MXPA00000414A

MXPA00000414A - Novel compounds

Info

Publication number: MXPA00000414A
Application number: MXPA/A/2000/000414A
Authority: MX
Inventors: Steven Mark Bromidge; Stephen Frederik Moss
Original assignee: Smithkline Beecham Plc
Priority date: 1997-07-11
Filing date: 2000-01-10
Publication date: 2001-11-21

Abstract

The invention relates to novel compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.

Description

DERIVATIVES OF SULFONAMIDE AS ANTAGONISTS OF 5-HTg RECEPTORS, AND PROCEDURE FOR PREPARATION DESCRIPTIVE MEMORY This invention relates to novel compounds having pharmacological activity, to processes for their preparation, to compositions containing them and to their use in the treatment of disorders of the central nervous system. EPA 0 021 580 and EPA 0 076 072 documents show sulfonamide derivatives and describe that they have antiarrhythmic activity. We have now discovered a structurally distinct class of compounds, which have been found to have 5HT6 receptor antagonistic activity. It is believed that 5HT6 receptor antagonists are of potential use in the treatment of certain central nervous system disorders such as anxiety, depression, epilepsy, obsessive-compulsive disorders, migraine, Alzheimer's disease, sleep disorders (including circadian rhythm disorders). , eating disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and / or head injury such as hydrocephalus. It is also expected that the compounds of the invention will be useful for improving cognitive memory. It is also expected that the compounds of the invention will be useful in the treatment of certain Gl (gastrointestinal) disorders such as IBS (irritable bowel syndrome). The present invention therefore provides, in a first aspect, a compound of the formula (I) or a salt thereof: (I) wherein: P is phenyl, naphthyl, anthracenyl, a bicyclic heterocyclic ring, a tricyclic heteroaromatic ring or is a 5- to 7-membered heterocyclic ring each containing 1 to 4 heterogeneous atoms selected from oxygen, nitrogen or sulfur; A is an individual bond, an alkylene group of C-i-β or an alkenylene group of C-6; B is SO2; R1 is halogen, C6.6 alkyl optionally substituted by one or more fluorine atoms, C3_6 cycloalkyl, C2_6 alkenyl, C2.6 alkynyl, C-? 6 alkanoyl, C? 6 alkoxy, OCF3 , hydroxy, hydroxylalkyl of Ci-β, hydroxyalkoxy of C- [alpha] 6, alkoxy of C- [alpha] 6-alkoxy of C6-6, nitro, cyano, NR10R11 wherein R10 and R1 are independently hydrogen, alkyl of C-? -6 or optionally substituted phenyl, SR11 wherein R11 is as defined above or R1 is optionally substituted phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5- to 7-membered heterocyclic ring each containing 1 to 4 heterogeneous atoms selected of oxygen, nitrogen or sulfur, or R1 together with a second substituent R1 forms a group -O-CH2-O-, OCH2CH2O-, -CH CH2CH- or -CH CH CH CH2-, n is O, 1, 2, 3 , 4, 5 0 6; R 2 is hydrogen, C 1-6 -alkyl, C 1-6 -arylalkyl or together with the group P form a 5- to 8-membered ring optionally substituted with one or more C? 6 alkyl groups; R3 is hydrogen, halogen, Ci-β alkyl, C3.6 cycloalkyl, C-? 6 alkanoyl, C? -6 alkoxy optionally substituted with one or more fluorine, hydroxy, hydroxyalkyl atoms of C -? - 6, Ci-β hydroxyalkoxy, C? -6-alkoxy of C-? 6, nitro, trifluoromethyl, cyano or aryl, or together with the group R5 forms a (CH2) 2O or (CH2) 3O group substituted optionally with one or more C -? --6 alkyl groups; R 4 is -X (CH 2) p-R 6, wherein X is an individual bond, CH 2, O, NH or N-alkyl and p is 0 to 6 and R 6 is an optionally substituted 4 to 7-membered heterocyclic ring containing 1 to 3 heterogeneous atoms selected from nitrogen, sulfur or oxygen, or R6 is NR7R8, wherein R7 and R8 are independently hydrogen, C-? 6 alkyl or C-uß arylalkylaryl; and R5 is a group R3 or together with R3 forms a group (CH2) 2O or (CH2) 3O optionally substituted with one or more C-? -6 alkyl groups.

The d-β alkyl groups, either alone or as part of another group, can be straight chain or branched. As used in the present, the term aryl, includes phenyl and naphthyl. When a group is defined as "optionally substituted", unless otherwise indicated, suitable substituents include halogen, C 1-6 alkyl, C 3 cycloalkyl. 6, C 1-6 alkanoyl, C 1-6 alkoxy optionally substituted with one or more fluorine atoms, hydroxy, C 1-6 hydroxyalkyl, Ci-β hydroxyalkoxy, C-? 6-alkoxy of C-? ? -6, nitro, trifluoromethyl or cyano. When P is a bicyclic heterocyclic ring, suitable examples include benzothiophene, indole, quinoline or isoquinoline. The bicyclic heterocyclic rings can also be partially saturated. When P is a tricyclic heteroaromatic ring, suitable examples include dibenzofuran. Suitable 5- to 7-membered heterocyclic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl. The heterocyclic rings can be linked to the rest of the molecule by any suitable carbon atom or, when present, a nitrogen atom. Preferably, P is phenyl or naphthyl. A is suitably an individual bond, a methylene or ethylene group or a group -CH = CH-. Preferably, A is an individual bond or methylene.

