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 - 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 Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is a non-substituted or X-substituted linear or branched C 1-10  alkyl, OR 4 , NR 5 R 6 , phenyl, a Y-substituted phenyl, styryl, 4-hydroxylstyryl, 4-hydroxy-3-methoxystyryl, 3-pyridinyl, alkenyl, or alkynyl, in which X is fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, aryloxy, phenyl, or a Y-substituted phenyl; Y is fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxy, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, or ethoxycarbonyl, and the Y group is at position 2, 3 or 4 of the phenyl ring; 
         R 2  is hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, a linear or branched C 1-6  alkyl, alkenyl, or alkynyl, and is at position 2, 3 or 4 of the phenyl ring; and when R 2  is 2-chloro, R 1  is not phenyl, and when R 2  is 2-halo, R 1  is not 3-pyridinyl; 
         R 3  is a linear or branched C 1-6  alkyl or a C 1-6  cycloalkyl; 
         R 4  is a linear or branched C 1-10  alkyl, or benzyl; and R 5  and R 6  each are a linear or branched C 1-6  alkyl, or NR 5 R 6  is 
       
       
         
           
           
               
               
           
         
       
     
     
         12 - 16 . (canceled) 
     
     
         17 . The method of  claim 11 , wherein R 1  is methyl, ethyl, propyl, t-butyl, tert-pentyl, phenoxymethyl, methoxy, ethoxy, isopropoxy, isobutoxy, benzyloxy, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —N(CH 3 )(CH 2 CH 3 ), 
       
         
           
           
               
               
           
         
       
       phenyl, 2-hydroxyphenyl, 2-acetoxyphenyl, 4-methoxyphenyl, 4-nitrophenyl, styryl, 4-hydroxylstyryl, 4-hydroxy-3-methoxystyryl, or 3-pyridinyl; R 2  is 2-fluoro or 2-chloro; and R 3  is methyl or ethyl. 
     
     
         18 . The method of  claim 11 , wherein the method achieves a therapeutic effect greater than or equivalent to that observed following the administration of clopidogrel. 
     
     
         19 . The method of  claim 11 , wherein the method results in the in vivo formation of the active metabolite of clopidogrel at a concentration greater than or equivalent to that observed following administration of clopidogrel. 
     
     
         20 . The method  claim 11 , wherein the onset of therapeutic action is at least 50% more rapid than that observed following administration of clopidogrel. 
     
     
         21 . The method of  claim 11 , wherein the effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is 1 mg-500 mg for oral administration, or 0.1 mg-250 mg for intravenous administration. 
     
     
         22 . A method of treating thrombosis and embolism related diseases in a patient in need thereof comprising administering a composition containing an effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is a non-substituted or X-substituted linear or branched C 1-10  alkyl, OR 4 , NR 5 R 6 , phenyl, a Y-substituted phenyl, styryl, 4-hydroxylstyryl, 4-hydroxy-3-methoxystyryl, 3-pyridinyl, alkenyl, or alkynyl, in which X is fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, aryloxy, phenyl, or a Y-substituted phenyl; Y is fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxy, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, or ethoxycarbonyl, and the Y group is at position 2, 3 or 4 of the phenyl ring; 
         R 2  is hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, a linear or branched C 1-6  alkyl, alkenyl, or alkynyl, and is at position 2, 3 or 4 of the phenyl ring; and when R 2  is 2-chloro, R 1  is not phenyl, and when R 2  is 2-halo, R 1  is not 3-pyridinyl; 
         R 3  is a linear or branched C 1-6  alkyl or a C 1-6  cycloalkyl; 
         R 4  is a linear or branched C 1-10  alkyl, or benzyl; and 
         R 5  and R 6  each are a linear or branched C 1-6  alkyl, or NR 5 R 6  is 
       
       
         
           
           
               
               
           
         
         wherein said administration avoids the side effects associated with clopidogrel. 
       
     
     
         23 . A method of treating thrombosis and embolism related diseases in a clopidogrel-resistance patient in need of such treatment, comprising administering an effective amount of a composition containing a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is a non-substituted or X-substituted linear or branched C 1-10  alkyl, OR 4 , NR 5 R 6 , phenyl, a Y-substituted phenyl, styryl, 4-hydroxylstyryl, 4-hydroxy-3-methoxystyryl, 3-pyridinyl, alkenyl, or alkynyl, in which X is fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, aryloxy, phenyl, or a Y-substituted phenyl; Y is fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxy, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, or ethoxycarbonyl, and the Y group is at position 2, 3 or 4 of the phenyl ring; 
         R 2  is hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, a linear or branched C 1-6  alkyl, alkenyl, or alkynyl, and is at position 2, 3 or 4 of the phenyl ring; and when R 2  is 2-chloro, R 1  is not phenyl, and when R 2  is 2-halo, R 1  is not 3-pyridinyl; 
         R 3  is a linear or branched C 1-6  alkyl or a C 1-6  cycloalkyl; 
         R 4  is a linear or branched C 1-10  alkyl, or benzyl; and 
         R 5  and R 6  each are a linear or branched C 1-6  alkyl, or NR 5 R 6  is 
       
       
         
           
           
               
               
           
         
       
     
     
         24 . A method of treating clopidogrel resistance in a patient in need of treatment or prophylaxis of thrombosis or embolisms, comprising administering an effective amount of a composition containing a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is a non-substituted or X-substituted linear or branched C 1-10  alkyl, OR 4 , NR 5 R 6 , phenyl, a Y-substituted phenyl, styryl, 4-hydroxylstyryl, 4-hydroxy-3-methoxystyryl, 3-pyridinyl, alkenyl, or alkynyl, in which X is fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, aryloxy, phenyl, or a Y-substituted phenyl; Y is fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxy, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, or ethoxycarbonyl, and the Y group is at position 2, 3 or 4 of the phenyl ring; 
         R 2  is hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, amino, amido, sulfonamido, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, a linear or branched C 1-6  alkyl, alkenyl, or alkynyl, and is at position 2, 3 or 4 of the phenyl ring; and when R 2  is 2-chloro, R 1  is not phenyl, and when R 2  is 2-halo, R 1  is not 3-pyridinyl; 
         R 3  is a linear or branched C 1-6  alkyl or a C 1-6  cycloalkyl; 
         R 4  is a linear or branched C 1-10  alkyl, or benzyl; and 
         R 5  and R 6  each are a linear or branched C 1-6  alkyl, or NR 5 R 6  is