342, 3122, 2879, 1700, 1664, 1573, 1515 cm "1 APCI MASS : 225 (M+H of free) NMR (DMSO-d 6 , δ) : 1.83 (IH, ) , 2.10 (IH, m) , 2.6-3.2 (5H, m) , 7.82 (IH, s), 9.06 ana 9.24 (4H, both br s) Example 13-3) To a mixture of 2-amιdmo-6-carboxy-4 , 5, 6, 7-tetrahydro- benzo [b] thiophene hydrochloride (0.91 g) , water (20 ml), and dioxane (40 ml) was dropwise added di-tert-butyl dicarbonate (0.88 ml) maintaining to pH 9.5-10, and was stirred at r.t. for 2 hours. The reaction mixture was adjusted to pH 4 with 6 N HCl, and was extracted with AcOEt. The separated organic layer was washed with water, and dried over MgSO^, and evaporated. The resulting precipitate was washed witn n-hexane to give 2- (N-^-tert-butoxycarbonylamidino) -6-carbcxy- 4 , 5, 6, 7-tetrahydrobenzo [b] thiophene (0.86 g) . NMR (DMSO-d β , δ) : 1.42 (9H, s), 1.83 1(1H, m) , 2.1C (IH, m) , 2.6-3.2 (5H, m) , 7.66 (IH, s), 8.91 (3h, br s) Example 13-4) To a mixture of 2- (N-^-tert-butoxycarbonylamidino) -6- carboxy-4, 5, 6, 7-tetrahydrobenzo [b] thiophene (0.40 g) , CH 2 C1 2 (10 m) , and dimethylformamide (DMF) (2 ml) was added triethylamme (0.17 ml) at r.t., and then O-benzotrιazol-1- yl-N, , N' , N ' -tetramethyluronium hexafluorophosphate (0.40 g) was added thereto. The reaction mixture was stirred at r.t. for 15 minutes. To the reaction mixture were added N,0- dimethylhydroxyamine hydrochloride (0.13 g) and triethylamme (0.19 ml), and the mixture was stirred at r.t. for 1 hour. After removal of solvents by nitrogen flow, the reaction mixture was added into a mixture of AcOEt and water. The separated organic layer was washed with water, and brme, and dried over MgS0 4 . After evaporation of the filtrate, tne resulting precipitate was washed with isopropyl ether to g ve 2- (N 1 -tert-butoxycarbonylamιdιno) -6- (N-metnyl-N-methoxy- carbamoyl ) - , 5, 6, 7-tetrahydrobenzo [b] thiopnene which was used in the following reaction without further purification. Example 13-5) A mixture of crude 2- (N -tert-butoxycarbonylamιdιno) -6- (N-metnyl-N-methoxycarbamoyl) -4,5,6, 7-te rahydrooenzo [o] - thiophene (0.05 g) , water (0.06 ml), and trifluoroacetic acid (TFA) (0.6 ml) was stirred at r.t. for 2 hours. After removal of solvent by nitrogen flow, the resulting precipitate was washed with Et 2 0 to give 2-amιdιno-6- (N- methyl-N-methoxycarbamoyl) - , 5, 6, 7-tetranydrobenzo [b] - thiophene trifluoroacetate (40.2 mg) . IR (KBr) : 3301, 3085, 1670, 1577, 1515 cm "1 APCI MASS : 268 (M+H of free) NMR (DMSO-d 6 , δ) : 1.83 (IH, m) , 2.10 (IH, ) , 2.6-3.2 (5H, m) , 3.15 (3H, s), 3.71 (3H, s), 7.84 (IH, s), 8.89 and 9.11 (4H, both br s) Example 13-6) To a mixture of 2- (N^-tert-butoxycarbonylamidino) -6- (N- methyl-N-methoxycarbamoyl) -4,5,6, 7-tetrahydrobenzo [b] - thiophene (0.37 g) , Et 0 (10 ml), and tetrahydrofuran (THF) (2 ml) was added lithium aluminum hydride (76.4 mg) at 0°C under nitrogen atmosphere. The reaction mixture was stirred under the same conditions for 30 minutes. To the reaction mixture was added a saturated aqueous solution of ammonium hydrochloride to quench the reaction. The reaction mixture was added into a mixture of AcOEt and water. After removal of resulting insoluble precipitates by filtration, the separated organic layer was washed with water, and brme, and dried over gSO^ . After evaporation of the filtrate, the resulting precipitate was washed with isopropyl ether to give 2- (N-^-tert-butoxycarbonylamidino) -6-formyl-4, 5,6,7- tetrahydrobenzo [b] thiophene (0.26 g) , which was used in the following next reaction without further purification. The following compound was obtained according to a similar manner to that of Example 13-5) . Example 13-7) 2-Amιdιno-6-formyl-4, 5,6, 7-tetrahydrobenzo [b] thiophen* trifluoroacetate mp : 191-194°C IR (KBr) : 3083, 1672, 1579, 1517 cm "1 MASS (z/e) : 209 (M+H) 4" of free NMR (DMSO-d 6 , δ) : 1.80 (IH, m) , 2.10 (IH, m) , 2.67 (2H, t, J=6.2Hz), 2.6-3.2 (3H, m) , 7.73 (IH, s), 8.95 and 9.11 (4H, both br s), 9.71 (IH, s) Example 14-1) The following compound was obtained according to a similar manner to that of Example 3. 