When R1 is a bicyclic heterocyclic ring or a 5- to 7-membered heterocyclic ring, suitable examples include those listed in the definition of P. It will be appreciated that when R1 combines with a second substituent R1, the two substituents must be attached to adjacent atoms in the P ring. Thus, when P is phenyl, groups such as methylenedioxyphenyl, ethylenedioxyphenyl, indane and tetrahydronaphthalene are within the scope of this invention. Suitably, R1 is hydrogen, halogen, phenyl, C-? -6 alkoxy, most preferably OMe, SR11 is most preferably SMe or C -? - 6 optionally substituted by one or more fluorine atoms, for example methyl or trifluoromethyl. Preferably, R1 is halogen. Preferably, n is 0, 1, 2, 3, 0 4. Suitably, R 2 is hydrogen, methyl or together with the group P forms a 5 or 6 membered ring. It will be appreciated that when groups P and R2 are bonded together the latter must be bonded to the adjacent carbon atom on the P ring, that is, with an ortho relation with respect to group A. It will be appreciated that when the R3 / R5 groups are linked together, the two groups should be attached to adjacent carbon atoms of the phenyl ring. Preferably, R3 is a group R5, in particular hydrogen. Preferably, R 4 is a meta with respect to substituent B. Preferably, X is a bond, p is 0 and R 6 is a 5- to 7-membered heterocyclic ring optionally substituted. The heterocyclic rings can be linked to the rest of the molecule by means of a carbon atom or, when present, a nitrogen atom. Optional substituents for these rings, which may be present on carbon and / or nitrogen atoms, include C-6 alkyl, in particular methyl or NR 9 R 10, wherein R 9 and R 10 are independently hydrogen or C-alkyl. ? -6. Most preferably, R 4 is an optionally substituted piperazine. Most preferably, R 4 is N-methylpiperazine or NH-piperazine. Preferably, R5 is for with respect to substituent B. In suitable form, R5 is C-i-β alkoxy. Preferably, R5 is methoxy. Particular compounds of the invention include: 4-Methoxy-3- (4-methylpiperazin-1 -yl) -? / - naphthalen-1-ylbenzenesulfonamide,? / - (4-chloronaphthalen-1-yl) -4-methoxy- 3- (4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - (3-Bromophenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - (3,4-dichlorobenzyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 6-Chloro-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,3, 4-tetrahydroisoquinoline, 1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -6-trifluoromethyl-2,3-dihydro-1 - / - indole, *. aunt. > . ^ at ^ 8fc »^ .- **» ttA ^^ BeiAfes¿-a-_A «-? / - (3-Chlorophenyl) -4-methoxy -? / - methyl-3- (4-methylpiperazin-1- il) -benzenesulfonamide, 1 - [4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonyl] -7-trifluoromethyl-1, 2,3,4-tetrahydroquinoline,? / - (3-Yodo-4 -methylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide,? / - (5-Yodo-2-methylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide,? / - (3,4-Methylenedioxyphenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 6-chloro-1- [4-methoxy-3- (4-methyl-piperazine-1) -yl) benzenesulfonyl] -5-methyl-2,3-dihydro-1 H-indole, 7,8-Dichloro-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] - 1, 2,3,4-tetrahydroisoquinoline, 7,8-dimethoxy-2- [4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 5- Bromo-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 8-chloro-7-methoxy-2- [4-methoxy-3 - (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 6J-dimethoxy-2- [4-methoxy-3- (4-met ilpiperazin-1-yl) -benzenesulfonyl] -1, 2,3,4-tetrahydroisoquinoline, 2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -7-phenyl-1, 2,3,4-tetrahydroisoquinoline, 8-Bromo-7-methoxy-2- [4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonyl] -1, 2,3,4-tetrahydroisoquinoline, 5, 6-Dichloro-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1, 2,3,4-tetrahydroisoquinoline, 5,8-dimethoxy-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1, 2,3,4-tetrahydroisoquinoline, -Iodo-1- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -5-methylthio-2,3-dihydro-1H-indole,? / - (3,4-dichlorophenyl) - 4-methoxy-3- (4-methyl-piperazin-1-yl-benzenesulfonamide,? / - (3-Iodophenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 6J, 8-trimethoxy-2- [4-methoxy-3- (4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 2- [4-methoxy-3- (4 -methylpiperazin-1-yl) -benzenesulfonyl] -6-pyridin-3-yl-2,3-dihydro-1 H-indole, 2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -5-pyridin-3-yl-2,3-dihydro-1 H-indole, 1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1, 2,3 , 5-tetrahydropyrrolo [2,3 - /] indole, ^^^^ Ü ^^ 1 - (4-Methoxy-3-piperazin-1 -ylbenzenesulfonyl) -7-trifluoromethyl-1, 2,3,4-tetrahydroquinoline, A / - (3-Bromophenyl) -4-methoxy -3-piperazin-1-ylbenzenesulfonamide? / - (2-Fluorophenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - (2-trifluoromethoxyphenyl) -4-methoxy-3- ( 4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - (2-Bromo-4-methylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide,? / - (4-iodophenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonamide,? / - (9, 10-Dioxo-9, 10-dihydroanthracen-1-yl) -4-methoxy-3- (4-methylpiperazine) -1 -yl) - benzenesulfonamide,? / - (2-H -droxymethylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide, 4-methoxy-3- (4- methylpiperazin-1-yl) -? / - (2-methylsulfanylphenyl) -benzenesulfonamide, 4-methoxy-3- (4-methylpiperazin-1-yl) -? / - (5,6,7,8-tetrahydronaphthalen-1-) il) -benzenesulfonamide,? / - (2-Ethylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonamide, 4-methoxy-N- (2-methylphenyl) -3- (4-methylpiperazine- 1-yl) benzenesulfonamide,? / - (3,4-Dimethylpheni) l) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide, 4-methoxy-? / - (2-methoxy-6-methylphenyl) -3- (4-methylpiperazin-1-yl) - benzenesulfonamide, A / - (3-Fluoro-5-pyridin-3-ylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide, 8-chloro-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, A / - (2-Chloro-4-fluorophenyl) -4-methoxy-3- (4-methyl-piperazin-1-) L) -benzenesulfonamide,? / - (2-trifluoromethylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide, 4-methoxy-3- (4-methylpiperazin-1-yl) -? / -quinolin-7-ylbenzenesulfonamide (E47)? / - (4-Bromophenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonamide,? / - (3-Bromo-4-methylphenyl) -4 -methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, A / - (3-Bromo-2-methylphenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, -Metoxy-N- (2-methoxydibenzofuran-3-yl) -3- (4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - (4-Cyclohexylphenyl) -4-methoxy-3- (4-methyl-piperazin-1) -yl) -benzenesulfonamide,? / - (2-Iodophenyl) -4-methoxy-3- (4-met) ilpiperazin-1-yl) benzenesulfonamide,? / - (2-Chloro-4-fluorophenyl) -4-methoxy-3- (4-methylpiperazin-1-yl-benzenesulfonamide,? / - (2-Bromo-4-fluorophenyl) -4 -methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide,? / - [4- (4-Chlorophenyl) thiazol-2-yl] -4-methoxy-3- (4-methylpiperazine-1-yl) ) -benzenesulfonamide, 4-methoxy-? / - (3-methylphenyl) -3- (4-methylpiperazin-1-yl) benzenesulfonamide,? / - (3-Ethylphenyl) -4-methoxy-3- (4-methylpiperazine) 1-yl) benzenesulfonamide,? / - (3-Chloro-4-bromophenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - (2-Acetylphenyl) -4-methoxy- 3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 4-methoxy-3- (4-methyl-piperazin-1-yl) -? / - (4-phenylaminophenyl) -benzenesulfonamide, 4-methoxy-3- (4-methylpiperazine) -1-yl) -? / - (4-pentyloxyphenyl) -benzenesulfonamide, 4-methoxy-3- (4-methylpiperazin-1-yl) -? / - (4-vinylphenyl) benzenesulfonamide, 4-methoxy-3- ( 4-methyl-piperazin-1-yl) -? / - (2-pyrrol-1-phenyl) -benzenesulfonamide, 4-methoxy-3- (4-methyl-piperazin-1-yl) -? / - [4- (4- nitrophenylsulfanyl) phenyl] benzenesulfonamide, 4-methoxy-3- (4-methyl-piperazin-1-yl) -? / - (3-oxazol-5-ylphenyl) -benzenesulfonamide,? / - (4-Bromo-3-trifluoromethyl-phenyl) -4-methoxy-3- (4-methyl-piperazin-1) -yl) - 10-benzenesulfonamide, 4-methoxy-A / - (2,3-dimethylphenyl) -3- (4-methylpiperazin-1-yl) -benzenesulfonamide,? / - (4-chloro-3-trifluoromethylphenyl) -4 -methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 15 1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -5-trifluoromethyl-2,3-dihydro-1 H-indole, 7-Bromo-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 5,8-Dichloro-2- [4- methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonyl] -20 1, 2,3,4-tetrahydroisoquinoline, 5J-Dichloro-1- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfon 1] - 1, 2,3,4-tetrahydroquinoline, = ^ i 1 - [4-Methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroquinoline, 1 - [4-methoxy-3- (4-methylpiperazine-1 - il) benzenesulfonyl] -6-methyl-1, 2,3,4-tetrahydroquinoline, 6-Fluoro-1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3, 4-tetrahydroquinoline, 5-Chloro-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -2-Hydrochloride, 3-dihydro-1H-isoindol,? / - (2-isopropylphenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride,? / - (4-chloronaphthalen-1-yl) -4-methoxy -3-piperazin-1-ylbenzenesulfonamide, 4-methoxy-A / -naphthalen-1-yl-3-piperazin-1-ylbenzenesulfonamide,? / - (3-Chloro-2-methylphenyl) -4-methoxy-3-piperazine -1-ylbenzenesulfonamide,? / - lndan-5-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-Fluorophenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide, 4-methoxy -? / - (2-methylsulfanylphenyl) -3-piperazin-1-ylbenzenesulfonamide, 4-methoxy-3-piperazin-1-yl -? / - (2-trifluoromethylphenyl) benzenesulfonamide, 4-methoxy-? / - ( 2-methylphenyl) -3-piperazin-1-yl-benzenesulfonamide,? / - (2-Ethylphenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide, 4-methoxy-3-piperazin-1-yl -? / - ( 3- trifluoromethylphenyl) benzenesulfonamide,? / - (3,4-Dimethylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-Bromophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 5? / - (3,4-Dichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (3-Yodofeni l) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, A / - (3,5-Dichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, A / - (3-Chlorophenyl) -4-methoxy -3-piperazin-1-ylbenzenesulfonamide,? / - (2-Chloro-3-fluoro-4-methylphenyl) -4-methoxy-3-piperazin-1-yl-10-benzenesulfonamide,? / - (4-Chloro-3 -methylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - Benzo [1, 3] dioxol-5-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 15? / - (2- Bromo-4-methylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, A / - (2,5-Dibromophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,5- Dichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-Chloro-4-methylphenyl) -4-methoxy-3-piperazin-1-yl-2-benzenesulfonamide,? / - (4-Bromophenyl) - 4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-lsopropenylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, Hg? A ^^ Éj? I 4-Methoxy -? / - (2-metü-5-n¡pofenil) -3-piperazin-1-ylbenzenesulfonamide,? / - (4-Iodophenyl) -4-methoxy-3- piperazin-1-ylbenzenesulfonamide,? / - (4-fer-Butylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (4-lsopropylphenyl) -4-methoxy-3-piperazin-1-lylbenzenesulfonamide, ? / - (4-Hexylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,4-Dibromonaphthalen-1-yl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 4- Methoxy -? / - (4-methoxybiphenyl-3-yl) -3-piperazin-1-ylbenzenesulfonamide,? / - (3-Fluoro-5-pyridin-3-phenyl) -4-methoxy-3-piperazin-1 -ylbenzenesulfonamide, A / -Biphenyl-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-Benzylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2 -Propylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-sec-Butylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-tert-Butylphenyl) ) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, A / - (2-Butylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (5-Yodo-2-methylphenyl) - 4-methoxy-3-piperazin-1-yl-benzenesulfonamide, 6-Chloro-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -5-methyl-2,3-dihydro-1 H-indole hydrochloride , 6-Iodo-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -5-methylsulfanyl-2,3-dihydro-1 H-indole, 6-Bromo-1- (4-methoxy-3-piperazine -1-alkylbenzene sulfonyl l) -1, 2,3,4-tetrahydroquinoline, 8-chloro-2- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1, 2,3,4-tetrahydroisoquinoline, 1- (4-methoxy) 3-piperazin-1-ylbenzenesulfonyl) -5-methyl-6-trifluoromethyl-2,3-dihydro-1 H-indole, 5,8-dimethoxy-2- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl hydrochloride ) -1, 2,3,4-tetrahydroisoquinoline, 5,8-dichloro-2- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride,? / - ( 3-Iodo-4-methylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 5,7-Dichloro-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1, 2,3,4 -tetrahydroquinoline,? / - (2-Chloro-3,5-difluorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (4-Chloro-2-trifluoromethoxyphenyl) -4-methoxy-3-piperazine -1-ylbenzenesulfonamide,? / - (2,4,5-Trichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (5-Chloro-2-methoxyphenyl) -4-methoxy-3- piperazin-1-ylbenzenesulfonamide,? / - (4-Chloro-2-trifluoromethylphenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide,? / - (3,5-Dibromophenyl) -4-methoxy-3-pi perazin-1-ylbenzenesulfonamide, ? / - (3-Bromo-2,5-dichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,3,5-Trichlorophenyl) -4-methoxy-3-piperazin-1- ilbencenesulfonamide,? / - (5-Bromo-2,3-dihydro-benzofuran-7-yl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide, A / - (2-Bromo-3,5-dichlorophenyl) - 4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (3-Bromo-5,6-dichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,5-Dibromo-3) -fluorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,5-Dibromo-3-chlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,3 , 5-Tribromophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 6-Iodo-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -2,3-dihydro-1 H-indole, -Iodo-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -2,3-dihydro-1 H-indole, 7-Bromo-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) - 1, 2,3,4-tetrahydroquinoline and pharmaceutically acceptable salts thereof. The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric acids. and methanesulfonic. The compounds of the formula (I) can also form solvates such as hydrates, and the invention also extends to these forms. When referring to it herein, it is understood that the term 'compound of formula (I)' also includes these forms. Certain compounds of formula (I) are capable of existing in 5 stereoisomeric forms, including diastereomers and enantiomers, and the invention extends to each of these stereoisomeric forms and to mixtures thereof, including racemates. The different stereoisomeric forms can be separated from one another by normal methods, or any isomer can be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof. The present invention also provides a process for the preparation of a compound of the formula (I) or a pharmaceutically salt Figure imgf000014_0001 of the same, which comprises the coupling of a compound of the formula (II): (l l) wherein R1, R2, n, P, and A are as defined in formula (I), or protected derivatives thereof with a compound of formula (III): (N i) 15 wherein B, R 3, R 4 and R 5 are as defined in formula (I), or protected derivatives thereof and L is a leaving group and optionally after: • removing any protecting group, • forming a salt pharmaceutically acceptable. Suitable leaving groups include halogen, in particular chlorine. The reaction of the compounds of formulas (II) and (III) is carried out by mixing the two reagents together, optionally in an inert solvent such as dichloromethane, with or without the addition of a suitable base such as triethylamine [or pyridine] . íifiíiÉitif Wl m rr rx - t? Those skilled in the art will appreciate that it may be necessary to protect certain groups. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981). The compounds of the formulas (II) and (III) are commercially available or can be prepared according to known methods or analogous to known methods. For example, to prepare the compounds of the formula (I) wherein R3 is H, R5 is OMe and R4 is 1-piperazine, it was found that a suitable protecting group in the intermediates of formula (III) was trichloroacetyl. In this manner, reacting 1- (2-methoxyphenyl) piperazine with trichloroacetyl chloride in a suitable solvent such as dichloromethane in the presence of a base such as diisopropylethylamine produced 2- (4-trichloroacetyl-piperazin-1-yl) anisol In the acid treatment Chlorosulfonic acid at 0 ° C in a suitable inert solvent such as dichloromethane gave 3- (4-trichloroacetylpiperazin-1-yl) -4-methoxybenzenesulfonyl chloride. Coupling of this compound with the compounds of formula (II) as described above followed by treatment with 20% aqueous potassium hydroxide gave the required compound. The pharmaceutically acceptable salts can be prepared conventionally by reaction with the appropriate acid or acid derivative.

