Acetylene derivatives having mglur 5 antagonistic activity

Abstract

The invention provides compounds of formula I wherein n, A, R, R′, R″, R o , X and Y are as defined in the description, and their preparation. The compounds of formula I are useful as pharmaceuticals.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         m is 0 or 1, 
         n is 0 or 1 and 
       
       A is hydroxy 
       X is hydrogen and 
       Y is hydrogen, or 
       A forms a single bond with X or with Y; 
       R 0  is hydrogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, trifluoromethyl, halogen, cyano, nitro, —COOR 1  wherein R 1  is (C 1-4 )alkyl or —COR 2  wherein R 2  is hydrogen or (C 1-4 )alkyl, and 
       R is —COR 3 , —COOR 3 , —CONR 4 R 5  or —SO 2 R 6 , wherein R 3  is (C 1-4 )alkyl, (C 3-7 )cycloalkyl or optionally substituted phenyl, 2-pyridyl or 2-thienyl, R 4  and R 5 , independently, are hydrogen or (C 1-4 )alkyl and R 6  is (C 1-4 )alkyl, (C 3-7 )cycloalkyl or optionally substituted phenyl, 
       R′ is hydrogen or (C 1-4 )alkyl and 
       R″ is hydrogen, or (C 1-4 )alkyl, or 
       R′ and R″ together form a group —CH 2 —(CH 2 ) p —
 wherein p is 0, 1 or 2, in which case one of n and p is different from 0, with the proviso that R 0  is different from hydrogen, trifluoromethyl and methoxy when m is 1, n is 0, A is hydroxy, X and Y are both hydrogen, R is COOEt and R′ and R″ together form a group —(CH 2 ) 2 —, 
 
       in free base or acid addition salt form. 
     
     
         2 . The compound of  claim 1  which is (−)-(3aR, 4S, 7aR)-4-hydroxy-4m-tolylethynyl-octahydroindole-1-carboxylic acid methyl ester in free base or acid addition salt form. 
     
     
         3 . A process for the preparation of a compound of formula I as defined in  claim 1 , or a salt thereof, which comprises the step of
 a) for the production of a compound of formula I wherein A is hydroxy, reacting a compound of formula II   
       
         
           
           
               
               
           
         
         wherein m, n, R, R′ and R″ are as defined in  claim 1 , with a compound of formula III 
       
       
         
           
           
               
               
           
         
         wherein R 0  is as defined in  claim 1 , or 
         b) for the production of a compound of formula I wherein A forms a single bond with X or with Y, dehydrating a compound of formula I wherein A is hydroxy, 
         and recovering the resulting compound of formula I in free base or acid addition salt form. 
       
     
     
         4 . A compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical. 
     
     
         5 . A compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for use in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5. 
     
     
         6 . A pharmaceutical composition comprising a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. 
     
     
         7 . The use of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5. 
     
     
         8 . The use of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for the manufacture of a pharmaceutical composition designed for the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by mGluR5. 
     
     
         9 . A method of treating disorders associated with irregularities of the glutamatergic signal transmission, and nervous system disorders mediated full or in part by mGluR5, which method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of  claim 1  in free base or pharmaceutically acceptable acid- addition-salt form. 
     
     
         10 . A combination comprising a therapeutically effective amount of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form and a second drug substance, for simultaneous or sequential administration.