Phenylacetic Acid Derivatives

Abstract

Compounds of formula (I) pharmaceutically acceptable salts thereof; and pharmaceutically acceptable esters thereof; which are useful for the treatment of COX-2 dependent disorders.

1 - 12 . (canceled) 
     
     
         13 . A method for the preparation of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R is methyl or ethyl; 
         R 3  is halo or C 1 -C 6  alkyl; 
         R 4  is C 1 -C 6  alkyl; 
         R 5  is halo; 
         the above mentioned C 1 -C 6  alkyl at R3 and R4 being optionally substituted by one or more halo groups; 
         which method comprises the step of:
 (a) coupling a compound of formula (II) or (III) 
 
       
       
         
           
           
               
               
           
         
         
           wherein
 Z is bromo or iodo; 
 R has meaning as defined above; 
 R a  is hydrogen, an alkali metal cation or lower alkyl, preferably isopropyl; and 
 R 6  and R 7  are lower alkyl; or R 6  and R 7 , together with the nitrogen atom, represent morpholino, piperidino or pyrrolidino; 
 
           with a compound of formula (IV) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 3 -R 5  have meaning as defined above in the presence of copper and cuprous iodide to obtain a compound of formula (V) or (VI) 
         
       
       
         
           
           
               
               
           
         
         
           and hydrolyzing the resulting compound of formula (V) or (VI) to a compound of formula (I); or 
           (b) condensing a compound of formula (VII) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 3 -R 7  have meaning as defined herein, with a reactive functional derivative of an acid, e.g., acetic acid, such as acetyl chloride, in a Friedel-Crafts acylation to reaction to obtain, e.g., a compound of the formula (VIII) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 3 -R 7  have meaning as defined herein, which is in turn hydrogenolyzed and then hydrolyzed to obtain a compound of formula (I), wherein R represents, e.g., ethyl; or 
           (c) hydrolyzing a lactam of formula (IX) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R and R 3 -R 5  have meaning as defined herein, with a strong base; and in above processes, if desired, temporarily protecting any interfering reactive groups and then isolating the resulting compound of the invention; and, if desired, converting any resulting compound into another compound of the invention; and/or if desired converting a free carboxylic acid of the invention into a pharmaceutically acceptable ester derivative thereof; and/or if desired, converting a resulting free acid into a salt or a resulting salt into the free acid or into another salt.