Thrombin inhibitors

Abstract

The invention relates to non-slow-binding thrombin inhibitors of the formula: A—B—C-Lys-D— wherein A is H, 2-hydroxy-3-cyclohexyl-proprionyl-, R 1 , R 1 —O—CO—, R 1 —SO 2 —, —(CHR 2 ) n COOR 3 , or an N-protecting group, wherein R 1 is selected from -(1-6C)alkylene-COOH, (1-12C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the aryl group of which may be substituted with (1-6C)alkyl, (2-12C)alkoxy, hydroxy, or halogen; R 2 is H or has the same meaning as R 1 , R 3 is selected from H, (1-12C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the aryl group of which may be substitute with (1-6C)alkyl, (2-12C)alkoxy, hydroxy or halogen; n is an integer of 1 to 3; B is a bond, L-asp or an ester derivative thereof, Leu, norLeu, —N(benzyl)-CH 2 —CO—, —N(2-indane)-CH 2 —CO—, D-1 Piq, D-3 Piq, D-Tiq, Atc or a D-amino acid having a hydrophobic aromatic side chain; C is Azt, Pro, Pec, norLeu(cyclo)Gly, an amino acid of one of the formulae —N[(3-8C)cycloalkyl]-CH 2 —CO— or —N(benzol)-CH 2 —CO—, D is selected from COOH, tetrazole, oxazole, thiazole and benxothiazole; or a prodrug thereof; or a pharmaceutically acceptable salt thereof, with the exception of the compound Me-D-Phe-Pro-Lys-COOH. The compounds can be used as antithrombotic agents

1 . A non-slow-binding thrombin inhibitor of the formula: 
       A—B—C-Lys-D 
       wherein 
 A is H, 2-hydroxy-3-cyclohexyl-propionyl-, R 1 , R 1 —O—CO—, R 1 —CO—, R 1 —SO 2 —, —(CHR 2 ) n COOR 3 , or an N-protecting group, wherein 
 R 1  is selected from -(1-6C)alkylene-COOH, (1-12C(alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the aryl group of which may be substituted with (1-6C)alkyl, (2-12C)alkoxy, hydroxy, or halogen;  
 R 2  is H or has the same meaning as R 1 ;  
 R 3  is selected from H, (1-12C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the aryl group of which may be substituted with (1-6C)alkyl, (2-12C)alkoxy, hydroxy, or halogen;  
 n is an integer of 1 to 3;  
 
 B is a bond, L-Asp or an ester derivative thereof, Leu, norLeu, -N(benzyl)-CH 2 —CO—, —N(2-indane)-CH 2 —CO—, D-1-Piq, D-3-Piq, D-Tiq, Atc or a D-amino acid having a hydrophobic aromatic side chain;  
 C is Azt, Pro, Pec, norLeu(cyclo)Gly, an amino acid of one of the formulae —N[(3-8C)cycloalkyl]-CH 2 —CO— or -N(benzyl)-CH 2 —CO—;  
 D is selected from COOH, tetrazole, oxazole, thiazole and benzothiazole;  
 or A and C have the aforesaid meanings, B is D-(3-8C)cycloalkylalanine, and D is tetrazole, oxazole, thiazole or benzothiazole;  
 or a prodrug thereof,  
 or a pharmaceutically acceptable salt thereof;  
 with the exception of the compound Me-D-Phe-Pro-Lys-COOH.  
 
     
     
         2 . The non-slow-binding thrombin inhibitor of  claim 1  wherein D is COOH.  
     
     
         3 . The non-slow-binding thrombin inhibitor of  claim 2  wherein A is H, (1-12C)alkyl, —CO-(7-15C)aralkyl, —SO 2 -(1-12C)alkyl, —SO 2 -(6-14C)aryl, or —SO 2 -(7-15C)aralkyl; B is a bond, L-Asp, norLeu, D-1-Piq, or D-Phe; and C is Pro, norLeu(cyclo)Gly, or -N(cyclopentyl)-CH 2 —CO—.  
     
     
         4 . The non-slow-binding thrombin inhibitor of  claim 3 , wherein A is —SO 2 -benzyl, B is a bond, and C is norLeu(cyclo)Gly, or wherein A is —SO 2 -ethyl, B is D-Phe, and C is Pro; or wherein A is hydrogen, B is D-1-Piq, and C is Pro.  
     
     
         5 . The non-slow-binding thrombin inhibitor of  claim 1 , wherein D is oxazole or thiazole.  
     
     
         6 . The non-slow-binding thrombin inhibitor of  claim 5 , wherein A is H, (1-12C)alkyl, 2-hydroxy-3-cyclohexyl-propionyl-, —CO—(7-15C)aralkyl, —CO—(CH 2 ) n COOH —SO 2 -(6-14C)aryl, —SO 2 -(7-15C)aralkyl, —SO 2 —(1-12C)alkyl, (CHR 2 ) n COOR 3 , R 2  being H or (1-12Calkyl) and R 3  being H, (1-12C)alkyl or benzyl; and C is Pro, norLeu(cyclo)Gly, or —N[(3-8C)cycloalkyl]-CH 2 —CO—.  
     
     
         7 . A process for preparing a non-slow-binding thrombin inhibitor of  claim 1 , the process including coupling suitably protected amino acids or amino acid analogs, followed by removing the protecting groups.  
     
     
         8 . A pharmaceutical composition comprising the non-slow-binding thrombin inhibitor of any one of claims  1 - 6  and pharmaceutically acceptable auxiliaries.  
     
     
         9 . The non-slow-binding thrombin inhibitor of any one of claims  1 - 6  for use in therapy.  
     
     
         10 . Use of the non-slow-binding thrombin inhibitor of any one of claims  1 - 6  for the manufacture of an antithrombotic medicament.