Arylethynyl derivatives

Abstract

The present invention relates to ethynyl derivatives of formula I wherein R 1 is phenyl, which is optionally substituted by 1-2 halogen atoms; selected from fluorine or chlorine; or to a pharmaceutically acceptable acid addition salt in enantiomerically pure form. It has been found that the compounds of general formula I are allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).

1 . An ethynyl derivative of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is phenyl, which is optionally substituted by 1-2 halogen atoms, selected from fluorine or chlorine; 
 
       or a pharmaceutically acceptable acid addition salt in enantiomerically pure form. 
     
     
         2 . An ethynyl derivative of formula I-A according to  claim 1   
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is phenyl which is optionally substituted by 1-2 fluorine atoms; 
 
       or a pharmaceutically acceptable acid addition salt in enantiomerically pure form. 
     
     
         3 . A compound of formula I according to  claim 1 , wherein the compound is
 (3aR,6aR)-1-(5-(phenylethynyl)pyridin-2-yl)hexahydrocyclopenta[b]pyrrol-2(1H)-one   (3aR,6aR)-1-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)hexahydrocyclopenta[b]pyrrol-2(1H)-one   (3aR,6aR)-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)hexahydrocyclopenta[b]pyrrol-2(1H)-one or   (3aR,6aR)-1-(5-((2,5-difluorophenyl)ethynyl)pyridin-2-yl)hexahydrocyclopenta[b]pyrrol-2(1H)-one.   
     
     
         4 . A process for preparation of a compound of formula I as described in  claim 1 , comprising the variants
 a) reacting a compound of formula II   
       
         
           
           
               
               
           
         
       
       wherein X is a halogen atom selected from bromine or iodine, and where the compound of formula II is a racemic mixture or in enantiomerically pure form with a suitable aryl-acetylene of formula III 
       
         
           
           
               
               
           
         
       
       to form a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein the substituents are described above, or if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts or
 b) reacting a compound of formula 
 
       
         
           
           
               
               
           
         
       
       with a compound of formula 
       
         
           
           
               
               
           
         
       
       to form a compound of formula 
       
         
           
           
               
               
           
         
       
       wherein the substituents are described in  claim 1 , or if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts. 
     
     
         5 . A method for treating or preventing diseases related to allosteric modulators of mGluR5 receptors in a patient, comprising administering a compound of  claim 1  to the patient. 
     
     
         6 . A pharmaceutical composition comprising at least one of the compounds according to  claim 1  as well as its pharmaceutically acceptable salt. 
     
     
         7 . The composition of  claim 6 , wherein the compound is present as in mixtures of enantiomers, diastereomers, or in enantiomerically pure form; as well as its pharmaceutically acceptable salt. 
     
     
         8 . A method for the treatment of schizophrenia, cognitive diseases, fragile X syndrome or autism in a patient, which method comprises administering to the patient an effective amount of a compound as defined in  claim 1 .