Benzamidine derivatives

Abstract

Benzamidine derivatives of formula (I) or pharmaceutically acceptable salts thereof exhibit excellent inhibitory activity against factor Xa and are useful for treating or preventing blood coagulation disorders: wherein R 1 represents a hydrogen atom, a halogen atom, an alkyl group or a hydroxyl group; R 2 represents a hydrogen atom, a halogen atom or an alkyl group, R 3 represents a hydrogen atom, an optionally substituted alkyl group, an aralkyl group, an optionally substituted alkanoyl group or an optionally substituted alkylsulfonyl group, R 4 and R 5 are the same as or different from each other and each represent a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group or an optionally substituted carbamoyl group, and R 6 represents a substituted pyrrolidine group or substituted piperidine group.

What is claimed is:  
     
         1 . A benzamidine derivative of the following formula (I) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1 -C 6  alkyl group and a hydroxyl group;  
 R 2  is selected from the group consisting of a hydrogen atom, a halogen atom and a C 1 -C 6  alkyl group;  
 R 3  is selected from the group consisting of a hydrogen atom; a C 1 -C 6  alkyl group; a C 1 -C 6  alkyl group which is substituted with a group selected from the group consisting of a hydroxyl group, a carboxyl group and a (C 1 -C 6  alkoxy)carbonyl group; a group of formula (II)  
                     
 (wherein R 7  is a C 1 -C 6  alkyl group, and m and n are the same as or different from each other and each is an integer from 1 to 6); a C 7 -C 15  aralkyl group; a C 1 -C 6  alkanoyl group; a hydroxy-C 2 -C 6 -alkanoyl group; a C 1 -C 6  alkylsulfonyl group; and a C 1 -C 6  alkylsulfonyl group which is substituted with a group selected from the group consisting of a carboxyl group and a (C 1 -C 6  alkoxy)carbonyl group;  
 R 4  and R 5  are the same as or different from each other and each is selected from the group consisting of a hydrogen atom, a halogen atom, a C 1 -C 6  alkyl group, a halogeno-C 1 -C 6 -alkyl group, a C 1 -C 6  alkoxy group, a carboxyl group, a (C 1 -C 6  alkoxy)carbonyl group, a carbamoyl group, a (C 1 -C 6  alkyl)carbamoyl group and a di(C 1 -C 6  alkyl)carbamoyl group; and  
 R 6  is selected from the group consisting of a 1-acetimidoylpyrrolidin-3-yl group and a 1-acetimidoylpiperidin-4-yl group.  
 
     
     
         2 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 1  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 4  alkyl group and a hydroxyl group.  
     
     
         3 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 1  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a hydroxyl group.  
     
     
         4 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 1  is selected from the group consisting of a hydrogen atom, a fluorine atom, a methyl group and a hydroxyl group.  
     
     
         5 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 1  is selected from the group consisting of a hydrogen atom and a hydroxyl group.  
     
     
         6 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 2  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom and a C 1 -C 4  alkyl group.  
     
     
         7 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 2  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group and an ethyl group.  
     
     
         8 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 2  is selected from the group consisting of a hydrogen atom, a fluorine atom and a methyl group.  
     
     
         9 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 2  is selected from the group consisting of a hydrogen atom and a fluorine atom.  
     
     
         10 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 2  is a hydrogen atom.  
     
     
         11 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 3  is selected from the group consisting of a hydrogen atom, a C 1 -C 4  alkyl group, a hydroxy-C 1 -C 4 -alkyl group, a carboxy-C 1 -C 4 -alkyl group, a (C 1 -C 4  alkoxy)carbonyl-C 1 -C 4 -alkyl group, a group of formula (II)  
       
         
           
           
               
               
           
         
       
       (wherein R 7  is a C 1 -C 4  alkyl group, and m and n are the same as or different from each other and each represents an integer from 1 to 4), a benzyl group, a naphthylmethyl group, a diphenylmethyl group, a phenethyl group, a C 1 -C 4  alkanoyl group, a hydroxyacetyl group, a 3-hydroxypropionyl group, a 4-hydroxybutyryl group, a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group, a hexanesulfonyl group, and a C 1 -C 4  alkylsulfonyl group which is substituted with a group selected from the group consisting of a carboxyl group and a (C 1 -C 4  alkoxy)carbonyl group.  
     
     
         12 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 3  is selected from the group consisting of a hydrogen atom, a C 1 -C 4  alkyl group, a 2-hydroxyethyl group, a carboxymethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a butoxycarbonylmethyl group, a group of formula (II)  
       
         
           
           
               
               
           
         
       
       (wherein R 7  represents a methyl group or ethyl group, and m and n are the same as or different from each other and each represents an integer of 1 or 2), a benzyl group, a phenethyl group, a formyl group, an acetyl group, a hydroxyacetyl group, a methanesulfonyl group, an ethanesulfonyl group, a butanesulfonyl group, and group selected from the group consisting of a methanesulfonyl group and an ethanesulfonyl group which is substituted with a group selected from the group consisting of a carboxyl group and a (C 1 -C 4  alkoxy)carbonyl group.  
     
