Novel thrombin inhibitors, the preparation and use thereof

Abstract

Compounds of the formula and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the meanings stated in the description, are described. Also disclosed are intermediates for their preparation. The compounds are suitable for controlling diseases.

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
       and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the following meanings:  
       A is  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       X 18 —O—CO—C 1-4 -alkylene-CO— where X 18  is H or C 1-4 -alkyl, C 1-2 -alkyl-CO—, C 1-10 -alkyl-NH—CO— phenyl-C 1-4 -alkylene-NH—CO—, α- or β-naphthyl-CO— or  
       
         
           
           
               
               
           
         
       
       where h is 2,  
       where in all the abovementioned A radicals the α-NH or α-NH 2  group can be mono- or disubstituted by C 1-12 -alkyl, phenyl-C 1-4 -alkylene, X 12 OC—C 1-6 -alkylene, X 12 OC—C 1-6 -alkylcarbonyl, -α- or β-naphthyl-C 1-4 -alkylene, C 1-12 -alkylcarbonyl, phenyl-C 1-4 -alkylcarbonyl, C 1-7 -alkoxycarbonyl, phenyl-C 1-5 -alkoxycarbonyl, -α- or β-naphythyl-C 1-4 -alkylcarbonyl-, C 1-6 -alkylaminocarbonyl or phenyl-C 1-4 -alkylaminocarbonyl  
       R 1  is H or C 1-4 -alkyl;  
       R 2  is H;  
       R 3  is H;  
       M is 0;  
       D is phenylene on which (CH 2 ) m  and (NH) n  are linked in the para or meta position to one another and which can be substituted in the ortho position to (CH 2 ) m  by F, Cl, Br, HO—CH 2 —, OH, NH 2 , NO 2 , C 1-4 -alkoxy, C 1-6 -alkyl or COX 21  where X 21  is H, C 1-4 -alkyl, C 1-4 -alkoxy, OH, NH 2 , NH—C 1-4 -alkyl-O—(CH 2 ) 1-3 —CO—X 21  or —(CH 2 ) 1-3 —CO—X 21 ,  
       pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene, on which (CH 2 ) m  and (NH) n  are linked in the para or meta position to one another and which can be substituted in the ortho position to (CH 2 ) m  by F, Cl, Br, OH, NH 2  C 1-4 -alkoxy or C 1-4 -alkyl,  
       1,4- or 1,3-cyclohexylene, in which one CH 2  group in the ortho position to (CH 2 ) m  can be replaced by NH, O, S or SO, or piperidinylene which is connected in the 3 or 4 position to the nitrogen to (CH 2 ) m , and in which the nitrogen atom itself carries the C(=NH)NHR 4  group,  
       n is 0 or 1; and  
       R 4  is H, —CO—C 1-20 -alkyl, —CO—O—C 1-20 -alkyl, OH or NH 2 .  
     
   
   
       2 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the following meanings: 
 A is  
                     
 where X 4  is H, F, Cl, Br, CF 3 , C 1-4 -alkyl, OH, OCH 3 , NO 2  or phenyl,  
 X 5  is H, F, Cl, Br, CH 3 , OH OCH 3  or phenyl,  
 X 6  is H, F, Cl, Br, CH 3 , OH or OCH 3 ,  
 X 7 is H or F and X 8  is H or F,  
 B is  
                     
 R 1  is H or CH 3 ;  
 R 2  is H;  
 R 3  is H;  
 R 4  is OH;  
 m is O or X  
 for —CH 2 ) m -D-(NH) n — with n=0  
                     
 for —CH 2 ) m -D-(NH) n — with n=0 or 1  
                     
 for —CH 2 ) m -D-(NH) n — with n is 0 or 1  
                     
 
   
   
       3 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the following meanings:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       R 4  is H, OH.