Aromatic sulfones and their medical use

Abstract

The invention provides compounds of formula (I): wherein A and B represent the groups —(CH 2 ) m — and —(CH 2 ) n — respectively; R 1 represents hydrogen or C 1-6 alkyl; R 2 represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxy C 1-6 alkyl, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy, —(CH 2 ) p C 3-6 cycloalkyl, —(CH 2 ) p OC 3-6 cycloalkyl, —COC 1-6 alkyl, —SO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —S—C 1-6 alkyl, —CO 2 C 1-6 alkyl, —CO 2 NR 5 R 6 , —SO 2 NR 5 R 6 , —(CH 2 ) p NR 5 R 6 , —(CH 2 ) p NR 5 COR 6 , optionally substituted aryl ring, optionally substituted heteroaryl ring or optionally substituted heterocyclyl ring; R 3 represents optionally substituted aryl ring or optionally substituted heteroaryl ring; R 4 represents hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, trifluoromethoxy, halogen, —OSO 2 CF 3 , —(CH 2 ) p C 3-6 cycloalkyl, —(CH 2 ) q OC 1-6 alkyl or —(CH 2 ) p OC 3-6 cycloalkyl; R 5 and R 6 each independently represent hydrogen, C 1-6 alkyl or, together with the nitrogen or other atoms to which they are attached, form an azacycloalkyl ring or an oxo-substituted azacycloalkyl ring; Z represents —(CH 2 ) r X— wherein the —(CH 2 ) r — group is attached to R 3 , or —X(CH 2 ) r — wherein X is attached to R 3 , and wherein any of the —CH 2 — groups may be optionally substituted by one or more C 1-6 alkyl groups; X represents oxygen, —NR 7 or —CH 2 — wherein the —CH 2 — group may be optionally substituted by one or more C 1-6 alkyl groups; R 7 represents hydrogen or C 1-6 alkyl; m and n independently represent an integer selected from 1 and 2; p independently represents an integer selected from 0, 1, 2 and 3; q independently represents an integer selected from 1, 2 and 3; r independently represents an integer selected from 0, 1, and 2; or a pharmaceutically acceptable salt or solvate thereof. The compounds are useful in therapy, in particular as antipsychotic agents.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 A and B represent the groups —(CH 2 ) m — and —(CH 2 ) n — respectively; 
 R 1  represents hydrogen or C 1-6 alkyl; 
 R 2  represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC 1-6 alkyl, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy, —(CH 2 ) p C 3-6 cycloalkyl, —(CH 2 ) p OC 3-6 cycloalkyl, —COC 1-6 alkyl, —SO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —S—C 1-6 alkyl, —CO 2 C 1-6 alkyl, —CO 2 NR 5 R 6 , —SO 2 NR 5 R 6 , —(CH 2 ) p NR 5 R 6 , —(CH 2 ) p NR 5 COR 6 , optionally substituted aryl ring, optionally substituted heteroaryl ring or optionally substituted heterocyclyl ring; 
 R 3  represents optionally substituted aryl ring or optionally substituted heteroaryl ring; 
 R 4  represents hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, trifluoromethoxy, halogen, —OSO 2 CF 3 , —(CH 2 ) p C 3-6 cycloalkyl, —(CH 2 ) q OC 1-6 alkyl or —(C H 2 ) p OC 3-6 cycloalkyl; 
 R 5  and R 6  each independently represent hydrogen, C 1-6 alkyl or, together with the nitrogen or other atoms to which they are attached, form an azacycloalkyl ring or an oxo-substituted azacycloalkyl ring; 
 Z represents —(CH 2 ) r X— wherein the —CH 2 ) r — group is attached to R 3 , or—X(CH 2 ) r — wherein X is attached to R 3 , and wherein any of the —CH 2 — groups may be optionally substituted by one or more C 1-6 alkyl groups; 
 X represents oxygen, -NR 7  or —CH 2 — wherein the —CH 2 — group may be optionally substituted by one or more C 1-6 alkyl groups; 
 R 7  represents hydrogen or C 1-6 alkyl; 
 m and n independently represent an integer selected from 1 and 2; 
 p independently represents an integer selected from 0, 1, 2 and 3; 
 q independently represents an integer selected from 1, 2 and 3; 
 r independently represents an integer selected from 0, 1, and 2; or a pharmaceutically acceptable salt or solvate thereof; 
 excluding 7-[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A compound of formula (I) according to  claim 1  wherein R 1  represents hydrogen or C 1-4 alkyl. 
     
     
         3 . A compound of formula (I) according to  claim 1  wherein R 2  represents hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or diC 1-6 alkylamino. 
     
     
         4 . A compound of formula (I) according to  claim 1  wherein R 3  represents phenyl. 
     
     
         5 . A compound of formula (I) according to  claim 1  wherein R 4  represents hydrogen, C 1-4 alkyl or C 1-4 alkoxy. 
     
     
         6 . A compound of formula (I) according to  claim 1  wherein R 5  and R 6  independently represent hydrogen or C 1-4 alkyl. 
     
     
         7 . A compound of formula (I) accordingly to  claim 1  which is:
 7-Methoxy-8-(3-phenoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;   7-Methoxy-3-methyl-8-(3-phenoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine;   7-(3-Benzyloxyphenylsulfonyl)-2,3,4,5-tetrahydro-3-benzazepine;   (4-Fluoro-benzyl)-[4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl)-phenyl]-amine;   [4-(8-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl)-phenyl]-phenyl-amine;   7-[4-(4-Chloro-phenoxymethyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;   4-Chloro-pheny)-[4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl)-benzyl]-amine;   7-[4-(4-Fluorobenzyl)benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;   7-[4-(3-Fluoro-benzyloxy)-benzenesulfonyl]-6-methoxy- 1,2, 3,4-tetrahydro-isoquinoline, and   5-Methoxy-2-methyl-6-[4-(3-trifluoromethyl-benzyloxy)-benzenesulfonyl]-2, 3-dihydro-1H-isoindole;   (2-Methoxy-benzyl)-[4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl)-phenyl]-amine;   7-[4-(4-Chloro-phenoxymethyl)-benzenesulfonyl]-8-ethoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;   [4-(8-Ethoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl)-benzyl]-(2-methoxy-phenyl)-amine;   {8-[4-(4-Fluoro-phenoxymethyl)-benzenesulfonyl]-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl}-dimethyl-amine;   6-Ethoxy-7-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-1,2,3,4-tetrahydro-isoquinoline hydrochloride;   (3-Methoxy-benzyl)-[4-(6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-phenyl]-methyl-amine hydrochloride;   7-[4-(4-Chlorophenoxymethyl)benzenesulfonyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride salt; and   3-Methyl-7-{(4-(2-methoxybenzyloxy)-phenylsulfonyl}-9-phenyl-1,2,4,5-tetrahydro-3-benzazepine;   or a pharmaceutically acceptable salt thereof.   
     
     
         8 . A pharmaceutical composition comprising a compound of formula (I) as claimed in  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         9 .- 14 . (canceled) 
     
     
         15 . A method of treating psychotic disorders, Parkinsons disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders, convulsions, epilepsy and gastric motility disorders, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt or solvate thereof.