Amidine compounds

Abstract

A compound of the formula [I] wherein R 1 , R 2 and R 3 are the same or different and each is hydrogen atom, hydroxy, lower alkyl or aryl, R is a group of the formula wherein each symbol is as defined in the specification, a salt thereof or a prodrug thereof. The compound of the present invention, a salt thereof and a prodrug thereof are useful as factor Xa inhibitor and blood coagulation inhibitor, and are useful for the prophylaxis and/or treatment of diseases caused by blood coagulation or thrombus.

What is claimed is:  
     
         1 . An amidine compound of the formula [I] 
       
         
           
           
               
               
           
         
       
       wherein 
 R is a group of the formula  
                     
 wherein  
 R 4  is hydrogen atom, hydroxy group, lower alkyl group, lower alkoxy group or halogen atom,  
 R 5  is hydrogen atom, cyano group, carboxy group or lower alkoxycarbonyl group,  
 R 6  is hydrogen atom, cycloalkyl group, hydroxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group 
 wherein said aralkyloxycarbonyl group is optionally substituted by halogen atom, nitro group, alkyl group, alkoxy group or trifluoromethyl group,  
 
 nitro group, amino group, lower alkylamino group, di(lower)alkylamino group, aryl group, heteroaryl group 
 wherein said aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from lower alkyl group, hydroxy group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, nitro group, amino group, acylamino group, amidino group and hydroxyamidino group,  
 
 5- to 7-membered saturated heterocycle having at least one nitrogen atom, 
 wherein said saturated heterocycle is optionally substituted by lower alkyl group, acyl group, di(lower)alkylamino(lower)alkanoyl group or imidoyl group,  
 
 or  
                     wherein Ak is lower alkyl group and Hal is halogen atom,    
 X 2  is oxygen atom, sulfur atom, —SO 2 —, —SO 2 NH— or a single bond,  
 X 3  is —(CH 2 ) m — wherein m is 0 or an integer of 1 to 3,  
 X 4  is —CO—, —C(═NH)—, —SO 2 —, —CONH—, —CSNH—, —SO 2 NH—, —(CH 2 ) r CONH—, —(CH 2 ) r CH(OH)—,  
                     wherein r is 0 or an integer of 1 to 3,    
 or a single bond,  
 X 5  is alkylene group having 1 to 6 carbon atoms, alkenylene group having 2 to 6 carbon atoms, or a single bond,  
 R 7  is hydrogen atom, lower alkyl group or  
                     wherein R 9  is oxygen atom, sulfur atom, NH, NR 11  
 wherein R 11  is lower alkyl group, aralkyl group 
 wherein said aralkyl group is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, halo alkyl group, cyano group, nitro group, amino group and acyloxy group,  
 
 or hydroxy group,  
   and R 10  is lower alkyl group, lower alkoxy group, amino group, lower alkylamino group or di(lower)alkylamino group,    
 R 8  is hydrogen atom, lower alkyl group, cycloalkyl group 
 wherein said cycloalkyl group is optionally substituted by lower alkyl group or carboxy group,  
 
 carboxy group, lower alkoxycarbonyl group, aryl group, heteroaryl group 
 wherein said aryl group or heteroaryl group is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group  
 wherein said lower alkyl group is optionally substituted by halogen atom, hydroxy group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group,  
 
 aralkyl group 
 wherein said aralkyl group is optionally substituted by 1 to 3 substituents selected from halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, haloalkyl group, cyano group, nitro group, amino group and acyloxy group,  
 
 or 5 to 7-membered saturated heterocycle having at least one nitrogen atom,  
 Y 1  is oxygen atom, —NH—, —CONH—, —NR 12 —
 wherein R 12  is lower alkyl group or —Y 6 —R 13  
 wherein R 13  is hydrogen atom, lower alkyl group or aryl group 
 wherein said lower alkyl group or aryl group is optionally substituted by carboxy group, lower alkoxycarbonyl group or aralkyloxycarbonyl group,  
 