     
         13 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 3  is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 2-hydroxyethyl group, a carboxymethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a butoxycarbonylmethyl group, an acetyl group, a hydroxyacetyl group, a methanesulfonyl group, an ethanesulfonyl group, a butanesulfonyl group, a methoxycarbonylmethanesulfonyl group, an ethoxycarbonylmethanesulfonyl group, a carboxymethanesulfonyl group, a 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group and a 2-carboxyethanesulfonyl group.  
     
     
         14 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 3  is selected from the group consisting of an isopropyl group, a 2-hydroxyethyl group, a carboxymethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, an ethanesulfonyl group, a methoxycarbonylmethanesulfonyl group, an ethoxycarbonylmethanesulfonyl group, a carboxymethanesulfonyl group, a 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group and a 2-carboxyethanesulfonyl group.  
     
     
         15 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 3  is selected from the group consisting of an isopropyl group, a carboxymethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylmethanesulfonyl group and a carboxymethanesulfonyl group.  
     
     
         16 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 3  is selected from the group consisting of an ethoxycarbonylmethanesulfonyl group and a carboxymethanesulfonyl group.  
     
     
         17 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 4  and R 5  are the same as or different from each other and each is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 4  alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a C 1 -C 4  alkoxy group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group and an N,N-dimethylcarbamoyl group.  
     
     
         18 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 4  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom and a trifluoromethyl group, and R 5  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 4  alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a C 1 -C 4  alkoxy group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group and an N,N-dimethylcarbamoyl group.  
     
     
         19 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 4  is selected from the group consisting of a hydrogen atom, a fluorine atom and a chlorine atom and R 5  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group and a carbamoyl group.  
     
     
         20 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 4  is a hydrogen atom and R 5  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a carbamoyl group.  
     
     
         21 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 4  is a hydrogen atom and R 5  is selected from the group consisting of a hydrogen atom, a chlorine atom, a methyl group and a carbamoyl group.  
     
     
         22 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 6  is a 1-acetimidoylpiperidin-4-yl group.  
     
     
         23 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein: 
 R 1  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 4  alkyl group and a hydroxyl group;    R 2  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom and a C 1 -C 4  alkyl group;    R 3  is selected from the group consisting of a hydrogen atom, a C 1 -C 4  alkyl group, a hydroxy-C 1 -C 4 -alkyl group, a carboxy-C 1 -C 4 -alkyl group, a (C 1 -C 4  alkoxy)carbonyl-C 1 -C 4 -alkyl group, a group of formula (II)                          (wherein R 7  represents a C 1 -C 4  alkyl group, and m and n are the same as or different from each other and each represents an integer from 1 to 4), a benzyl group, a naphthylmethyl group, a diphenylmethyl group, a phenethyl group, a C 1 -C 4  alkanoyl group, a hydroxyacetyl group, a 3-hydroxypropionyl group, a 4-hydroxybutyryl group, a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group, a hexanesulfonyl group and a C 1 -C 4  alkylsulfonyl group which is substituted with a group selected from the group consisting of a carboxyl group and a (C 1 -C 4  alkoxy)carbonyl group; and    R 4  and R 5  are the same as or different from each other and each is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 4  alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a C 1 -C 4  alkoxy group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group and an N,N-dimethylcarbamoyl group.    
     
     
         24 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein: 
 R 1  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a hydroxyl group;    R 2  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group and an ethyl group;    R 3  is selected from the group consisting of a hydrogen atom, a C 1 -C 4  alkyl group, a 2-hydroxyethyl group, a carboxymethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a butoxycarbonylmethyl group, a group of formula (II)                          (wherein R 7  is selected from the group consisting of a methyl group and an ethyl group, and m and n are the same as or different from each other and each represents an integer of 1 or 2), a benzyl group, a phenethyl group, a formyl group, an acetyl group, a hydroxyacetyl group, a methanesulfonyl group, an ethanesulfonyl group, a butanesulfonyl group, and a group selected from the group consisting of a methanesulfonyl group and an ethanesulfonyl group which is substituted with a group selected from the group consisting of a carboxyl group or a (C 1 -C 4  alkoxy)carbonyl group;    R 4  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom and a trifluoromethyl group, and R 5  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1 -C 4  alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a C 1 -C 4  alkoxy group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group and an N,N-dimethylcarbamoyl group; and    R 6  is a 1-acetimidoylpiperidin-4-yl group.    
     
     
         25 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein: 
 R 1  is selected from the group consisting of a hydrogen atom, a fluorine atom, a methyl group and a hydroxyl group;    R 2  is selected from the group consisting of a hydrogen atom, a fluorine atom and a methyl group;    R 3  is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a 2-hydroxyethyl group, a carboxymethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a butoxycarbonylmethyl group, an acetyl group, a hydroxyacetyl group, a methanesulfonyl group, an ethanesulfonyl group, a butanesulfonyl group, a methoxycarbonylmethanesulfonyl group, an ethoxycarbonylmethanesulfonyl group, a carboxymethanesulfonyl group, a 2-methoxycarbonylethanesulfonyl group, 2-ethoxycarbonylethanesulfonyl group and a 2-carboxyethanesulfonyl group;    R 4  is selected from the group consisting of a hydrogen atom, a fluorine atom and a chlorine atom, and R 5  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group and a carbamoyl group; and    R 6  is a 1-acetimidoylpiperidin-4-yl group.    
     
