Sulphonamide derivatives

Abstract

The present invention relates to the potentiation of glutamate receptor function using certain sulphonamide derivatives. It also relates to novel sulphonamide derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

We claim:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 one or both of R a  and R b  are selected independently from F, CF 3  and —OR c  wherein R c  is hydrogen or (1-4C)alkyl, and any remainder is hydrogen; or R a  and R b  together represent ═O or ═CH 2 ;  
 R 1  represents a naphthyl group or a phenyl, furyl, thienyl or pyridyl group which is unsubstituted or substituted by one or two substituents selected independently from halogen; nitro; cyano; hydroxyimino; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl; (CH 2 ) y X 1 R 9  in which y is 0 or an integer of from 1 to 4, X 1  represents O, S, NR 10 , CO, COO, OCO, CONR 11 , NR 12 CO, NR 12 COCOO or OCONR 13 , R 9  represents hydrogen, (1-10C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R 10 , R 11 , R 12  and R 13  each independently represents hydrogen or (1-10C)alkyl, or R 9  and R 10 , R 11 , R 12  or R 13  together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyldihydrothiazolyl; (1-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R 14 -(L a ) n -X 2 -(L b ) m  in which X 2  represents a bond, O, NH, S, SO, SO 2 , CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH 2 CONH or CH═CH, La and Lb each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R 14  represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, nitro, cyano, hydroxyimino, (1-10C) alkyl, (2-10C)alkenyl, (2-10C)alkynyl, (3-8C)cycloalkyl, 4-(1,1-dioxotetrahydro-1,2-thiazinyl), halo(1-10C)alkyl, cyano(2-10C)alkenyl, phenyl, and (CH 2 ) z X 3 R 15  in which z is 0 or an integer of from 1 to 4, X 3  represents O, S, NR 16 , CO, CH(OH), COO, OCO, CONR 17 , NR 18 CO, NHSO 2 , NHSO 2 NR 17 , NHCONH, OCONR 19  or NR 19 COO, R 15  represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, (1-10C)haloalkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, (N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy and R 16 , R 17 , R 18  and R 19  each independently represents hydrogen or (1-10C)alkyl, or R 15  and R 16 , R 17 , R 18  or R 19  together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and  
 R 2  represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoroalkyl, (1-6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R 3 R 4 N in which R 3  and R 4  each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound as claimed in  claim 1 , wherein R a  represents F, CF 3  or methoxy and Rb represents hydrogen; or R a  and R b  together represent ═O or ═CH 2 .  
     
     
         3 . A compound as claimed in  claim 2 , wherein R a  represents methoxy and R b  represents hydrogen.  
     
     
         4 . A compound as claimed in any one of  claims 1  to  3  wherein R 2  represents (1-6C)alkyl, (1-6C)fluoroalkyl, (2-6C)alkenyl, or a group of formula R 3 R 4 N in which R 3  and R 4  each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group.  
     
     
         5 . A compound as claimed in  claim 4 , wherein R 2  represents methyl, ethyl, propyl, 2-propyl, butyl, 2-methylpropyl, cyclohexyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl, ethenyl, prop-2-enyl, methoxyethyl, phenyl, 4-fluorophenyl, or dimethylamino.  
     
     
         6 . A compound as claimed in  claim 5 , wherein R 2  represents ethyl, 2-propyl or dimethylamino.  
     