 Y 6  is —CO—, CO 2 —, —COCO 2 —, —SO 2 —, —SO 2 (CH 2 ) r — or —(CH 2 ) r —
 wherein r is 0 or an integer of 1 to 3,  
 
 
 
 or a single bond,  
 Y 2  is oxygen atom, sulfur atom or a single bond,  
 Y 3  is  
                     wherein s and t are the same or different and each is an integer of 1 to 3,    
 or a single bond,  
 Y 4  is oxygen atom, —CO—, —CO 2 —, —SO 2 —, —CONH—, —CH═CH— or a single bond,  
 Y 5  is —(CH 2 ) p —, —(CH 2 ) p′ —CHAk—(CH 2 ) p″ —, —(CH 2 ) p′ —CAk Ak′—(CH 2 ) p″ —,  
                     wherein Ak, Ak′ are the same or different and each is lower alkyl group, p is 0 or an integer of 1 to 3, p′ and p″ are the same or different and each is 0 or an integer of 1 or 2,    
 or a single bond,  
 ring A is  
                     wherein R 14  is carboxy group, lower alkoxycarbonyl group or aralkyloxycarbonyl group 
 wherein said aralkyloxycarbonyl group is optionally substituted by halogen atom, nitro group, alkyl group, alkoxy group or trifluoromethyl group,  
   
 j is 1 or 2,  
 k is 0 or 1, and  
 m and n are the same or different and each is 0 or an integer of 1 to 3; and  
 R 1 , R 2  and R 3  are the same or different and each is hydrogen atom, hydroxy group, lower alkyl group or aryl group,  
 or a salt thereof or a prodrug thereof.  
 
     
     
         2 . The amidine compound of the formula [I] according to  claim 1 , wherein R is a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 4 , R 5 , R 6 , X 2 , X 3 , X 4 , X 5 , j and k are as defined above, or a salt thereof or a prodrug thereof.  
     
     
         3 . The amidine compound of the formula [I] according to  claim 2 , wherein R is a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 4 , R 5 , R 6 , X 2 , X 3 , X 4 , X 5 , j and k are as defined above, or a salt thereof or a prodrug thereof.  
     
     
         4 . The amidine compound of the formula [I] according to  claim 3 , wherein R is a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 4 , R 5 , R 6 , X 2 , X 3 , X 4 , X 5 , j and k are as defined above, or a salt thereof or a prodrug thereof.  
     
     
         5 . The amidine compound of the formula [I] according to  claim 4 , wherein X 3  is —(CH 2 ) m — wherein m is as defined above and X 4  is a group of the formula  
       
         
           
           
               
               
           
         
       
       and j is 1, or a salt thereof or a prodrug thereof.  
     
     
         6 . The amidine compound of the formula [I] according to  claim 5 , wherein R 6  is hydrogen atom, X 2  is oxygen atom, and X 5  is a single bond, or a salt thereof or a prodrug thereof.  
     
     
         7 . The amidine compound of the formula [I] according to  claim 1 , wherein R is a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5  ring A, m and n are as defined above, or a salt thereof or a prodrug thereof.  
     
     
         8 . The amidine compound of the formula [I] according to  claim 7 , wherein ring A is a group of the formula  
       
         
           
           
               
               
           
         
       
       or a salt thereof or a prodrug thereof.  
     
