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.

We claim:  
     
         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:  
       
         
           
           
               
               
           
         
       
       X 13 —SO 2 —CH 2 —CH 2 —CHNH 2 —CO—H 2 N—CH 2 —CO—, H 2 N—CHX 13 —CO—
 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-naphthyl-C 1-4 -alkylcarbonyl-, C 1-6 -alkylaminocarbonyl or phenyl-C 1-4 -alkylaminocarbonyl -  
 also A: X 1 -NH—CH 2 —CH 2 —CO—, X 1 -NH—CH 2 —CH 2 —CH 2 —CO— 
 X 15 -(CH 2 ) f —SO 2 — (f=0,1,2,3,4, X 15 a phenyl or α- or β-naphthyl radical which is unsubstituted or substituted by 1-3 CH 3  and/or CH 3 O groups, or one of the radicals  
                     
 X 18 -O—CO—C 1-4 -alkylene-CO— (X 18 =H, C 1-4 -alkyl),  
 C 1-12 -alkyl-CO—, C 1-10 -alkyl-NH—CO—, phenyl-C 1-4 -alkylene-NH—CO—, α- or β-naphthyl-CO— or C 3-7 -cycloalkyl-CO—,  
                     
 R 1 : H or C 1-4 -alkyl  
 R 2 : H or C 1-4 -alkyl  
 R 3 : H, C 1-8 -alkyl, phenyl, phenyl-C 1-4 -alkylene, CH 2 OH, —CO-X 20 , —CO—CO-X 20 , (X 20 =H, C 1-4 -alkoxy, C 1-4 -alkyl, phenyl, phenyl-C 1-4 -alkylene, phenyl-C 1-4 -alkoxy, CF 3 , C 2 F 5 , an N-terminally linked natural amino acid, CH 2 OH, —CH 2 —O—C 1-4 -alkyl, —NH—(C 1-4 -alkylene)-phenyl or NH—C 1-6 -alkyl),  
 m: 0, 1, 2 or 3  
 D: 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 (CH2) m  by F, Cl, Br, HO—CH 2 —, OH, NH 2 , NO 2 , C 1-4 -alkoxy, C 1-6 -alkyl, COX 21  (X 21 =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, HO—CH 2 —, OH, NH 2 , NO 2 , C 1-4 -alkoxy, C 1-6 -alkyl or COX 21 (X 21 =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 ,  
  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: 0 or 1  
 R 4 : H, —CO—C 1-20 -alkyl, —CO—O—C 1-20 -alkyl, OH or NH 2 .  
 
     
     
         2 . A compound of the formula I as claimed in  claim 1  for use for controlling diseases.  
     
     
         3 . A compound of the formula II  
       
         
           
           
               
               
           
         
       
       in which R 1 , R 2 , R 3  and D have the meanings stated for formula I, and 
 R 5 : is H, C 1-4 -alkoxy-CO— or phenyl-C 1-3 -alkoxy-CO—,  
 R 6 : is cyano, amidino or guanidino in the m or p position to C(R 2 , R 3 ) and  
 p: is 1,2 or 3.