MXPA99005997A - Sulfonamide compounds having 5-ht receptor activity - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof in which A is methylene or -O-;B is methylene or -O-;g is 0, 1, 2, 3 or 4;U is an alkylene chain optionally substituted by one or more alkyl;Q represents a divalent group containing nitrogen atoms;and T represents an aryl or heteroaryl group, have utility in the treatment of central nervous system disorders, for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress and spasticity.

Description

SULFONAMIDE COMPOUNDS WITH ACTIVITY IN THE 5-HT RECEIVER The present invention relates to novel heteroarylsulfonamide compounds that have affinity for 5-HT? A and / or D2-like receptors (subtypes D2, D3, and D4), to processes for their preparation, to pharmaceutical compositions which contain them and their use in the treatment of disorders in the central nervous system, for example, depression, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette syndrome, sexual dysfunction, addiction to drugs, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behavior, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin-dependent diabetes mellitus, hyperglycemia , constipation, arrhythmia, disorders of the neuroendocrine system, stress and spasticity. The present invention provides the compounds of the formula I I including the enantiomers and pharmaceutically acceptable salts thereof, in which A is methylene or -O-; B is methylene or -O-; g is 0, 1, 2, 3 or 4; Ri represents an alkyl group containing from 1 to 3 carbon atoms, optionally substituted by one or more halo; an alkoxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; halo; 6,7-methylenedioxy optionally substituted in C by one or two alkyl groups containing from 1 to 3 carbon atoms; or an alkylthio group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; the substituents represented by Ri being the same or different when g is 2, 3 or 4; R2 is H, an alkyl group containing from 1 to 3 carbon atoms or an alkoxy group containing from 1 to 3 carbon atoms; R3 and R4f which are the same or different, are H or an alkyl group containing from 1 to 3 carbon atoms; U is an alkylene chain containing from 1 to 3 carbon atoms, optionally substituted by 1 or more alkyl groups each containing from 1 to 3 carbon atoms; Q represents a divalent group of the formula lia, Ilb, or lie Rs? • - N V - - llb wherein V is the group (CH2) n in which n is 0, 1, 2 or 3, optionally substituted by one or more alkyl groups each containing from 1 to 3 carbon atoms; V is an alkylene chain containing 2 to 6 carbon atoms, optionally substituted by one or more alkyl groups each containing from 1 to 3 carbon atoms; E is an alkylene chain containing 0 to 2 carbon atoms, and E 'is an alkylene chain containing 1 to 4 carbon atoms, as long as the total number of carbon atoms in E and E' represents 3 or 4; R5 and R6 which may be the same or different, are H or an alkyl group containing from 1 to 4 carbon atoms; and T represents phenyl, 1- or 2-naphthyl, 5-naft [2, ld] [1,2,3] oxadiazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2 - or 3-thienyl, 2- or 3-furyl, 2-, 3- or 7- benzo [b] furanyl, 2,3-dihydro-7-benzo [b] furanyl, 2-, 3- or -7-benzo [b] thiophenyl, 3-, 4- or 5-pyrazolyl, 1, 2, 3 -triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, -triazol-2-yl, 5-tetrazolyl, 2-, 3- or 4-quinolinyl, 2- or 4-quinazolinyl , 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4-, or 5-izothiazolyl or 2-, 4- or 5-thiazolyl each of which may be optionally substituted by one or more substituents selected from: a) halo, b) an alkyl group containing from 1 to 4 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group containing from 1 to 3 carbon atoms optionally substituted by one or more halo e) hydroxy, f) an acyloxy group containing from 1 to 3 carbon atoms, g) hydroxymethyl , h) cyano, i) an alkanoyl group containing from 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing from 2 to 6 carbon atoms, k) a carbamoyl group or carbamoylmethyl group each optionally substituted in N by one or two alkyl groups each containing from 1 to 3 carbon atoms, 1) a sulfamoyl or sulfamoylmethyl group each optionally substituted in N by one or two alkyl groups each containing from 1 to 3 carbon atoms, m) an amino group optionally substituted by one or two alkyl groups each containing from 1 to 5 carbon atoms carbon, n) 1-pyrrolidinyl or 1-piperidinyl, o) nitro or p) acetamido.

In the preferred compounds of the formula I, A is -0-.

In the preferred compounds of the formula I, B is -0-, In the most preferred compounds of the formula I, A and B are -0-. In the preferred compounds of the formula I, g, is 0 or 1. When g e_. 1, Ri is preferably halo or an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, for example, trifluoromethyl. In the most preferred compounds of formula I, g is 1 and Ri is halo. Most preferably, g is 1 and Ri is 7-chloro. In the preferred compounds of the formula I, R2 is H.

In the preferred compounds of the formula I, R3 and R4 are both H. In the preferred compounds of the formula I, U is methylene. In the preferred compounds of the formula I, Q is a group of the formula wherein E and E 'are both ethylene, V is methylene and Re is H. In the preferred compounds of the formula I, T represents phenyl, - or 2-naphthyl, 5-naft [2, ld] [1, 2, 3] oxodiazolyl, or 2- or 3-pyridyl, each of which may be optionally substituted by one or more substituents, which may be equal or different, selected from an alkyl group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, an alkoxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, nitro, acetamido, halo or an amino group optionally substituted by one or more alkyl groups each containing from 1 to 3 carbon atoms. In the most preferred compounds of the formula I, T represents phenyl, 1- or 2-naphthyl, 5-naft [2, ld] [1,2,3] oxodiazolyl, or 2- or 3-pyridyl, each of the which may be optionally substituted by one or more substituents, which may be the same or different, selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, nitro, acetamido, halo, or an amino group optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms. In the especially preferred compounds of the formula I, T is 1-naphthyl, 2-naphthyl, 5-naft [2, ld] [1,2,3] oxadiazolyl, 2-pyridyl, 3-pyridyl, phenyl, 4-methylphenyl , 2, 4, 6-trimethylphenyl, 2,3,4,5,6-pentamethylphenyl, 2-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 2,3,4-trifluorophenyl, 2 chlorophenyl, 4-chlorophenyl, 2,5-dibromophenyl, 4-iodophenyl, 2,5-dibromo-3,6-difluorophenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxy-2 , 3, 6-tri-ethylphenyl, 5-chloro-2-methoxyphenyl, 5-fluoro-2- methylphenyl, 4-trifluoromethoxyphenyl, 2,5-bis (2,2,2-trifluoroethoxy) phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 4-acetatophenyl, 2-nitrophenyl, 3-nitrophenyl , 4-nitrophenyl, 2-dinitrophenyl, 4-methyl-3,5-dinitrophenyl, 5- (diethylamino) -1-naphthyl, 2,3-dichlorophenyl or 3-chloro-4-fluorophenyl. In a group of the preferred compounds of the formula I, A is -0-, B is -0-, g is 1, Ri is preferably halo or an alkyl group containing from 1 to 3 carbon atoms optionally substituted by one or more halo, R2 is H, R3 and R4 both are H, U is methylene, Q is a group of the formula where E and E 'are both ethylene, V is methylene, R? is H and T is 1-naphthyl, 2-naphthyl, 5-naft [2, ld] [1, 2, 3] oxadiazolyl, 2-pyridyl, 3-pyridyl, phenyl, 4-methylphenyl, 2, 4, 6 trimethylphenyl, 2,3,4,5,6-pentamethylphenyl, 2-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2, 5-dibromophenyl, 4-iodophenyl, 2,5-dibromo-3,6-difluorophenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl, 5-chloro-2-methoxyphenyl, 5-fluoro-2-methylphenyl, 4-trifluoromethoxyphenyl, 2,5-bis (2,2,2-trifluoroethoxy) phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4- trifluoromethylphenyl, 4- acetamidophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 4-methyl-3, 5-dinitrophenyl, 5- (diethylamino) -1-naphthyl, 2,3-dichlorophenyl or 3-chloro-4-fluorophenyl. The compounds of the formula I can exist as salts with pharmaceutically acceptable acids. Examples of these salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates, [e.g. (+) - tartrates, (-) - tartrates, or mixtures thereof, including mixtures racemic agents], succinates, benzoates and salts with amino acids such as glutamic acid. The compounds of the formula I and their salts may exist in the form of solvates (for example hydrates). It will be understood that any group mentioned herein which contains a chain of 3 or more atoms means a group in which the chain can be linear or branched. For example, an alkyl group may comprise propyl, the cul includes n-propyl, and isopropyl, and butyl, which includes n-butyl, sec-butyl, isobutyl and tert-butyl. The term "halo" as used herein means fluorine, chlorine, bromine and iodine The compounds of the formula I and the intermediates in their preparation contain 1 or more chiral centers and exist in different optically active forms. compounds of the formula I and the intermediates in their preparation contain a chiral center, the compounds exist in two enantiomeric forms and the present invention includes the enantiomers and the mixtures of the enantiomers. The enantiomers can be resolved by methods known to those skilled in the art, for example by the formation of diastereoisomeric salts which can be separated, for example by crystallization; formation of diastereoisomeric derivatives or complexes that can be separated, for example by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer with a specific reagent of the enantiomer, for example, enzymatic esterification; or gas-liquid or liquid chromatography in a chiral medium, for example in a chiral support, for example, silica, with a bound chiral ligand, or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted to another chemical entity by one of the separation methods described above, another step is required to release the desired enantiomeric form. Otherwise, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents or by converting one enantiomer into another by asymmetric transformation.

When a compound of formula I contains more than a chiral center it can exist in diastereoisomeric forms. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization, and the individual enantiomers within each pair can be separated as already described. The present invention includes each of the diastereomers of the compounds of the formula I and mixtures thereof. Certain compounds of the formula I and their salts may exist in more than one crystal form and the present invention includes each crystalline form and mixtures thereof. Certain compounds of the formula I and their salts may also exist in the form of solvates, for example, hydrates, and the present invention includes each of the solvates and mixtures thereof. The specific compounds of the formula I are: N-. { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-sulfonamide; 4- [N- (7-chloro-l, 4-benzodioxan-2-ylmethyl) aminomethyl] -1- (2-pyridinesulfonyl) piperidine; N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-sulfonamide; N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-nitrobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-fluorobenzenesulfonamide; N-. { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 3, 4-dimethoxy-benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2,4-difluorobenzenesulfonamide; 4-acetamido-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; N { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methoxybenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidi1] methyl} - 2, β-difluorobenzenesulfonamide; N { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-chlorobenzenesulfonamide; N { [1- (7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] ethyl} -pyridine-2-sulfonamide N { [1- (7-bromo-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2,3-dichlorobenzenesulfonamide 2,3-dichloro-N. { [1- (7-trifluoromethyl-1,4-benzodioxan-2-yl ethyl) -4-piperidyl] methyl} -benzenesulfonamide N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2,4-dinitrobenzenesulfonamide N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2, 5-bis (2, 2, 2-trifluoroethoxy) benzenesulfonamide 2-chloro-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidi1] methyl} -4-trifluoromethylbenzenesulfonamide N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2, 4-dinitrobenzenesulfonamide; N { [1- (7-chloro-1, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2,5-bis (2,2,2-trifluoroethoxy) benzenesulfonamide; 2-chloro- N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidi1] methyl} -4-trifluoromethylbenzenesulfonamide; N { [1- (7-chloro-l, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-iodobenzenesulfonamide; N { [1- (7-chloro-l, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 4-methoxy-2,3,6-trimethylbenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -naft [2, 1-d] [1,2,3] oxadiazole-5-sulfonamide; N { [1- (7-chloro-l, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2,4,6-trimethyl-benzenesulfonamide; N { [1- (7-chloro-l, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2,3,4,5,6-pentamethylbenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -5- (diethylamino) naphthalene-1-sulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-trifluoromethylbenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 3-nitrobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-methyl-3,5-dinitrobenzenesulfonamide; 5-chloro-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methoxy-benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 3-trifluoromethylbenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-trifluoromethoxy-benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-naphthalenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 1-naphthalenesulfonamide; N { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2, 5-dimethoxybenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-methy1benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; N ([1- (7-chloro-1, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl]} - 5-fluoro-2-methyl-benzenesulfonamide; 2,5-dibromo-N { 1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl.} - benzenesulfonamide; N {. [1- (7-chloro-l, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl.}. 2-nitrobenzenesulfonamide; N { [1- (7-chloro-l, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2, 3, 4-trifluorobenzenesulfonamide; 2, 5-dibromo- N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 3,6-difluorobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2-fluorobenzenesulfonamide; 2-chloro-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; 3-chloro-N ([1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-fluorobenzenesulfonamide; 2,3-dichloro-N { [1 - (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl.} - benzenesulfonamide; 4-acetamido-N { [1- (7-chloro-l, 4-benzodioxan- 2-ylmethyl) -4-piperidyl] ethyl.}. -benzenesulfonamide; N {. [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl}. fluorobenzenesulfonamide; N {. [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2-chlorobenzenesulfonamide; N {. [1- (7-chloro- 1, 4-benzodioxan-2-ylmethyl) -piperidyl] methyl} -2,4-difluorobenzenesulfonamide; 3-chloro-N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl.} -4-fluorobenzenesulfonamide; 2,3-dichloro-N- {- [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} .-benzenesulfonamide; And pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates or mixtures of enantiomers. Specific enantiomeric forms of the compounds of formula I include: (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-sulfonamide; (S) -4- [N- (7-chloro-l, 4-benzodioxan-2-ylmethyl) aminomethyl] -1- (2-pyridinesulfonyl) -piperidine); (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-sulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-nitrobenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-fluorobenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -3,4-dimethoxybenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2, 4-difluoro-benzenesulfonamide; (S) -4-acetamido-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] ethyl} -benzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methoxybenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,6-difluorobenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-chlorobenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-pyridine-2-sulfonamide (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2, 3-dichlorobenzenesulfonamide (S) -2, 3-dichloro-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2, 4-dinitrobenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2,5-bis (2,2,2-trifluoroethoxy) -benzenesulfonamide; (S) -2-chloro-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-trifluoromethylbenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-iodobenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methoxy-2,3,6-trimethylbenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -naft [2,1-] [1,2,3] oxadiazole-5-sulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2,4,6-trimethylbenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2, 3,4,5, 6-pentamethylbenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -5- (diethylamino) naphthalene-1-sulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-trifluoromethylbenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -3-nitrobenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methyl-3, 5-dinitrobenzenesulfonamide; (S) -5-chloro-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methoxybenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -3-trifluoromethylbenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-trifluoromethoxybenzenesulfonamide; (S) -N-[[1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-naphthalenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -l-naphthalenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,5-dimethoxybenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methylbenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} benzenesulfonamide (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -5-fluoro-2-methylbenzenesulfonamide; (S) -2, 5-dibromo-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-nitrobenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2, 3, 4-trifluorobenzenesulfonamide; (S) -2, 5-dibromo-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 3,6-difluorobenzenesulfonamide; (S) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-fluorobenzenesulfonamide; (S) -2-chloro-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; (S) -3-chloro-N-. { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-fluoro-benzenesulfonamide; (S) -2, 3-dichloro-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; (S) -4-acetamido-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; (S) -N-. { [1- (7-bromo-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-fluorobenzenesulfonamide; (S) -N-. { [1- (7-bromo-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-chlorobenzenesulfonamide; (S) -N-. { [1- (7-bromo-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,4-difluorobenzenesulfonamide; (S) -3-chloro-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-fluorobenzenesulfonami a; (S) -2, 3-dichloro-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] ethyl} -benzenesulfonamide; and the pharmaceutically acceptable salts thereof. A particularly preferred compound is N-. { [1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridin-2,3-dichlorobenzenesulfonamide including the enantiomers and the pharmaceutically acceptable salts thereof. Those skilled in the art will appreciate that the term '1,4-benzodioxan' as used in the above lists and through this specification is synonymous with the term * 2, 3-dihydro-l, 4-benzodioxin. "The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of the formula I or a salt thereof together with a pharmaceutically acceptable diluent or carrier. is used hereafter, the term "active compound" defines a compound of the formula I or a salt thereof. In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. In this manner, the therapeutic compositions of the present invention can take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Suitable pharmaceutically acceptable carriers for use in these compositions are well known in the art of pharmacy. The compositions of the invention may contain 0.01-99% by weight of the active compound. The compositions of the invention are generally prepared in unit dosage forms. Preferably, the unit dosage of the active ingredient is 1-500 mg. The excipients used in the preparation of these compositions are the excipients known in the pharmaceutical art. The compositions for oral administration are the preferred compositions of the invention, and these are the known dosage forms for this administration, for example, tablets, capsules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are the excipients known in the pharmaceutical art. The tablets can be prepared by mixing the active compound with an inert diluent such as calcium phosphate, in the presence of disintegrating agents, for example starch, and lubricating agents, for example. example magnesium stearate, and tabletting the mixture by the known methods. The tablets can be formulated in a manner known to those skilled in the art in order to obtain a sustained release of the compounds of the present invention. These tablets may, if desired, be provided with enteric coatings by the known methods, for example by the use of cellulose acetate phthalate. In the same way, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients can be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets and capsules can conveniently each contain from 1 to 500 mg of the active compound. Other compositions for oral administration, include, for example, aqueous suspensions containing the active compound in an aqueous medium, in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example peanut oil. The active compound can be formulated in granules with or without additional excipients. The granules can be ingested directly by the patient or can be added to a suitable liquid carrier (for example water) before ingestion. The granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium. Compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases. The pharmaceutical compositions can also be administered parenterally (for example, by subcutaneous, intramuscular, intradermal and / or intravenous routes [such as by injection and / or infusion]) in the known pharmaceutical dosage forms for parenteral administration (by exemplary sterile suspensions in aqueous and / or oily medium and / or sterile solutions in suitable solvents, preferably isotonic with the blood of the proposed patient). The parenteral dosage forms can be sterilized (for example by microfiltration and / or using suitable sterilizing agents [such as ethylene oxide]). Optionally, one or more of the following pharmaceutically acceptable adjuvants, suitable for parenteral administration, may be added to the parenteral dosage form: local anesthetics, preservatives, buffering agents and / or mixtures thereof. Parenteral dosage forms may be stored in suitable sterile sealed containers (eg, ampoules and / or small bottles) until use. To improve stability during storage, the parenteral dosage form can be frozen after filling the container and the fluid (eg, water) can be removed under reduced pressure. The pharmaceutical compositions can be administered by nasal route in the pharmaceutical forms known for such administration (for example, sprays, aerosols, solutions and / or nebulized powders). It is possible to use metered dose systems known to those skilled in the art (for example, aerosols and / or inhalers). The pharmaceutical compositions can be administered to the buccal cavity (for example sublingually) in known pharmaceutical forms for such administration (for example, slow-dissolving tablets, chewable gums, troches, lozenges, gels, pastes, mouth rinses, enjugues and / or powders). The compositions for topical administration may consist of a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are kept in contact with the skin to deliver the compounds transdermally. A suitable transdermal composition can be prepared by mixing the pharmaceutically active compound with a topical carrier, such as a mineral oil, petrolatum and / or a wax, for example paraffin wax or beeswax, together with a potential transdermal accelerator, such as dimethylsulfoxide or propylene glycol . Otherwise, the active compounds may be dispersed in a pharmaceutically acceptable cream or ointment base. The amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time during which it is proposed that the topical formulation be on the skin. The compounds of the present invention can also be administered by continuous infusion from an external source, for example by intravenous infusion, or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound that is to be continuously released, for example, by osmosis and implants that can be: (a) liquids such as a suspension or solution in a pharmaceutically acceptable oil of the compound to be subjected to infusion, for example in the form of a derivative very sparingly soluble in water, such as a dodecanoate salt or ester, or (b) solid in the form of an implanted support, for example of synthetic resin or waxy material, so that the compound be submitted to infusion. The support can be a single body containing all the compound or a series of several bodies each containing part of the compound to be supplied. The amount of the active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a prolonged period. In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by energy grinding of a fluid. In the compositions of the present invention the active compound can, if desired, be associated with other pharmacologically active, compatible ingredients. The present invention also consists in the use of a compound of the formula I as a medicament. The compounds of the formula I or the salts thereof, or the pharmaceutical compositions containing a therapeutically effective amount of a compound of the formula I, or a salt thereof can be used to treat depression, anxiety, psychosis (eg schizophrenia) ), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, Obsessive-compulsive behavior, panic attacks, social phobias, eating disorders, anorexia, cardiovascular and cerebrovascular disorders, diabetes mellitus not dependent on insulin, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress and spasticity in humans. Although the precise amount of the active compound that is administered in such treatment will depend on various factors, for example the age of the patient, the severity of the condition and the previous medical history and will always be within the discretion of the physician administering it, the amount of the active compound that is administered via is in the range of 1 to 1000 mg, preferably 5 to 500 mg administered in a single dose or divided dose, one or more times during the day. Another aspect of the present invention provides the use of a compound of formula I in the manufacture of a medicament for treating depression, anxiety, psychosis (eg schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behavior, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-dependent diabetes mellitus of insulin, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress and spasticity in humans. The present invention also provides a method of treatment of depression, anxiety, psychosis (eg schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette syndrome, sexual dysfunction, drug addiction, drug abuse, disorders. cognitive, Alzheimer's disease, senile dementia, obsessive-compulsive behavior, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system , stress and spasticity in humans, which consists of administering a therapeutically effective amount of a compound of formula I to a patient in need thereof. The processes for the preparation of the compounds of the formula I will now be described. These processes form another aspect of the present invention. The processes of preference are carried out at atmospheric pressure, at a temperature in the range of 0-200 ° C, preferably in the range of 20-150 ° C. Substituents are as defined for formula I above unless otherwise indicated.