     
         9 . The amidine compound of  claim 1 , which is selected from the group consisting of 
 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(quinolin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    N-methyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide oxime,    N-phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyrdin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid methyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyrimidin-4-yl)piperidine-4-carboxylic acid,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-[N-[5-amidino-1-(1-phenylethylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]carbamoyl]benzoic acid,    4-[N-[5-amidino-1-(4-benzyloxyphenylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]carbamoyl]benzoic acid,    2-[4-(pyrrolidin-3-yloxy)phenoxymethyl]-1-(2-methoxyethyl)benzimidazole-5-carboxamidine,    2-[4-(1-acetimidoylpyrrolidin-3-yloxy)phenoxymethyl]-1-(2-methoxyethyl)benzimidazole-5-carboxamidine,    7-[1-(2-hydroxyethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(pyridin-4-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-hydroxy-2-phenylethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid N-methylamide,    7-(1-acetylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-(1-benzylsulfonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-naphthylsulfonyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-(1-acetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-(1-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]acetamide,    N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]benzamide,    3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester,    4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester,    4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid,    6-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    1-[2-(benzothiazol-2-yl)-2-oxyethyl]-2-phenoxymethylbenzimidazole-5-carboxamidine,    trans-4-[2-[4-(1-acetimidoylpiperidin-4-yloxy)phenoxymethyl]-5-amidinobenzimidazol-1-ylacetylaminomethyl]cyclohexanecarboxylic acid,    trans-4-[2-[4-(1-acetimidoylpiperidin-4-yloxy)phenoxymethyl]-5-(N-methylamidino)benzimidazol-1-ylacetylaminomethyl]cyclohexanecarboxylic acid,    trans-4-[2-[4-(1-acetimdoylpiperidin-4-yloxy)phenoxymethyl]-5-[amino(hydroxyimino)methyl]benzimidazol-1-ylacetylaminomethyl]cyclohexanecarboxylic acid,    2-[4-(piperidin-4-yloxy)phenoxymethyl]-1-phenacylbenzimidazole-5-carboxamidine,    2-[4-(1-acetimidoylpiperidin-4-yloxy)phenoxymethyl]-1-phenacylbenzimidazole-5-carboxamidine,    2-[2-[4-ethoxycarbonyl-1-(pyridin-4-yl)piperidin-4-yl]ethyl]-1-(cyclohexylcarbamoylmethyl)benzimidazole-5-carboxamidine,    4-[2-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-yl]ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    1-(cyclohexylcarbamoylmethyl)-2-[N-[1-(pyridin-4-yl)piperidin-4-yl]-N-ethoxalylaminomethyl]benzimidazole-5-carboxamidine,    N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[1-(pyridin-4-yl)piperidin-4-yl]aminooxalic acid,    2-[N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]-N-ethoxycarbonylmethylaminomethyl]-1-(cyclohexylcarbamoylmethyl)benzimidazole-5-carboxamidine,    N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]carbamoylbenzoic acid,    2-[N-[4-(1-amidinopiperidin-4-yloxy)phenyl]-N-(4-methoxycarbonylbenzoyl)aminomethyl]-1-(cyclohexylcarbamoylmethyl)benzimidazole-5-carboxamidine,    N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-amidinopiperidin-4-yloxy)phenyl]carbamoylbenzoic acid,    N-[5-amidino-1-(cyclohexylcarbamoylmethyl)benzimidazol-2-ylmethyl]-N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]sulfamoylacetic acid,    7-[1-(pyridin-4-ylacetyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(3-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-hydroxybenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(pyridin-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylmethyl]indole-1-carboxylic acid methyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid benzyl ester,    N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carboxamide,    7-[1-(indol-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid,    N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetamide,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylaminoacetic acid,    7-[1-(5-nitropyridin-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-nitrobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-(1-hexaneimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide,    N-butyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide,    N-cyclohexyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-sulfonamide,    N-(2-nitrophenyl)-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-carbothioamide,    7-[1-(benzimidazol-2-yl)piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid ethyl ester,    3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-aminopyridin-5-ylcarbonyl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(3-aminopropionyl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(imidazol-4-ylacetyl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(piperidin-4-ylsulfamoyl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-dimethylaminoacetylpiperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-3-ylcarbamoyl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-dimethylaminoacetylpiperidin-2-ylcarbonyl)piperidine-4-carboxylic acid ethyl ester,    4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-4-carboxypiperidin-1-yl]-1-methylpyridinium chloride,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(4-amidinophenyl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid,    7-[2-(4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, and    4-(2-amidino-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    or a salt thereof or a prodrug thereof.    
     