     
         26 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein: 
 R 1  is selected from the group consisting of a hydrogen atom and a hydroxyl group;    R 2  is selected from the group consisting of a hydrogen atom and a fluorine atom;    R 3  is selected from the group consisting of an isopropyl group, a 2-hydroxyethyl group, a carboxymethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, an ethanesulfonyl group, a methoxycarbonylmethanesulfonyl group, an ethoxycarbonylmethanesulfonyl group, a carboxymethanesulfonyl group, 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group and a 2-carboxyethanesulfonyl group;    R 4  is a hydrogen atom, and R 5  is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a carbamoyl group; and    R 6  is a 1-acetimidoylpiperidin-4-yl group.    
     
     
         27 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein: 
 R 1  is selected from the group consisting of a hydrogen atom and a hydroxyl group;    R 2  is selected from the group consisting of a hydrogen atom and a fluorine atom;    R 3  is selected from the group consisting of an isopropyl group, a carboxymethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylmethanesulfonyl group and a carboxymethanesulfonyl group;    R 4  is a hydrogen atom, and R 5  is selected from the group consisting of a hydrogen atom, a chlorine atom, a methyl group and a carbamoyl group; and    R 6  is a 1-acetimidoylpiperidin-4-yl group.    
     
     
         28 . A benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein: 
 R 1  is selected from the group consisting of a hydrogen atom and a hydroxyl group;    R 2  is selected from the group consisting of a hydrogen atom and a fluorine atom;    R 3  is selected from the group consisting of an ethoxycarbonylmethanesulfonyl group and a carboxymethanesulfonyl group;    R 4  is a hydrogen atom, and R 5  is selected from the group consisting of a hydrogen atom, a chlorine atom, a methyl group and a carbamoyl group; and    R 6  is a 1-acetimidoylpiperidin-4-yl group.    
     
     
         29 . A benzamidine derivative according to  claim 1  which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof: 
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate,  
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-chlorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate,  
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-methylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate,  
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-carbamoylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate,  
 N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid,  
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-fluorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid,  
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-chlorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid,  
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-methylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid,  
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-trifluoromethylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid,  
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-carbamoylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid,  
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)-3,5-dichlorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate,  
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3,5-dichlorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid, and  
 N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]-N-[3-(3-amidinophenyl)-2-fluoro-2-(Z)-propenyl]sulfamoylacetic acid.  
 
     
     
         30 . A benzamidine derivative according to  claim 29 , which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate.    
     
     
         31 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-chlorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate.  
 
     
     
         32 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-methylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate.  
 
     
     
         33 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-carbamoylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate.  
 
     
     
         34 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid.  
 
     
     
         35 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-fluorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid.  
 
     
     
         36 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-chlorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid.  
 
     
     
         37 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-methylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid.  
 
     
     
         38 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-trifluoromethylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid.  
 
     
     
         39 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3-carbamoylphenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid.  
 
     
     
         40 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 ethyl N-[4-(1-acetimidoylpiperidin-4-yloxy)-3,5-dichlorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetate.  
 
     
     
         41 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 N-[4-(1-acetimidoylpiperidin-4-yloxy)-3,5-dichlorophenyl]-N-[3-(3-amidinophenyl)-2-(E)-propenyl]sulfamoylacetic acid.  
 
     
     
         42 . A benzamidine derivative according to  claim 29  which is selected from the group consisting of the following compound and pharmaceutically acceptable salt thereof: 
 N-[4-(1-acetimidoylpiperidin-4-yloxy)phenyl]-N-[3-(3-amidinophenyl)-2-fluoro-2-(Z)-propenyl]sulfamoylacetic acid.  
 
     
     
         43 . A pharmaceutical composition comprising a therapeutically effective amount of a benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 29 , together with a pharmaceutically acceptable carrier or diluent.  
     
     
         44 . A method for the treatment or prevention of a blood coagulation disorder, thrombotic disease, cerebral infarction, myocardial infarction, or peripheral circulation disorder in a warm-blooded animal, which comprises administering to a warm-blooded animal in need of such treatment or prevention an effective amount of a benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 29 .  
     
     
         45 . A method according to  claim 44  wherein the warm-blooded animal is a human.  
     
     
         46 . A pharmaceutical composition comprising a therapeutically effective amount of a benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , together with a pharmaceutically acceptable carrier or diluent.  
     
     
         47 . A method for the treatment or prevention of a blood coagulation disorder, thrombotic disease, cerebral infarction, myocardial infarction, or peripheral circulation disorder in a warm-blooded animal, which comprises administering to a warm-blooded animal in need of such treatment or prevention an effective amount of a benzamidine derivative or a pharmaceutically acceptable salt thereof according to  claim 1 .  
     
     
         48 . A method according to  claim 47  wherein the warm-blooded animal is a human.