2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9h-pyrido (3,4-b) indole-3-carboxylic acid esters/amides useful as antithrombotic agents

Abstract

The present invention relates to antithrombotic compounds 2-alkyl aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid esters/amides, pharmaceutically acceptable salts and compositions thereof to be used in the treatment of intravascular thrombosis such as myocardial ischemia and stroke. The compound has the following general structure wherein R represents methyl ester or amide and R 1 represents alkyl, aryl and heteroaryl moiety.

1 . A process for the preparation of a 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid ester of formula I  
     
       
         
         
             
             
         
       
     
     wherein R is selected from methyl ester and amide; and R 1  is selected from the group consisting of alkyl, aryl, and heteroaryl moiety, the process comprising condensing an alkyl or aryl sulphonyl chloride with dimethyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate of formula 2  
     
       
         
         
             
             
         
       
     
     in the presence of a base and an organic solvent to obtain a corresponding 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indo.le-3-carboxylic acid ester of formula 1.  
   
   
       2 . A method as claimed in  claim 1  wherein the aryl is selected from the group consisting of substituted phenyl substituted by hydrogen, halogen, alkyl or alkoxy, sunstituted napthyl substituted by hydrogen or dimethyl amino; and heteroaryl.  
   
   
       3 . A method as claimed in  claim 2  wherein the heteraryl is quinoline.  
   
   
       4 . A method as claimed in  claim 1  wherein the reaction is carried out at a temperature in the range of 30° C. to 120° C. and for 8 to 24 hours.  
   
   
       5 . A method as claimed in  claim 2  wherein the halogen is selected from the group consisting of chlorine, bromine fluorine, iodine, and mixtures thereof; alkoxy is selected from the group consisting of C 1 -C 10  oxy; alkyl is selected from the group consisting of C 1 -C 10  alkyl, and heteroaryl is selected from the group consisting of C 4 -C 10  heteroaryl.  
   
   
       6 . A method for the preparation of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid amide of formula I  
     
       
         
         
             
             
         
       
     
     wherein R is selected from methyl ester and amide; and R 1  is selected from the group consisting of alkyl, aryl, and heteroaryl moiety by condensing an alkyl or aryl sulphonyl chloride wherein aryl is selected from the group consisting of substituted phenyl substituted by hydrogen, halogen, alkyl or alkoxy; substituted napthyl substituted by hydrogen or dimethyl amino; and heteroaryl consisting of quinoline with dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide of formula 3  
     
       
         
         
             
             
         
       
     
     in the presence of a base and an organic solvent to obtain a corresponding 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid amide.  
   
   
       7 . A method as claimed in  claim 6  wherein the reaction is carried out at a temperature in the range of 30° C. to 120° C. for 8 to 24 hours.  
   
   
       8 . A method as claimed in  claim 6  wherein the halogen is selected from the group consisting of chlorine, bromine fluorine, iodine, and mixtures thereof, alkoxy is selected from the group consisting of C 1  to C 10  oxy; alkyl is selected from the group consisting of C 1  to C 10  alkyl, and heteroaryl is selected from the group consisting of C 4 -C 10  heteroaryl.  
   
   
       9 . A method for the preparation of 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid amides comprising reacting a 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid ester with methanolic ammonia for 24 to 48 hours to obtain the corresponding 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid amide.  
   
   
       10 . A process as claimed in  claim 1  wherein the reaction is carried out in the presence of a solvent selected from the group consisting of acetone, DMF, THF and dioxane; a base selected from the group consisting of TEA, K 2 CO 3 . Na 2 CO 3 , pyridine or any combination thereof and at a temperature in the range of 30° C. to 120° C. and a period of 8 to 24 hours.  
   
   
       11 . A process as claimed in  claim 1  wherein molar ratio of substituted sulphonyl chloride to dl methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylate/dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-amide is 1:2.  
   
   
       12 . A process as claimed in  claim 10  wherein the amount of solvent is in the range of 0.8-2.2 ml per mmol.  
   
   
       13 . A process as claimed in  claim 10  wherein molar ratio of the base to the dl methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate/dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide is 1:4.  
   
   
       14 . A pharmaceutical composition comprising a pharmaceutically effective amount of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid ester/amide of formula 1  
     
       
         
         
             
             
         
       
     
     wherein R is selected from the methyl ester and amide; and R 1  is selected from the group consisting of alkyl, aryl, and heteroaryl moiety, and a pharmaceutically acceptable carrier.  
   
   
       15 . A method for the treatment of intravascular thrombosis in mammals comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition consisting of a pharmaceutically effective amount of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid amide of formula 1  
     
       
         
         
             
             
         
       
     
     wherein R is selected from methyl ester and amide; and R 1  is selected from the group consisting of alkyl, aryl and heteroaryl moiety, with a pharmaceutically acceptable carrier.  
   
   
       16 . A method for the treatment of myocardial ischemia in mammals, comprising by administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition consisting of a pharmaceutically effective amount of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid ester/amide of formula 1  
     
       
         
         
             
             
         
       
     
     wherein R is selected from methyl ester and amide; and R 1  is selected from the group consisting of alkyl, aryl and heteroaryl moiety, with a pharmaceutically acceptable carrier.  
   
   
       17 . A method for the treatment of stroke in mammals, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition consisting of a pharmaceutically effective amount of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid ester/amide of formula 1  
     
       
         
         
             
             
         
       
     
     wherein R is selected from methyl ester and amide; and R 1  is selected from the group consisting of alkyl, aryl and heteroaryl moiety, with a pharmaceutically acceptable carrier.  
   
   
       18 . A method for treating a condition in mammals, selected from the group consisting of myocardial ischemia, intravascular thrombosis and stroke, which comprises administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition consisting of a pharmaceutically effective amount of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid ester/amide of formula 1  
     
       
         
         
             
             
         
       
     
     wherein R is selected from methyl ester and amide; and R 1  is selected from the group consisting of alkyl, aryl and heteroaryl moiety, with or without a pharmaceutically acceptable carrier.  
   
   
       19 . The method as claimed in  claim 15  wherein the amount of compound of formula 1 is in the range of 10 μM to 30 μM per kilogram body weight of subject.  
   
   
       20 . The method as claimed in  claim 16  wherein the amount of compound of formula 1 is in the range of 10 μM to 30 μM per kilogram body weight of subject.  
   
   
       21 . The method as claimed in  claim 17  wherein the amount of compound of formula 1 is in the range of 10 μM to 30 μM per kilogram body weight of subject.  
   
   
       22 . The method as claimed in  claim 18  wherein the amount of compound of formula 1 is in the range of 10 μM to 30 μM per kilogram body weight of subject.