6-Amidino-2, 3-dihydro-l- (ethoxycarbonyiacetyl) thieno- [2, 3-b] [1, ] thiazine hydrochloride (+) APCI MASS : 314 (M+H) + NMR (DMSO-dg, δ) : 1.1-1.3 (3H, m) , 3.3-3.5 (2H, m) , 3.83 (2H, s), 3.9-4.2 (4H, ) , 8.51 (IH, s), 9.17 (4H, s) Example 14-2) The following compound was obtained according to a similar manner to that of Example 9-2). 6-Amidino-l-carboxyacetyl-2, 3-dihydrothieno [2, 3-b] [ 1, 4 ] t hiazine hydrochloride IR (Nujol) : 1700, 1655, 1625 cm "1 NMR (DMSO-d 6 , δ) : 3.0-3.2 (2H, m) , 3.25 (2H, s), 3.4- 3.6 (2H, m) , 7.51 (IH, s), 8.97 and 9.14 (4H, each s) Example 15 The following compound was obtained according to a similar manner to that of Example 3. 6-Amidmo-l-benzoyl-2, 3-dihydrothieno [2, 3-b] [1,4]- thiazine hydrochoride (+) APCI MASS : 304 (M+H) + NMR (DMSO-dg, δ) : 3.3-3.5 (2H, m) , 3.9-4.1 (2H, m) , 7.53 (5H, s), 8.29 (IH, s), 9.19 (4H, s) Exampl e 1 6 The following compound was obtained according to a similar manner to that of Example 3. l-A.cetyl-6-amidino-2, 3-dihydrothieno [2, 3-b] [1,4] thiazme hydrochloride ( + ) APCI MASS : 242 (M-t-K) " NMR (DMSO-dg, δ) : 2.25 (3H, s), 3.3-3.4 (2H, mi, 3.9- 4.1 (2H, m) , 8.44 (IH, s > , 9.24 (4K, br s) Example 17-1) The following compound was obtained according to a similar manner to that of Example 1, which was used m the next reaction without further purification. 6-Amιdino-2, 3-dihydro-l-ethylthieno [2, 3-b] [1,4] thiazme hydrochloride Example 17-2) The following compound was obtained according to a similar manner to that of Example 13-3) . 6- (N'-tert-Butoxycarbonylamidmo) -2, 3-dihydro-l- ethylthieno [2 , 3-b] [1,4] thiazine (->-) APCI MASS : 328 (M+H) + NMR (DMSO-d 6 , δ) : 1.06 (3H, t, J=7.0Hz), 1.42 (9H, s), 3.0-3.2 (2H, m) , 3.25 (2H, q, J=7.0Hz), 3.4-3.5 (2H, m) , 7.73 (IH, s), 8.87 (2K, br s) Example A. solution of 6- (N -tert-butoxycarbonylamidmo) -2 , 3- dihydro-l-ethylthieno[2, 3-b] [1, 4] thiazme (0.51 g) in trifluoroacetic acid (4.5 ml) and water (0.5 ml) was stirred for 72 hours at room temperature. The solvent was evaporated in vacuo and the residue was pulverized from diethyl ether to give 6-amιdmo-2 , 3-dihydro-1-ethylthieno [ [2, 3-b] [1, 4] thiazme trifluoroacetate (0.50 g) . (T) APCI MASS : 228 (M+H) + NMR (DMSO-d 6 , δ) : 1.0-1.2 (3H, m) , 3.1-3.6 (6H, m) , 7.74 (IK, s) , 9.02 (4H, br ≤) 20 ?5

Claims: CLAIMS A compound of the formula ' R in which R 1 is hydrogen, optionally substituted lower alkylcarbamoyl ( lower) alkylidene, lower alkylidene, lower alkyl, optionally substituted ar (lower) alkyl, cyclo (lower) al yl ( lower) alkyl, protected carboxy (lower) alkyl, carboxy (lower) alkyl, hydroxy ( lower) alkyl, optionally substituted lower alkylcarbamoyl (lower) alkyl, lower alkylthio (lower) alkyl, carboxy (lower) alkanoyl, protected carboxy (lower) alkanoyl, aroyl, lower alkanoyl, or optionally substituted arylcarbamoyl ( lower) alkyl, R- is hydrogen, carboxy, protected carboxy, formy.. or N- lower) alkyl-N- (lower) alKoxycarba oyl, R is hyyddrrooggeenn oorr aammiiddimnoo--pprrootteecctive group, A is lower alkylene or carbonyl, X is —c- -CH— or —N— Y is lower alkylene, -S- or -S0 2 -, the line: - ' z ^ is a single bond or a double bond, or pharmaceutically acceptable salts tnereof. 2. The copound of Claim 1, wherein R 1 is hydrogen; lower alkylcarbamoyl (lowe ) alkylidene optionally substituted by halogen; lower alkylidene; lower alkyl; ar (lower) alkyl optionally substituted by the group consisting of lower alkyl, lower alkoxy and lower alkylenedioxy; cyclo (lower) alkyl (lower) alkyl; lower al oxycaroonyl (lower) alkyl; carboxy ( lower) al yl ; hydroxy (lower ) alkyl ; lower alkylcarbamoyl (lower) alkyl optionally substituted by halogen; lower alkylthio ( lower ) alkyl ; carboxy ( lower) alkanoyl ; lower alkoxycarbonyl (lower ) alkanoyl ; aroyl; lower alkanoyl; or arylcarbamoyl ( lower ) alkyl optionally substituted by the group consisting of lower alkyl, lower alkoxy and lower alkylenedioxy; R is hydrogen, carboxy, lower alkoxycarbonyl, formyl, or N- (lower) alkyl-N- (lower) alkoxycarbamoyl, and R° is hydrogen or lower alkoxycarbonyl. 3. The compound of Claim 2, wherein X is _c— or —CK— , and Y is lower alkylene. 4. The compound of Claim 2, wherein R 1 is hydrogen; lower alkyl; ar ( lower ) alkyl optionally substituted oy the group consisting of lower alkyl, lower alkoxy and lower alkylenedioxy; cyclo (lower) alkyl (lower) alkyl; lower alkoxycarbonyl (lower) alkyl; carboxy (lower) alkyl; hydroxy (lower ) alkyl ; lower alkylcarbamoyl (lower) alkyl optionally substituted by halogen; lower alkylthio ( lower ) alkyl ; carboxy ( lower) alkanoyl; protected carboxy (lower) alkanoyl; aroyl; lower alkanoyl; or arylcarbamoyl (lower ) alkyl optionally substituted by the group consisting of lower alkyl, lower alkoxy and lower alkylenedioxy; X is -N- Y is -S- or -S0 2 -, and Z is -S-. 5. A process for the preparation of a compound of the formula : in which R 1 , R 2 , R 3 , A, X, Y, Z and the line: are each as defined in Claim 1, or salts thereof, which comprises ' a) converting the ester moiety of a compound of the formula : or a salt thereof to the amidino moiety to give a compound of the formula : a salt thereof; or (b) reducing a compound of the formula or a salt thereof to give a compound of the formula or a salt thereof; or ' c) reacting a compound of the formula or a salt thereof witn ammonia or a salt tnereof to give a compound of the formula (I-a), or a salt thereof; cr (d) subjecting a compound of the formula : or a salt thereof to a removal reaction of the ι carboxy-protective group m R to give a compound of the formula : or a salt thereof; or !e) subjecting a compound of the formula or a salt thereof to a removal reaction of the carboxy- protective group in R^ to give a compound of the formula : or a salt thereof introducing an amidmo-protective group into a compound of the formula : or a salt thereof, to give a compound of the formula : or a salt thereof; or [ q ) reacting a compound of the formula or its reactive derivative at the carboxy group, or a salt thereof, with N- ( lower) alkyl-N- (lov/er) alkoxyamine or a salt thereof, to give a compound of the formula : or a salt thereof; or (h) subjecting a compound of the formula or a salt tnereof, to a removal reaction of the amidmo-protective group of R:j, to give a compound of tne formula (I-a) or a salt thereof; or i) reducing a compound of the formula R 1 or a salt thereof, to give a compound of tne formula or a salt thereof; m which P 1 , R 2 , R 3 , A, X, Y, Z and the line: are each as defined above, R g is optionally substituted lower alkylcarbamoyl- (lower) alkylidene or lower alkylidene, Rg is optionally substituted lower alkylcarbamoyl- (lower) alkyl or lower alkyl, R is protected carboxy (lower ) alkyl, R^ is carboxy (lower) lkyl, R- is protected carooxy, R s N- (lower) alkyl-N- (lower) alkoxycarbamoyl, Prj is amidmo-protective group, R^" is ester residue, I I X a is —CH— or —F— • 6. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof m admixture with pharmaceutially acceptable carriers or excipients 7. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament . 8. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament. 9. A method for the prophylactic and/or the therapeutic treatment of diseases initiated by uror.mase which co prises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.

Inventors: MIZUNO HIROAKI, SAKURAI MINORU, TANAKA AKITO, MIZUNO, HIROAKI, SAKURAI, MINORU, TANAKA, AKITO
Applicants: FUJISAWA PHARMACEUTICAL CO, MIZUNO HIROAKI, SAKURAI MINORU, TANAKA AKITO, FUJISAWA PHARMACEUTICAL CO., LTD., MIZUNO, HIROAKI, SAKURAI, MINORU, TANAKA, AKITO
Application year: 1997
Main classification: C07D333
IPC codes: A61K31, A61P9, A61P15, A61P19, A61P27, A61P35, C07D307, C07D333, C07D513