Cyanobiphenyl derivatives

Abstract

Intermediates represented by the following formula: (wherein R 1 is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group or the like; X is a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a formyl group, —CH 2 —Y, —CHZ 1 Z 2 , —CH(OR 4 )OR 5 or the like), in the synthesis of biphenylamidine derivatives to be used as inhibitors for an activated blood coagulation factor X, and a process for preparing the same.

1 . A cyanobiphenyl derivative represented by the following formula (1):  
       
         
           
           
               
               
           
         
         [wherein R 1  is a hydrogen atom, a C 1 -C 8  alkyl group, an aryl group or an aralkyl group; X is a carboxyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a formyl group, the formula:  
         —CH 2 —Y  
         {wherein Y is a chlorine atom, a bromine atom, an iodine atom, an azide group, —OR 2  (wherein R 2  is a hydrogen atom, a C 1 -C 8  alkylsulfonyl group (wherein a C 1 -C 8  alkylsulfonyl group may be optionally substituted with more halogen atoms)), an arylsulfonyl group or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 -C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group), or —NHR 3  (wherein R 3  is hydrogen atom or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 . C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}, the formula:  
         
           
             
             
                 
                 
             
           
         
         {wherein Z 1  and Z 2  are each independently a chlorine atom, a bromine atom or an iodine atom}, or the formula:  
         
           
             
             
                 
                 
             
           
         
         {wherein R 4  and R 5  are each independently a hydrogen atom, a C 1 -C 8  alkyl group or a C 1 -C 8  alkylcarbonyl group or both together may form a ring when R 4  and R 5  are each a C 1 -C 8  alkyl group}], or its salts thereof.  
       
     
     
         2 . The cyanobiphenyl derivative or its salts thereof according to  claim 1 , wherein, in the above formula (1), R 1  is a hydrogen atom or a C 1 -C 8  alkyl group; X is a C 1 -C 8  alkoxycarbonyl group, a formyl group, the formula:  
       —CH 2 —Y  {wherein Y is a chlorine atom, a bromine atom, an iodine atom, an azide group, —OR 2      (wherein R 2  is a hydrogen atom or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 -C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group)), or —NHR 3  (wherein R 3  is as defined above), the formula:                          {wherein Z 1  and Z 2  are each as defined above}, or the formula:,                          {wherein R 4  and R 5  are each as defined above}.    
     
     
         3 . The cyanobiphenyl derivative or its salts thereof according to  claim 2 , wherein, in the above formula (1), X is a formyl group or the formula:  
       —CH 2 —Y  {wherein Y is a chlorine atom, a bromine atom, an iodine atom, —OR 2  (wherein R 2  is a hydrogen atom or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 -C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group)), or —NHR 3  (wherein R 3  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 -C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}.    
     
     
         4 . The cyanobiphenyl derivative or its salt thereof according to  claim 3 , wherein, in the above formula (1), X is a formyl group or the formula:  
       —CH 2 —Y  {wherein Y is a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group or —NHR 3  (wherein R 3  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 -C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}.    
     
     
         5 . The cyanobiphenyl derivative or its salts thereof according to  claim 4 , wherein, in the above formula (1), X is the formula:  
       —CH 2 —Y  {wherein Y is —NHR 3  (wherein R 3  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 . C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}.    
     
     
         6 . The cyanobiphenyl derivative or its salts thereof according to  claim 1 , wherein, in the above formula (1), R 1  is a hydrogen atom, a CC 1 -C 8  alkyl group, an aryl group or an aralkyl group; X is a carboxyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group, aralkoxycarbonyl group, formyl group, the formula:  
       —CH 2 —Y  {wherein Y is a chlorine atom, an iodine atom, —OR 2  (wherein R 2  is a C 1 -C 8  alkylsulfonyl group (the C 1 -C 8  alkylsulfonyl group may further be substituted with a halogen atom), an arylsulfonyl group or 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 5 -C 8  alkoxycarbonyl group or an aryloxycarbonyl group)), —NHR 3  (wherein R 3  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 5 -C 8  alkoxycarbonyl group or an aryloxycarbonyl group))}, the formula:                          {wherein Z 1  and Z 2  are each as defined above}, or the formula:                          {wherein R 4  and R 5  are each as defined above}.    
     
     
         7 . The cyanobiphenyl derivative or its salts thereof according to  claim 6 , wherein, in the above formula (1), R 1  is a hydrogen atom or a C 1 -C 8  alkyl group; X is a carboxyl group, a C 1 -C 8  alkoxycarbonyl group, a formyl group, or the formula:  
       —CH 2 —Y  {wherein Y is —OR 2  (wherein R 2  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 5 -C 8  alkoxycarbonyl group or an aryloxycarbonyl group)), —NHR 3  (wherein R 3  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 5 -C 8  alkoxycarbonyl group or an aryloxycarbonyl group))}.    
     
     
         8 . The cyanobiphenyl derivative or its salts thereof according to  claim 7 , wherein, in the above formula (1), X is a formyl group or the formula:  
       —CH 2 —Y  {wherein Y is —NHR 3  (wherein R 3  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group is substituted with a C 5 -C 8  alkoxycarbonyl group or an aryloxycarbonyl group))}.    
     
     
         9 . A process for preparing a cyanobiphenyl derivative represented by the following formula (3):  
       
         
           
           
               
               
           
         
         {wherein R 1  is as defined in the formula (2); Y 1  is —NHR 3  (wherein R 3  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 -C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))} or its salt thereof, comprising carrying out a dehydration condensation of a compound represented by the following formula (2):  
         
           
             
             
                 
                 
             
           
         
         (wherein R 1  is a hydrogen atom, a C 1 -C 8  alkyl group, an aryl group or an aralkyl group), with a compound represented by the formula:  
         Y 1 —H  
         {wherein Y 1  is —NHR 3  (wherein R 3  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 -C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}, and subsequently conducting a reducing reaction.  
       
     
     
         10 . A process for preparing a cyanobiphenyl derivative represented by the following formula (5):  
       
         
           
           
               
               
           
         
         (wherein R 1  is as defined in the formula (4); Y 1  is as defined in the above formula (3)) or its salt, comprising reacting a compound represented by the following formula (4):  
         
           
             
             
                 
                 
             
           
         
         (wherein R 1  is a hydrogen atom, a C 1 -C 8  alkyl group, an aryl group or an aralkyl group; Y 2  is a chlorine atom, a bromine atom or an iodine atom), with a compound represented by  
         Y 1 —H  
         {wherein Y 1  is —NHR 3  (wherein R 3  is 4-piperidinomethyl group (a nitrogen atom in the 4-piperidinomethyl group may be substituted with a C 1 -C 8  alkyl group, a C 1 -C 8  alkylcarbonyl group, an arylcarbonyl group, a C 1 -C 8  alkoxycarbonyl group, an aryloxycarbonyl group or an aralkoxycarbonyl group))}.