4-oxo-4,6,7,8-Tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide compounds

Abstract

Compound of formula (I): wherein: represents 1-oxidopyridyl substituted by the remainder of the molecule in any one of the positions 2, 3 and 4, m and n, which may be identical or different, each represent an integer of from 1 to 3, R 1 represents hydrogen or alkyl, R 2 and R 3 , which may be identical or different, each represent an atom or group selected from hydrogen, halogen, alkyl, hydroxy, acyloxy and alkoxy, or, together with the carbon atom carrying them, form a cycloalkane having from 3 to 6 carbon atoms, R 4 and R 5 each represent hydrogen, or are adjacent and, together with the carbon atoms carrying them, form a benzo ring, Ar represents aryl or heteroaryl. Medicinal products containing the same which are useful as thrombin inhibitors.

1 . A method of treating a living animal body, including a human, afflicted with a condition selected from stable and unstable angina; disorders of thrombotic origin and/or giving rise to thrombotic complications; complications of vascular and cardiovascular diseases, including atherosclerosis, arteritis, and venous disease; and disorders involving thrombin formation and/or activity, comprising the step of administering to the living animal body, including a human, a therapeutically effective amount of a compound of formula (I): 
     
       
         
         
             
             
         
       
       wherein: 
     
     
       
         
         
             
             
         
       
       
         represents 1-oxidopyridyl substituted by the remainder of the molecule in any one of the positions 2, 3 and 4, 
         m and n, which may be identical or different, each represent an integer of from 1 to 3, 
         R 1  represents hydrogen or linear or branched (C 1 -C 6 )alkyl, 
         R 2  and R 3 , which may be identical or different, each represent an atom or group selected from hydrogen, halogen, linear or branched (C 1 -C 6 )alkyl, hydroxy, linear or branched (C 1 -C 6 )acyloxy and linear or branched (C 1 -C 6 )alkoxy, or, together with the carbon atom carrying them, form a cycloalkane having from 3 to 6 carbon atoms, 
         R 4  and R 5  each represent hydrogen, or are adjacent and, together with the carbon atoms carrying them, form a benzo ring, 
         Ar represents aryl or heteroaryl, 
       
       or an enantiomer or addition salt thereof with a pharmaceutically acceptable acid, 
       it being understood that: 
       “aryl” may be phenyl, biphenylyl or naphthyl, each of those groups being optionally substituted by one or more identical or different groups selected from:
 halogen, 
 linear or branched (C 1 -C 6 )alkyl optionally substituted by a hydroxy, carboxy or carbamoyl group, the carbamoyl group being itself optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl, 
 linear or branched (C 1 -C 6 )alkoxy, 
 hydroxy, 
 trihalo-(C 1 -C 6 )alkyl in which the alkyl moiety may be linear or branched, 
 amino optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl, 
 carboxymethoxy, 
 and carbamoylmethoxy optionally N-substituted by one or two groups selected from linear or branched (C 1 -C 6 )alkyl, hydroxy-(C 1 -C 6 )alkyl in which the alkyl moiety may be linear or branched, alkoxyalkyl in which the alkoxy and alkyl moieties are each linear or branched C 1 -C 6 , and pyridylalkyl in which the alkyl moiety is linear or branched C 1 -C 6 , 
 
       and “heteroaryl” may be a mono- or bi-cyclic aromatic group having from 5 to 12 ring members and containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl may be optionally substituted by one or more identical or different groups selected from:
 halogen, 
 linear or branched (C 1 -C 6 )alkyl optionally substituted by a hydroxy, carboxy or carbamoyl group, the carbamoyl group being itself optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl, 
 hydroxy, 
 oxo, 
 linear or branched (C 1 -C 6 )alkoxy, 
 trihalo-(C 1 -C 6 )alkyl in which the alkyl moiety may be linear or branched, 
 amino optionally N-substituted by one or two linear or branched (C 1 -C 6 )alkyl groups, 
 carboxymethoxy, 
 and carbamoylmethoxy optionally N-substituted by one or two groups selected from linear or branched (C 1 -C 6 )alkyl, hydroxy-(C 1 -C 6 )alkyl in which the alkyl moiety may be linear or branched, alkoxyalkyl in which the alkoxy and alkyl moieties are each linear or branched C 1 -C 6 , and pyridylalkyl in which the alkyl moiety is linear or branched C 1 -C 6 . 
 
     
   
   
       2 . The method of  claim 1 , wherein the configuration of the asymmetric centre at the alpha position with respect to the amide of the compound of formula (I) is (S). 
   
   
       3 . The method of  claim 1 , wherein m is 1. 
   
   
       4 . The method of  claim 1 , wherein n is 1. 
   
   
       5 . The method of  claim 1 , wherein R 1  represents hydrogen. 
   
   
       6 . The method of  claim 1 , wherein R 2  represents hydrogen. 
   
   
       7 . The method of  claim 1 , wherein R 3  represents hydrogen. 
   
   
       8 . The method of  claim 1 , wherein R 4  and R 5  each represent hydrogen. 
   
   
       9 . The method of  claim 1 , wherein R 4  and R 5  are adjacent and, together with the carbon atoms carrying them, form a benzo ring. 
   
   
       10 . The method of  claim 1  wherein Ar represents phenyl, thienyl or pyridyl, each of those groups being unsubstituted or substituted by one or more identical or different groups selected from:
 halogen,   linear or branched (C 1 -C 6 )alkyl optionally substituted by hydroxy, carboxy or carbamoyl, the carbamoyl group being itself optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl,   linear or branched (C 1 -C 6 )alkoxy,   hydroxy,   trihalo-(C 1 -C 6 )alkyl in which the alkyl moiety may be linear or branched,   amino optionally substituted by one or two linear or branched (C 1 -C 6 )alkyl,   carboxymethoxy,   and carbamoylmethoxy optionally N-substituted by one or two groups selected from linear or branched (C 1 -C 6 )alkyl, hydroxy-(C 1 -C 6 )alkyl in which the alkyl moiety may be linear or branched, alkoxyalkyl in which the alkoxy and alkyl moieties are each linear or branched C 1 -C 6 , and pyridylalkyl in which the alkyl moiety is linear or branched C 1 -C 6 .   
   
   
       11 . The method of  claim 10 , wherein Ar represents phenyl unsubstituted or substituted by one or more identical or different halogen selected from fluorine and chlorine. 
   
   
       12 . The method of  claim 1 , wherein the compound of formula (I) is selected from: 
     3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-N-(2-fluorobenzyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, and its (6S) enantiomer, 
     3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-N-(2,6-difluorobenzyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, and its (6S) enantiomer, 
     3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-N-(2-chlorobenzyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, and its (6S) enantiomer; 
     3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-N-(2,5-difluorobenzyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, and its (6S) enantiomer, 
     3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-N-(2,3-difluorobenzyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, and its (6S) enantiomer, 
     and 3-{[2,2-difluoro-2-(1-oxido-2-pyridyl)ethyl]amino}-N-(2,3,6-trifluorobenzyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, and its (6S) enantiomer. 
   
   
       13 . The method of  claim 1 , wherein the compound of formula (I) is administered in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.