Triazolo-pyridazine derivatives as ligands for GABA receptors

Abstract

A class of substituted 1,2,4-triazolo[4,3-b]pyridazine derivatives, possessing a difluoro- or trifluoro-substituted phenyl ring at the 3-position, a triazolyl-methoxy moiety at the 6-position, and a tert-butyl group at the 7-position, are selective ligands for GABA A receptors, in particular having high affinity for α2 and/or α3 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of disorders of the central nervous system, including anxiety and convulsions.

1 . A compound of formula I, or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 Y represents hydrogen and Z represents fluoro, or Y represents fluoro and Z represents hydrogen or fluoro; and  
 R 1  represents methyl or ethyl.  
 
     
     
         2 . A compound of formula I as depicted in  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y and Z both represent fluoro; and R 1  represents methyl or ethyl.  
     
     
         3 . A compound as claimed in  claim 1  represented by formula IA, and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein Y, Z and R 1  are as defined in  claim 1 .  
     
     
         4 . A compound as claimed in  claim 3  represented by formula IIA, and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is as defined in  claim 1 .  
     
     
         5 . A compound as claimed in  claim 3  represented by formula IIB, and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is as defined in  claim 1 .  
     
     
         6 . A compound as claimed in  claim 3  represented by formula IIC, and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is as defined in  claim 1 .  
     
     
         7 . A compound as claimed in any one of the preceding claims wherein R 1  represents methyl.  
     
     
         8 . A compound as claimed in any one of  claims 1  to  6  wherein R 1  represents ethyl.  
     
     
         9 . A compound selected from: 
 3-(2,5-difluorophenyl)-7-(1,1-dimethylethyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine;    3-(2,5-difluorophenyl)-7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine;    and pharmaceutically acceptable salts thereof.    
     
     
         10 . A compound selected from: 
 3-(2,6-difluorophenyl)-7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine;    and pharmaceutically acceptable salts thereof.    
     
     
         11 . A compound selected from: 
 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2,3,6-trifluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine;    7-(1,1-dimethylethyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2,3,6-trifluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine;    7-(1,1-dimethylethyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-(2,3,6-trifluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine;    and pharmaceutically acceptable salts thereof.    
     
     
         12 . A pharmaceutical composition comprising a compound of formula I as defined in  claim 1  or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.  
     
     
         13 . The use of a compound of formula I as defined in  claim 1  or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of anxiety.  
     
     
         14 . A process for the preparation of a compound as claimed in  claim 1 , which comprises: 
 (A) reacting a compound of formula III with a compound of formula IV:                           wherein Y, Z and R 1  are as defined in  claim 1 , and L 1  represents a suitable leaving group; or    (B) reacting a compound of formula XI (or its 1,2,4-triazolo[4,3-b]pyridazin-6-one tautomer) with a compound of formula XII:                           wherein Y, Z and R 1  are as defined in  claim 1 , and L 3  represents a suitable leaving group; or    (C) reacting trimethylacetic acid with a compound of formula XIII:                           wherein Y, Z and R 1  are as defined in  claim 1;  in the presence of silver nitrate and ammonium persulphate; or    (D) reacting a compound of formula XIV with a compound of formula XV:                           wherein Y, Z and R 1  are as defined in  claim 1 , M represents —B(OH) 2  or —Sn(Alk) 3  in which Alk represents a C 1-6  alkyl group, and L 4  represents a suitable leaving group; in the presence of a transition metal catalyst.    
     
     
         15 . A method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined in  claim 1  or a pharmaceutically acceptable salt thereof.