     
         7 . A compound as claimed in any one of claims. 1 to 6, wherein R 1  represents 2-naphthyl or a group of formula  
       
         
           
           
               
               
           
         
       
       in which 
 R 20  represents halogen; nitro; cyano; hydroxyimino; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; hydroxy(3-BC)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl; (CH 2 ) y X 1 R 9  in which y is 0 or an integer of from 1 to 4, X 1  represents O, S, NR 10 , CO, COO, OCO, CONR 11 , NR 12 CO, NR 12 COCOO or OCONR 13 , R 9  represents hydrogen, (1-10C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R 10 ′ R 11 , R 12  and R 13  each independently represents hydrogen or (1-10C)alkyl, or R 9  and R 10 , R 11 , R 12  or R 13  together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C) alkylpiperazinyl; N-phenyl (1-4C) alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C) alkoxycarbonyldihydrothiazolyl; (1-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R 14 -(L a ) n -X 2 -(L b ) m  in which X 2  represents a bond, O, NH, S, SO, SO 2 , CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH or CH═CH, L a  and L b  each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R 14  represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; hydroxyimino, (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; 4-(1,1-dioxotetrahydro-1,2-thiazinyl), halo(1-10C)alkyl; cyano(2-10C)alkenyl, phenyl, (CH 2 ) z X 3 R 15  in which z is 0 or an integer of from 1 to 4, X 3  represents O, S, NR 16 , CO, CH(OH), COO, OCO, CONR 17 , NR 18 CO, NHSO 2 , NHSO 2 NR 17 , NHCONH, OCONR 19  or NR 19 COO, R 15  represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, (1-10C)haloalkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, (N-(1-4C)alkoxycarbonyl) (1-4C)alkylsulfonylamino(1-4C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, (3-8C)cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy and R 16 , R 17 , R 18  and R 19  each independently represents hydrogen or (1-10C)alkyl, or R 15  and R 16 , R 17 , R 18  or R 19  together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; and  
 R 21  represents a hydrogen atom, a halogen atom, a (1-4C)alkyl group or a (1-4C)alkoxy group.  
 
     
     
         8 . A compound according to  claim 1  wherein R a  is F and R b  is hydrogen.  
     
     
         9 . A compound according to  claim 1  wherein R a  is F and R b  is F.  
     
     
         10 . A compound according to  claim 9  wherein R 2  is isopropyl.  
     
     
         11 . A compound according to  claim 10  wherein R 2  is isopropyl.  
     
     
         12 . A compound as claimed in  claim 7 , wherein R 1  represents 2-naphthyl, 4-bromophenyl, 4-benzamidophenyl, 4-methylphenyl, 4-isopropylphenyl, 4-isobutylphenyl, 4-t-butylphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-cyclopentylphenyl, 4-cyclohexylphenyl, 4-(2-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)phenyl, 4-(2-furyl)phenyl, 4-(3-furyl)phenyl, 4-(2-thienyl)phenyl, 4-(3-thienyl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl, 3-chloro-4-piperidin-1-ylphenyl, 4-benzyloxyphenyl, 4-(2-fluorophenyl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)phenyl, 4-(4-formylphenyl)phenyl, 4-(4-methylphenyl)phenyl, 4-(4-hydroxphenyl)phenyl, 4-(2-methoxyphenyl)phenyl or 4-(4-methoxyphenyl)phenyl.  
     
     
         13 . A compound selected from the group consisting of:  
       
         
           
                 
                 
               
                     
                 
                     
                 
                     
                     
                 
                   a 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   b 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   c 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   d 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   e 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       and the pharmaceutically acceptable salts thereof.  
     
     
         14 . A pharmaceutical composition, which comprises a compound as claimed in  claim 1  and a pharmaceutically acceptable diluent or carrier.  
     
     
         15 . A method of potentiating glutamate receptor function in a mammal requiring such treatment, which comprises administering an effective amount of a compound as claimed in  claim 1 .  
     
     
         16 . A method of treating a cognitive disorder; a neuro-degenerative disorder; age-related dementia; age-induced memory impairment; movement disorder; reversal of a drug-induced state; depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis; or drug-induced psychosis in a patient, which comprises administering to a patient in need thereof an effective amount of a compound as claimed in  claim 1 .  
     
     
         17 . A method for improving memory or learning ability in a patient, which comprises administering to a patient in need thereof an effective amount of a compound as claimed in  claim 1.