Composition for the treatment or prophylaxis of thrombosis or embolism

Abstract

The description herein relates to a method of ameliorating the drawbacks of anti-platelet drug named clopidogrel. The method of the description herein comprises administration of an acyl derivative of the Formula IIA in its free or pharmaceutically acceptable salt form for alleviating the symptoms of thrombosis or embolism by inhibiting blood platelet aggregation. Compositions for use in such methods are also provided.

We claim: 
     
         1 . A composition comprising a compound of Formula IIA 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R is an acyl group. 
     
     
         2 . The composition of  claim 1 , further comprising a proton pump inhibitor. 
     
     
         3 . The composition of  claim 1 , further comprising a proton pump inhibitor compound, or an anti-platelet agent selected from the group consisting of aspirin, cilostazol and dipyridamol. 
     
     
         4 . The composition of  claim 1 , wherein R is an acyl group having the formula R 1 —CO— wherein R 1  is alkyl. 
     
     
         5 . The composition of  claim 4 , wherein R 1  is methyl. 
     
     
         6 . The composition of  claim 4 , wherein R 1  has two to eight carbon atoms. 
     
     
         7 . The composition of  claim 6 , wherein R 1  is ethyl, n-propyl, 1-methylethyl, n-butyl, n-pentyl, or 1,1-dimethylethyl. 
     
     
         8 . The composition of  claim 1 , wherein R is an acyl group having the formula R 1 —CO— wherein R 1  is selected from the group consisting of aryl, alkenyl and alkynyl. 
     
     
         9 . The composition of  claim 8 , wherein R 1  is a straight or branched alkenyl having from two to ten carbon atoms. 
     
     
         10 . The composition of  claim 9 , wherein R 1  is selected from the group consisting of ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. 
     
     
         11 . The composition of  claim 8 , wherein R 1  is a straight or branched alkynyl having from two to twelve carbon atoms. 
     
     
         12 . The composition of  claim 11 , wherein R 1  is ethynyl. 
     
     
         13 . The composition of  claim 8 , wherein R 1  is an aryl group having six to fourteen carbon atoms. 
     
     
         14 . The composition of  claim 13 , wherein R 1  is phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl. 
     
     
         15 . The composition of  claim 14 , wherein said R 1  is further substituted by a C 1 -C 6  alkyl group or halogen atom. 
     
     
         16 . The composition of  claim 1 , wherein said composition ameliorates clopidogrel resistance. 
     
     
         17 . A fixed dose composition of a compound of Formula IIA 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein R is an acyl group; characterized in that said composition comprises a dose of 5 mg-35 mg of said Formula IIA or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. 
     
     
         18 . The fixed dose composition of  claim 17 , further comprising a proton pump inhibitor compound, or an anti-platelet agent selected from the group consisting of aspirin, cilostazol and dipyridamol. 
     
     
         19 . The fixed dose composition of  claim 17 , wherein the composition reduces or alleviates inter individual platelet response variability and metabolic loading in humans in the treatment or prophylaxis of thrombosis or embolisms observed following administration of clopidogrel. 
     
     
         20 . The composition of  claim 17 , wherein R is an acyl group having the formula R 1 —CO— wherein R 1  is alkyl. 
     
     
         21 . The composition of  claim 20 , wherein R 1  is methyl. 
     
     
         22 . The composition of  claim 20 , wherein R 1  has two to eight carbon atoms. 
     
     
         23 . The composition of  claim 22 , wherein R 1  is ethyl, n-propyl, 1-methylethyl, n-butyl, n-pentyl, or 1,1-dimethylethyl. 
     
     
         24 . A pharmaceutical composition for the treatment or prophylaxis of thrombosis or embolisms in a clopidogrel non-responder- or poor-responder-patient in need of such treatment, said composition comprising a compound of Formula IIA 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R is an acyl group. 
     
     
         25 . The pharmaceutical composition of  claim 24 , further comprising a proton pump inhibitor compound, or an anti-platelet agent selected from the group consisting of aspirin, cilostazol and dipyridamol. 
     
     
         26 . The composition of  claim 24 , wherein R is an acyl group having the formula R 1 —CO— wherein R 1  is alkyl. 
     
     
         27 . The composition of  claim 26  wherein R 1  is methyl. 
     
     
         28 . The composition of  claim 26 , wherein R 1  has two to eight carbon atoms. 
     
     
         29 . The composition of  claim 28 , wherein R 1  is ethyl, n-propyl, 1-methylethyl, n-butyl, n-pentyl, or 1,1-dimethylethyl.