Amidinophenylalanine Derivatives as Thrombin Inhibitors

Abstract

The compounds of the formula I and pharmaceutically acceptable salts thereof and a process for preparing the same and pharmaceutical compositions containing the same are described wherein the substituents have the meaning as specified in the description. The compounds are used as thrombin inhibitors.

1 . The compound of the formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  represents a residue of the formula  
                     
 wherein R 4  is selected from the group consisting of H, alkyl (C 1 -C 3 ), OH, O-alkyl (C 1 -C 3 ), and NH 2 ;  
 R 2  is selected from the group consisting of a residue of the formula  
                     
 wherein R 5  is selected from the group consisting of H, alkyl (C 1 -C 3 ), CF 3 , and COOR 9 ;  
 R 6  is selected from the group consisting of H, alkyl (C 1 -C 3 ), CF 3 , and COOR 9 ;  
 R 7  is selected from the group consisting of alkyl (C 1 -C 3 ), cycloalkyl and (C 3 -C 6 );  
 R 8  is selected from the group consisting of alkyl (C 1 -C 3 ), and cycloalkyl (C 3 -C 6 );  
 R 9  is selected from the group consisting of H, and alkyl (C 1 -C 3 );  
 R 10  is selected from the group consisting of H, alkyl (C 1 -C 3 ), and benzyl;  
 R 11  is selected from the group consisting of H, SO 2 Me, and CO 2 Me;  
 R 3  is selected from the group consisting of a residue of the formula  
                     
 wherein R 12  is selected from the group consisting of H, H 3 C—, and acetyl  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound as claimed in  claim 1 , of formula I wherein R 2  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound as claimed in preceding  claim 1  or  claim 2  wherein R 3  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound as claimed in  claim 1  wherein said compound is selected from the group consisting of: 
 N′-hydroxy-3-{[1-[(2-methyl-I -piperidinyl)carbonyl] -2-(2-naphthylsulfonyl) hydrazino]methyl}benzenecarboximidamide;    N′-Hydroxy-3-({2-[(6-methoxy-2-naphthyl)sulfonyl] -1-[(2-methyl-1-piperidinyl) carbonyl]hydrazino}methyl)benzenecarboximidamide;    Imino [3-({2-[(6-methoxy-2-naphthyl)sulfonyl] -1-[(2-methyl-1-piperidinyl)carbonyl]hydrazino}methyl)phenyl]methanaminium chloride;    N′-Hydroxy-3-{[1-[(4-methyl-1-piperidinyl)carbonyl] -2-(2-naphthylsulfonyl) hydrazino]methyl}benzenecarboximidamide;    Imino(3-{[ 1-[(4-methyl-I -piperidinyl)carbonyl] -2-(2-naphthylsulfonyl)hydrazino]methyl}phenyl)methanaminium chloride;    N′-Hydroxy-3-({2-[(6-methoxy-2-naphthyl)sulfonyl] -1-[(4-methyl-1-piperidinyl) carbonyl]hydrazino}methyl)benzenecarboximidamide;    Imino [3-({2-[(6-methoxy-2-naphthyl)sulfonyl] -1-[(4-methyl-1-piperidinyl)carbonyl]hydrazino}methyl)phenyl]methanaminium chloride.    
     
     
         5 . A method for inhibiting blood coagulation comprising contacting a sample of blood or plasma with a compound of formula I according to  claim 1 .  
     
     
         6 . A process for preparing a compound of the formula I according to  claim 1 , comprising: 
 converting 3-cyanobenzaldehyde of formula (II)                          with BOC-carbazate of the formula (III)                          to a compound of formula (IV),                          reducing the compound of formula (IV) by catalytic hydrogenation or with NaCNBH 3  to a compound of formula (V),                          reacting the compound of formula (V) with triphosgene and an amine of formula (VI),                          wherein R 5  and R 6  have the same meanings as in the formula (I),    or with triphosgene and an amine of W+e formula (VII or VIII),                          or with triphosgene and an amine of the formula (IX),                          wherein R 7  and R 8  have the same meanings as in the formula (I), or with triphosgene and an amine of We formula (X),                          wherein R 10  has the same meaning as in the formula (I), to yield a compound of formula (XI),                          wherein R 2  has the same meaning as in formula (I);    removing the protecting BOC group with HCl (g) in HOAc at room temperature to obtain a compound of formula (XII),                          wherein R 2  has the same meaning as in the formula (I);    reacting the compound of formula (XII) with aromatic sulfonylchloride to yield a compound of formula (XIII)                          wherein R 2  and R 3  have the same meanings as in the formula (I); and    converting the compound of formula (XIII) to the a compound of formula (I)                          
     
     
         7 . A method for treating blood coagulation disorders in man and other mammals comprising administering a therapeutically effective amount of a compound of formula I as claimed in  claim 1 , to a subject in need thereof.  
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as claimed in  claim 1  and pharmaceutically acceptable auxiliary substances.  
     
     
         9 . A pharmaceutical composition according to  claim 8 , for inhibiting thrombin in man and other mammals, wherein the compound of formula I has a trypsin K i  to thrombin K i  ratio of about 5 or more.  
     
     
         10 . A pharmaceutical composition according to  claim 8 , for inhibiting thrombin in man and other mammals, wherein the compound of formula I has a thrombin K i  of about 0.6 μM or less.  
     
     
         11 . A method for inhibiting thrombin in the blood of man and other mammals comprising administering a therapeutically effective amount of a compound of formula I of as claimed in claim  49 .  
     
     
         12 . A method for inhibiting thrombin in man and other mammals comprising administering a therapeutically effective amount of a compound of formula I as claimed in  claim 10.