Triazolo-pyridine derivatives as ligands for GABA receptors

Abstract

A class of substituted or 6,7-ring fused 1,2,3-triazolo[4,5-b]pyridine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 3-position and a substituted alkoxy moiety at the 5-position, are selective ligands for GABA A receptors, in particular having high affinity for the 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 salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 Y represents hydrogen or C 1-6  alkyl; and  
 Z represents C 1-6  alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkenyl, C 6-8  bicycloalkyl, aryl, C 3-7  heterocycloalkyl, heteroaryl, C 2-7  alkoxycarbonyl or di(C 1-6 )alkylamino, any of which groups may be optionally substituted; or  
 Y and Z are taken together with the two intervening carbon atoms to form a ring selected from C 5-9  cycloalkenyl, C 6-10  bicycloalkenyl, tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be optionally benzo-fused and/or substituted;  
 R 1  represents C 3-7  cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any of which groups may be optionally substituted; and  
 R 2  represents C 3-7  cycloalkyl(C 1-6 )alkyl, aryl(C 1-6 )alkyl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted.  
 
     
     
         2 . A compound as claimed in  claim 1  represented by formula IIA, and salts and prodrugs thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 Y 1  represents hydrogen or methyl;  
 Z 1  represents C 1-6  alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkenyl, C 6-8  bicycloalkyl, aryl, C 3-7  heterocycloalkyl, heteroaryl, C 2-7  alkoxycarbonyl or di(C 1-6 )alkylamino, any of which groups may be optionally substituted;  
 R 1  is as defined in  claim 1;   
 m is 1 or 2; and  
 R 12  represents aryl or heteroaryl, either of which groups may be optionally substituted.  
 
     
     
         3 . A compound as claimed in  claim 2  represented by formula IIB, and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is as defined in  claim 1;   
 Q represents the residue of a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl or thienyl ring;  
 R 5  represents hydrogen, methyl or fluoro; and  
 R 6  represents hydrogen, methyl, ethyl or n-propyl.  
 
     
     
         4 . A compound as claimed in  claim 2  represented by formula IIC, and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is as defined in  claim 1;  and  
 R 6  is as defined in  claim 3 .  
 
     
     
         5 . A compound as claimed in  claim 1  represented by formula IID, and salts and prodrugs thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is as defined in  claim 1;  and  
 m and R 12  are as defined in  claim 2 .  
 
     
     
         6 . A compound as claimed in  claim 5  represented by formula IIE, and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is as defined in  claim 1;  and  
 R 6  is as defined in  claim 3 .  
 
     
     
         7 . A compound selected from: 
 3-phenyl-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-methoxycarbonyl-1,2,3-triazolo[4,5-b]pyridine;    3,6-diphenyl-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    and salts and prodrugs thereof.    
     
     
         8 . A compound selected from: 
 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-phenyl-1,2,3-triazolo[4, 5-b]pyridine;    3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-(thien-3-yl)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-(thien-2-yl)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-(2,2-dimethylpropyl)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-cyclobutyl-1,2,3-triazolo[4,5-b]pyridine;    and salts and prodrugs thereof.    
     
     
         9 . A compound selected from: 
 3-(2-fluorophenyl)-6-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-6-(3-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-6-(4-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-6-(2-furyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-6-(3-furyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-6-(3-thienyl)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-6-(2-thienyl)-1,2,3-triazolo[4,5-b]pyridine;    3-(2-fluorophenyl)-6-(3-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2,6-difluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-(3-thienyl)-1,2,3-triazolo[4,5-b]pyridine;    3-(2,6-difluorophenyl)-6-(3-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    6-cyclobutyl-3-(2,6-difluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2,6-difluorophenyl)-6-(3-furyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    6-cyclobutyl-3-(2,6-difluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    6-(1,1-dimethylethyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,3-triazolo[4,5-b]pyridine;    6-(1,1-dimethylethyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,3-triazolo[4,5-b]pyridine;    6-(1,1-dimethylethyl)-5-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,3-triazolo[4,5-b]pyridine;    6-(1,1-dimethylethyl)-3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    6-(1,1-dimethylethyl)-5-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,3-triazolo[4,5-b]pyridine;    6-(1,1-dimethylethyl)-3-(2-fluorophenyl)-5-(2-propyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    6-(1,1-dimethylethyl)-3-(2-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2,5-difluorophenyl)-6-(1,1-dimethylethyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2,5-difluorophenyl)-6-(1,1-dimethylethyl)-5-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2,5-difluorophenyl)-6-(1,1-dimethylethyl)-5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    3-(2,6-difluorophenyl)-6-(1,1-dimethylethyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    6-(1,1-dimethylethyl)-3-(2-fluoro-6-methoxyphenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine;    5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,3-triazolo[4,5-c]isoquinoline;    5-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,3-triazolo[4,5-c]isoquinoline;    3-phenyl-5-(2-propyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-c]isoquinoline;    5-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,3-triazolo[4,5-c]isoquinoline;    3-phenyl-5-(pyridin-2-ylmethoxy)-1,2,3-triazolo[4,5-c]isoquinoline;    and salts and prodrugs thereof.    
     
     
         10 . A pharmaceutical composition comprising a compound of formula I as defined in  claim 1  or a pharmaceutically acceptable salt thereof or a prodrug thereof in association with a pharmaceutically acceptable carrier.  
     
     
         11 . The use of a compound of formula I as defined in  claim 1  or a pharmaceutically acceptable salt thereof or a prodrug thereof for the manufacture of a medicament for the treatment and/or prevention of anxiety.  
     
     
         12 . 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:                      R 2 —L 1   (IV)   wherein Y, Z, R 1  and R 2  are as defined in  claim 1 , and L 1  represents a suitable leaving group; or    (B) reacting a compound of formula VIII with a compound of formula IX:                      R 2 —OH  (IX)   wherein Y, Z, R 1  and R 2  are as defined in  claim 1 , and L 2  represents a suitable leaving group; or    (C) reacting a compound of formula X with a compound of formula XI:                      Z—E  (XI)   wherein Y, Z, R 1  and R 2  are as defined in  claim 1 , and E represents the residue of an organometallic reagent, or E represents —B(OH) 2 ; in the presence of a transition metal catalyst; or    (D) reacting sodium nitrite with a compound of formula XV:                          wherein Y, Z, R 1  and R 2  are as defined in  claim 1;  and    (E) subsequently, if desired, converting a compound of formula I initially obtained into a further compound of formula I by standard methods.    
     
     
         13 . 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 or a prodrug thereof.