Phenylethynyl and styryl derivatives of imidazole and fused ring heterocycles

Abstract

This invention relates to a compound and the use of the compound of the formula wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the description, A signifies —CH═CH— or —C≡C—; and B signifies wherein R 6 to R 26 , X and Y are as defined in the specification or a pharmaceutically acceptable salt thereof, for use in pharmaceutical compositions for the treatment or prevention of mGluR5 receptor mediated disorders.

1 . A compound of formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n -halogen, lower alkoxy, —(CH 2 ) n —NRR′, —(CH 2 ) n —N(R)—C(O)-lower alkyl, aryl, unsubstituted heteroaryl and heteroaryl substituted by one or more lower alkyl;  
 R, R′ and R″ are independently selected from the group consisting of hydrogen and lower alkyl;  
 B is selected from the group consisting of  
                     
 wherein  
 R 6  is selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —C(O)OR and halogen;  
 R 7  is selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —C(O)OR′, halogen, nitro, unsubstituted heteroaryl and heteroaryl substituted by lower alkyl or cycloalkyl;  
 R 8  is selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —(CH 2 ) n —C(O)OR″ and aryl;  
 R 9  is lower alkyl;  
 R 10  is selected from the group consisting of hydrogen, lower alkyl and halogen;  
 R 11  is selected from the group consisting of hydrogen and alkyl;  
 R 12  is (CH 2 ) n —N(R)—C(O)-lower alkyl;  
 R 13  is selected from the group consisting of hydrogen and lower alkyl;  
 R 14 , R 15 , R 16 and R   17  are independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n -halogen or lower alkoxy;  
 R 18 , R 19  and R 20  are independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n -halogen and lower alkoxy;  
 R 21  is selected from the group consisting of hydrogen and lower alkyl;  
 R 22  is selected from the group consisting of hydrogen, lower alkyl and lower alkyl substituted by at least one substitutent selected from hydroxy or halogen;  
 R 23  is selected from the group consisting of hydrogen, lower alkyl, lower alkanoyl and nitro;  
 R 24 , R 25  and R 26  are independently selected from the group consisting of hydrogen or lower alkyl;  
 n is 0, 1, 2, 3, 4, 5 or 6;  
 X is selected from the group consisting of —CH 2 —, —O— and —S—; and  
 Y is selected from the group consisting of-CH=and —N═;  
 or a pharmaceutically acceptable salt thereof;  
 with the exception of  
 1-methyl-2-phenylethynyl-1H-imidazole,  
 1-methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole,  
 1-methyl-5-phenylethynyl-1H-imidazole, and  
 1-methyl-4-phenylethynyl-1H-imidazole.  
 
     
     
         2 . A compound of  claim 1  wherein B is B1.  
     
     
         3 . A compound of  claim 1  wherein B is B2.  
     
     
         4 . A compound of  claim 1  wherein B is B3.  
     
     
         5 . A compound of  claim 1  wherein B is B4.  
     
     
         6 . A compound of  claim 1  wherein B is B5.  
     
     
         7 . A compound of  claim 1  wherein B is B6.  
     
     
         8 . A composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         9 . A method of treating a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, pain, epilepsy, amyotrophic lateral sclerosis (ALS) comprising administering a therapeutically effective amount of a compound of  claim 1 .  
     
     
         10 . A compound of formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n -halogen, lower alkoxy, —(CH 2 ) n —NRR′, —(CH 2 ) n —N(R)—C(O)-lower alkyl, aryl or unsubstituted heteroaryl, heteroaryl substituted by at least one lower alkyl;  
 R, R′ and R″ are independently selected from the group consisting of hydrogen and lower alkyl;  
 R 6  is selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —C(O)OR and halogen;  
 R 7  is selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —C(O)OR′, halogen, nitro, unsubstituted heteroaryl and heteroaryl substituted by lower alkyl or cycloalkyl; and  
 R 8  is selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —(CH 2 ) n —C(O)OR″ or aryl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         11 . A composition comprising a therapeutically effective amount of a compound of  claim 10  and a pharmaceutically acceptable carrier.  
     
     
         12 . A method of treating a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, pain, epilepsy, amyotrophic lateral sclerosis (ALS) comprising administering a therapeutically effective amount of a compound of  claim 10 .  
     
     
         13 . A compound of formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , R 4  and R 5  are independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n -halogen, lower alkoxy, —(CH 2 ) n —NRR′, —(CH 2 ) n —N(R)—C(O)-lower alkyl, aryl, unsubstituted heteroaryl and heteroaryl substituted by at least one lower alkyl;  
 R and R′ are independently selected from the group consisting of hydrogen and lower alkyl;  
 R 9  is lower alkyl;  
 R 10  is halogen; and  
 R 11  is selected from the group consisting of hydrogen and alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         14 . A composition comprising a therapeutically effective amount of a compound of  claim 13  and a pharmaceutically acceptable carrier.  
     
     
         15 . A method of treating a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, pain, epilepsy, amyotrophic lateral sclerosis (ALS) comprising administering a therapeutically effective amount of a compound of  claim 13.