Polycyclic lpa1 antagonist and uses thereof

Abstract

Described herein is the LPA1 antagonist 1-{4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 1), or pharmaceutically acceptable salts thereof. Also described are methods of preparing the LPA1 antagonist, or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions suitable for administration to a mammal that include the LPA1 antagonist, or pharmaceutically acceptable salt thereof, and methods of using such pharmaceutical compositions for treating LPA-dependent or LPA-mediated diseases or conditions.

1 .- 18 . (canceled) 
     
     
         19 . A process for the preparation of 1-{4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (Compound 1) comprising Step (1) and Step (2): (1) treatment of a compound of Formula XVIII with diphenylphosphoryl azide in the presence of (R)-(+)-1-phenylethanol: 
       
         
           
           
               
               
           
         
         Wherein, 
         R 1  is C 1 -C 6  alkyl; 
         to provide a compound of Formula X: 
       
       
         
           
           
               
               
           
         
         Or (1) reacting a compound of Formula VII: 
       
       
         
           
           
               
               
           
         
         Wherein,
 x is a leaving group; 
 
         With a compound of Formula VIII: 
       
       
         
           
           
               
               
           
         
         Wherein,
 R 1  is C 1 -C 6  alkyl; and B is a boronic acid or boronate ester; 
 
         in the presence of a coupling catalyst, a suitable base, and in a suitable solvent, to provide a compound of Formula X: 
       
       
         
           
           
               
               
           
         
         or 
         (1) reacting a compound of Formula IX: 
       
       
         
           
           
               
               
           
         
         wherein,
 B is a boronic acid or boronate ester; 
 
         With a compound of Formula XII: 
       
       
         
           
           
               
               
           
         
         wherein,
 R 1  is C 1 -C 6  alkyl; and X is a leaving group; 
 
         In the presence of a coupling catalyst, a suitable base, and in a suitable solvent, to provide a compound of formula X: 
       
       
         
           
           
               
               
           
         
         and 
         (2) hydrolysis of the ester moiety of the compound of Formula X to provide Compound 1. 
       
     
     
         20 . The process according to  claim 19 , wherein step (2) comprises treatment of the compound of Formula X with sodium hydroxide in a suitable solvent followed by a pH adjustment.