     
         10 . The amidine compound of  claim 3 , which is selected from the group consisting of 
 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(quinolin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    N-methyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide oxime,    N-phenyl-7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyrdin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid methyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyrimidin-4-yl)piperidine-4-carboxylic acid,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    7-[1-(2-hydroxyethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(pyridin-4-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-hydroxy-2-phenylethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylglycine ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid N-methylamide,    7-(1-acetylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-(1-benzylsulfonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-naphthylsulfonyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-(1-acetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-(1-phenylacetimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]acetamide,    N-[2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-5-yl]benzamide,    3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester,    4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid methyl ester,    4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridine-3-carboxylic acid,    6-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylthio)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylmethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylamino)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-ylsulfonylaminomethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    7-[1-(pyridin-4-ylacetyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-hydroxybenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(pyridin-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    2-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylmethyl]indole-1-carboxylic acid methyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid benzyl ester,    N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carboxamide,    7-[1-(indol-2-ylmethyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetic acid,    N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-acetamide,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-ylacetylaminoacetic acid,    7-[1-(5-nitropyridin-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-nitrobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-[1-(2-aminobenzyl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    7-(1-hexaneimidoylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    N-benzyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide,    N-butyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide,    N-cyclohexyl-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-sulfonamide,    N-(2-nitrophenyl)-4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidine-1-carbothioamide,    7-[1-(benzimidazol-2-yl)piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid ethyl ester,    3-[4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]propionic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-aminopyridin-5-ylcarbonyl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(3-aminopropionyl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(imidazol-4-ylacetyl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(piperidin-4-ylsulfamoyl)piperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-dimethylaminoacetylpiperidine-4-carboxylic acid,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-3-ylcarbamoyl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-dimethylaminoacetylpiperidin-2-ylcarbonyl)piperidine-4-carboxylic acid ethyl ester,    4-[4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-4-carboxypiperidin-1-yl]-1-methylpyridinium chloride,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(4-aminophenyl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2-methylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(1-ethylpiperidin-4-yl)piperidine-4-carboxylic acid,    7-[2-(4-cyanopiperidin-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine,    4-[2-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)ethyl]-1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester,    4-(2-amidino-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid, and    4-(2-amidino-6-methyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(pyridin-4-yl)piperidine-4-carboxylic acid,    or a salt thereof or a prodrug thereof.    
     
     
         11 . A pharmaceutical composition comprising an amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof, and a pharmaceutically acceptable additive.  
     
     
         12 . A blood coagulation inhibitor comprising an amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof as an active ingredient.  
     
     
         13 . A factor Xa inhibitor comprising an amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof as an active ingredient.  
     
     
         14 . An agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus, which comprises an amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof as an active ingredient.  
     
     
         15 . A method for inhibiting coagulation of blood, which comprises administering the amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof.  
     
     
         16 . A method for inhibiting factor Xa, which comprises administering the amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof.  
     
     
         17 . A method for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus, which comprises administering the amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof.  
     
     
         18 . Use of the amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof for the production of a blood coagulation inhibitor.  
     
     
         19 . Use of the amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof for the production of a factor Xa inhibitor.  
     
     
         20 . Use of the amidine compound of any of  claim 1  to  claim 10  or a salt thereof or a prodrug thereof for the production of an agent for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus.  
     
     
         21 . A commercial package comprising the blood coagulation inhibitor of  claim 12  and a written matter associated therewith, the written matter stating that the inhibitor can or should be used for inhibiting coagulation of blood.  
     
     
         22 . A commercial package comprising the factor Xa inhibitor of  claim 13  and a written matter associated therewith, the written matter stating that the inhibitor can or should be used for inhibiting factor Xa.  
     
     
         23 . A commercial package comprising the agent for the prophylaxis or treatment of  claim 14  and a written matter associated therewith, the written matter stating that the agent can or should be used for the prophylaxis or treatment of diseases caused by blood coagulation or thrombus.