Anti-thrombotic compounds

Abstract

New compounds, namely, (7aS,2′S)-2-oxoclopidogrel and its pharmaceutically acceptable salts thereof are disclosed for treatment or prophylaxis of thrombo-embolism and/or cardiovascular diseases.

1 . A compound of formula IIA, its salts, wherein the asterisk denotes chiral carbon center having (S,S) absolute stereochemical configuration. 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound as claimed in  claim 1 , wherein the compound is isolated substantially free from its other chiral isomers of formula IIB, wherein the asterisk denotes chiral carbon center, and structural isomers of formula VI and/or VII. 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of Formula IIA, according to  claim 2 , wherein the other isomers of Formula IIB, VI or VII are individually or cumulatively less than 10% by weight. 
     
     
         4 . The compound of Formula IIA, according to  claim 2 , wherein the other isomers of Formula IIB, VI and/or VII are less than 3% by weight. 
     
     
         5 . The compound of Formula IIA, according to  claim 2 , wherein the other isomers of Formula IIB, VI and/or VII are less than 1.0% by weight. 
     
     
         6 . The compound of Formula IIA, according to  claim 1 , wherein the salt is selected from the group consisting of hydrogen sulphate salt, methane sulphonate, or benzene sulphonate. 
     
     
         7 . An isolated Methyl (7aS,2′S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate or its salts, solvates, complexes. 
     
     
         8 . Methyl (7aS,2′S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate hydrogen sulfate. 
     
     
         9 . Methyl (7aS,2′S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate methane sulphonate. 
     
     
         10 . Methyl (7aS,2′S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate benzene sulphonate. 
     
     
         11 . (canceled) 
     
     
         12 . A pharmaceutical composition comprising an isolated compound of formula IIA or its pharmaceutically acceptable salt(s). 
     
     
         13 . The pharmaceutical composition according to  claim 12 , wherein the compound of formula IIA is Methyl (7aS,2′S)-2-(2-chlorophenyl)-2-(2,4,5,6,7,7a-hexahydrothieno[3,2-c]-5-pyridin-2-one)acetate hydrogen sulfate. 
     
     
         14 . A pharmaceutical combination comprising the compound of formula IIA or its salts according to  claim 1  and a second anti-platelet/cardiovascular agent. 
     
     
         15 . The combination according to  claim 14 , wherein the second antiplatelet/cardiovascular agent is selected from the group consisting of aspirin, cilostazol, and dipyridamole. 
     
     
         16 . A pharmaceutical combination comprising the compound of  claim 1  and a gastric pH regulating agent. 
     
     
         17 . The combination according to  claim 16 , wherein the gastric pH regulating agent is selected from the group consisting of a proton pump inhibitor, and ranitidine. 
     
     
         18 . A method of treatment and/or prophylaxis of thrombosis and/or embolisms in a patient in need of such treatment, while avoiding and/or alleviating the side effects associated with the clopidogrel metabolites at least of Formula IV, comprising administering an effective amount of (7aS,2′S)-2-oxo-clopidogrel or a pharmaceutically acceptable salt thereof. 
     
     
         19 . An improved method for delivering the active clopidogrel metabolite in vivo for the treatment and/or prophylaxis of thrombosis and/or embolisms in a human in need of such treatment while avoiding or alleviating the side effects associated with inactive clopidogrel metabolites at least of Formula IV, the method comprises administering an effective amount of (7aS,2′S)-2-oxo-clopidogrel or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A method for minimizing inter individual platelet reactivity variability and metabolic loading in the treatment and/or prophylaxis of thrombosis and/or embolisms observed following administration of a dose of clopidogrel, said method comprising administering (7aS,2′S)-2-oxo-clopidogrel or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method of  claim 20 , wherein the inter-individual variability is due to CYP450 isoforms and their polymorphic manifestations. 
     
     
         22 . The method of  claim 21 , wherein the CYP450 isoforms are CYP2C19*2 allele or CYP2C19*17 allele. 
     
     
         23 . A method according to  claim 20 , wherein the inter-individual variability is due to P-glycoprotein efflux transports.