Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereof

Abstract

Optically active 2-hydroxytetrahydrothienopyridine derivatives represented by Formula I and pharmaceutically acceptable salts, preparation method and use in the manufacture of a medicament thereof are disclosed. The pharmacodynamic experiment results show that the present compounds of Formula I are useful for inhibiting platelet aggregation. The pharmacokinetic experiment results show that the present compound of Formula I can be converted in vivo into pharmacologically active metabolites and are therefore useful for inhibiting platelet aggregation. Therefore, the present compounds are useful for the manufacture of a medicament for preventing or treating thrombosis and embolism related diseases.

1 - 4 . (canceled) 
     
     
         5 . A compound or a pharmaceutically acceptable salt or hydrate thereof, wherein the compound is
 (S)-methyl 2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-3;   (S)-methyl 2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-4;   (S)-methyl 2-(2-(2-acetoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-5;   (S)-methyl 2-(2-pivaloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-7;   (S)-methyl 2-(2-(2,2-dimethylbutanoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-8;   (S)-methyl 2-(2-cinnamoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-9;   (S)-methyl 2-(2-(4-methoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-11;   (S)-methyl 2-(2-phenylacetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-12;   (S)-methyl 2-(2-(phenoxyacetoxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-13;   (S)-methyl 2-(2-(ethoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-14;   (S)-methyl 2-(2-(isobutoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-15;   (S)-methyl 2-(2-(isopropoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-16;   (S)-methyl 2-(2-(benzyloxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-17;   (S)-methyl 2-(2-(N,N-dimethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-18;   (S)-methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate I-19;   (S)-methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-chlorophenyl)-acetate I-20;   (S)-methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-phenyl-acetate I-21;   (S)-methyl 2-(2-(pyrrolidine-1-carbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-22;   (S)-methyl 2-(2-(methoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-23;   (S)-methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromophenyl)-acetate I-24;   (S)-ethyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate I-25;   (S)-ethyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-26;   (S)-ethyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromophenyl)-acetate I-27;   (S)-methyl 2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate I-28;   (S)-methyl 2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromophenyl)-acetate I-29;   (S)-ethyl 2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate I-30;   (S)-ethyl 2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-31;   (S)-ethyl 2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromophenyl)-acetate I-32;   (S)-methyl 2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate I-33;   (S)-methyl 2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromophenyl)-acetate I-34;   (S)-ethyl 2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate I-35;   (S)-ethyl 2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-36;   (S)-ethyl 2-(2-butanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-bromophenyl)-acetate I-37;   (S)-ethyl 2-(2-pivaloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-38;   (S)-ethyl 2-(2-(2,2-dimethylbutanoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-39;   (S)-methyl 2-(2-feruloyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-40;   (S)-methyl 2-(2-benzoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl)-acetate I-41;   (S)-methyl 2-(2-nicotinoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-chlorophenyl)-acetate I-42;   (S)-methyl 2-(2-(2-hydroxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-43;   (S)-methyl 2-(2-(t-butoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-44;   (S)-methyl 2-(2-(N,N-diethylcarbamoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-45; and   (S)-methyl 2-(2-(piperdine-1-carbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate I-46.   
     
     
         6 - 10 . (canceled) 
     
     
         11 . A method of treating thrombosis and embolism related diseases comprising administering to a patient in need thereof an effective amount of a compound of  claim 5 , or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method according to  claim 11 , wherein the thrombosis and embolism related disease is atherosclerosis, myocardial infarction, stroke, ischemic cerebral thrombosis, peripheral arterial disease, acute coronary syndrome, or thrombosis after percutaneous coronary intervention (PCI). 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 5  or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein for an adult, the pharmaceutical composition contains said compound 0.1 mg-1000 mg for oral administration, or 0.01 mg-500 mg for intravenous administration. 
     
     
         15 . The pharmaceutical composition according to  claim 13 , wherein for an adult, the pharmaceutical composition said 1 mg-500 mg for oral administration, or 0.1 mg-250 mg for intravenous administration. 
     
     
         16 . The pharmaceutical composition according to  claim 13 , wherein said pharmaceutical composition is in the form of a tablet, capsule, sustained release tablet, granule, powder, syrup, oral solution, or injection.