The compounds of the formula (I) and their pharmaceutically acceptable salts have 5HT6 receptor antagonistic activity and are believed to be of potential use in the treatment of certain central nervous system disorders such as anxiety, depression, epilepsy, obsessive-compulsive disorders. , migraine, Alzheimer's disease, sleep disorders (including circadian rhythm disorders), eating disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia and also disorders associated with spinal trauma and / or head injury such as hydrocephalus. It is also expected that the compounds of the invention will be useful in the treatment of certain Gl disorders, such as IBS. In this manner, the invention also provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders. The invention further provides a method of treating or prophylaxis of the above disorders in mammals, including humans, which comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of the above disorders. The present invention also provides a pharmaceutical composition, which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition of the invention, which can be prepared by mixing, suitably at room temperature and atmospheric pressure, is normally adapted for oral, parenteral or rectal administration, and therefore it can be in the form of tablets, capsules, oral liquid preparations, powders, granules, pills, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binders, fillers, tacking lubricants, disintegrants and acceptable wetting agents. The tablets can be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, solutions, suspensions, emulsions, aqueous or oily syrups or elixirs, or may be in the form of a dry product for constitution with water or other suitable vehicle before use. These preparations ß ^ ^^^^^^^^^ liquid may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and. if desired, conventional flavors or colorants. For parenteral administration, unit dosage forms in fluid are prepared using a compound of the invention or a pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and the concentration used, can be suspended or dissolved in the vehicle. In the preparation of solutions, the compound can be dissolved for injection and sterilized by filtration before filling it in a suitable vial or vial and sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and pH regulating agents are dissolved in the vehicle. To improve stability, the composition can be frozen after filling it in the bottle and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization can not be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in a normal manner with the seriousness of the disorders, the patient's weight and other similar factors. However, as a general guide, suitable unit doses may be from 0.05 to 1000 mg, very suitably from 0.05 to 20.0 mg, for example 0.2 to 5 mg; and said unit doses may be administered more than once a day, for example two or three times a day, such that the total daily dosage is on the scale of about 0.5 to 100 mg; and such therapy may be extended for a number of weeks or months. No unacceptable toxicological effects are expected with the compounds of the invention when administered in accordance therewith. The following descriptions and examples illustrate the preparation of the compounds of the invention.

DESCRIPTION 1 2-.4-Methylpiperazin-1-iDanisol (D1) To a stirred and ice-cooled suspension of lithium-aluminum hydride (7.9 g, 0.21 mol) in dry tetrahydrofuran (150 ml) was added a solution of 1- (2-methoxyphenyl) piperazine (10 mg, 52 mmol) in dry tetrahydrofuran (150 ml) for 0.5 hour under argon. A solution of ethyl formate (12.6 ml, 0.156 mol) in dry tetrahydrofuran (25 ml) was added to the cold mixture for 0.25 hours and the resulting suspension was stirred for an additional 2 hours at room temperature. The diluted sodium hydroxide solution (15%, 8 ml) was added slowly to the cooled mixture, followed by water (24 ml) and everything was allowed to stir for 0.25 hours. The mixture was filtered and the filtrate was concentrated to an oil which was separated between dichloromethane and water. The organic phase was dried and concentrated to an oil which was purified by column chromatography on silica gel, eluting with a gradient of methanol / dichloromethane to give the title compound as a colorless oil; (5.7 g, 53%) dH (250 MHz, CDCL3), 2.36 (3H, s) 2.63 (4H, br s), 3.10 (4H, br s), 3.86 (3H ,. s), 6.84-7.03 (4H , m).

DESCRIPTION 2 3-.4-Methylpiperazin-1-yl-4-methoxybenzenesulfonyl chloride (D2) 2- (4-Methylpiperazin-1-yl) anisole (200 mg, 1 mmol) was added in portions over 10 minutes to stirred and chilled chlorosulfonic acid (1.2 ml) under argon. The resulting brown solution was stirred at 0 ° C for 0.25 hours and then at room temperature for an additional 1.25 hours. The solution was poured slowly onto crushed ice (50 g). Dichloromethane (50 ml) was added to the mixture, followed by saturated sodium carbonate solution to obtain a pH of 10 in the aqueous phase. The layers were separated and the aqueous phase was further extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated to an oil. The oil was stirred with hexane (4 mL) to give the title compound as a cream colored solid (210 mg, 71%). dH (250 MHz, CDCL3), 2.43 (3H, s) 2.71 (4H, br t, J = 4.2), 3.20 (4H, br t, J = 4.2), 4.00 (3H, s), 6.97 (1 H, d, J8.7), 7.48 (1H, d, J2.2), 7.72 (1H, dd, J2.2, 8.7), MS: m / z (MH +) = 305.

DESCRIPTION 3 2- (4-Trichloroacetylpiperazin-1-iDanisol (D3) A solution of 1- (2-methoxyphenyl) piperazine (7.0 g) in dichloromethane (30 ml) was added over 0.25 hours to a stirred solution of trichloroacetyl chloride (4.06 ml) in dichloromethane (40 ml) at room temperature under argon. Then diisopropylethylamine (5.95 ml) was added and everything was stirred for 18 hours. The reaction mixture was washed with water (2 x 100 ml), dried (Na2SO4) and concentrated to give the title compound (D3) as an oil (11.2 g, 91%). MH + 337/339.

DESCRIPTION 4 3- (4-Trichloroacetylpiperazin-1-yl) -4-methoxybenzenesulfonyl chloride (D4) A solution of 2- (4-trichloroacetylpiperazin-1-yl) anisole (D3) (10 g) in dichloromethane (115 ml) was added over 0.3 hour to ice-cold chlorosulfonic acid (52 ml). After 0.5 hours at 0 ° C and then 1 hour at room temperature, the solution was poured onto a mixture of ice-water (500 g) and dichloromethane (500 ml) with rapid stirring. The layers were separated and the organic phase was washed with water (2 x 800ml), dried (MgSO) and concentrated to give a title compound (D4) as a foam (6.0 g, 46%). MH + 435/437.

DESCRIPTION 5 6-Iodo-2,3-dihydro-1 H-indole (D5) This compound was prepared as previously described (Heterocycles, 1987, 26, 2817).

DESCRIPTION 6 5-Iodo-2,3-dihydro-1 H-indole (D6) This compound was prepared as described above (Chem. Pharm. Bull. 1987, 35, 3146).

DESCRIPTION 7 3,5-Dibromoaniline (D7) A suspension of 3,5-dibromonitrobenzene (J. Amer. Chem. 5 Soc, 1950, 72, 793) (1.0 g, 3.6 mmol) in methanol (30 ml) was added in portions to a stirred mixture of powdered iron (0.52). g, 9.3 mmol) in a saturated solution of ammonium chloride (50 ml) at 60 ° C. The mixture was refluxed for 2 hours, filtered and the filtrate was extracted with dichloromethane (2 x 70 ml). The organic extract was dried (Na2SO4) and concentrated in vacuo to give the title compound (D7) as an oil (0.787g, 87%), MH + 250/252.

DESCRIPTION 8 2-Bromo-3,5-dichloro-4-nitroaniline (D8) 15 A solution of N-bromosuccinimide (2.6 g, 14.5 mmol) in N.N'-dimethylformamide (DMF) (70 mL) was added over 20 minutes. minutes to a stirred solution of 2,5-dichloro-4-nitroaniline (3.0 g, 14.5 mmol) in DMF (30 ml) at room temperature under argon. After stirring for 18 hours the mixture was poured into water (11) and extracted with dichloromethane (500 ml). The organic extract was washed with water (5 x 500 ml), dried (MgSO) and concentrated to an oil which was purified by column chromatography on silica gel eluting with a gradient of ethyl acetate / hexane to give the title compound (D8) as a yellow solid (1.0g, 24%), MH + 285/287.

DESCRIPTION 9 3-Bromo-2,5-dichloronitrobenzene (D9) Concentrated sulfuric acid (2.2 ml) was slowly added to a suspension of 2-bromo-3,5-dichloro-4-nitroaniline (D8) (0.9 g, 3.1 mmol) in ethanol (20 ml). The resulting solution was heated to reflux and crushed sodium nitrite (478 mg, 6.9 mmol) was added in two portions. After 0.5 hours at reflux, the mixture was cooled, diluted with dichloromethane (50 ml) and saturated sodium bicarbonate solution (50 ml) was added. The layers were separated and the organic phase was dried (Na2SO) and concentrated to an oil which was purified by column chromatography on silica gel eluting with a gradient of ethyl acetate / hexane to give the title compound (D9) as an orange solid (0.67g, 80%), MH + 269/271.

DESCRIPTION 10 3-Bromo-2,5-dichloroaniline (D10) 3-Bromo-2,5-dichloronitrobenzene (D9) was treated with powdered iron in the manner described in description 7 to give a title compound (D10) as a solid (77%), MH + 240/242.

DESCRIPTION 11 2.3.6-Trichloro-4-nitroaniline (D11) To a suspension of 2,5-dichloro-4-nitroaniline (4.0 g, 19.3 mmol) in ethanol (50 ml) was added concentrated hydrochloric acid (20 ml) and water (20 ml). The mixture was heated to 50 ° C and 27.5% hydrogen peroxide (6 ml) was added over 15 minutes. The mixture was kept at this temperature for a further 2 hours, cooled to room temperature, the solid filtered and washed with water (2 x 20 ml) to give the title compound (D11) (4.1 g, 88%) , MH + 241/243.

