TGR5 Modulators and Methods of Use Thereof

Abstract

The invention relates to compounds of Formula A: or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The compounds of Formula A are TGR5 modulators useful for the treatment of various diseases, including obesity, insulin sensitivity, inflammation, cholestasis, and bile desaturation.

What is claimed is: 
     
         1 . A method of preparing a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1 , R 2 , and R 3  are hydroxy, 
         R 4  is hydrogen or lower alkyl, 
         R 5  is methyl, and 
         R 6  is hydrogen; 
         the method comprising the steps of: 
         protecting the hydroxy groups of Compound 1 with 3,4-dihydro-2H-pyran to form Compound 2: 
       
       
         
           
           
               
               
           
         
         alkylating the C-23 carbon of Compound 2 with methyl iodide followed by treatment with methanolic HCl to form Compound 3: 
       
       
         
           
           
               
               
           
         
         and hydrolyzing the ester of Compound 3 with NaOH to form the compound of Formula I. 
       
     
     
         2 . The method of  claim 1 , wherein the protection of the hydroxy groups of Compound 1 is conducted in the presence of p-toulenesulfonic acid. 
     
     
         3 . The method of  claim 2 , wherein the protection is conducted in dioxane. 
     
     
         4 . The method of  claim 1 , wherein the alkylation of the C-23 carbon of Compound 2 is conducted in tetrahydrofuran using lithium diisopropylamide as a base. 
     
     
         5 . The method of  claim 4 , wherein the alkylation is run at about −78° C. 
     
     
         6 . The method of  claim 1 , wherein the hydrolysis of the ester of Compound 3 is conducted in methanol. 
     
     
         7 . The method of  claim 1 , wherein R 4  is ethyl. 
     
     
         8 . The method of  claim 1 , wherein R 4  is methyl. 
     
     
         9 . The method of  claim 1 , wherein R 4  is hydrogen. 
     
     
         10 . The method of  claim 1 , wherein R 5  is in the S-configuration. 
     
     
         11 . The method of  claim 1 , wherein R 1  is α-hydroxy. 
     
     
         12 . The method of  claim 1 , wherein R 2  is α-hydroxy. 
     
     
         13 . The method of  claim 9 , wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 9 , wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 8 , wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 8 , wherein the compound of Formula I is: