1,2,4-triazolo[4,3-B]pyrido[3,2-D]pyridazine derivatives and pharmaceutical compositions containing them

Abstract

Heterocyclic compounds of formula (I), wherein R 1 represents a hydrogen atom or a —(CH 2 ) M —Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl, alkoxy, alkoxycarbonyl, C 3 -C 7 cycloalkyl, norbornyl or phenylalkenyl group, or an aromatic group which aromatic group ^ may optionally be substituted by one or more halogen atoms; R 2 represents an aromatic group which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C 3 -C 6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups, and R 3 represents a hydrogen or halogen atom or an alkyl group, and pharmaceutically acceptable salts thereof, processes for preparing the same. The compounds are phosphodiesterase 4 inhibitors.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein; 
 R 1  represents a hydrogen atom or a —(CH 2 ) m —Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl, alkoxy, alkoxycarbonyl, C 3 -C 7  cycloalkyl, norbornyl or phenylalkenyl group, or an aromatic group which aromatic group Y may optionally be substituted by one or more halogen atoms;  
 R 2  represents an aromatic group which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C 3 -C 6  cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and  
 R 3  represents a hydrogen or halogen atom or an alkyl group,  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein the alkyl, haloalkyl and alkoxy groups have up to 6 carbon atoms, the alkoxycarbonyl groups have up to 7 carbon atoms and the phenylalkenyl groups have up to 12 carbon atoms.  
     
     
         3 . A compound according to  claim 1  or  2  wherein R 1  represents —(CH 2 ) m —Y wherein m is 0 or 1 and Y represents C 1-6  alkyl or C 3-7  cycloalkyl.  
     
     
         4 . A compound according to any one of the preceding claims wherein R 2  represents a phenyl group, naphthyl group or thienyl group which group R 2  may optionally be substituted by one or more halogen atoms, methyl groups, methoxy groups, cyclopentoxy groups, nitro groups or dimethyl amino groups.  
     
     
         5 . A compound according to  claim 4  wherein R 2  represents a phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl or 3-nitrophenyl group.  
     
     
         6 . A compound according to any one of the preceding claims wherein R 3  represents a hydrogen atom, a C 1-6  alkyl group or a chlorine atom at the 8- or 9-position of the 1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine skeleton.  
     
     
         7 . A compound according to  claim 1  which is 6-(4-fluorophenyl)-3-isobutyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, 3-cyclopropylmethyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, 3-cyclopropyl-6-phenyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine and 3-cyclobutylmethyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine.  
     
     
         8 . A process for preparing a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein; 
 R 1  represents a hydrogen atom or a —(CH 2 ) m —Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl, alkoxy, alkoxycarbonyl, C 3 -C 7  cycloalkyl, norbornyl or phenylalkenyl group, or an aromatic group which aromatic group Y may optionally be substituted by one or more halogen atoms;  
 R 2  represents an aromatic group which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C 3 -C 6  cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and  
 R 3  represents a hydrogen or halogen atom or an alkyl group,  
 which process comprises formation of the 1,2,4-triazine ring present in formula (I) by cyclisation of a hydrazide of formula (IV)  
                     
 wherein R 1 , R 2  and R 3  are as defined above.  
 
     
     
         9 . A composition comprising a compound according to any one of  claims 1  to  7  or pharmaceutically acceptable salt thereof mixed with a pharmaceutically acceptable diluent or carrier.  
     
     
         10 . A compound according to anv one of  claims 1  to  7  or pharmaceutically acceptable salt thereof or a composition according to  claim 9  for use in a method of treatment of the human or animal body.  
     
     
         11 . Use of a compound according to any one of  claims 1  to  7  or pharmaceutically acceptable salt thereof or a composition according to  claim 9  for the manufacture of a medicament for the treatment of a condition whose known treatment is to inhibit phosphodiesterase 4 including allergic reaction and disease states, inflammation, ulcers and immunological disease.  
     
     
         12 . A method of treating a condition whose known treatment is to inhibit phosphodiesterase 4 which comprises administering to a human or animal subject in need of such treatment an effective amount of compound according to any one of  claims 1  to  7  or pharmaceutically acceptable salt thereof or a composition according to claim  9 .