DESCRIPTION 12 2.3.6-Trichloro-4-nitroaniline (D11) 2,3,6-Trichloro-4-nitroaniline (D11) was deaminated as described in description 9 to give the title compound (D12) (64%), MH + 226/228.

DESCRIPTION 13 2,3,5-Trichloroaniline (D13) 2, 3, 5-trichloron-trobenzene (D12) was reduced with powdered iron as described in description 7 to give the title compound (D13) (68%), MH + 196/198. f?,. r • --Ajfeiiir DESCRIPTION 14 7-Amino-5-bromo-2,3-dihydrobenzofuran (D14) Concentrated sulfuric acid (8.8 ml) was added over 5 minutes to a stirred mixture of 5-bromo-2,3-dihydrobenzofuran-7-carboxylic acid (0.55 g, 2.3 mmol) in chloroform (2.7 ml) at 45 ° C. Then sodium azide (0.737 g, 11.3 mmol) was added in portions over 0.5 hours and the temperature was maintained for an additional 1 hour, after which the mixture was poured onto ice (100 g) and extracted with chloroform (2 x). 50 ml). The aqueous phase was made basic to pH 12 with 40% sodium hydroxide solution and extracted with chloroform (2 x 50 ml). The extract was dried (Na2SO4), concentrated and the residue was purified by column chromatography on silica gel eluting with a gradient of acetone / toluene to give the title compound (D14) as a solid (63 mg, 13%) , MH + 214/216.

DESCRIPTION 15 7-Bromo-1,2,3,4-tetrahydroquinoline (D15) A solution of 7-bromoquinoline (J. Amer. Chem. Soc, 1947, 69, 705) (362 mg, 174 mmol) in glacial acetic acid (10 ml) was treated portionwise with sodium cyanoborohydride (437 mg, 7.0 mmol. ) under argon at room temperature. After 18 hours at this temperature the mixture was cooled in an ice bath and water (35 ml) and 50% aqueous sodium hydroxide were added until a pH of 14 was reached. The mixture was extracted with dichloromethane and the organic phase it was washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo to a residue which was purified by column chromatography on silica eluting with a gradient of methanol / dichloromethane to give the title compound (D15 ) (168 mg, 46%). MH + 212/214.

DESCRIPTION 16 3- (4-Methyl-1-piperazin-1-yl) -4-methoxybenzenesulfonamide (D16) The title compound (D16) was prepared in a 35% yield by treating the sulfonyl chloride (D2) with excess aqueous ammonia in acetone. Many of the intermediates used in the preparation of the compounds of this invention can be prepared by known methods. These are shown in table A. ^^^^. ..r.,., ^^^^^^ TABLE A EXAMPLE 1 4-Methoxy-3- (4-methyl-piperazin-1-yl) -? / - naphthalen-1-l-benzenesulfonamide (E1) 1-Naphthylamine (29 mg, 0.2 mmol) was added to a stirred solution of 3- (4-methyl-1-piperazinyl) -4-methoxybenzenesulfonyl chloride (D2) (60 mg, 0.2 mmol) in acetone (1 ml). at room temperature. After stirring for 18 hours the precipitated material was filtered and washed with acetone and diethyl ether to give the title compound (E1) as a cream colored solid (60 mg, 67%). dH (250 MHz, DMSO-d6) 2.88 (3H, s), 2.90-2.97 (2H, m), 3.15- 3.30 (2H, m), 3.37-3.56 (4H, m), 3.89 (3H, s), 7.11 (1 H, d J = 8.8), 7.22-7.59 (6H, m), 7.86 (1 H, d, J = 8.3), 7.96 (1 H, d, J = 9.0), 8.10 (1 H, d , J = 7.0), 10.18 (1 H, s), 10.55 (1 H, br s). MS: m / z (MH + -HCl) = 412. The compounds of Tables 1 and 2 were prepared in a manner similar to those of Example 1 using 3- (4-methyl-piperazin-1-yl) -4-methoxybenzenesulfonyl chloride ( D2) and the appropriate amine. All amines are commercially available or can be prepared by methods as indicated in Table A above. If required, purification is carried out by recrystallization or alternatively by a basic aqueous treatment (K2CO3) followed by column chromatography.

TABLE 1 15 20 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ TABLE 2 iÉÉ ^^ j ^ MM ^ a ^ Q ^ jjJMHMÍM¿¡M ^^^ «l ^^ 10 fifteen g ü ^. ^^ m ^ nm ¡« EXAMPLE 78 5-Chloro-2-F4-methoxy-3- (4-methyl-piperazin-1-iD-benzenesulfonyl-2,3-dihydro-1H-isoindol hydrochloride (E78) Sodium hydride (20 mg of a 60% dispersion in mineral oil, 0.5 mmol) was added to a solution of 3- (4-methyl-1-piperazin-1-yl) -4-methoxybenzenesulfonamide (D16) (53 mg , 0.19 mmole) in DMF (2 ml) in one portion at room temperature under argon. Stirring was continued for 1 hour before a solution of, 2-bis bromomethyl-4-chlorobenzene (119 mg, 0.37 mmol) in DMF (0.5 ml) was added. The reaction was heated at 60 ° C for 3 hours, cooled and then separated between water and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel to give the material which was converted to the title compound by treatment with 1M ethereal HCl MS: m / z (MH +) = 422/424.

EXAMPLE 29 (1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -7-trifluoromethyl-1, 2,3,4-tetrahydroquinoline hydrochloride (E29) A solution of 1- [4-methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonyl] -7-trifluoromethyl-1, 2,3,4-tetrahydroquinoline (E8) (70 mg, 0.15 mmol) and chloroformate 1-Chloro-ethyl (0.08 ml, 0.75 mmol) in 1,2-dichloroethane (2 ml) was heated under reflux for 18 hours, and then cooled to room temperature. N, N-diisopropylethylamine (0.05 ml, 0.26 mmol) was added and the resulting solution was heated under reflux for 2 hours. The solvent was removed, the residue was dissolved in methanol (4 ml), and the reaction was heated under reflux for 18 hours. The solvent was partially removed, dichloromethane (20 ml) was added and the solution was washed with saturated aqueous sodium bicarbonate (10 ml), dried (MgSO) and then evaporated. The residue was purified by column chromatography on silica gel eluting with a gradient of methanol-dichloromethane to give the sulfonamide derivative as a yellowish oil. The oil was dissolved in acetone (0.5 ml) and a 1 M solution of hydrogen chloride in diethyl ether (0.1 ml) was added. The solution was evaporated and the residue coevaporated with dry benzene (3 x 2 ml) to give the title compound (E25) as a cream colored solid (38 mg, 52%). dH (250MHz, DMSO-de), 1 -58 (2H, m), 2.51 (2H, m), 3.01 (4H, br s), 3.16 (4H, br s), 3.79 (2H, t, J = 5.80 ), 3.85 (3H, s), 6.83 (1 H, d, J = 2.10), 7.13 (1H, d, J = 8.74), 7.33 (2H, m), 7.44 (1H, d, J = 8.11), 7.95 (1 H, s), 9.1 (2H, br s). MS: m / z (MH +) = 346.

EXAMPLE 30 N- (3-Bromophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide (E30) The title compound was prepared using a procedure similar to that of Example E29 using? / - (3-bromophenyl) -4-methoxy-3- (4-methylpiperazin-1-yl-benzenesulfonamide (E3) and 1-chloroethyl chloroformate. (250MHz, DMSO-de), 2.84 (8H, m), 3.81 (3H, s), 7.01-7.20 (5H, br s), 3.16 (4H, br s), 3.79 (2H, t, J = 5.80) , 3.85 (3H, s), 6.83 (1 H, d, J = 2.10), 7.13 (1 H, d, J = 8.74), 7.33 (1 H, m), 7.36 (1 H, m), MS: m / z (MH +) = 426.

IV- (2-isopropylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide hydrochloride (E79) Pyridine (0.28 ml) of a stirred solution of 2-isopropylaniline (98 mg) and (4-trichloroacetylpiperazin-1-yl) -4-methoxybenzenesulfonyl chloride (D4) (300 mg) in dichloromethane (4 ml) was added at room temperature. ambient. After 18 hours the solution was washed with 1 M hydrochloric acid (5 ml) and then water (5 ml). The organic phase was vigorously stirred with 20% aqueous potassium hydroxide (0.5 ml) for 18 hours. Then a 10% aqueous solution of KH2PO4 (8 ml) was added to the mixture and after 0.25 hours of stirring the layers were separated. The organic layer was dried (Na2SO), made acidic with 1M ethereal hydrogen chloride (2ml) and concentrated to an oil which was stirred with acetone / diethyl ether to give the title compound (E79) with a white solid. (0.224g, 83%). MH + 390. The compounds of Table 3 were prepared in a manner similar to that of Example 79, using 3- (4-trichloroacetylpiperazin-1-yl) -4-methoxybenzenesulfonyl chloride (D4) and the appropriate amine. All amines are commercially available or can be prepared by the methods described above. a »^. ^ .to ^, h¿ai» AMa «.

TABLE 3 15 20 §3¡ | j¡¡ggg | | ^ j M? ® »? i ^ ¿^ ¡^ ¿^ _.

EXAMPLE 120 6-Chloro-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -5-methyl-2,3-dihydro-1 H-indole hydrochloride (E120) Pyridine (0.28 ml) was added to a stirred solution of 6-chloro-5-methyl-2, 3-dihydro-1H-indole (WO-9501976) (0.116g) and 3- (4-trichloroacetyl-piperazin-1-yl) -4 chloride -methoxybenzenesulfonyl (D4) (300 mg) in dichloromethane (4 ml) at room temperature. After 18 hours the solution was washed with 1 M hydrochloric acid (5 ml), water (5 ml), dried (MgSO) and || j || ^ ^ ^ concentrated to give an oil. The oil was dissolved in 1,4-dioxane (13 ml) and a 0.15 M potassium hydroxide solution (6.5 ml) was added. The solution was stirred at room temperature for 4 hours and then concentrated to remove the organic solvent, diluted with water (10 ml) and the solution extracted with dichloromethane (20 ml). The organic phase was dried (NaSO4), made acidic with 1M ethereal hydrogen chloride (2 ml), concentrated to a solid and stirred with acetone to give the title compound (0.175g, 55%): MH + 422 / 424 The compounds of Table 4 were prepared in a manner similar to that of Example 120, using 3- (4-trichloroacetylpiperazin-1-yl) -4-methoxybenzenesulfonyl chloride (D4) and the appropriate amine. All amines are commercially available or can be prepared by the methods described above. jÉ ^ j ^ gji ^^ TABLE 4 EXAMPLE 125 5,8-Dimethoxy-2- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1,2,4,4-tetrahydroisoquinoline hydrochloride (E125) A solution of 1-chloroethyl chloroformate (0.12 ml, 1.11 mmol) and 5,8-dimethoxy-2- [4-methoxy-3- (4-methyl-1-piperazinyl) i) encensulfonl] -1, 2 3,4-tetrahydroisoquinoline (E21) (11 mg: 0.223 mmol) in 1,2-dichloroethane (3 ml) was refluxed for 0.75 hours, cooled, diluted with diisopropylethylamine (0.19 ml, 1.11 mmol) and filtered. led to reflux for an additional 2.5 hours. The solution was concentrated to a residue which was redissolved in methanol, refluxed for 1 hour and then stirred at room temperature for 24 hours. The mixture was concentrated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried, concentrated to a residue and purified by column chromatography on silica gel using a solvent gradient methanol / dichloromethane. The title compound was prepared by dissolving the pure free base material from the chromatography in acetone / dichloromethane and acidifying with 1M ethereal HCl (53 mg, 49%). MH + 456/458.

EXAMPLE 126 5.8-Dichloro-2- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride (E126) The title compound was prepared from its analog N-methylpiperazine (E72) by a method as described in E125, but the reaction was maintained at room temperature and diisopropylethylamine was added at the start of the reaction. MH + 456/458.

EXAMPLE 127 / V- (3-Vodo-4-methylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide hydrochloride (E127) The title compound was prepared from its analog N-methylpiperazine (E9) by a method as described in E125. MH + 488.

EXAMPLE 128 5,7-Dichloro-1- (4-methoxy-3-piperazin-1-yl-benzenesulfonyl) -1,2,3,4-tetrahydroquinoline hydrochloride (E128) The title compound was prepared from its analog N-methylpiperazine (E73) by a method as described in E125. MH + 456-458.

Pharmacological data Method for testing the antagonistic activity of 5-HT6 The test compounds were dissolved in polyethylene glycol dimethyl sulfoxide (1: 1) at 1 or 10 mM and diluted to 0.1 mM using 5 mM tris pH buffer (pH 7.7 @ 25 ° C) . The solution was assisted by the addition of 0.02 ml of 5M HCl plus heating at 40 ° C and sonification for 10 minutes. Serial dilutions of & i¡ £ 3r. drugs in the same pH regulator using a TECAN 5052 or Biomek 2000 Wokstation. Samples of the diluted test compounds (0.05 ml) were mixed with 0.05 ml of radioligand [3H] -LSD prepared in the incubation pH buffer, and 0.4 ml of a suspension of a preparation of the washed membranes of HeLa_5HT6 cells (purchased from Dr. D. Sibley, NIH, Bethesda, see Ref 1) (see Table 1), also in the pH buffer of incubation. The details of the incubation conditions for each test are shown in table 2. The incubation pH regulator was 50 mM Trizma (Sigma, UK) pH 7.7 @ 25 ° C, 4 mM MgCl2.

After incubation at 37 ° C, the mixtures were filtered using a Packard Filtermate in Packard TopCount format. The filters were washed with 4 x 1 ml aliquots of ice-cold incubation buffer. The filters were dried and impregnated with 0.04 ml of Microscint 20 (Packard). The IC5o values of the counts per minute were calculated using an adjustment of logistic curve of four parameters in EXCEL (2). The K values were calculated, using the method of Cheng and Prusoff (3). plC50 and pK, are the negative Iog10 of the IC50 and K, molars respectively. ^^ g ^^^^^^^^^^ TABLE 1 Details of the methods used to prepare membranes for binding tests TABLE 2 Summary of the conditions of the receptor binding test References 1.- MONSMA, F.J., SHEN, Y., WARD, R.P. HAMBLIN, M.W. SIBLEY, D.R. 1993. Cloning expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol. Pharmacol., 43, 320-327. 2.- BOWEN, W.P. JERMAN, J.C., 1995. Nonlinear regression using spreadsheets Trends in Pharmacol. Sci., 16, 413-417. 3. - CHENG, Y.C., PRUSSOF, W.H., 1973. Relationship between inhibition constant (Ki) and the concentration of inhibitor wich cause 50% inhibition (IC50) of an enzymatic reaction. Biochem. Pharmacol., 92, 881-894. All tested compounds showed adequate selective 5-HT6 receptor antagonist activity, with pKi values 7.5 - 9.5 in receptors -HT6 cloned from human. Particularly preferred compounds demonstrated pKi > 8.5 and selectivity > 100. Examples of such compounds include: 3, 8, 21, 29, 32, 37-39, 41, 44, 45, 53, 54, 57-59, 63, 67, 69, 72, 73, 79, 85, 88, 89, 91, 93-95, 100, 104, 107, 113, 117-119, 121-128, 131, 132, 134-143, 145. j ^ j ^^ ^ í

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - a compound of the formula (I) or a salt thereof:

(I) wherein: P is phenyl, naphthyl, anthracenyl, a bicyclic heterocyclic ring, a tricyclic heteroaromatic ring or is a 5- to 7-membered heterocyclic ring each containing 1 to 4 heterogeneous atoms selected from oxygen, nitrogen or sulfur; A is an individual bond, an alkylene group of C-? _ 6 or an alkenylene group of C? .6; B is SO2; R1 is halogen, C1.6 alkyl optionally substituted by one or more fluorine atoms, C3-6 cycloalkyl, C2.6 alkenyl, C2-6 alkynyl, Cl-6 alkanoyl, d-β alkoxy, OCF3 , hydroxy, hydroxyalkyl of C -? - 6, hydroxyalkoxy of C -? - 6, C -? - 6 alkoxy of C -? - 6, nitro, cyano, NR10R11 wherein R10 and R11 are independently hydrogen, alkyl of C? _6 or optionally substituted phenyl, SR11 wherein R1 is as defined above or R1 is optionally substituted phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5- to 7-membered heterocyclic ring each containing 1 to 4 atoms heterogeneous selected from oxygen, nitrogen or sulfur, or R1 together with a second substituent R1 forms a group -O-CH2-O-, OCH2CH2O-, -CH2CH2CH2- or -CH2CH2CH2CH2-; n is 0, 1, 2, 3, 4, 5 or 6; R2 is hydrogen, C? -6 alkyl, arylC1-6 alkyl or together with the group P form a 5- to 8-membered ring optionally substituted with one or more C? .6 alkyl groups; R3 is hydrogen, halogen, C1.6 alkyl, C3.6 cycloalkyl, C1.6 alkanoyl, C1.6 alkoxy optionally substituted with one or more fluorine atoms, hydroxy, C1.6 hydroxyalkyl, C1 hydroxyalkoxy .6, C? -6-alkoxy of C? .6, nitro, trifluoromethyl, cyano or aryl, or together with the group R5 forms a group (CH2) 2O or (CH2) 3O optionally substituted with one or more groups C? .6 alkyl; R 4 is -X (CH 2) p-R 6, wherein X is an individual bond, CH 2, O, NH or N-alkyl and p is 0 to 6 and R 6 is an optionally substituted 4 to 7-membered heterocyclic ring containing 1 to 3 heterogeneous atoms selected from nitrogen, sulfur or oxygen, or R6 is NR7R8, wherein R7 and R8 are independently hydrogen, C6-6alkyl or C1-6alkylarylkylaryl; and R5 is a group R3 or together with R3 forms a group (CH2) 2O or (CH2) 3O optionally substituted with one or more C1-6 alkyl groups. 2. A compound according to claim 1, wherein P is phenyl or naphthyl.

3. A compound according to claim 1 or 2, wherein R1 is hydrogen, halogen, C1-6 alkoxy or C1-6 alkyl optionally substituted by one or more halogen atoms.

4. - A compound according to any of claims 1 to 3, wherein R 4 is an optionally substituted piperazine ring.

5. A compound according to any of claims 1 to 4, wherein R5 is methoxy.

6. A compound according to claim 1, which is: 4-methoxy-3- (4-methylpiperazin-1-yl) -A / -naphthalen-1-ylbenzenesulfonamide,? / - (4-chloronaphthalen-1) -yl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - (3-bromophenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl-benzenesulfonamide,? / - (3 , 4-dichlorobenzyl) -4-methoxy-3- (4-methyl-piperazin-1-yl-benzenesulfonamide, 6-chloro-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1, 2, 3,4-tetrahydroquinoline, 1- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -6-trifluoromethyl-2,3-dihydro-1 H-indole, A / - (3-chlorophenyl) -4-methoxy-A / -methyl-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) ) -benzenesulfonyl] -7-trifluoromethyl-1, 2,3,4-tetrahydroquinoline,? / - (3-iodo-4-methylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide, ? / - (5-iodo-2-methylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide,? / - (3,4-methylenedioxyphenyl) -4-methoxy-3- (4 -methylpiperazin-1-yl) benzenesulfonamide, 6-chloro -1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -5-methyl-2,3-dihydro-1 H-indole, 7,8-dichloro-2- [4-methoxy] 3- (4-Methylpiperazin-1-yl) benzenesulfonyl] -1, 2,3,4-tetrahydroisoquinoline, 7,8-dimethoxy-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 5-bromo -2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 8-chloro-7-methoxy-2- [4-methoxy-3-] (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 6,7-dimethoxy-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1, 2,3,4-tetrahydroisoquinoline, 2- [4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonyl] -7-phenyl-1, 2,3,4-tetrahydroisoquinoline, 8-bromine -7-methoxy-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 5,6-dichloro-2- [4-methoxy] 3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline, 5,8-dimethoxy-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) - benzenesulfonyl] -1, 2,3,4-tetrahydroisoquinoline, 6-iodo-1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -5-methylthio-2,3-dihydro-1 H-indole,? / - (3,4-dichlorophenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfone Measure,? / - (3-iodophenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide, 6,7,8-trimethoxy-2- [4-methoxy-3- (4-methoxy -3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1, 2,3,4-tetrahydroisoquinoline, 2- [4-methoxy-3- (4-methyl-piperazin-1-yl) - benzenesulfonyl] -6-pyridin-3-yl-2,3-dihydro-1 H-indole, 2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -5-pyridin-3- il-2,3-dihydro-1 H-indole, 1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1, 2,3,5-tetrahydropyrrolo [2,3 - / jindol, 1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -7-trifluoromethyl-1, 2,3,4-tetrahydroquinoline,? / - (3-bromophenyl) -4-methoxy-3-piperazine -1-lylbenzenesulfonamide,? / - (2-fluorophenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonamide,? / - (2-trifluoromethoxyphenyl) -4-methoxy-3- (4-methylpiperazine) -1-yl) - benzenesulfonamide, A / - (2-bromo-4-methylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide,? / - (4-iodophenyl) -4- methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonamide,? / - (9,10-dioxo-9,10-dihydroanthracen-1-yl) -4-methoxy-3- (4- me Tilpiperazin-1-yl) - Benzenesulfonamide, V- (2-Hydroxymethylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide, 4-methoxy-3- (4-methyl-piperazin-1-yl) -? / - (2-methylsulfanylphenyl) -benzenesulfonamide, 4-methoxy-3- (4-methylpiperazin-1 - \\) - N- (5,6,7,8-tetrahydronaphthalen-1-yl) -benzenesulfonamide,? / - (2-Ethylphenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl-benzenesulfonamide, 4-methoxy-N- (2-methylphenyl) -3- (4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - (3,4-Dimethylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) -benzenesulfonamide, 4-methoxy-? / - (2-methoxy-6-methylphenyl) -3- (4-methylpiperazine) -1 -yl) -benzenesulfonamide,? / - (3-fluoro-5-pyridin-3-ylphenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 8-chloro-2- [ 4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroisoquinoline,? / - (2-chloro-4-fluorophenyl) -4-methoxy-3- (4- methyl-piperazin-1-yl) -benzenesulfonamide, N- (2-trifluoromethyl-phenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 4-methoxy-3- (4-methyl-piperazine) -1-il) -? / - qu¡nol¡n-7- Lbencenesulfonamide,? / - (4-bromophenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonamide,? / - (3-bromo-4-methylphenyl) -4-methoxy-3- (4 -methylpiperazin-1-yl) -benzenesulfonamide,? / - (3-bromo-2-methylphenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 4-methoxy-N- (2- methoxydibenzofuran-3-yl) -3- (4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - (4-cyclohexyl-phenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) - benzenesulfonamide,? / - (2-iodophenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonamide,? / - (2-chloro-4-iodophenyl) -4-methoxy-3- (4 -methylpiperazin-1-yl) -benzenesulfonamide, / V- (2-bromo-4-fluorophenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide,? / - [4- (4- chlorophenyl) thiazol-2-yl] -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 4-methoxy-? / - (3-methylphenyl) -3- (4-methyl-piperazin-1-yl) ) benzenesulfonamide,? / - (3-ethylphenyl) -4-methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonamide,? / - (3-chloro-4-bromophenyl) -4-methoxy-3- ( 4- methylpiperazin-1-yl) -benzenesulfonamide, A / - (2-acetylphenyl) -4-methoxy-3- (4- me Tilpiperazin-1-yl) benzenesulfonamide, 4-methoxy-3- (4-methyl-piperazin-1-yl) -? / - (4-5-phenylaminophenyl) -benzenesulfonamide, 4-methoxy-3- (4-methyl-piperazin-1-yl) -? / - (4 - pentyloxyphenyl) -benzenesulfonamide, 4-methoxy-3- (4-methylpiperazin-1-yl) -? / - (4-vinylphenyl) benzenesulfonamide, 4-methoxy-3- (4-methylpiperazin-1-yl) -A / - (2-pyrrol-1-ylphenyl) -benzenesulfonamide, 4-methoxy-3- (4-methylpiperazin-1-yl) -? / - [4- (4-nitrophenylsulfanyl) phenyl] benzenesulfonamide, 4-methoxy-3- (4-methylpiperazin-1-yl) -? / - 10 (3-oxazol-5-ylphenyl) -benzenesulfonamide,? / - (4-bromo-3-trifluoromethylphenyl) -4- methoxy-3- (4-methylpiperazine- 1-yl) -benzenesulfonamide, 4-methoxy -? / - (2,3-dimethylphenyl) -3- (4-methylpiperazin-1-yl) -benzenesulfonamide,? / - (4-chloro-3-trifluoromethylphenyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonamide, 1- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -5-trifluoromethyl-2, 3-dihydro-1H-15 indole, 7-bromo-2- [4-methoxy-3- (4-methylpiperazin-1-yl) benzenesulfonyl] -1, 2,3,4-tetrahydroisoquinoline, 5,8-dichloro- 2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfoni l] -1, 2,3,4-tetrahydroisoquinoline, 5,7-dichloro-1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroquinoline, 1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1,2,3,4-tetrahydroquinoline, 1 - [4-methoxy-3- (4-methylpiperazin-1- il) benzenesulfonyl] -6-methyl-1, 2,3,4-tetrahydroquinoline, 6-fluoro-1 - [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl] -1, 2,3, 4-tetrahydroquinoline, 5-chloro-2- [4-methoxy-3- (4-methyl-piperazin-1-yl) -benzenesulfonyl hydrochloride] -2.3- - ^^^ to »Mf? ftiwrfia dihydro-1 H-isoindole,? / - (2-isopropylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide hydrochloride,? / - (4-chloronaphthalene-1-yl) ) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 4-methoxy -? / - naphthalen-1-yl-3-piperazin-1-ylbenzenesulfonamide,? / - (3-chloro-2-methylphenyl) -4- methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - indan-5-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-fluorophenyl) -4-methoxy-3-piperazin-1 - ilbencenesulfonamide, 4-methoxy-? / - (2-methylsulfanylphenyl) -3-piperazin-1-ylbenzenesulfonamide, 4-methoxy-3-piperazin-1-yl-? / - (2-trifluoromethylphenyl) benzenesulfonamide, 4-methoxy-? / - (2-methylphenyl) -3-piperazin-1-ylbenzenesulfonamide, / V- (2-ethylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 4-methoxy-3-piperazin-1-yl-? / - (3-trifluoromethylphenyl) benzenesulfonamide,? / - (3,4-dimethylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-bromophenyl) -4-methoxy-3-piperazin-1 -ylbenzenesulfonamide,? / - (3,4-dichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (3-yodofe nyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (3,5-dichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (3-chlorophenyl) -4- methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-chloro-3-fluoro-4-methylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (4-chloro-3-methylphenyl) ) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - benzo [1, 3] dioxol-5-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-bromo-4) -methylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,5-dibromophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,5-dichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-chloro-4-methylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (4-bromophenyl) -4-methoxy -3-piperazin-1-ylbenzenesulfonamide, A / - (2-isopropenylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 4-methoxy-? / - (2-methyl-5-nitrophenyl) -3-piperazine -1-ylbenzenesulfonamide,? / - (4-iodophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, / - (4-fer-butylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (4-isopropylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (4-hexylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,4-dibromonaphthalene -1 -yl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 4-methoxy-? / - (4-methoxybiphenyl-3-yl) -3-piperazin-1-ylbenzenesulfonamide,? / - (3-fluoro -5-pyridin-3-ylphenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide,? / - biphenyl-2-yl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,? / - (2-benzylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide, A / - (2-propylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-sec-butylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-rer-Butylphenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2-butylphenyl) -4-methoxy-3 -piperazin-1-l-benzenesulfonamide, A / - (5-iodo-2-methylphenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide, 6-chloro-1- (4-methoxy-3-piperazine hydrochloride -1-ylbenzenesulfonyl) -5-methyl-2,3-dihydro-1 H-indole, 6-iodo-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -5-methylsulfanyl-2,3-dihydro -1 H-indole, 6 -bromo-1 - (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1, 2,3,4-tetrahydroquinoline, 8-chloro-2- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1 , 2,3,4-tetrahydroisoquinoline, 1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -5-methyl-6-trifluoromethyl-2,3-dihydro-1 H-indole , 5,8-dimethoxy-2- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1, 2,3,4-tetrahydroisoquinoline hydrochloride, 5,8-dichloro-2- (4-methoxy) hydrochloride 3-piperazin-1-ylbenzenesulfonyl) -1, 2,3,4-tetrahydroisoquinoline,? / - (3-iodo-4-methylphenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide, 5,7- dichloro-1 - (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1, 2,3,4-tetrahydroquinoline,? / - (2-chloro-3,5-difluorophenyl) -4-methoxy-3-piperazine -1-lylbenzenesulfonamide,? / - (4-chloro-2-trifluoromethoxyphenyl) -4-methoxy-3-piperazin-1-l-benzenesulfonamide,? / - (2,4,5-trichlorophenyl) -4-methoxy-3-piperazine -1-lylbenzenesulfonamide,? / - (5-chloro-2-methoxy-phenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (4-chloro-2-trifluoromethylphenyl) -4-methoxy-3-piperazine -1 -ilbencen osufonamide,? / - (3,5-dibromophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (3-bromo-2,5-dichlorophenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide ,? / - (2,3,5-trichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (5-bromo-2,3-dihydro-benzofuran-7-yl) -4-methoxy -3-piperazin-1-ylbenzenesulfonamide,? / - (2-bromo-3,5-dichlorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (3-bromo-5,6-dichlorophenyl) ) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,5-dibromo-3-fluorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide,? / - (2,5- dibromo-3-chlorophenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide,? / - (2,3,5-tribromophenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide, 6-iodo-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -2,3-dihydro-1 H-indole, 5-iodo-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -2,3-dihydro -1 H-indole, 7-bromo-1- (4-methoxy-3-piperazin-1-ylbenzenesulfonyl) -1, 2,3,4-tetrahydroquinoline and pharmaceutically acceptable salts thereof.

7. A compound according to any of claims 1 to 6 for use in therapy.

8. - A pharmaceutical composition comprising a compound according to any of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient.

9. A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises the coupling of a compound of the formula (II): (l l) wherein R1, R2, n, P, and A are as defined in formula (I), or protected derivatives thereof with a compound of formula (III): (l l l) wherein B, R, R * and R ° are as defined in formula (I), or protected derivatives thereof and L is a leaving group and optionally thereafter: • removing any protecting group, • forming a pharmaceutically acceptable salt.

10. The use of a compound according to any of claims 1 to 6 in the manufacture of a medicament for the treatment of anxiety and / or depression.