The compounds of the formula I, in which Q is a group of the formula lia in which R5 is H and V is (CH2) n where n is 1, 2 or 3, can be prepared by the reaction of a compound of formula III wherein m is 0, 1 or 2, with a compound of formula IV wherein Z is a leaving group, for example, toluene-4-sulfonyloxy, optionally in the presence of a suitable solvent, for example acetonitrile, optionally in the presence of a base, for example potassium carbonate and optionally in the presence of a catalyst, for example potassium iodide. The compounds of the formula III can be prepared by the reaction of a compound of the formula IV. > = N-CH2 (CH2) m- < ^ wherein D is a protecting group, for example benzylidene, with a sulfonylating agent of the formula X-S02-T in which X is a leaving group, for example, halo or hydroxy in the presence of a base, for example triethylamine, in a suitable solvent, for example dichloromethane, followed by elimination of the group procector, for example by acid-catalyzed hydrolysis. The compounds of the formula IV in which Z is toluene-4-sulfonyloxy can be prepared by the reaction of a compound of the formula VI. with toluene-4-sulfonyl chloride, optionally in the presence of a base, for example, pyridine. The compounds of the formula VI in which A and B both are -O-, U is methylene, and R2, R3 and 4 are all H, can be prepared by cyclization of a compound of the formula VII. wherein R is H or an alkyl group containing 1 to 4 carbon atoms, using a base, for example carbonate of potassium The compounds of the formula VII can be prepared by oxidation of a compound of the formula VIII. wherein R is H or an alkyl group containing from 1 to 4 carbon atoms, with a peroxy acid, for example 3-chloroperoxy benzoic acid. The compounds of the formula VIII can be prepared by alkylation of a compound of the formula IX. wherein R is H or an alkyl group containing 1 to 4 carbon atoms, with a compound of formula X CH2-CH-CH2Z / O wherein Z is a leaving group, for example chloro or toluene-4-sulfonyloxy, in a suitable solvent, for example dimethylformamide, in the presence of a base, for example potassium carbonate. When a form is used Suitable enantiomerically pure of a compound of the formula X, for example (R) -glycidyl 4-toluenesulfonate, the (S) -individual enantiomer of a compound of the formula VI can be prepared. The compounds of the formula I in which U is methylene and Q is a group of the formula lia in which R5 is H and V is (CH2) n where n is 1, 2 or 3, can be prepared by reaction of a compound of formula XI. with a compound of formula III, followed by reduction of the imine intermediate with a suitable reducing agent, for example, sodium borohydride. The compounds of the formula XI can be prepared by oxidation of a compound of the formula VI in which U is methylene, with a suitable oxidizing agent, for example pyridinium chlorochromate. The compounds of the formula I in which Q is a group of the formula IIb can be prepared by reaction of a compound of the formula XII wherein D 'is H, with a compound of the formula IV in which Z is a leaving group, for example, toluene-4-sulfonyloxy, optionally in the presence of a base, for example potassium carbonate, optionally in the presence of a suitable solvent, for example acetonyl, and optionally in the presence of a catalyst, for example potassium iodide. The compounds of the formula XII in which D 'is H can be prepared by deprotection of a compound of the formula XII in which D' is a protective group, for example tert-butoxycarbonyl, for example by hydrolysis in the presence of an acid , for example trifluoroacetic acid. The compounds of the formula XII in which D 'is a protecting group can be prepared by reaction of a compound of the formula XIII. wherein D 'is a protective group, tert-butoxycarbonyl, with a compound of the formula X-S02-T in which X is a leaving group, for example halo or hydroxy, in the presence of a base, for example triethylamine, in a suitable solvent such as dichloromethane.

The compounds of the formula I in which Q is a group of the formula lie in which V is (CH 2) n wherein n is 1, 2 or 3, can be prepared by reaction of a compound of the formula XIV. wherein D 'is H, and m is 0, 1 or 2, with a compound of the formula IV in which Z is a leaving group, for example, toluene-4-sulfonyloxy, optionally in the presence of a base, for example potassium carbonate, optionally in the presence of a suitable solvent, for example acetonitrile, and optionally in the presence of a catalyst, for example potassium iodide. The compounds of the formula IV in which D 'is H can be prepared by deprotection of a compound of the formula IV in which D' is a protective group, for example tert-butoxycarbonyl, for example by hydrolysis in the presence of an acid , for example trifluoroacetic acid. Compounds of the formula XIV in which D 'is a protecting group can be prepared by reaction of a compound of the formula XV XV wherein D 'is a protecting group, tert-butoxycarbonyl, and m is 0, 1 or 2, with a compound of the formula X-S02-T in which X is a leaving group, for example halo or hydroxy, in the presence of a base, for example triethylamine, in a suitable solvent such as dichloromethane. The compounds of the formula I in which Q is a group of the formula Ie can also be prepared by reaction of a compound of the formula XVI. with a sulfonylating agent of the formula X-S02-T in which X is a leaving group, for example halo or hydroxy, in the presence of a base, for example triethylamine, in a suitable solvent such as dichloromethane. The compounds of the formula XVI in which Rβ is H can be prepared from the compounds of the formula XVII wherein D is a protecting group, for example 5-bromo-2-hydroxybenzylidene, by hydrolysis catalyzed by acid or base. The compounds of the formula XVII can be prepared by reaction of a compound of the formula XVIII.

XVIII wherein D is a protecting group, for example 5-bromohydroxybenzylidene, with a compound of formula IV, optionally in the presence of a base such as triethylamine. The compounds of formula XVIII can be prepared by reaction of a compound of formula XIX. with a protective reagent, for example, 5-bromo-2-hydroxybenzaldehyde. The compounds of the formula I in which R5 is an alkyl group can also be prepared by alkylation of a compound of the formula I in which R5 is H with, for example, formaldehyde and formic acid, or an aldehyde or a reducing agent as sodium cyanoborohydride. The ability of the compounds of formula I to interacting with the 5-hydroxytryptamine (5-HT) receptors have been demonstrated by the following test that determines the ability of the compounds to inhibit the binding of the tritiated ligand to 5-HT receptors in vitro and in particular to the receptors of 5-HTIA. The hippocampal tissue of the brains of male Charles River CD rats weighing 150-250 g were homogenized in ice-cold tris-HCl buffer (pH 7.7) causing it to be measured at 25 ° C, 1:40 p / v) and centrifuged at 30,000 g at 4 ° C for 10 minutes. The package was rehomogenized in the same buffer, incubated at 37 ° C for 10 minutes and centrifuged at 30,000 g at 4 ° C for 10 minutes. The final package was resuspended in 50 mM tris-HCl buffer (pH 7.7) with a content of 4 mM CaCl 2, 0.1% L-ascorbic acid and 10 μM pargyline hydrochloride. (equivalent to 6.25 mg wet tissue weight / ml) and used immediately in the binding assay. The aliquots (400 μl, equivalent to 2.5 mg of tissue / tube wet weight) of this suspension were added to tubes containing the ligand (50 μl, 2 nM) and distilled water (50 μl, total binding) or 5-HT (50 μl). μl; 10 μM; non-specific binding) or the test compound (50 μl; at a single concentration of 10 or 10 concentrations in the range from 10 -10 μM). The ligand was [3H] 8-hydroxy-2- (dipropylamino) tetralin ([H] 8-OH-DPAT) and the mixture was incubated at 25 ° C for 30 minutes before the incubation was finished by rapid filtration. The filters were washed with ice-cold tris-HCl buffer and dried. The filters were introduced in small flasks, the scintillation fluid was added and the reactivity was determined by scintillation in liquid. The percent displacement of the specific binding of the tritiated ligand was calculated for the single concentration (10 ~ Ti) of the test compound. The displacement curves were then produced for these compounds that shifted = 50% of the specific binding of the tritiated ligand to 10 M using a range of compound concentrations. The concentration that gave 50% inhibition of the specific binding (IC50) was obtained from the curve. The inhibition coefficient Ki was then calculated using the formula: IC50 Ki = 1+ ([ligand] / KD) in which [ligand] is the concentration of the tritiated ligand that was used and KD is the equilibrium dissociation constant for the ligand. The ability of the compounds of formula I to interacting with dopamine receptors has been demonstrated by the following test that determines the ability of the compounds to inhibit the binding of the triacylated ligand to the dopamine receptors in vitro and, in particular, to the dopamine receptors similar to D2. The striatal tissue from the brains of male Charles River CD male rats weighing 140-250 g were homogenized in 50 mM tris-HCl buffer (pH 7.7 measured at 25 °) and centrifuged at 40,000 g for 10 minutes. The package was resuspended in tris salts buffer (tris buffer -HCl 50mM) with a content of 120 mM NaCl, 5 mM, KCl, 2 mM CaCl2 and 1 mM MgCl2 with the addition of 6 mM ascorbic acid; pH 7.7 measured at 25 ° C) and again centrifuged at 40,000 g for 10 minutes. The final package was stored at -80 ° C. Before each test, the package was resuspended in tris salts buffer (equivalent to 2 mg wet tissue weight / ml). Aliquots (720 μl, equivalent to 1.44 mg of tissue / tube wet weight) of this suspension were then added to tubes containing the ligand (40 μl, 1 nM and tris salts buffer (40 μl, total binding) or spiroperidol ( 40 μl, 10 nM, non-specific binding) or the test compound 40 μl, at a single 10"concentration, or 6 concentrations in the range from 10" n-10 ~ 4M). The ligand was tritiated with (S) -sulpiride and the mixture was incubated at 4 ° C for 40 minutes before the incubation was terminated by rapid filtration.

The filters were washed with ice-cold tris-HCl buffer and dried. The filters were introduced into small flasks, the fluid was added for scintillation and left for approximately 20 minutes before being counted by scintillation spectrophotometry. The percent displacement of the specific binding of the tritiated ligand was calculated for the single concentration (10 ~ M) of the test compound. The displacement curves were then produced over a range of concentrations for those compounds that shifted = 50% of the specific binding of the tritiated ligand to 10 ~ ^ _ using a range of compound concentrations. The concentration that gave 50% inhibition of the specific binding (IC50) was obtained from the curve. The inhibition coefficient Ki was then calculated using the formula: IC50 Ki = l + ([ligand] / KD) in which [ligand] is the concentration of the tritiated ligand used and KD is the equilibrium dissociation constant for the ligand. Ki values obtained in the previous tests for binding to 5-HT? A and similar to D2 for each of the Final products of the examples are given below in Table 1 below. TABLE 1 TABLE 1 (continued) The percent figures in Table 1 are for displacement percent to 10 ~ l. The advantageous compounds of the present invention have a Ki of less than 100 nM for 5-HT? A or a binding affinity for 5-HT1A greater than 90% at 10 ~ M and a Ki less than 100 nM for D2-like receptors or a binding affinity for D2-like receptors greater than 90% at 10"^ .. The invention is illustrated by the following examples which are given by way of example only: The final products of the examples were characterized by one or more of the following procedures: gas-liquid chromatography, high-resolution liquid chromatography, elemental analysis, nuclear magnetic resonance spectroscopy and infrared spectroscopy.

Example 1 Pyridine (1.85 ml) was added to a stirring solution of 4- (aminomethyl) -1- (tert-butoxycarbonyl) piperidine (4.46 g) and pyridine-2-sulfonyl chloride (3.7 g) in dichloromethane (110 ml). ) at -10 ° C under a nitrogen atmosphere. The reaction was then heated to room temperature for 16 hours and drained in water (300 ml). The organic layer was separated and further washed with hydrochloric acid (1M, 2 x 200 ml), saturated aqueous sodium bicarbonate solution (200 ml) and brine (200 ml). AfterAfter drying over anhydrous magnesium sulfate, the solution was evaporated to dryness to produce N-. { [1- (tert-butoxycarbonyl) -4-piperidyl] methyl} pyridine-2-sulfonamide; (3.5 g) as an oil. Trifluoroacetic acid (12.5 ml) was added to a solution of the product from the previous reaction (2.0 g) in dichloromethane (12.5 ml) and the mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to produce N- (4-piperidylmethyl) pyridine-2-sulfonamide trifluoroacetate; raw. A stirring mixture of this material, 4-toluenesulfonate of (R) -7-chloro-l, 4-benzodioxan-2-ylmethyl (1.77 g), prepared as described in WO97 / 03071), potassium carbonate (7.6 g) ) and potassium iodide (10 mg) in acetonitrile (150 ml) was heated to reflux, under nitrogen, for 60 hours. The reaction was cooled, filtered and concentrated under reduced pressure to yield a viscous brown oil (5.8 g) which was purified by flash chromatography on silica gel eluting with pure ethyl acetate. The appropriate fractions were combined and the solvent removed under reduced pressure to yield a colorless oil (0.6 g). Hydrogen chloride gas was bubbled through a solution of the oil in a mixture of dichloromethane (10 ml) and diethyl ether (20 ml), until pH 1 was obtained. The solvent was removed under pressure reduced and the resulting hygroscopic yellow gum was immediately dried at 80 ° C under reduced pressure to produce (S) - (-) - N- monohydrochloride. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-sulfonamide (0.6 hydrate as a cream solid foam (0.5 g), melting point 143 ° C (dec), [a] D23 -51.6 ° (c = 1.03, weOH).

Example 2 Triethylamine (6.3 ml) was added to a cloudy solution of N-benzylidene-4-piperidylmethylamine (4.05 g) and pyridine-2-sulfonyl chloride (4.0 g) in dichloromethane (100 ml) and the resulting light yellow solution was stirred for 14 hours. Removal of the solvent under reduced pressure yielded a yellow solid which, with the addition of diethyl ether (100 ml), was partially dissolved. The insoluble white solid (triethylamine hydrochloride) was separated by filtration. Evaporation of the filtrate afforded a flocculent yellow solid which was recrystallized from ethanol to give 4- [N- (benzylidene) to inomethyl] -1- (2-pyridinesulfonyl) piperidine as a white crystalline solid (4.7 g). A solution of the above reaction product (4.5 g) and potassium acid sulfonate (8.76 g) in water (110 ml) was stirred for 20 hours. The resulting reaction was washed with diethyl ether (3 x 100 ml) basified to pH 14 using aqueous sodium hydroxide solution (5 M) and extracted with diethyl ether (4 x 100 ml). These last ether layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness to give crude 4- (aminomethyl) -1- (2-pyridinesulfonyl) piperidine as a yellow oil (2.7 g). A mixture of this stirring material, (R) -7-chloro-l, 4-benzodioxan-2-ylmethyl 4-toluenesulfonate, potassium carbonate (2.73 g) and potassium iodide (10 mg) in acetonitrile (125 ml) ) was heated to reflux, under nitrogen, for 20 hours. The reaction was cooled and stirred at room temperature for another 24 hours. The excess potassium carbonate was removed by filtration and the filtrate concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 19: 1 mixture of ethyl acetate and methanol gave a yellow oil (2.1 g). Trituration with diethyl ether (50 ml) yielded 0.8 hydrate of (S) - (-) -4- [N- (7-chloro-l, 4-benzodioxan-2-ylmethyl) aminomethyl] -1- (2-pyridine sulfonyl) ) piperidine as a whitish solid (1.68 g); melting point 71-74 ° C [a] D22 -40.9 ° (c = 0.33, MeOH).

Example 3 Triethylamine (2.4 ml) was added to an orange solution of (S) -4- (aminomethyl) -1-7-chloro-l, 4-benzodioxan-2-ylmethyl) piperidine (1.67 g), prepared as HE described in WO97 / 03071,) and pyridin-3-sulfonyl chloride (2.0 g) in dichloromethane (60 ml) under nitrogen, and the solution was stirred for 3 hours. The reaction was concentrated under reduced pressure then purified by flash chromatography on silica gel eluting with a 9: 1 mixture of dichloromethane and methanol to yield an orange oil (2.0 g). Trituration with hot diethyl ether yielded 0.8 (S) - (-) -N- hydrate. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-sulfonamide as a pale pink solid (1.2 g); melting point 127-128 ° C, [a] D22 -38.5 ° (c = 1.02, MeOH).

Example 4 Triethylamine (0.62 ml) was added to a cloudy solution of (S) -4- (aminomethyl) -1-7-chloro-l, 4-benzodioxan-2-ylmethyl) piperidine (0.44 g) and 4-chloro Nitrobenzenesulfonyl (0.65 g) in dichloromethane (22 ml) under nitrogen. The resulting solution was stirred for 3 hours then left to stand for 14 hours. The reaction was diluted with dichloromethane (100 ml) washed with water (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield an orange oil (0.95 g). Purification by flash chromatography on silica gel eluting with a 19: 1 mixture of dichloromethane and methane produced (S) - (-) - N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4- piperidyl] -methyl} -4-nitrobenzenesulfonamide as a light brown solid (0.5 g); melting point 147-148 ° C, [a] D22"5 -23.5 ° (c = 1.02, CH2C12).

Example 5 Triethylamine (0.62 ml) was added to a solution of (S) -4- (aminomethyl) -1-7-chloro-l, 4-benzodioxan-2-ylmethyl) piperidine (0.44 g) and 4-fluorobenzenesulfonyl chloride (0.65 g) in dichloromethane (22 ml) under nitrogen and stirred for 3 hours. The reaction was allowed to stand for 14 hours, then diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 19: 1 mixture of dichloromethane and methanol yielded a yellow oil which upon grinding with diethyl ether yielded (S) - (-) - N-. { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-fluorobenzenesulfonamide as a yellow solid (0.4 g); melting point 127-129 ° C, [a] D22 -41.3 ° (c = 0.72, MeOH).

Example 6 Triethylamine (0.62 ml) was added to a solution of (S) -4- (aminomethyl) -1-7-chloro-l, 4-benzodioxan-2-ylmethyl) piperidine (0.44 g) and chloride 3, 4 -dimetoxybenzene sulfonyl (0.65 g) in dichloromethane (22 ml) under nitrogen. The reaction was stirred for 3 hours then allowed to stand for 14 hours before the addition of dichloromethane (100 ml). The solution was then washed with water (2 x 30 ml) and brine (2 x 50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to produce a brown oil. Purification by flash chromatography on silica gel eluting with a 40: 1 mixture of dichloromethane and methanol yielded a colorless oil (0.48 g) which crystallized on standing. Trituration with hot diethyl ether yielded (S) - (-) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -3,4-dimethoxybenzenesulfonamide as a white solid (0.3 g); melting point 99-101 ° C, [a] D23 -41.0 ° (c = 0.52, MeOH).

Example 7 Triethylamine (0.62 ml) was added to a solution of (S) -4- (aminomethyl) -1-7-chloro-l, 4-benzodioxan-2-ylmethyl) piperidine (0.44 g), and chloride of 2, 4-difluorobenzenesulfonyl (0.62 g) in dichloromethane (22 ml) under nitrogen. The reaction was stirred for 3 hours, then allowed to stand for 14 hours. The dichloromethane (100 ml) was added and the reaction was washed with water (2 x 30 ml) and brine (2 x 50 ml). The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to produce a brown oil. Purification by flash chromatography on silica gel eluting with a 40: 1 mixture of dichloromethane and methanol yielded a yellow oil (0.30 g). Trituration with diethyl ether produced (S) - (-) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,4-difluorobenzenesulfonamide as a beige solid (0.14 g); melting point 119-121 ° C, [a] D23 -41.4 ° (c = 0.16, MeOH).

Example 8 Triethylamine (0.62 ml) was added to a cloudy solution of (S) -4- (aminomethyl) -1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) piperidine (0.44 g), and 4-Acetamidobenzene sulfonyl (0.65 g) in dichloromethane (62 ml) under nitrogen. The resulting solution was stirred for 20 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml) and brine (100 ml). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to produce an orange oil. Purification by flash chromatography on silica gel eluting with a 15: 1 mixture of dichloromethane and methanol yielded an orange gum. Trituration with diethyl ether (20 ml) yielded (S) - (-) -4-acetamido-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} benzenesulfonamide as a pale orange solid (0.34 g); melting point 173- 176 ° C, [a] D22 -39. 3 ° (c = 0. 37, MeOH) Example 9 Triethylamine (0.62 ml) was added to a solution of (S) -4- (aminomethyl) -1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) piperidine (0.44 g), and 4-methoxybenzenesulfonyl (0.61 g) in dichloromethane (22 ml) under nitrogen. The reaction was stirred for 20 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml) and brine (100 ml). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to produce an orange oil. Purification by flash chromatography on silica gel eluting with a 20: 1 mixture of dichloromethane and methanol yielded a colorless gum. Trituration with diethyl ether (20 ml) yielded (S) - (-) - N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methoxybenzenesulfonamide as a white solid (0.20 g); melting point 130-131 ° C, [a] D22-5 -28.9 ° (c = 0.51, CH2C12) EXAMPLE 10 Triethylamine (0.62 ml) was added to a solution of (S) -4- (aminomethyl) -1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) piperidine (0.44 g), and sodium chloride. , 6-difluorobenzenesulfonyl (0.62 g) in dichloromethane (22 ml) under nitrogen, and It was stirred for 20 hours. The reaction was diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to produce an orange oil. Purification by flash chromatography on silica gel eluting with a 20: 1 mixture of dichloromethane and methanol yielded an orange gum. Trituration with petroleum ether (bp 40-60 ° C) yielded (S) - (-) -N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,6-difluorobenzenesulfonamide as a whitish solid (0.29 g); melting point 122-124 ° C, [a] D22-5 -22.1 ° (c = 1.0, CH2C12).

EXAMPLE 11 Triethylamine (0.62 ml) was added to a solution of (S) -4- (aminomethyl) -1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) piperidine (0.44 g), and sodium chloride. -chlorobenzene sulfonyl (0.62 g) in dichloromethane (22 ml), under nitrogen, and was stirred for 20 hours. The reaction was diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 20: 1 mixture of dichloromethane and methanol yielded (S) - (-) - N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4- chlorobenzenesulfonamide as a white solid (0.30 g); melting point 152-154 ° C, [] D22'5 -23.8 ° (c = 0.97, CH2C12).

Example 12 Trifluoroacetic acid (10 ml) was added to a solution of N-. { [1-tert-butoxycarbonyl) -4-piperidyl} methyl } pyridine-2-sulfonamide [sic] (1.45 g) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to produce N- (4-piperidylmethyl) pyrindin-2-sulfonamide trifluoroacetate. A mixture of this material, 4-toluenesulfonate of (R) -7-trifluoromethyl-l, 4-benzodioxan-2-ylmethyl (1.0 g), potassium carbonate (3.6 g) and potassium iodide (10 mg) in acetonitrile (130 ml) was heated to reflux, with stirring, under nitrogen for 24 hours. The reaction was cooled, filtered and concentrated under reduced pressure to produce a viscous brown oil. Purification was carried out by flash chromatography on silica gel eluting with a 95: 5 mixture of dichloromethane and methanol. Suitable fractions were combined and the solvent removed under reduced pressure to yield a yellow oil (1.0 g) containing some impurities. The oil was dissolved in ethyl acetate (100 ml) and the solution was extracted with dilute hydrochloric acid (5 M).; 3 x 300 ml). The aqueous phase was basified to pH 14 by adding a dilute aqueous solution of sodium hydroxide (5 M) and the product was extracted into ethyl acetate (3 x 100 ml). The organic extracts were combined, dried over anhydrous magnesium sulfate and evaporated to dryness to yield a clear oil which was triturated with diethyl ether (10 ml) to yield (S) - (-) - N-. { [1- (7-trifluoromethyl-1, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-sulfonamide (0.22 g); melting point 138-140 ° C, [a] D21 -44.7 ° (c = 0.438, MeOH).

Example 13 A mixture of 4-toluenesulfonate of (R) -7-bromo-1,4-benzodioxan-2-ylmethyl (6.5 g, prepared as described in WO97 / 03071), N-benzylidene-4-piperidylmethylamine (3.0 g ), potassium carbonate (4.1 g), and potassium iodide (10 mg) in acetonitrile (200 ml) was heated to reflux, with stirring, under nitrogen for 24 hours. The reaction was cooled, filtered and concentrated under reduced pressure to yield (S) -N-benzylidene-1- [1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methylamine (6.3 g ) as a viscous orange-brown oil. The crude product from the above reaction (6.3 g) was stirred in aqueous potassium acid sulfate solution (0.6 M, 125 ml) for 3 hours at room temperature. The solution was washed with ether (3 x 200 ml), basified using aqueous sodium hydroxide solution (5 M) then extracted with ether (3 x 200 ml). The combined ether layers were washed with water (200 ml), dried over magnesium sulfate and evaporated to dryness to yield (S) -4- (aminomethyl) -1- (7-bromo-1,4-benzodioxan-2-yl). -ethyl) piperidine (4.0 g) as a brown oil. Triethylamine (0.63 ml) was added to a solution of (S) -4- (aminomethyl) -1- (7-bromo-1,4-benzodioxan-2-ylmethyl) piperidine (0.5 g), and 2.3 chloride Dichlorbenzenesulfonyl (0.74 g) in dichloromethane (15 ml) and was stirred under nitrogen for 24 hours. The reaction was diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 9: 1 mixture of dichloromethane and methanol yielded (S) - (-) - N-. { [1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,3-dichlorobenzenesulfonamide as a cream solid (0.8 g); melting point 93-95 ° C, [a] D22 -37.1 ° (c = 0.93, MeOH).

EXAMPLE 14 Hexamethylenetetramine (47.5 g) was added in portions to a stirring solution of 4-trifluoromethylphenol (50 g) in trifluoroacetic acid (680 ml) and the mixture was heated to reflux temperature for 24 hours. After cooling, water (355 ml) was added followed by aqueous sulfuric acid (50% v / v), 190 ml) and the reaction was stirred at room temperature for 4 hours. The aqueous acid phase was extracted with diethyl ether (3 x 500 ml). The combined organic extracts were washed with hydrochloric acid (5 M, 3 x 500 ml) then with water (500 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica eluting with a 4: 1 mixture of petroleum ether (bp 40-60 ° C) and ethyl acetate. Suitable fractions were combined and the solvent removed under reduced pressure to give 5-trifluoromethyl-2-hydroxybenzaldehyde (25 g) as a light pink solid. A mixture of (R) -glycidyl 4-toluenesulfonate (24 g), 5-trifluoromethyl-2-hydroxybenzaldehyde (20 g) and potassium carbonate (16 g) in dimethylformamide (550 ml) was stirred and heated to 60 ° C. for 72 hours. After cooling, brine (1.5 1) was added and the resulting mixture was extracted with ether (4 x 500 ml). The combined ether extracts were washed with brine (2 x 500 ml), then with water (500 ml) and dried over magnesium sulfate. The residue was purified by flash column chromatography on silica eluting with a 3: 1 mixture of petroleum ether (bp 40-60 ° C) and ethyl acetate to give (R) -5-trifluoromethyl-2- (2 , 3- epoxypropoxy) benzaldehyde (18.7 g) as a yellow oil. A mixture of the above reaction product (18.7 g) and 3-chloroperoxybenzoic acid (57-86%, 48.7 g) in dichloromethane (1L) was heated to reflux for 24 hours, then allowed to cool to room temperature. The mixture was washed with aqueous sodium bicarbonate, saturated (3 x 700 ml), water (2 x 700 ml) and brine (700 ml), then dried over magnesium sulfate. The solvent was evaporated to format (R) -5-trifluoromethyl-2- (2,3-epoxypropoxy) phenyl (16.7 g). A mixture of the product of the above reaction (16.7 g), tetrahydrofuran (220 ml) and a saturated aqueous solution of potassium carbonate (175 ml) was stirred vigorously at room temperature for 24 hours. Water (500 ml) was added and the organic phase was eliminated. The aqueous phase was extracted with ethyl acetate (3 x 300 ml) and the combined organic extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash column chromatography on silica eluting with a 4: 1 gradient to 1: 1 mixture of petroleum ether (bp 40-60 ° C) and ethyl acetate. The appropriate fractions were combined and the solvent was removed under reduced pressure to give (S) -7-trifluoromethyl-1,4-benzodioxan-2-ylmethanol (12 g) as a yellow oil.

A solution of 4-toluenesulfonyl chloride (9.6 g) in dichloromethane (60 ml) was added dropwise to a solution of the above reaction product (10.7 g) and 4-dimethylamino pyridine (6.7 g) in dichloromethane (90 ml). ) between 0-5 ° C. The mixture was stirred at room temperature for 4 hours, then left to stand for 18 hours. The solution was washed with dilute hydrochloric acid (5 M, 2 x 300 ml) dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 4-toluenesulfonate of (R) -7-trifluoromethyl-1,4-benzodioxan- 2-ylmethyl (15.5 g), as a white solid. A mixture of the above reaction product (2 g), N-benzylidene-4-piperidylmethylamine (1 g), potassium carbonate (1.35 g) and potassium iodide (10 mg) in acetonitrile (75 ml) was heated to reflux, with stirring, under nitrogen for 24 hours. The reaction was cooled, filtered and concentrated under reduced pressure to yield (S) -N-benzylidene-1- [1- (7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methylamine (6.3 g ) as a yellow viscous oil. The crude product of the previous reaction was stirred in aqueous potassium acid sulfate solution (0.6 M, 36 ml) for 5 hours at room temperature, then left to stand for 18 hours. The solution was washed with ether (2 x 50 ml) basified using aqueous sodium hydroxide solution (5 M) then extracted with ether (3 x 100 ml). The combined ether layers were dried over magnesium sulfate and evaporated to dryness to yield (S) -4- (aminomethyl) -1- (7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) piperidine (0.87 g) as a orange oil. A mixture of the product of the above reaction (0.87 g), 2,3-dichlorobenzenesulfonyl chloride (1.29 g), triethylamine (1.1 ml) and dichloromethane (40 ml) was stirred under nitrogen for 3 hours, then left to stand for 18 hours. hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with a 40: 1 mixture of dichloromethane and methanol to give (S) - (-) -2, 3-dichloro-N-. { [1- (7-trifluoromethyl-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} benzenesulfonamide as a cream solid (0.72 g), melting point 139-140 ° C, [a] D22 -36.7 ° (c = 0.18, MeOH).

Examples 15-39 General procedure Triethylamine (0.042 ml, 0.3 mmol) was added to a small 2 ml screw-capped flask containing a standard solution of (S) -4- (aminomethyl-1- (7-chloro-1, 4 -benzodioxan-2-ylmethyl) piperidine in dichloromethane (0.1 M; 1 ml, 0.1 mmol) and an aryl sulfonyl chloride (0.2 mmol). The reaction flasks were sealed with a screw cap and then stirred at room temperature for 66 hours. The lid was removed and the solvent was initially removed under a stream of nitrogen, then under reduced pressure at 40 ° C. The residues were redissolved in dichloromethane (1 ml) and an aliquot (0.020 ml) was removed and added in digol (2 ml). The digol solution was stirred until homogeneity and the mixture was analyzed in in vitro biological assays. Each of the following compounds was prepared by selecting the appropriate aryl sulfonyl chloride, as a crude sample using the general procedure detailed above: Example 15 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,4-dinitrobenzenesulfonamide Example 16 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2, 5-bis (2,2,2-trifluoroethoxy) benzenesulfonamide Example 17 (S) -2-chloro-N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-trifluoromethyl benzenesulfonamide Example 18 (S) -N-. { [7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-iodo-benzenesulfonamide Example 19 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -methoxy-2, 3,6-trimethylbenzenesulfonamide Example 20 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} Naphthyl [2,1-d] [1,2,3] oxadiazole-5-sulfonamide Example 21 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,4,6-trimethylbenzenesulfonamide Example 22 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2, 3, 4, 5, 6-pentamethylbenzenesulfonamide Example 23 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -5- (diethylamino) naphthalene-1-sulfonamide Example 24 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-trifluoromethyl benzenesulfonamide Example 25 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -3-nitrobenzenesulfonamide Example 26 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methyl-3, 5-dinitrobenzenesulfonamide Example 27 (S) -5-chloro-N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methoxy benzenesulfonamide Example 28 (S) -N-. { [7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -3-trifluoromethyl benzenesulfonamide Example 29 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-trifluoromethoxy benzenesulfonamide Example 30 (S) -N-. { [7-chloro-1,4-benzodioxan-2-ylmethyl) -piperidyl] methyl} -2-naphthalenesulfonamide Example 31 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -1-naphthalenesulfonamide Example 32 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,5-dimethoxybenzenesulfonamide Example 33 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methylbenzenesulfonamide Example 34 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} benzenesulfonamide Example 35 (S) -N-. { [7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -5-fluoro-2-methyl benzenesulfonamide Example 36 (S) -2,5-dibromo-N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} benzenesulfonamide Example 37 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-nitro-benzenesulfonamide Example 38 (S) -N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2, 3, 4-trifluorobenzenesulfonamide Example 39 (S) -2,5-dibromo-N-. { [7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -3,6-difluorobenzenesulfonamide Examples 40-49 General procedure Standard solutions of the appropriate initial amine of formula XVI in dichloromethane (0.1 M, 0.3-0.8 ml, 0.03-0.08 mmol) and triethylamine in dichloromethane (50% v / v, 3 equivalents) were added to different small flasks 2 ml, with screw cap, each containing a different arylsulfonyl chloride (2 equivalents). East process was repeated for each of the three different amines. The small reaction flasks were then sealed agitated on an orbital shaker at room temperature for 14 hours. The layers were removed and the solvent was allowed to evaporate at room temperature, then under reduced pressure at 40 ° C. The residues were redissolved in dichloromethane for a standard concentration of 0.1 M then again diluted to 10 M with digol. The digol solution was stirred until it was homogeneous and the mixture containing the active compound was analyzed in the in vitro biological assays. The following compounds were prepared in a single batch, as the main component in a mixture (purities indicated). Examples 40-43 used (S) -4- (aminomethyl) -1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -piperidine, prepared as described in Example 1 of WO97 / 03071, as Initial amine: Example 40 ((S) - (-) - N - { [1- (7-Chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl.} -2-fluorobenzenesulfonamide, HPLC 56 % (3.03 min), m / z 455 (MH +).

Example 41 ((S) - (-) -2-chloro-N- { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl.}. Benzenesulfonamide, 73% HPLC (3.14 min); m / z 471 (MH +).

Example 42 ((S) - (-) - 3-chloro-N- { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl.} -4- fluorobenzenesulfonamide, HPLC 62% (3.35 min), m / z 489 (MH ').

Example 43 ((S) - (-) -2, 3-dichloro-N- { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] ethyl} benzenesulfonamide HPLC 66% (3.39 min) m / z 505 (MH *).

Examples 43-47 used (S) -4- (aminomethyl) -1- (7-bromo-1,4-benzodioxan-2-ylmethyl) piperidine, prepared as in example 13 as the starting amine: Example 44 (S) - (-) -4-Acetamido-N-. { [1- (7-bromo-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} benzenesulfonamide, HPLC 76% (2.74 min); m / z 538, 540 (MH +).

Example 45 (S) - (-) - N-. { [1- (7-Bromo-l, 4-benzodioxan-2-ylmethyl) -4- piperidyl] methyl} -2-fluorobenzenesulfonamide, 50% HPLC (3.04 min); m / z 499, 501 (MH +).

Example 46 (S) - (-) - N-. { [1- (7-Bromo-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-cl? Robennesulfonamide, HPLC 83% (3.18 min); m / z 515, 517 (MH +).

Example 47 (S) - (-) - N-. { [1- (7-Bromo-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2, -difluorobenzenesulfonamide, 88% HPLC (3.14 min); mh 517, 519 (MH ').

Example 48 (S) - (-) -3-Chloro-N-. { [1- (7-bromo-l, 4-benzodioxan-2-ylmethyl) 4-piperidyl] methyl} -4-fluorobenzenesulfonamide, HPLC 74% (3.39 min); m / z 533, 535, (MH +).

Example 49 (S) - (-) -2, 3-dichloro-N-. { [1- (6,7-methylenedioxy-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} benzenesulfonamide, HPLC 71% (3.07 min); m / z 515 (MH ').

Example 49 used (S) 4- (aminomethyl) -1- (6,7-methylenedioxy-1,4-benzodioxan-2-ylmethyl) piperidine prepared as described below, as the initial amine. A mixture of 4-toluenesulfonate 4-toluenesulfonate of (R) -6,7-methylenedioxy-l, 4-benzodioxan-2-ylmethyl (2.0 g), N-benzylidene-4-piperidylmethylamine (1.11 g), carbonate of potassium (3.8 g) and potassium iodide (100 mg) in acetonitrile (50 ml) was heated to reflux with stirring, under nitrogen for 24 hours. The reaction was cooled, filtered and concentrated under reduced pressure to yield (S) -N-benzylidene-1- [1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methylamine (6.3 g ) like a rubber band. The crude product of the previous reaction (6.3 g) was stirred in aqueous potassium acid sulfate solution (1 M, 100 ml) for 14 hours at room temperature. The solution was washed with ether (3 x 200 ml) basified using aqueous sodium hydroxide solution (5 M) then extracted with dichloromethane (3 x 100 ml). The combined extracts were washed with water (200 ml), dried over magnesium sulfate and evaporated to dryness to yield (S) -4- (aminomethyl) -1- (6,7-methylenedioxy-1,4-benzodioxan-2-) ilmethyl) piperidine (1.18 g), [a] D23 -63.4 ° (c = 0.4, MeOH) as a viscous oil. The analytical conditions for Examples 40 to 49 are as follows: HPLC conditions - C18 peco column, 3 cm x 3 mm d.i .; 100% aqueous ammonium acetate (1.0 M), adjusted to pH 4. 55 with acetic acid, up to 100% acetonitrile linear gradient in 5 minutes, 2 ml / min; band of detection of the wavelength 250-320 nm, detection time 5 minutes. The percent purity was determined by integration of the detectable peak areas. Mass spectrometric conditions-chemical ionization at atmospheric pressure, mass detection range 150-500 Da.

Example 50 The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" defines any compound of the invention, but particularly any compound that is the final product of one of the above examples. a) Capsules In the preparation of capsules, 10 parts by weight of the active compound and 250 parts by weight of lactose are disaggregated and mixed. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of the active compound. b) Tablets Tablets are prepared from the following ingredients Parts by weight Active compound 10 Lactose 190 Corn starch 2 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, lactose and some of the starch are disaggregated, combined and the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. The dried granulate is mixed with magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of the active compound.

Enteric coated tablets The tablets are prepared by the method described in (b) above. The tablets are coated with an enteric layer in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in Ethanol: dichloromethane (1: 1). d) Suppositories In the preparation of the suppositories, 100 parts by weight of the active compound are incorporated into 1300 parts by weight of base for triglyceride suppositories and the mixture is formed into suppositories each containing a therapeutically effective amount of the active ingredient.

Claims (9)

1. The compounds of the formula I including the enantiomers and pharmaceutically acceptable salts thereof, in which A and B are -0-; g is 0, 1, 2, 3 or 4; Ri represents an alkyl group containing from 1 to 3 carbon atoms, optionally substituted by one or more halo; an alkoxy group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; halo; 6,7-methylenedioxy optionally substituted in C by one or two alkyl groups containing from 1 to 3 carbon atoms; or an alkylthio group containing from 1 to 3 carbon atoms optionally substituted by one or more halo; the substituents represented by Ri being the same or different when g is 2, 3 or 4; R2 is H, an alkyl group containing 1 to 3 atoms of carbon or an alkoxy group containing 1 to 3 carbon atoms; R3 and R4, which are the same or different, are H or an alkyl group containing from 1 to 3 carbon atoms; U is an alkylene chain containing from 1 to 3 carbon atoms, optionally substituted by one or more alkyl groups, each containing from 1 to 3 carbon atoms; Q represents a divalent group of the formula lie in which E and E 'both are ethylene, V is methylene, and R6 is H T represents phenyl, 1- or 2-naphthyl, 5-naft [2, ld] [1, 2, 3] oxadiazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 7-benzo [b] furanyl, 2,3-dihydro-7-benzo [b] furanyl, 2-, 3- or -7-benzo [b] thiophenyl, 3-, 4- or 5-pyrazolyl, 1, 2, 3-triazol-4-yl, 1,2,3-triazol-5-yl, 1, 2,4-triazol-2-yl , 5-tetrazolyl, 2-, 3- or 4-quinolinyl, 2- or 4-quinazolinyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4-, or 5 -zothiazolyl or 2-, 4- or 5-thiazolyl each of which may be optionally substituted by one or more substituents selected from: a) halo, b) an alkyl group containing from 1 to 4 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms carbon optionally substituted by one or more halo, d) an alkylthio group containing from 1 to 3 carbon atoms optionally substituted by one or more halo e) hydroxy, f) an acyloxy group containing from 1 to 3 carbon atoms, ) hydroxymethyl, h) cyano, i) an alkanoyl group containing from 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing from 2 to 6 carbon atoms, k) a carbamoyl group or carbamoylmethyl group each optionally substituted in N by one or two alkyl groups each containing from 1 to 3 carbon atoms, 1) a sulfamoyl or sulfamoylmethyl group each optionally substituted in N by one or two alkyl groups each containing from 1 to 3 carbon atoms, ) an amino group optionally substituted by one or two alkyl groups each containing from 1 to 5 carbon atoms, n) 1-pyrrolidinyl or 1-piperidinyl, or) nitro op) acetamido.

2. The compounds of the formula I, as mentioned in claim 1, wherein A is -0-, B is -0-, g is 1, Ri is preferably halo or an alkyl group containing 1 to 3 atoms of carbon optionally substituted by one or more halo, R2 is H, R3 and R4 both are H, U is methylene, Q is a group of the formula lo in which E and E 'both are ethylene, V is methylene, R6 is H and T is 1-naphthyl, 2-naphthyl, 5-naphth [2, 1-d] [1,2,3] oxadiazolyl, 2-pyridyl, 3-pyridyl, phenyl, 4-methylphenyl, 2,, 6- trimethylphenyl, 2,3,4,5,6-pentamethylphenyl, 2-fluorophenyl, 4-fluorophenyl, 2,6- difluorophenyl, 2,4-difluorophenyl, 2,3,4-trifluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2,5-dibromophenyl, 4-iodophenyl, 2, 5-dibromo-3,6-difluorophenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl, 5-chloro-2-methoxyphenyl, 5- fluoro-2-methylphenyl, 4-trifluoromethoxyphenyl, 2,5-bis (2,2,2-trifluoroethoxy) phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 4-acetamidophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 4-methyl-3,5-dinitrophenyl, 5- (diethylamino) -1-naphthyl, 2,3-dichlorophenyl or 3-chloro-4-fluorophenyl.

3. The compounds of formula I, as mentioned in claim I, selected from: N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-2-sulfonamide; N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} pyridine-3-sulfonamide; N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-nitrobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-fluorobenzenesulfonamide; N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 3, 4-dimethoxy-benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2,4-difluorobenzenesulfonamide; 4-acetamido-N-. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methoxybenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2,6-difluorobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-chlorobenzenesulfonamide; N { [1- (7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -pyridine-2-sulfonamide N { [1- (7-bromo-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2,3-dichlorobenzenesulfonamide 2,3-dichloro-N. { [1- (7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide N { [1- (7-chloro-1, -benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2,4-dinitrobenzenesulfonamide N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2, 5-bis (2,2,2-trifluoroethoxy) benzenesulfonamide 2-chloro-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-trifluoromethylbenzenesulfonamide N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,4-dinitrobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] ethyl} -2, 5-bis (2,2,2-trifluoroethoxy) benzenesulfonamide; 2-chloro- N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] ethyl} -4-trifluoromethylbenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-iodobenzenesulfonamide; N { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 4-methoxy-2,3,6-trimethylbenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -naft [2, 1-d] [1,2,3] oxadiazole-5-sulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,4,6-trimethyl-benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2,3,4,5,6-pentamethylbenzenesulfonamide; N { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 5- (diethylamino) naphthalene-1-sulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-trifluoromethylbenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 3-nitrobenzenesulfonamide; N { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-methyl-3, 5-dinitrobenzenesulfonamide; 5-chloro-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-methoxy-benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 3-trifluoromethylbenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-trifluoromethoxy-benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2-naphthalenesulfonamide; N { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -1-naphthalenesulfonamide; N { [1- (7-chloro-i, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 2, 5-dimethoxybenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 4-methylbenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 5-fluoro-2-methyl-benzenesulfonamide; 2, 5-dibromo-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} • 2-nitrobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2, 3, 4-trifluorobenzenesulfonamide; 2, 5-dibromo- N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} 3,6-difluorobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2-fluorobenzenesulfonamide; 2-chloro-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; 3-chloro-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-fluorobenzenesulfonamide; 2, 3-dichloro-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; 4-acetamido-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; N { [1- (7-chloro-1,4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} - 2-fluorobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2-chlorobenzenesulfonamide; N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -2,4-difluorobenzenesulfonamide; 3-chloro-N. { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -4-fluorobenzenesulfonamide; 2,3-dichloro- N { [1- (7-chloro-l, 4-benzodioxan-2-ylmethyl) -4-piperidyl] methyl} -benzenesulfonamide; And pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates or mixtures of enantiomers.

4. The compounds of the formula I, as mentioned in claim 1 for use in the treatment of depression, anxiety, psychosis, tardive dyskinesia, Parkinson, obesity, hypertension, Tourette syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, dementia senile, obsessive-compulsive behavior, panic attacks, social phobias, eating disorders and anorexia, cardicular and cerebrcular disorders, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress and spasticity in humans , which consists in the administration of a therapeutically effective amount of a compound of the formula I, as mentioned in claim 1, to a patient in need thereof.

5. The use of a compound of formula I, as mentioned in claim 1, in the manufacture of a medicament for treating depression, anxiety, psychosis, tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette syndrome, dysfunction sexual, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behavior, panic attacks, social phobias, eating disorders and anorexia, cardicular and cerebrcular disorders, diabetes mellitus not dependent on insulin, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress and spasticity.

6. A method for the treatment of depression, anxiety, psychosis, tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behavior, panic attacks, social phobias, eating disorders and anorexia, disorders cardicular and cerebrcular diseases, non-insulin dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress and spasticity in humans, which consists in the administration of a therapeutically effective amount of a compound of the formula I, as mentioned in claim 1, a patient in need thereof.

7. A process for the preparation of the compounds of the formula I, wherein Q is a group of the formula lie, which comprises the pre-action of a compound of the formula XIV wherein D 'is H and m is 0, 1 or 2, with a compound of formula IV wherein Z is a leaving group, optionally in the presence of a base, optionally in the presence of a suitable solvent and optionally in the presence of a catalyst.

8. A pharmaceutical composition containing a compound of the formula I, as mentioned in claim 1, together with a pharmaceutically acceptable diluent or carrier.

9. A compound of formula I, as mentioned in claim 1 for use as a medicament.