Substituted isoquinoline derivatives and their use as anticonvulsants

Abstract

This invention relates to substituted isoquinoline derivatives and their use as anticonvulsants.

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       where Q is a monocyclic or heteroaryl ring, 
 R 1  is hydrogen, , C 1-6  alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkylCO—, formyl, CF 3 CO— or C 1-6 alkylSO 2 —,  
 R 2  is hydrogen, hydroxy or up to three substituents selected from halogen, NO 2 , CN, N 3 , 
 CF 3 O—, CF 3 S—, CF 3 CO—, trifluoromethyldiazirinyl, C 1-6 alkyl, C 1-6 alkenyl,  
 C 1-6 alkynyl, C 1-6 perfluoroalkyl, C 3-6 cycloalkyl,  
 C 3-6 cycloalkyl-C 1-4 alkyl-, C 1-6 alkylO—, C 1-6 alkylCO—,  
 C 3-6 cycloalkylO—, C 3-6 cycloalkylCO—, C 3-6 cycloalkyl-C 1-4 alkylO—,  
 C 3-6 cycloalkyl-C 1-4 alkylCO—, acetoxy, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C 1-4 alkyl-, C 1-6 alkylS—, C 1-6 alkylSO 2 —, (C 1-4 alkyl) 2 NSO 2 —, (C 1-4 alkyl)NHSO 2 —, (C 1-4 alkyl) 2 NCO—, (C 1-4 alkyl)NHCO— or CONH 2 ;  
 or —NR 3 R 4  where R 3  is hydrogen or C 1-4  alkyl, and  
 R 4  is hydrogen, C 1-4 alkyl, formyl, —CO 2 C 1-4 alkyl or —COC 1-4 alkyl;  
 or two R 2  groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by —OH or ═O; and  
 
 X is hydrogen, halogen, C 1-6  alkoxy, C 1-6  alkyl, amino or trifluoroacetylamino;  
 but when X is hydrogen excluding compounds 7-(2-bromobenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline, 7-(2-fluorobenzamido)-1,2,3,4-tetrahydroisoquinoline and 7-(3,4,5-trimethoxybenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline and compounds in which R 2  is 2-alkoxy and when X is halogen excluding the compounds, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-trifluoromethyldiazirinylbenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromethyldiazirinylbenzamide.  
 
     
     
         2 . A compound of formula (IA) or (IB):  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and X are as defined in  claim 1 .  
     
     
         3 - 6 . (Cancelled)  
     
     
         7 . A process for the preparation of a compound according to  claim 2 , which comprises reacting a compound of formula (II)  
       
         
           
           
               
               
           
         
       
       where R 1A  is R 1  as defined for formula (I) or a group convertible to R 1  
 and X is as defined in  claim 1   
 with a compound of formula (III)  
                     
 where Q is as defined in formula (I), Y is Cl or OH, and R 2A  groups are independently R 2  as defined for formula (I) or groups convertible to R 2 ,  
 and where required converting an R 1A  or R 2A  group to a R 1  or R 2  group,  
 converting one R 1  or R 2  group to another R 1  or R 2  group,  
 converting a salt product to the free base or another pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt.