MXPA99005900A - Sulphonamide derivatives, process for their preparation, and their use as medicaments - Google Patents

Sulphonamide derivatives, process for their preparation, and their use as medicaments

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Publication number
MXPA99005900A
MXPA99005900A MXPA/A/1999/005900A MX9905900A MXPA99005900A MX PA99005900 A MXPA99005900 A MX PA99005900A MX 9905900 A MX9905900 A MX 9905900A MX PA99005900 A MXPA99005900 A MX PA99005900A
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MX
Mexico
Prior art keywords
methoxy
phenyl
methyl
piperazin
benzenesulfonamide
Prior art date
Application number
MXPA/A/1999/005900A
Other languages
Spanish (es)
Inventor
David King Francis
Mark Bromidge Steven
Adrian Wyman Paul
Original Assignee
Smithkline Beecham Plc
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Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of MXPA99005900A publication Critical patent/MXPA99005900A/en

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Abstract

Novel sulphonamide derivatives having CNS activity, processes for their preparation and their use as medicaments.

Description

DERIVATIVES OF SULFONAM1DA, PROCEDURE FOR ITS PREPARATION, AND ITS USE AS MEDICINES BACKGROUND OF THE INVENTION This invention relates to compounds having pharmacological activity, methods of their preparation, compositions containing them and their use in the treatment of CNS disorders. EPA 0 021 580 and EPA 0 076 072 describe the sulfonamide derivatives that are published as having antiarrhythmic activity. A structurally distinct class of compounds has now been discovered that have been found to have 5HT6 receptor antagonist activity. The 5HTß receptor antagonist is believed to be of potential use in the treatment of certain CNS disorders of anxiety, depression, epilepsy, compulsive obsessive disorders, migraine, increased cognitive memory for example for the treatment of Alzheimer's disease, disorders of the sleep, eating disorders such as anorexia bulimia, panic attacks, withdrawal from drug abuse, such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal injuries and / or head injury such as hydrocephalus . It is expected that the compounds of this invention will also be used in the treatment of certain (gastrointestinal) disorders Gl such as IBS (Irritable Bowel Syndrome).
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof: (OR where: P is phenyl, naphthyl, or bicyclic heterocyclic ring or is a 5- to 7-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur; A is a single bond, a group of alkylene of d-6 or an alkenylene group of C-i ^; R1 is halogen, C1-6 alkyl optionally substituted by one or more halogen atoms, C3-6 cycloalkyl, C6-C6 alkyl, C6-6 alkoxy, OCF3, hydroxy, hydroxyalkyl of C? -6) hydroxyalkoxy of C? -6, alkoxy of C1-6 alkoxy of C -? - 6, C -? - 6 alkanoyl, nitro, amino, C? -6 alkylamino or C? -6 dialkylamino, cyano or R1 is phenyl, naphthyl, or bicyclic heterocyclic ring or is a heterocyclic ring of 5 to 7 members containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; n is O, 1, 2,3,4,5, 0,6, R 2 is hydrogen, C 1-6 alkyl or C? -6 arylalkyl; R3 is a group R5 or together with R5 forms a group (CH2) 2O or (CH2) 3? or R3 binds to R2 to form a group (CH2) or (CH2) 3; R4 is X (CH2) p-R6 where X is a single bond, CH2, O, NH or N-C6 alkyl -6 and p is 0 to 6 and R6 is an optionally substituted 5- to 7-membered heterocyclic ring containing from 1 to 3 heteroatoms selected from nitrogen, sulfur or oxygen, or R6 is NR7R8 where R7 and R8 are independent of hydrogen, C-? 6 alkyl or Ci-β arylalkyl; and R5 is hydrogen, halogen, C6-6alkyl, C3-6 cycloalkyl, Ci -6 alkyl CO, C6-6 alkoxy, hydroxy, hydroxy-C- [alpha] -6, d-6-hiroxyalkoxy, C 1-6 alkoxy, d-6 alkoxy, Ci-β alkanoyl, nitro, trifluoromethyl, cyano or aryl. Alkyl groups of C? -6, either alone or as part of another group, can be straight or branched chain. Preferred alkyl groups are usually methyl and ethyl. As used herein the term "aryl" includes optionally substituted phenyl and naphthyl. When P is a bicyclic heterocyclic ring, available examples include benzothiophene, quinoline or isoquinoline. When P is a 5- to 7-membered heterocyclic ring, the available examples include thienyl, furyl, pyrrolyl, thiazolyl, diazolyl, midazolyl, oxazolyl, thiazolyl, exadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl. The heterocyclic rings can be linked to the rest of the molecules by means of suitable carbon atoms or, when present, a nitrogen atom. Suitable substituent atoms for these rings include R5 groups as defined above.
Preferably P is phenyl, thiophene, benzothiophene or naphthyl. Preferably A is a single bond, an ethylene group or a group -CH = CH. Preferably A is a simple link. When R1 is a heterocyclic group, suitable examples include those listed above. Preferably R1 is halogen or C6-6 alkyl optionally substituted by one or more halogen atoms, for example methyl or trifluoromethyl. Preferably n is 0,1, 2, or 3, particularly 1 or 2. Suitable R 2 is hydrogen or C 6 alkyl. Preferably R2 is hydrogen. It will be appreciated that when the R3 / R5 groups are linked the two groups must join adjacent carbon atoms of the phenyl ring. Preferably R3 is a group R5 in a particular hydrogen. Preferably R4 is meta in relation to the sulfonamide linkage.
Preferably X is a bond, p is 0 and R6 is an optionally substituted heterocyclic ring of 5 to 7 members. 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 substituent atoms for these rings, which may be present on carbon and / or nitrogen atoms, include C? -6 alkyl, in particular methyl. Preferably R4 is N-piperazine optionally replaced by alkyl, particularly not replaced by piperazine.
Preferably R5 is C1-6 alkoxy, preferably methoxy. Preferably R5 is para relative to the sulfonamide linkage. A preferred meaning for PA is benzo [b] thiophen-2-yl or benzo [b] thiophen-3-yl optionally replaced by one or two R 1 groups, especially 5-chloro-3-methyl-benzo [2] thiophen-2 -il. Particular compounds of the invention include: 4-Bromo-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) phenyl] -benzenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) ) phenyl] -2-thiophenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -5- (pyridin-2-yl) -2-thiophenesulfonamide , 2,5-Dichloro-N- [4-methoxy-3- (4-methylpiperazin-17I) phenyl] -3-thiophenesulfonamide, 4-Bromo-5-chloro-N- [4-methoxy-3- (4- methylpiperazin-1-yl) phenyl] -2-thiophenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, 3-Bromo-5-chloro-N- [4-methoxy] 3- (4-methyl-piperazin-1-yl) phenyl] -2-thiophenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 2-Bromo-N- [4-methoxy] -3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 3-Bromo-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 3-chloro-N- [4 -methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -4-methyl-benzenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -irap7-styrenesulfonamide, 3,4-Dichloro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 3,5-Dichloro-N- [4-methoxy-3- (4-methyl-piperazin-1- il) phenyl] benzenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] - [2,1, 3] benzothiadiazole-4-sulfonamide, 5-chloro-N- [4- methoxy-3- (4-methylpiperazin-1-yl) phenyl] -3-methyl-2-benzothiophenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -2-methyl-5 -nitro-benzenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -2-trifluoromethyl-benzenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl)] phenyl] -3-trifluoromethyl-benzenesulfonamide, 2,5-dimethoxy-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -benzenesulfonamide, Fluoro-N- [4-methoxy-3-] (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, 4-Chloro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 4-iodo-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl) ] benzenesulfonamide, 4-Ethyl-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, 4-7er-Butyl-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 4-lsopropyl-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) phenyl] benzenesulfonamide, 4-rer-Amyl-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl)] phenyl] -4-trifluoromethoxy-benzenesulfonamide, 4-n-Butoxy-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, N- [4-methoxy-3- (4- methyl-piperazin-1-yl) phenyl] -4-methylbenzenesulfonamide, 5-Chloro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -2-thiophenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -1-naphthalenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -2-naphthalenesulfonamide, 5- (Dimethylamino) -N- [4-methoxy-3- (4-methylpiperazine- 1-yl) phenyl] -1-naphthalenesulfonamide, 4-Bromo-N- [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] -benzenesulfonamide, 4-methoxy-N- [ 4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, 4-n-Butyl-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, 4- Amino-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 2-Chloro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] benzenesulfonamide, 3-chloro-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, 2,3,4-trichloro-N- [4-methoxy-3- (4-methylpiperazin- 1-yl) phenyl] benzenesulfonamide, 4-chloro-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -2,5-dimethyl-benzenesulfonamide, N- [4-methoxy-3-] (4-methylpiperazin-1-yl) phenyl] -3-methylbenzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1- il) phenyl] -2,3,5,6-tetramethyl-benzenesulfonamide, 5-chloro-2-methoxy-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -benzenesulfonamide, 3- Fluoro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 3,4-difluoro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] benzenesulfonamide, 4-chloro-N- [4-methoxy -3- (4-methylpiperazin-1-yl) phenyl] -3-nitro-benzenesulfonamide, 3-chloro-N- [4-methoxy] -3- (4- methylpiperizin-1-yl) phenyl] -2-methyl-benzenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) phenyl] -8-quinolinesulfonamide, N- [4-methoxy-3 - (4 -methylpiperazin-1-yl) phenyl] -4-phenylbenzenesulfonamide, 3,4-dimethoxy-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -benzenesulfonamide, N- [4-methoxy] 3- (4-methylpiperazin-1-yl) phenyl] -3,5-dimethyl-1-4-isoxazolesulfonamide, 4-Bromo-N- [4-methoxy-3- (4-ethylpiperazin-1-yl) phenyl] benzenesulfonamide, 2,3-Dichloro-N- [4-methoxy-3- (4-methyl) perazin-1-yl) phenyl] -benzenesulfonamide, 5-iodo-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -. 2-methyl-benzenesulfonamide, 3-iodo-N- [ 4-methoxy-3- (4-methyl-piperazin-1-yl) phenyl] -benzenesulfonamide, 3-iodo-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -4-methyl-benzenesulfonamide, [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide of 5-chloronaphthalene-2-sulfonic acid, [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide of acid 5-chloronaphthalene-1-suphonic, 4-chloronaphthalene-1-suphonic acid [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide, [4-methoxy-3- (4-methyl-piperazin-1) 7-chloronaphthalene-1-sulfonic acid, [4-methoxy-3- (4-methyl-piperazin-1-yl) -phene] -5-chloro-2-methyl-benzo [b] thiophene-3-phenyl] -idene; sulfonic acid, [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide of benzofuran-2-sulfonic acid, [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide of 1-methyl-1 H-indole-2-sulfonic acid, 5-pyridin-2-ylthiophen-2-sulfonic acid, (4-methoxy-3-piperazin-1-ylphenyl) amide, N- (4-Me Toxo-3-piperazin-1-ylphenyl) -3-trifluoromethylbenzenesulfonamide, 3-iodo-N- (4-methoxy-3-piperazin-1-phenyl) benzenesulfonamide, (4-methoxy-3-piperazin-1- phenyl) 3,5-dimethylisoxazole-4-suphonic acid amide, 3, 5-Dichloro-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, 2,5-Dibromo-3,6-difluoro- N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, naphthalene-1-suphonic acid (4-methoxy-3-piperazin-1-ylphenyl) -amide, (4-methoxy-3-piperazin-1-) ilphenyl) 2-bromo-5-chlorothiophene-2-sulfonic acid amide, 2-chloro-4-fluoro-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, 3-Bromo-N- (4 -methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, 3-chloro-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, (4-methoxy-3-piperazin-1-ylphenyl) acid amide 5-chloronaphthalene-2-sulfonic acid, 4-bromo-5-chlorothiophen-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) amide (4-methoxy-3-piperazin-1-ylphenyl) amide of 2,5-Dichlorothiophen-3-suifonic acid, 4-Bromo-N- (4-methoxy-3-piperazin-1-yl) phenyl) benzenesulfonamide, 5-chloro-3-methylbenzo [b] thiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) (4-methoxy-3-piperazin-1-ylphenyl) 5-chloro-2-methylbenzo [b] thiophene-3-sulfonic acid amide, 1-methyl-1 H-indole-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) amide, (4 3-piperazin-1-ylphenyl) -amido-benzofuran-2-sulfonic acid, (4-methoxy-3-piperazin-1-ylphenyl) -amide-2-sulfonic acid, (4-methoxy-3-piperazine) 5-chloronaphthalene-suphonic acid-1-ylphenyl), 4-Chloro-2,5-dimethyl-N- (4-methoxy-3-piperazin-1-phenyl) benzenesulfonamide, 3,4-Dichloro-N- ( 4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, 3-chloro-N- (4-methoxy-3-piperazin-2-ylphenyl) -4-methyl-benzenesulfonamide, 2-trifluoromethyl-N- (4-methoxy) -3-piperazin-1-ylphenyl) benzenesulfonamide 4-iodo-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, 4-tert-Butyl-N- (4-methoxy-3-piperazine) 1-ylphenyl) benzenesulfonamide, [7- (4-methyl-piperazin-1-yl) -2, 3-dihydrobenzofuran-5-yl] -amide of acid naphthalene-1 -suiphonic, [7- (4-methylpiperazin-1-yl) -2, 3-dihydrobenzofuran-5-yl] thiophene-2-sulfonic acid, [7- (4-methylpiperazin-1- L) -2, 3-dihydrobenzofuran-5-yl] -idene-2-sulfonic acid, [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] -amide acid -Chlorothiophen-2-sulphonic, [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] -5-pyridin-2-ylthiophen-2-sulfonic acid, [7- ( 2, 5-dichlorothiophen-3-sulfonic acid, 4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] -amide, [7- (4-methyl-piperazin-1-yl) -2, 3 4-bromo-5-chlorothiophen-2-sulfonic acid-dihydrobenzofuran-5-yl], [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] -amide acid 3-bromo-5-chlorothiophen-2-su! Phonic, 4-chloro-2, 5-dimethyl-N- [7- (4-methylpiperazin-1-yl) -2, 3-dihydrobenzofuran-5-yl] benzenesulfonamide, [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] -5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid, [7- (4-methylpiperazine- 1-yl) -2-, 3-dihydrobenzofuran-5-yl] naphthalene-2-sulfonic acid amide, 3-Bromo-N- [7- (4-methyl-piperazin-1-yl) -2,3-h'drobenzofuran -5-ylbenzenesulfonamide, 3,5-Dichloro-N- [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl-benzenesulfonamide, 4-fer-Butyl-N- [7- (4- methylpiperazin-1-yl) -2,3-dihydrobenzofuran-5-yl-benzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N- [7- (4-methyl-piperazin-1-yl) -2, 3 -dihydrobenzofuran-5-yl] benzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N- (7-methylpiperazin-1-yl-2,3-dihydrobenzofuran-5-yl) benzenesulfonamide, 4-chloro-2 , 5-dimethyl-N- (7-piperazin-1-yl-2,3-dihydrobenzofuran-5-yl) benzenesulfonamide, [3- (4-cyclopropylmethyl-piperazin-1-yl) -4-methoxy -phenyl] -amide of 5-chloro-3-methyl b enzo [b] thiophene-2-sulphonic, [3- (4-benzyl-piperazin-1-yl) -4-methoxy-phenyl] -amido-5-chloro-3-methyl-benzo [b] thiophen-2 -amide sulfonic acid, [4-hydroxy-3- (4-methyl-piperazin-1-yl) -phenyl] -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonic acid, [4-benzyloxy-3- ( 5-Chloro-3-methyl benzo [b] thiophene-2-sulfonic acid, 4-methyl-piperazin-1-yl) -phenyl] - [4-ethoxy-3- (4-methyl-piperazin-1-yl) -pheni] ] 5-chloro-3-methyl benzo [b] thiophen-2-suphonic acid amide, 5-chloro [4-isopropoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide] -3-methyl benzo [b] thiophene-2-sulfonic acid, [5-chloro-3-methyl benzo [4-methoxy-3- (1-methyl-piperazin-3-yloxy] -phenyl] -amide] ] thiophen-2-sulfonic acid, [2-bromo-5- (4-methylpiperazin-1-yl) phenyl] -amide-2-sulfonic acid amide, [4-chloro-3- (4-methylpiperazine-1-yl)] 5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid, 5-naphthalene-2-sulfonic acid [4-bromo-3- (4-methyl-piperazin-1-yl) -phenyl] -amide , [3- (2-dimethylaminoethoxy) -4-Iodophenyl] ami 5-chloro-3-methylbenzo [b] thiophene-2-sulphonic acid, [1- (2-dithmetholaminoetyl) -2,3-dihydro-1H-indol-6-yl] amide of 5-chloro-3-methylbenzo [b] thiophene-2-sulfonic acid 1- (5-chloro-3-methyl-benzo [b] thiophen-2-sulfonyl) -6- (4-methyl-piperazin-1-yl) -2 , 3-dihydro-1H-indole, 1- (5-chloro-3-methylbenzo [b] thiophen-2-sulfonyl) -5-methoxy-6- (4-methylpiperazin-1-yl) -2,3- 5-Chloro-3-methylbenzo [b] thiophene-5-chloro-3-methylbenzo [b] thiophene-5-chloro-3-methyl-benzo [3-methoxy-2-methyl-3- (4-methyl-piperazin-1-yl) phenyl] -amide 2-Sulfonic acid [2- (2-hydroxyethyl) -4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonic acid chloride hydrochloride of 1 - (5-Chloro-3-methylbenzo [b] thiophen-2-sulfonyl) -5-methoxy-4- (4-methylpiperazin-1-yl) -2,3-dihydro-1 H-indole [3-methoxy] 5-Chloro-3-methyl-benzo [b] thiophene-2-sulphonic acid 4-methyl-piperazin-1-yl] -phenyl] -amide 4-Bromo-N- [4-methoxy-3- (1-methyl) -1, 2,3,6-tetrahydropyridin-4-yl) phenyl] benzenesulfonamide, [4-methoxy-3- (1-methyl-1, 2,3,6-tetrahydropyridin-4-yl) phenyl] acid amide 5-chloro- 5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [3-methylbenzo [b] thiophene-2-sulfonic acid [4-methoxy-3- (1-methylpiperidin-4-yl) -phenyl] -amide] Naphthalene-2-sulfonic acid [3- (4-methyl-piperazin-1-yl) -phenyl] -amide 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 and methanesulfonic acids. The compounds of formula (I) can also form solvates as hydrates, and the invention also extends to these forms. When it refers to here, it is understood that the term 'compound of formula (I)' also includes these forms. Certain compounds of formula (I) are capable of existing in 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 common methods, or any given isomer can be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric form and mixtures thereof. The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises coupling a compound of formula (II): (ll) wherein R1, n, P, and A are as defined in formula (I) or protected derivatives thereof and L is an leaving group with a compound of formula (III): (ni) wherein R2, R3, R4 and R5 are as defined in formula (I) or protected derivatives thereof and optionally hereafter: removing any of the protecting groups, forming a pharmaceutically acceptable salt. Suitable leaving groups include halogen, in particular chlorine. The reaction of a compound of formulas (II) and (III) is carried out by mixing the two reagents, optionally in an inert solvent such as acetone. Such a reaction can be carried out in the presence of base. 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 transfer 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). For example, suitable protecting groups for the piperazine group include BOC, COCCI3, COCF3 and methyl, the latter of which can be removed by treatment with a chloroformate of 1-chloroethyl according to standard procedures. which can be removed by treatment with a chloroformate of 1-chloroethyl in accordance with standard procedures. The N-substituted piperazines can be prepared by acylation or alkylation of the appropriate piperazine NH compound in accordance with standard procedures. The compounds of formulas (II) and (III) are commercially available or should be prepared in accordance with known methods or analogous to known methods. The pharmaceutically acceptable salts can be prepared conventionally by reaction with the appropriate acid or acid derivative. The compounds of formula (I) and their pharmaceutically acceptable salts have an activity of the 5HT6 receptor antagonist and are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimer's disease (increased cognitive memory), sleep disorders (including heart rhythm disturbances), eating disorders such as anorexia and bulimia, panic attacks, drug abuse separation such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia and also disorders associated with spinal injury and / or head injury such as hydrocephalus. The compounds of the invention are expected to be useful for the treatment of certain Gl disorders such as IBS. Therefore, the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment of prophylaxis of the above disorders. The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the victim a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. On the other hand, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment or prophylaxis of the above disorders. The present invention also provides a pharmaceutical composition, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable agent. A pharmaceutical composition of the invention, which can be prepared by mixing, suitably at room temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may 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, lubricants for tabletting, disintegrants and acceptable wetting agents. The tablets can be covered in accordance with methods known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of dry products for reconstitution with water or other suitable vehicles before use. Said liquid preparations 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, single-dose fluid forms 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. When preparing solutions, the compound can be dissolved by injection and sterilization of the filter before filling it into a suitable vial or ampoules and sealing it. Advantageously, auxiliaries such as local anesthetics, preservatives and pH regulating agents dissolve in the vehicle. To increase the stability, the composition can be cooled before filling in the jars and the water removed in vacuum. Parenteral suspensions are prepared in the substantially equal form, only that the compound is suspended in the vehicle instead of being dissolved, and sterilization can not be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or a 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 can vary in a common way with the severity of the disorders, the weight of the victim, and other similar factors. However, as a general rule, the appropriate unit dose can be 0.05 to 1,000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and said single doses should be administered more than once a day, for example two or three a day, so that the total daily dose is on the scale of approximately 0. 5 to 100 mg; and such therapy extends for a number of weeks or months. When administered according to the invention, no unacceptable toxicological effects are expected with the compounds of the invention. The following Descriptions and Examples illustrate the preparation of the compounds of the invention.
DESCRIPTION 1 1 - (2-Methoxy-5-nitrophenol) piperazine (D1) A solution of 5M sulfuric acid (114ml) was added over 0.3 h to 1- (2-methoxyphenyl) piperazine (110g) at 0 ° C with stirring. For the agitated and cooled suspension with ice, concentrated sulfuric acid (560 ml) was then added for 1.75 h and the temperature was maintained for 1.5 h. additional Potassium nitrate (71.5 g) was subsequently added in portions for 1.5 h to the cold and agitated viscous mixture, which was subsequently left for 18 h. The solution was poured onto ice (2 kg) and the resulting cooled mixture was brought to pH 12 by the addition of 40% sodium hydroxide solution. The oily mixture which was extracted with ethyl acetate (2x2L) and the combined organic extracts were washed with water (3L), dried (Na2SO4), and concentrated to a residue which was stirred with diethyl ether (700 ml) to give the title compound (D1) as a yellow solid, mp 84-87 ° C (95g, 70%). MH + 238.
DESCRIPTION 2 4-tert-Butoxycarbonyl-1- (2-methoxy-5-nitrophenyl) piperazine (D2) For a stirred heterogeneous solution of 1- (2-methoxy-5-nitrophenyl) piperazine (D1) (99.2 g) in tetrahydrofuran (1.1 L) and water (1.1 L), a solution of di-tert-butyldicarbonate (91.3 g) was added. g) in tetrahydrofuran (300 ml) for 0.5 h. Potassium carbonate (60.7 g) was then added in portions over 0.5 h and the mixture was stirred at room temperature for 18 h. All was concentrated to remove the organic solvent and the resulting mixture was extracted with dichloromethane (2x1 L). The combined organic phases were washed with water (1 L), dried (Na 2 SO 4) and concentrated to a residue which was stirred with diethyl ether (500 ml) and hexane (750 ml) to face the title compound (D2) as a solid yellow color, mp 136-7 ° C (125g, 89%). MH + 338.
DESCRIPTION 3 4-tert-Butoxycarbonyl-1 - (5-amino-2-methoxyphenyl) piperazine (D3) A suspension of 10% palladium on carbon (10g) in a solution of 4-tert-butoxycarbonyl-1- (2-methoxy-5-nitrophenyl) piperazine (D2) (124.5 g) in ethanol (3.5L) and water ( 50 ml) was stirred with hydrogen at room temperature and atmospheric pressure for 18 h. The reaction mixture was filtered and the filtrate concentrated to face the title compound (D3) as a gum (112g, 99%). MH + 308.
DESCRIPTION 4-14 General preparation of N-r4-methoxy-3- (4-t-butoxycarbonyl-1-piperazine-phenyl) arylsulfonamides (D4-D14) A solution of 4-t-butoxycarbonyl-1- (5-amino-2-methoxyphenyl) piperazine (D3) (15.6 mmol), diisopropylethylamine (15.6 mmol) and the appropriate arylsulfonyl chloride (15.6 mmol) in dichloromethane (100 ml) was stirred at room temperature for 18h. The mixture was concentrated and the residue was chromatographed on silica gel eluting with a dichloromethane / methanol gradient to give the following pure title products.
* Intermediates used raw without isolation DESCRIPTION 10-5-Chloro-3-methylbenzo-T-thiophen-2-suphonic acid (4-methoxy-3- (4-tert-butoxycarbonyl) -piperazin-1-yl) -pheniPamidade (D10) Pyridine (60 ml) was added to a stirred solution of 4-tert-butoxycarbonyl-1- (5-amino-2-methoxyphenyl) piperazine (D3) (112g) in dichloromethane (1L) at room temperature under argon. To this solution, a solution of 5-Chloro-3-methylbenzo [b] thiophene-2-sulfonyl chloride (102.5 g) in dichloromethane (2.1 L) was added and the purple solution was stirred for 18 h. Subsequently, the mixture was washed with 1M hydrochloric acid solution (3L), with water, (3L), dried with (Na 2 S 4), and concentrated to a foam which was stirred with acetone (800 ml) and water (800 ml). ) to face the title compound (D10) as a brown solid, mp 100-103 ° C (194.9g, 97%). MH + 552/554. DESCRIPTION 15 1 - (2-Methoxy-5-nitrophenyl) -4-trichloroacetylpiperazine (D15) A solution of 5-nitro-1- (2-methoxyphenyl) piperazine (D1) (44g) in dichloromethane (300 ml) was added to a stirred solution of trichloroacetylchloride (32 ml) in dichloromethane (200 ml) for 0.25h. After 3 days, the reaction mixture was concentrated and the residue recrystallized from the chloroform to give the title compound (D15) as a yellow solid (43g, 61%). Found MH + 552/554.
DESCRIPTION 16 1 - (2-Amino-2-methoxyphenyl) -4-trichloroacetylpiperazine (D15) A solution of stannous chloride dihydrate (27g) in concentrated HC1 (60 ml) was added slowly to a stirred suspension of 1- (2-methoxy-5-nitrophenyl) -4-trichloroacetylpiperazine (D15) (15 g) in HC1 / concentrated ethanol (1: 2, 120ml). After 24 hours, the mixture was filtered, diluted with dichloromethane (600 ml) and basified with Na2SO3 solution. The layers were separated, the organic phase was dried, concentrated to 1/3 volume and acidified with 1 M ethereal HC1 solution to face the title compound (D16) as a green solid (2.5g, 15%). Found MH + 352.
DESCRIPTION 17 Cyclopropyl-r4- (2-methoxy-5-nitrophenyl) -piperazin-1-yl] methanone (D17) To a solution of 1- (2-methoxy-5-nitrophenyl) -piperazine (500 mg, 2.1 mmol) in dichloromethane (50 ml) at 0 ° C under argon was added triethylamine (0.59 ml, 4.2 mmol) and cyclopropanecarbonyl chloride (2.1 mmol). Stirring was continued for 12 hours. The reaction mixture was concentrated in vacuo and partitioned between saturated aqueous NaHCO3 and dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound (D17) in 90% yield. Found MH + 306.
DESCRIPTION 18 r4- (2-Methoxy-5-nitrophenyl) -piperazin-1-ipphenyl methanone (D18) The title compound was prepared in an 85% yield using the procedure outlined in D17 using benzonyl chloride. Found MH + 342.
DESCRIPTION 19 r4- (5-Amino-2-methoxy-phenyl) -piperazin-1-in-cyclopropyl-methane (D19) A solution of cyclopropyl- [4- (2-methoxy-5-nitrophenyl) -piperazin-1-yl] methanone (D17) (1.8 mmol) in ethanol was hydrogenated over 10% palladium on carbon catalyst during 12 hours at room temperature to give the title compound a 91% yield. Found MH + 276.
DESCRIPTION 20 r4- (5-Amino-2-methoxy-phenyl) -piperazin-1-phenyl-methane (D20) The title compound was prepared in 95% yield using the procedure outlined in D19. Found MH + 312.
DESCRIPTION 21 3- (4-Cyclopropylmethyl-piperazin-1-yl) -4-methoxy-phenylamine (D21) To a solution of [4- (5-amino-2-methoxy-phenyl) -piperazin-1-yl] cyclopropyl methanone (D19) (1.6 mmol) in dry THF (10 ml) under argon was added LiA1 H4 (240 mg, 6.4mmol). The resulting mixture was heated to reflux for 12 hours and cooled before cooling with water (0.25ml), 10% aqueous NaOH (0.25ml) and finally water (0.75ml). Filtration through celite and vacuum concentration facing the title compound (D21) in 75% yield. Found MH + 262.
DESCRIPTION 22 3- (4-Benzyl-piperazin-1-yl) -4-methoxy-phenylamine (D22) The title compound was prepared in a proportion of 75% using the procedure outlined in D21. Found MH + 298.
DESCRIPTION 23 1 -Methyl pyrrolidin-3-yl ester of methano-suifonic acid (D23) To a solution of 1-methyl-pyrrolidin-3-ol (2.0 g, 20 mmol) in triethylamine (3 ml, 22 mmol) and in dichloromethane (25 ml) at 0 ° C under argon was added methanesulfonyl chloride (2.4 g, 21 mmol) . Stirring was continued at 0 ° C at room temperature for one hour before dividing it between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo to cope with the crude mesylate (3.6 g) which was used directly in the next step.
DESCRIPTION 24 3- (2-Methoxy-5-nitro-phenoxy) -1-methyl-pyrrolidine (D24) A solution of 2-methoxy-5-nitro phenol (5.1 g, 30 mmol) in DMF (10 ml) was added to sodium hydride (1.6 g)., 66mmol) under argon. After one hour a solution of crude mesylate (D23, 3.6g, 20mmol) in DMF (10ml) was added and the reaction mixture was heated at 50 ° C for 48 hours. The reaction was cooled, warmed with water and concentrated in vacuo before being partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel to face the title compound (D24). Found MH + 253.
DESCRIPTION 25 4-Methoxy-3- (1-methyl-pyrrolidin-3-yloxy) phenylamine (D25) A solution of 3- (2-methoxy-5-nitro-phenoxy) -1-methyl-pyrrolidine (3.0g, 0.12 mmol) in ethanol (50ml) was hydrogenated over 10% palladium on carbon catalyst for 2 hours to cope to the title compound (D25). Found MH + 223.
DESCRIPTION 26 1 - (4-Bromo-3-nitrophenyl) -4-methylpiperazine (D26) A solution of 1-methyl-4- (3-nitrophenyl) piperazine (EP0533267A) (1.Og, 4.5 mmol) in glacial acetic acid (25 ml) was treated with bromine (0.23 ml, equivalent to 1). The reaction mixture was stirred at 75 ° overnight, then cooled, filtered, and the sticky yellow solid was partitioned between potassium carbonate (aq) and 2% methanol in dichloromethane. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to leave the title compound (D26) as a viscous orange oil (928 mg, 68%) MH + = 300/302.
DESCRIPTION 27 2-Bromo-5- (4-methylpiperazin-1-p-phenylamine (D27) A suspension of iron powder (1.77g, 31.6mmol) in a saturated aqueous ammonium chloride solution (140ml) at 100 ° C was treated dropwise with a solution of 1- (4-bromo-3-nitrophenyl) -4-methylpiperazine (D26) (3.54 g, 11.8 mmol) in methanol (70 ml). The mixture was refluxed for more than 1 h, and subsequently cooled and partitioned between water and 3% methanol and in dichloromethane. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to give a crude product. This was purified by chromatography on silica gel, washing with methanol and dichloromethane to give the title compound (D 27) as a white solid (2.18g, 68%) MH + = 270/272.
DESCRIPTION 28 2-Methoxy-6-methylphenylamine (D28) A solution of 1-methoxy-3-methyl-2-nitrobenzene (15.04 g, 0.09 mol) in ethanol (250 ml) was hydrogenated over 10% palladium on carbon (4g) at atmospheric pressure and at room temperature for 18 h. The catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure to leave the title compound (D28) as an amber oil, which crystallized upon being (11.18 g, 91%). 1 H NMR (250 MHz, CDCl 3) d (ppm): 6.75-6.65 (m, 3 H), 3.81 (s, 3 H), 3.72 (br s, 2 H), 2.19 (s, 3 H).
DESCRIPTION 29 1 - (2-Methoxy-6-methylphenyl) -4-methylpiperazine (D29) A mixture of 2-methoxy-6-methylphenylamine (D28) (3.62 g, 26.4 mmol), mechlorethamine hydrochloride (12.7 g, 66 mmol) and potassium carbonate (15 g) in chlorobenzene (90 ml) was put under reflux under argon. for 20 h. The mixture was cooled and filtered, and the filtrate evaporated under reduced pressure to leave the title compound (D29) as a red oil which crystallized slowly as it was (5.4 g, 93%) MH + = 221.
DESCRIPTION 30 1 - (6-Methoxy-2-methyl-3-nitrophenyl) -4-methylpiperazine (D30) A solution of 1- (2-methoxy-6-methylphenyl) -4-methylpiperazine (D29) (6.2 g, 28 mmol) in concentrated sulfuric acid (50 ml) was treated in portion with potassium nitrate (3.3 g, 33 mmol) for 5 minutes, maintaining the temperature at 25-30 ° C. The mixture was stirred overnight at room temperature, then added to the ice, and basified with 40% sodium hydroxide solution. The mixture was extracted with dichloromethane and the organic phase was dried (Na2SO4) and evaporated under reduced pressure to give a crude compound. Purification by silica gel chromatography washed with methanol and dichloromethane confronted the title compound (D30) (4.56 g 61%) MH + = 266.
DESCRIPTION 31 2-r3-Methoxy-2- (4-methylpiperazin-1 -n-6-nitrophenipetanol (D31) A mixture of 1- (6-methoxy-2-methyl-3-nitrophenyl) -4-methylpiperazine (D30) (360 mg, 1.36 mmol), dry dimethyl sulfoxide (3 ml), paraformaldehyde (82 mg, 2.72 mmol) and potassium tert-butoxide (52 mg, 0.46 mmol) was heated at 70-75 ° for 30 h. After cooling, the mixture was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4), evaporated under reduced pressure and purified by chromatography on silica gel, washing with methanol and dichloromethane to give the title compound (D31) as a yellow solid (152 mg, 38%) MH + = 296 DESCRIPTION 32 2-r6-Amino-3-methoxy-2- (4-methylpiperazin-1-yl) phenylethanol (D32) The title compound (D32) was prepared from 2- [3-methoxy-2- (4-methylpiperazin-1-yl) -6-nitrophenyl] ethanol (D31) (142 mg, 0.48 mmol) using the method of the Description 28 as a clear oil that crystallizes when present (94 mg, 74%) MH + = 266.
DESCRIPTION 33 4-Methoxy-2-methyl-3 (4-methylpiperazin-1-Q-phenylamine (D33) The title compound (D33) was prepared from 1- (6-methoxy-2-methyl-3-nitrophenyl) -4-methylpiperazine (D30) (150 mg, 0.56 mmol) using the method of Description 28 as a colored powder cinnamon (78 mg, 59%) MH + = 236.
DESCRIPTION 34 1 - (2-Methoxy-4-nitrophenyl) -4-methylpiperazine (D34) A mixture of N-methylpiperazine (216 mg, 2.15 mmol), 2-bromo-5-nitroanisole (1 g, 4.3 mmol), potassium carbonate (447 mg, 3.23 mmol), copper bromide (I) (86.6 mg, 0.30 mmoles) in pyridine (0.5 ml) and toluene (2 ml) was heated at 100 ° C overnight. After cooling, the mixture was partitioned between water and ether and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and evaporated under reduced pressure to give the crude product. This was purified by chromatography on silica gel, washed with methanol and dichloromethane, to give the title compound (D34) as a yellow / brown oil (80 mg, 15%) MH + = 252.
DESCRIPTION 35 3-Methoxy-4- (4-methylpiperazin-1-p-phenylamine (D35) The title compound (D35) was prepared from 1- (2-methoxy-4-nitrophenyl) -4-methylpiperazine (D34) (80 mg, 0.319 mmol) using the method of Description 28 (50 mg, 71%) MH + = 222.
DESCRIPTION 36 4- (2-Methoxy-5-nitropheninpyridine (D36) A stirred mixture of 2-bromo-4-nitroanisole (7.6g, 32.7 mmol), 4-pyridineboronic acid (4.07 g, 33 mmol) and powdered sodium carbonate (13.8 g, 5 equivalents) in 1: 1, 2-dimethoxyethane: water (1, 360 ml) was degassed for 0.5 hr, by passing an argon stream. Palladium tetrakistriphenylphosphine (0) (1.35 g) was added, and the mixture was cooled, the solvents evaporated under reduced pressure to about half the volume and the aqueous residue was acidified with 5N hydrochloric acid and washed with ethyl acetate. The acid phase was then basified with solid potassium carbonate, and extracted into ethyl acetate, the organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the title compound (D36) as a pale yellow solid ( 3.4g, 45%). 1 H NMR (250 MHz, CDCl 3) d (ppm): 8.7 (d, 2 H), 8.32 (d, 1 H), 8.29-8.25 (m, 1 H), 7.47 (d, 2 H), 7.09 (d, 1 H), 3.96 (s, 3H).
DESCRIPTION 37 4- (2-Methoxy-5-nitrophenyl) -1-methyl-1, 2,3,6-tetrahydropyridine (D37) A solution of 4- (2-methoxy-5-nitrophenyl) pyridine (D36) (3.4 g, 14.8 mmol) in acetone (150 ml) was treated with excess iodomethane (5 ml) and the mixture was stirred at room temperature. atmosphere all night. The precipitated quaternary salt was filtered, washed with acetone and dried, yielding 5.02 g. This dissolved in ethanol 1: 1: water (230 ml) and treated in portion at room temperature, under argon, with sodium borohydride (1.23 g, 32.4 mmoles). The mixture was stirred for 1 h at room temperature then potassium carbonate (10 g) was added and the organic layer was separated from the aqueous phase, which was back-extracted with ethyl acetate. The organic phases were combined and dried (Na2SO4) and evaporated under reduced pressure to give the title compound (D37) as an orange oil, which slowly crystallized (3.05 g, 91%). 1 H NMR (250 MHz, CDCl 3) d (ppm): 8.15 (d, 1 H), 8.05 (s, 1 H), 6.9 (d, 1 H), 5.9-5.84 (m, 1 H), 3.9 (s, 3H), 3.15-3.05 (m, 2H), 2.7-2.61 (m, 2H), 2.6-2.5 (m, 2H), 2.4 (s, 3H).
DESCRIPTION 38 4-Methoxy-3- (1-methylpiperidin-1-di-phenylamine (D38) A solution of 4- (2-methoxy-5-nitrophenyl) -1-methyl-1, 2,3,6-tetrahydropyridine (D37) 1.0 g, 4 mmol) in ethanol (50 ml) and glacial acetic acid (5 ml) ) was hydrogenated on 10% palladium in carbon at 50 ° C and 3.52 kg / cm2 for 4 days. The catalyst was removed by filtration, the filtrate evaporated under reduced pressure and the residue divided between potassium carbonate (ac) and dichloromethane. The organic phase was dried (Na2SO) and evaporated under reduced pressure to give the title compound (D38) as a brown oil which was rapidly crystallized to a tan powder (760 mg, 86%). MH + = 221.
DESCRIPTION 39 4-Methoxy-3- (1-methyl-1, 2,3,6-tetrahydropyridine-4-iD-phenylamine hydrochloride (D39) A solution of 4- (2-methoxy-5-nitrophenyl) -1-methyl-1, 2,3,6-tetrahydropyridine (D37) (570 mg, 2 mmol), in ethanol (35 ml, was heated to 60 ° C). C and treated in drops with a solution of stannous chloride (2g) in concentrated hydrochloric acid (4 ml) The mixture was heated for more than 2 h after the addition, and allowed to cool. The precipitate was filtered and washed with ethanol to give the title compound (D39) as a pale yellow powder (580 mg, 99%). MH + = 219.
GENERAL PREPARATION OF CHLORHYDRATES OF ARIL-N- (4-METOXY-3- PIPERAZIN-1-IDBENCENSULFONAMIDE IN SOLID PHASE DESCRIPTION 40 Preparation of 1- (2-methoxy-5-nitropheni Piperazin-4-yl bound to Merrifield resin A solution of 1- (2-methoxy-5-nitrophenyl) piperazine (9.7g) in N-methylpyrrolidin-2-a (NMP) (150 ml) was heated with chloromethylpolystyrene-divinylbenzene resin (Merrifield, 150-300 bond) at 60 ° C for 24 h under argon. The resin was then filtered, washed (NMP, trichloromethane / ethanol gradient) and dried to give the title compound (6.9g) which was used directly in Description 41.
DESCRIPTION 41 Preparation of 1- (5-amino-2-methoxyphenyl) piperazine-4-yl bound to the Merrifield resin A solution of stannous chloride dihydrate (9g) in N, N-dimethylformamide (DMF) (120ml) was stirred for 72 h at room temperature under argon with the resin of Description 40 (6.9 g). The resin was filtered, washed (DMF, dichloromethane / methanol gradient) and dried to give the title compound (6.6g) which was used directly in Description 42.
DESCRIPTION 42 General preparation of aryl-N- (4-methoxy-3- (4-polyimerylpiperazin-1-iP-benzenesulfonamide bound to Merrifield resin A solution of arylsulfonic chloride (0.4 mmol) and diisopropylethylamine (1 mmol) in dichloromethane (3 ml) was stirred for 24 h at room temperature with resin (0.1 mmol) of Description 41. The resin was subsequently filtered, washed (dichloromethane, dichloromethane gradient). methanol: methanol) to give the title compound that was used directly in Examples 133-137.
DESCRIPTION 43 (S) -1 -Methyl-2- (2-methoxy-5-nitrofenoxp-pyrrolidine (D43) A solution of 2-methoxy-5-nitrophenol (5.58 g, 0.033 mmol), (S) -1-methyl-2-hydroxymethylpyrrolidine (3.45 g, 0.03 mol) and triphenylphosphine (8.65 g, 0.033 mmol) in dry THF (80 ml) ) was cooled to 5 ° and treated with DEAD (5.2ml, 0.033 moles) for 15mil. The reaction mixture was allowed to stand at RT for 16 h, then it was evaporated in vacuo and 5% NaOH (aq) / Et20 was divided. The organic phase was separated and extracted with 10% HCl (aq). The aqueous extract was washed with Et20, basified with 40% NaOH (aq) and extracted with Et20. The organic extracts were washed with H2O, dried over Na2SO4 and evaporated in vacuo to give the title compound (D43) (6.79g, 85%) MH + = 267.
DESCRIPTION 44 (S) -1-methyl-2 - (2-methoxy-5-aminophenoxypyrrolidine (D44) A solution of (S) -1-methyl-2- (2-methoxy-5-nitrophenoxy) pyrrolidine (D43) (6.79g, 0.0255 mmol) in ethanol (200 ml) was hydrogenated in the presence of 5% Pd / C catalyst (0.5g added as an aqueous paste) at atmospheric pressure and RT for 16 hours. The catalyst was removed by filtration through the Kieselguhr apparatus and the filtrate was evaporated in vacuo to give the title compound (D44) (5.64g, 93%) MH + = 237.
EXAMPLE 1 N-r4-methoxy-3- (4-methyl-1-piperaziniP-phenynthiophen-2-ylsulfonamide A solution of thiophene-2-sulfonyl chloride (82mg, 0.45mmol) in acetone (2ml) was added to a solution of 4-methoxy-3- (4-methylpiperazin-1-yl) aniline (100mg, 0.45mmol). ) in acetone (2ml) and the mixture was overnight at room temperature. The resulting crystalline solid was filtered and washed with acetone then diethyl ether, to face the title compound as the hydrochloride salt. (153mg, 84%). MS: m / z = 368. The following compounds were prepared in a similar manner.
PREPARATION OF ARIL-N- (4-METOXY-3-PIPERAZIN-1- ILFENlLiBENCENSULFONAMIDAS These compounds were prepared by using one of the three general methods as summarized below.
GENERAL METHOD 1 Examples 68-75 were prepared by the following general method of the corresponding N-methylpiperazine analogues: A solution of chloroethylchloroformate (1.7 mmol) and N- [4-methoxy-3- (4-metii-1-p-piperazine) 1) phenyl] -arylsulfonamide (0.34 mmol) in 1,2-dichloroethane (4 ml) was refluxed for 0.75 h, cooled, diluted with diisopropylethylamine (1.7 mmol) and put under reflux for 2.5 hours. The solution was concentrated to a residue which was a re-dissolved methanol, put under reflux for 1 hour and then stirred at room temperature for 24 h. The mixture was concentrated, and the residue divided between the ethyl acetate and the 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 hydrochloride salt of the product was prepared by dissolving the pure chromatography material in acetone / dichloromethane and acidified with ethereal HC1.
Examples 76-86 were prepared by following the general method of the appropriate N-Boc derivative (D4-D14): A stirred solution of the appropriate N-Boc derivative (D4-D14) (10.3 mmole) in methanol (100 ml) and HC1 ethereal 1 M (51.6 ml) was heated at 60 ° C for 1.5 h. Subsequently the mixture was concentrated and the residue stirred with acetone to confront the following title compounds as hydrochloride salts.
EXAMPLE 83 5-Chloro-3-methylbenzeneyl thiophen-2-suphonic acid (4-methoxy-3-piperazin-1-ylphen-5-chlorohydrate (E83) A stirred suspension of 5-chloro-3-methylbenzene [b] thiophene-2-sulfonic acid (4-tert-butoxycarbonylpiperazin-1-yl) phenylamide (D10) (193 g) in tetrahydrofuran id roturan (820 ml) and concentrated hydrochloric acid (180 ml) was heated under reflux for 1.75 h after which a solution was obtained.The solution was concentrated and the residue was dissolved in hot ethanol (600 ml). a solid precipitate that was filtered and recrystallized (ethanol / water 1: 1) to give the title compound (E83) as a white solid, mp 276-280 ° C (dec.) (142 g, 83 %) dH (250 MHz, D6-dmso) 2.29 (3H, s), 2.90 (4H, br s), 3.01 (4H, br s), 3.55 (3H, s) 6.54-6.71 (3H, m), 7.42 (1 H, d, J 8.8 Hz), 7.85 (1 H, s), 7.93 (1 H, d, J 8.8 Hz), 9.03 (2 H, br s), 10.3 (1 H, br s), MH + 452 .
GENERAL METHOD 3 Examples 87-94 were prepared by the following general method: A solution of appropriate arylsulfonyl chloride (0.47 mmol) and the aniline of D16 (0.47 mmol) in dichloromethane (4 ml) and pyridine (2.4 mmol) was stirred for 18 h room temperature. The mixture was washed with 1 M aqueous HC1 subsequently with water. The layers were separated and for the organic one 4.4M aqueous KOH (1.4 mmol) was added with vigorous stirring for 18 h. A similar volume of 10% phosphate buffer was added to the heterogeneous mixture. The layers were again separated and the organic phase was dried and diluted with 1M ethereal HC1 to face the hydrochloride salts of the following compounds as can be seen.
EXAMPLES 95-108 The derivative dihydrobenzofuran, below, was prepared as WO 95/11243 (Glaxo) and coupled with the appropriate arylsulfonyl chlorides in a manner described in the Example to face the following compounds: EXAMPLES 109-110 The following compounds were prepared from the corresponding N-methyl analogs by means of the general method described by Examples 68-75: EXAMPLE 111 r3- (4-cyclopropylmethyl-piperazin-1-iP-4-methoxy-feninamide 5-chloro-3-methylbenzofb1thiophen-2-suphonic acid (E111) For a solution 3- (4-benzyl-p¡perazin-1-yl) -4-methoxy-phenylamine (D22) (1 mmole) in acetone (5 ml) was added 5-chloro-3-methylbenzothiophen-2 chloride -sulphonyl (1 mmol). Stirring was continued at room temperature for 14 hours. The hydrochloride salt of the sulfonamide was combined by filtration, triturated with diethyl ether and dried under vacuum in 42% yield. Found MH + 506/508.
EXAMPLE 112 I3- (4-benzyl-p-piperazin-1-p-4-methoxy-phen-amide of 5-chloro-3-methylbenzene-bophioth-2-sulphonic acid (E112) The title compound was prepared in a 32% yield using the procedure outlined for E111. Found MH + 542/544.
EXAMPLE 113 5-Chloro-3-methyl-benzorbltiophen-2-sulfonic acid (4-methyl-piperazin-1-yl) -phene-3-hydroxy-3-methyl-3-methyl-3-hydroxy-3-methyl (E113) For a suspension of boron tribromide-dimethyl sulfide complex (620 mg, 2 mmol) in 1,2-dichloroethane (30 ml) under argon was added [4-methoxy-3- (4-methyl-pirerazin-1-yl) 5-chloro-3-methyl-benzo [b] thiophene-2-suphonic (E17) phenyl] (0.2 mmole). The reaction mixture was heated to reflux for 12 hrs, cooled, quenched by the addition of water (20 ml) and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel to face the title compound (E113). Found MH + 452/454.
GENERAL METHOD FOR THE PREPARATION OF EXAMPLES 114-116 A solution of 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [4-hydroxy-piperazin-1-yl) -phenyl] -amide (E113) (100 mg , 0.22 mmole) and 18-Crown-6 (58 mg, 0.22 mmol) in DMF (0.5 ml) was added to potassium hydride (35% dispersion in mineral oil, 50 mg, 0.44 moles) at room temperature under argon. After 10 minutes a solution of the alkylating agent (0.22 mmoles) in DMF (0.3 ml) was added and stirring continued for 12 hrs. The reaction mixture was warmed with water and then concentrated in vacuo before being partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica to face the following final alkylation compounds.
EXAMPLE 114 5-Chloro-3-methyl-benzofbltiofen-2-suphonic acid (4-methyl-piperazin-1-yl) -phene-3-benzyloxy-3-methyl-4-methyl-4-methyl-3-benzofbltiophen-2-sulfonic acid (E114) Prepared in a yield of 22% using benzyl bromide. Found MH + 542/544.
EXAMPLE 115 5-Chloro-3-methyl-benzoyltiofen-2-suphonic acid (4-methyl-piperazin-1-yl) -pheno-3-methyl-3-methyl-4-methyl-4-methyl-3-methyl (E115) Prepared in a yield of 28% using the procedure summarized above using ethyl iodide. Found MH + 480/482.
EXAMPLE 116 f4-5-chloro-3-methyl-benzorbltiophen-2-sulfonic acid (4-methyl-piperazin-1-iP-phenan-3-methyl-3-methyl-4-methyl-4-methyl-4-methyl-4-methyl-4-methyl) Prepared in a yield of 20% using the procedure summarized above using 2-iodopropane. Found MH + 494/496.
EXAMPLE 117 r4-methoxy-3- (1-methyl-pyrrolidin-3-yloxy) -phenn-amide of 5-chloro-3-methyl-benzorbltiophen-2-suphonic acid (E117) The title compound was prepared in a 48% yield of D25 and 5-chloro-3-methylbenzothiophen-2-sulfonyl chloride as described for E11. Found MH + 467/469.
EXAMPLE 118 f2-bromo-5- (4-methylp-eperazin-1-vPfenin-naphthalene-2-sulfonic acid amide (E118) The title compound (E118) was prepared from the naphthalene-2-sulfonyl chloride (100 mg, 0.44 mmol) and 2-bromo-5- (4-methylpiperazin-1-yl) phenylamine (D27) (120 mg, 0.44 mmol) using the method of Example 1 (85 mg, 35%) MH + = 460/462.
EXAMPLE 119 5-Chloro-3-methylbenzorbltiophen-2-suphonic acid 4-chloro-3- (4-methyl-piperazin-1-yl) -phenip-amide (E119) The title compound (E119) was prepared from 4-chloro-3- (4-methylpiperazin-1-yl) benzenamine (EP 0533267A, intermediate 42) (50 mg, 0.22 mmol) and 5-chloro-3-methylbenzoyl chloride [b] thiophene-2-sulfonyl (62 mg, 0.22 mmol) using the method of Example 1 (49 mg, 44%) MH + = 470/472.
EXAMPLE 120 Naphthalen-2-Suphonic acid (4-methyl-piperazin-1-yl) -phenyl-1-amido-4-bromo-3 (4-methyl-piperazin-1-yl) -phenyl-1-amide (E120) The title compound (E120) was prepared from 4-bromo-3- (4-methylpiperazin-1-yl) benzenamine (EP 0533267A, intermediate 61) (600 mg, 2.23 mmol) and naphthalene-2-sulfonyl chloride (504). mg, 2.23 mmoles) using the method of Example 1 (939 mg, 92%) MH + = 460/462.
EXAMPLE 121 r3- (5-Chloro-3-methylbenzorbltiophen-2-sulphonic acid (2-dimethylaminoethoxy-4-iodophen-amide) (E121) The title compound was prepared from 3- (2-dimethylaminoethoxy) -4-iodoaniline (WO95-15954, Description 50) (109 mg, 0.36 mmol) and 5-cyclo-3-methylbenzo [b] thiophen-2-chloride. sulfonyl (100 mg, 0.36 mmol) using the method of Example 1 (70 mg, 36%) MH + = 551/553.
EXAMPLE 122 f1 - (2-dimethylaminoetiP-2,3-dihydro-1 H-indol-6-in-amide of 5-chloro-3-methylbenzorbltiophen-2-suphonic acid (E122) The title compound (E122) was prepared from 1- (2-dimethylaminoethyl) -2,3-dihydro-1 H-indol-6-ylamine (WO95 / 32967 Description 4) (100 mg, 0.49 mmol) and sodium chloride. -chloro-3-methylbenzo [b] thiophene-2-sulfonyl (137 mg, 0.49 mmol) using the method of Example 1 (40 g, 18%) MH + = 450/452.
EXAMPLE 123 1- (5-Chloro-3-methylbenzofethiofen-2-sulfoniP-6- (4-methylpiperazin-1-yl) -2,3-dihydro-1H-indole (E123).
The title compound (E123) was prepared from 6- (4-methylpiperazin-1-yl) -2,3-dihydro-1 H-indoI (prepared from 3-nitroaniline, using WO95 / 06637 Intermediate 39 (39 mg, 0.18 mmol) and 5-chloro-3-methylbenzo [b] thiophene-2-sulfonyl chloride (50 mg, 0.18 mmol) using the Example 1 (75 mg, 84%) MH + = 462/464.
EXAMPLE 124 1- (5-Chloro-3-methylbenzorbltiophen-2-sulfonyl) -5-methoxy-6- (4-methyl-piperazin-1-yl) -2,3-dihydro-1H-indole (E124) .
The title compound (E124) was prepared from 5-methoxy-6- (4-methylpiperazin-1-yl) -2,3-dihydro-1 H-indole (WO95 / 06637 Intermediate 3) (99 mg, 0.4 mmol ) and 5-chloro-3-methylbenzo [b] thiophene-2-sulfonyl chloride (113 mg, 0.4 mmol) using the method of Example 1 (194 mg, 92%) MH + = 492/494.
EXAMPLE 125 r-Methoxy-2-methyl-3- (4-methyl-piperazin-1-yl) -phenol-5-chloro-3-methylbenzofbltiofen-2-suphonic acid (E125) The title compound (E125) was prepared from 4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) penilamine (D33) (58 mg, 0.247 mmol) and 5-chloro-3- chloride. methylbenzo [b] thiophene-2-sulfonyl (70 mg, 0.247 mmol) using the method of Example 1 (103 mg, 81%). MH + = 480/482.
EXAMPLE 126 F2- (2-hydroxyetiD-4-methoxy-3- (4-methyl-piperazin-1-ylamide of 5-chloro-3-methylbenzorbltiophen-2-suphonic acid (E126)) The title compound (E126) was prepared from 2- [6-amino-3-methoxy-2- (4-methylpiperazin-1-yl) phenol] ethanol (D32) (74 mg, 0.28 mmol) and 5-chloro-3-methylbenzo [b] thiophene-2-sulfonyl (78 mg, 0.28 mmol) using the method of Example 1 (18 mg, 13%). MH + = 510.
EXAMPLE 127 1 - (5-Chloro-3-methyl-benzyl-1-thiophen-2-sulfonyl) -5-methoxy-4- (4-methyl-piperazin-1-yl) -2,3-dihydro-1H-indole hydrochloride (E127) A mixture of 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [2- (2-hydroxyethyl) -4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide (E126) (218 mg, 0.25 mmol) and triphenyl phosphine (183 mg, 0.375 mmol) in THF (5 ml) under argon, was treated with a solution of diethylazodicarboxylate (110 mg, 0.375 mmol) in dry THF (5 ml). The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was partitioned between dilute hydrochloric acid and ethyl acetate. The acid layer was basified with 40% sodium hydroxide and back extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the crude product, which was purified by chromatography on silica gel, washed with methanol and dichloromethane and the hydrochloride salt was formed (52 mg, 23%) MH + = 492/494.
EXAMPLE 128 5-Chloro-3-methylbenzofbltiofen-2-suphonic acid f3-methoxy-4- (4-methyl-piperazin-1-yl) phenin-amide (E128) A solution of 3-methoxy-4- (4-methylpiperazin-1-yl) phenol amine (D35) (50 mg, 0.23 mmol) and 5-chloro-3-methyl-benzo [b] thiophen-2-sulfonyl chloride ( 64 mg, 0.23 mmole) in dichloromethane (2 ml) was allowed to stand at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with potassium carbonate (aq), which was back-extracted with additional dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated under reduced pressure to give a crude product, which was purified by chromatography on silica gel, washing with methanol and dichloromethane. This gave the title compound (E128) as a whitish solid (36 mg, 34%) MH + = 466.
EXAMPLE 129 4-Bromo-N-r4-methoxy-3- (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-pfenipbenzenesulfonamide (E129) The title compound (E129) was prepared from 4-methoxy-3 (1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl) phenylamine (free base of D39) (107 mg, 0.49 mmol) and 4-bromobenzenesulfonyl chloride (125 mg, 0.49 mmol) using the method of Example 1 (179 mg; %) MH + = 437/439.
EXAMPLE 130 r4-methoxy-3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) 5-chloro-3-methylbenzorb-thiophen-2-suphonic acid phenylamide (E130) The title compound (E130) was prepared from 4-methoxy-3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenylamine (free base of D39) (100 mg, 0.46 mmol) and 5-Chloro-3-methylbenzoyl [b] thiophene-2-sulfonyl chloride (129 mg, 0.46 mmol) using the method of Example 1 (177 mg, 77%). MH + = 463/465.
EXAMPLE 131 5-Chloro-3-methylbenzorb] thiophene-2-suphonic acid 4-methoxy-3- (1-methylpiperidin-4-ylphenyl] amide (E131) The title compound (E131) was prepared from 4-methoxy-3- (1-methylpiperidin-1-yl) phenylamine (D38) (150 mg, 0.68 mmol) and 5-chloro-3-methylbenzoyl chloride [b ] thiophen-2-sulfonyl (192 mg, 0.68 mmol) using the method of Example 1 (108 mg, 32%) MH + = 465/467.
EXAMPLE 132 r3- (4methylpiperzin-1-yl) fenipamide of naphthalene-2-suphonic acid (E132) The title compound (E132) was prepared from 3- (4-methylpiperazin-1-yl) benzenamine and naphthalene-2-sulfonyl chloride according to the method of Example 1 MH + = 382.
Preparation of aryl-N- (4-methoxy-3-piperazin-1-yl) -benzenesulfonamide hydrochloride in solid phase (Examples 133-137) The resin of description 42 was stirred for 24 h at room temperature with a solution of 1-chloroethylchloroformate (1.1 mmol) in dichloromethane (2 ml) subsequently filtered and washed with chloromethane. The filtrate was concentrated and the residue redissolved in methanol (3 ml) and the solution was refluxed for 5 h. Subsequently the solution was concentrated to give the title compound. The following compounds were prepared as described above: EXAMPLE 138 2,3-Dichloro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide (E138) MS (MH +) 430/432 was prepared according to the general method of Example.
EXAMPLES 139-141 The following compounds were prepared in a manner analogous to Examples 68-75.
EXAMPLE 142 r4-Methyl-3- (4-methyl-piperazin-1-yl) -phennamide of 5-chloro-3-methylbenzo-T-thiophen-2-sulfonic acid (E142) The title compound (E142) was prepared from 5-chloro-3-methylbenzo [b] thiophene-2-sulfonyl chloride and 4-methyl-3- (4-methylpiperazin-1-yl) benzenamine according to the method of Example 1 MH + = 448/450.
EXAMPLE 143 (S) -5-Chloro-3-methylbenzorb] thiophene-2-suphonic acid (S143) r4-methoxy-3- (1-methylpyrrolidin-2-ylmethoxy) phenamide.
A solution of (S) -1-methyl-2- (2-methoxy-5-aminophenoxy) pyrrolidine (D44) (0.22; 9.3 x 10"4 moles) in DCM (10 ml) containing DIPEA (0.162 ml; 9.3 x 10" 4 moles) was treated with 5-chloro-3-methylbenzene-2-sulfonium chloride (0.262). 9.3 x 10"4 moles) in portion, stirred at RT for 18 h, then evaporated in vacuo and the residue purified by silica gel column chromatography Sep-Pak with 2% MeOH / DCM as eluent to give the title as a clear, colorless gum (0.14 g, 31%) This was converted to hydrochloride salt with HCl in Et20 (0.31 ml of a 1.0 M solution) with trituration to give the title compound (E143) as the salt as a solid white crystalline (0.13) MH + = 481/483.
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 a 5 mM tris 5 pH regulator (pH 7.7). @ 25 ° C). The solution was aided with the addition of 0.02 ml of 5M HCl plus heating at 40 ° C and sound treatment for 10 minutes. The attenuated serial solutions of drugs in the same pH regulator were carried out using a TECAN 5052 or Biomek 2000 workstation. Samples of the diluted test compounds (0.05 ml) were combined with 0.05 ml of radio-ligand [ 3H] -LSD prepared in the pH buffer of incubation and 0.4 ml of a suspension of a washed membrane preparation of HeLa_5HT6 cells (purchased from Dr. D. Sibley, NIH, Bethesda, see Ref 1) (see Table 1), also in the incubation pH regulator. The details of the incubation conditions for each assay are shown in Table 2. The incubation pH regulator was 50 mM Trizma (Sigma, UK) pH 7.7 @ 25 ° C, MgCl24 mM. After incubation at 37 ° C, the mixtures were filtered using a Packard filter in Packard TopCount format. The filters were washed with 4 x 1 ml aliquots of the cold ice incubation pH regulator. The filters were dried and impregnated with 0.04 ml of Microscint 20 (Packard). The Clß values were estimated from the counts per minute using a 4-parameter logistic curve fitted within EXCEL (2). The K i values were calculated using the Cheng and Prusoff method (3). plC50 and pKi are log 10 negatives of molar Cl50 and K1 respectively.
TABLE 1 Details of the methods used to prepare the membranes to join the assays TABLE 2 Summary of the conditions of the receptor binding assay References 1. MONSMA, F.J., SHEN, Y., WARD, R.P., HAMBLIN, M.W., SIBLEY, D.R., 1993. Cloning and 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 causes 50% inhibiton (IC50) of an enzymatic reaction. Biochem. Pharmacol., 92, 881-894. The compounds of examples 11, 15, 17, 61, 65, 70, 72, 77, 78, 79, 83, 84, 87 and 90 are all shown to be particularly good selective 5-HT6 receptor antagonist activity, having pKi values above 8.0 at 5-HT6 receptors cloned in humans.

Claims (16)

NOVELTY OF THE INVENTION CLAIMS
1. - A compound of the formula (I) or a salt thereof:
(OR where: P is phenyl, naphthyl, or bicyclic heterocyclic ring or is a 5- to 7-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur; A is a single bond, an alkylene group of C? -6 or an alkenylene group of C? -6, R1 is halogen, C6 alkyl optionally substituted by one or more halogen atoms, C3 cycloalkyl. 6, CO-C6 alkyl, C6-6 alkoxy, OCF3, hydroxy, hydroxy-C6 alkyl, C6-6 hydroxyalkoxy, C6-6 alkoxy-C6-alkoxy, alkanoyl of C -? - 6, acyl, nitro, amino, C 1-6 alkylamino or C? -6 dialkylamino, cyano or R 1 is phenyl, naphthyl, or bicyclic heterocyclic ring or is a 5- to 7-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; n is O, 1, 2,3,4,5, 0,6, R 2 is hydrogen, d-6 alkyl or arylalkyl of Ci-β; R3 is a group R5 or together with R5 forms a group (CH2) 2O or (CH2) 3O or R3 is attached to R2 to form a group (CH2) 2 or (CH2) 3; R4 is X (CH2) p-R6 where X is a single bond, CH 2, O, NH or N-C 1-6 alkyl and p is 0 to 6 and R 6 is an optionally substituted 5- to 7-membered heterocyclic ring containing from 1 to 3 heteroatoms selected from nitrogen, sulfur or oxygen, or R6 is NR7R8 where R7 and R8 are independent of hydrogen, C? -6 alkyl or aryl-alkyl of d.6; and R5 is hydrogen, halogen, C---6 alkyl, C3.6 cycloalkyl, C alquilo? --6 alkyl, C? -6 alkoxy, hydroxy, C? -6 hydroxyalkyl, C h h h hiroxyalkoxy. ? -6, C? -6 alkoxy, C? -6 alkoxy, C1-6 alkanoyl, nitro, trifluoromethyl, cyano or aryl. Whenever when the group R4 is (CH2) P-NR7R8 and A is a single bond, then P is not naphthyl or quinolino. 2. A compound according to claim 1, wherein P is phenyl, thiophene, benzothiophene or naphthyl.
3. A compound according to claim 1 or 2, wherein R1 is halogen or C6 alkyl optionally substituted by one or more halogen atoms.
4. A compound according to any of claims 1 to 3, wherein R2 is hydrogen.
5. A compound according to any of claims 1 to 4, wherein R4 is a piperazine ring optionally substituted by C-? -6 alkyl.
6. - A compound according to any of claims 1 to 5, wherein R4 is a non-substitutable piperazine ring.
7. A compound according to any of claims 1 to 6, wherein R5 is a C6_6 alkoxy.
8. A compound according to any of claims 1 to 7, wherein R5 is para in relation to the sulfonamide linkage.
9. A compound according to any of claims 1 to 8, wherein P-A is 5-chloro-3-methyl-benzo [2] thiophen-2-yl.
10. A compound according to claim 1 which is: 4-Bromo-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, N- [4-methoxy-3-] (4-methylpiperazin-1-yl) phenyl] -2-thiophenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -5- (pyridin-2-yl) - 2-thiophenesulfonamide, 2,5-Dichloro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -3-thiophenesulfonamide, 4-Bromo-5-chloro-N- [ 4-methoxy-3- (4-methyl-piperazin-1-yl) -pheno] -2-thiophenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 3-Bromo-5 -chloro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -2-thiophenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 2-Bromo-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 3-Bromo-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl) ] benzenesulfonamide, 3-chloro-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -4-methyl-benzenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1- il) phenyl] -frans-styrenesulfonamide, 3,4-Dichloro-N- [4-methoxy-3- (4-methylpiperazine -1-yl) phenyl] benzenesulfonamide, 3,5-Dichloro-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, N- [4-Methoxy-3- (4-methylpiperazin-1-yl) phenyl] - [2,1, 3] benzothiadiazole-4-sulfonamide, 5-Chloro-N- [4-methoxy-3- (4 -methylpiperazin-1-yl) phenyl] -3-methyl-2-benzothiophenesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) phenyl] -2-methyl-5-nitro-benzenesulfonamide, N - [4-Methoxy-3- (4-methylpiperazin-1-yl) phenyl] -2-trifluoromethyl-benzenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -3-trifluoromethyl -benzenesulfonamide, 2,5-dimethoxy-N [4-methoxy-3- (4-methylpiperazin-1-l) phenyl] -benzenesulfonamide, 4-Fluoro-N [4-methoxy-3- (4-methyl-piperazin-1- l) fenii] benzenesulfonamide, 4-chloro-N [4-methoxy-3- (4-methylpiperazin-1-l) phenyl] benzenesulfonamide, 4-iodo-N [4-methoxy-3- (4-methylpiperazine-1 - l) phenyl] benzenesulfonamide, 4-Ethyl-N- [4-methoxy-3- (4-methylpiperazin-1-l) phenyl] benzenesulfonamide, 4-7er-Butyl- [4-methoxy] 3- ( 4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, 4-lsopropyl-N [4-methoxy-3- (4-methylpiperazin-1-: l) phenyl] benzenesulfonamide, 4-Ter-Amyl-N [4-methoxy] 3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, N- [4- Methoxy-3- (4-methyl-piperazin-1-yl) phenyl] -4-trifluoromethoxy-benzenesulfonamide, 4-n-Butoxy-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide , N- [4-Methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -4-methyl-benzenesulfonamide, 5-CIOR-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -2-thiophenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -1-naphthalenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -2-naphthalenesulfonamide, 5- (D-methylamino) -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -1-naphthalenesulfonamide, 4-Bromo-N- [7 - (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] -benzenesulfonamide, 4-methoxy-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 4-n-ButyI-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 4-amino-N- [4-methoxy-3- (4-methyl-piperazine-1-yl) phenyl] benzenesulfonamide, 2-chloro-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, 3-chloro-N- [4-methoxy-3- (4-methyl-piperazin-1-) il) phenyl] benzenesulfonamide, 2,3,4-trichloro-N- [4-methoxy-3- (4-methyl) perazin-1-yl) phenyl] benzenesulfonamide, 4-chloro-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -2,5-d, methyl-benzenesulfonamide, N- [ 4-Methoxy-3- (4-methylpiperazin-1-yl) phenyl] -3-methylbenzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N- [4-methoxy-3- (4-methylpiperazin-1- il) phenyl] benzenesulfonamide, N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -2,3,5,6-tetramethyl-benzenesulfonamide, 5-chloro-2-methoxy-N- [ 4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -benzenesulfonamide, 3-Fluoro-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonam da, 3,4-Difluoro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 4-chloro-N- [4-methoxy-3- (4-methyl-piperazin-1) -yl) phenyl] -3-nitro-benzenesulfonamide, 3-Chloro-N- [4-methoxy -3- (4-methylpiperizin-1-yl) phenyl] -2-methyl-benzenesulfonamide, N- [4- Methoxy- 3- (4-methyl-piperazin-1-yl) phenyl] -8-quinolinesulfonamide, N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -4-phenylbenzenesulfonamide, 3,4-D-methoxy -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] -benzenesulfonamide, N- [4- Methoxy-3- (4-methylpiperazin-1-yl) phenyl] -3,5-dimethyl-1-4-isoxazolesulfonamide, 4-Bromo-N- [4-methoxy-3- (4-ethylpiperazin-1-yl) phenyl ] benzenesulfonamide, 2,3-Dichloro-N- [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -benzenesulfonamide, 5-iodo-N- [4-methoxy-3- (4-methylpiperazine -1-yl) phenyl] -. 2-methy1-benzenesulfonamide, 3-Iodo-N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] benzenesulfonamide, 3-Yodo-N- [4- methoxy-3- (4-methyl-piperazin-1-yl) phenyl] -4-methyl-benzenesulfonamide; [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide; 5-chloronaphthalene-1-sulfonic acid, 4-methoxy-3- (4-methylpiperazine-1-chloronaphthalene-2-sulphonic acid, [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide] 4-Chloronaphthalene-1-sulfonic acid, [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide of 7-chloronaphthalene-1-suphonic acid, [4-methoxy] 5-Chloro-2-methyl-benzo [b] thiophene-3-sulfonic acid, 3- [4-methyl-piperazin-1 -yl) -phenyl] -amide, [4-methoxy-3- (4-methyl-piperazin-1-yl) -phenyl] benzofuran-2-sulfonic acid amide, [ 4-methoxy-3- (4-methyl-piperazin-1-yl) -phene] 1-methyl-1H-indole-2-sulfonic acid amide5-Pyridin-2-ylthiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) -amide, N- (4-methoxy-3-piperazin-1-ylphenyl) -3-trifluoromethylbenzenesulfonamide; -Yodo-N- (4-methoxy-3-piperazin-1-phenyl) benzenesulfonamide, 3,5-dimethylisoxazole-4-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) amide, 3,5- Dichloro-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, (4) sulfonate-2-bromo-5-chlorothiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) -amide 2-bromo-5-chlorothiophene-2-sulphonic acid-methoxy-3-piperazin-1-phenyl-amide; -Cloro-4-fluoro-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, 3-Bromo-N- (4-methoxy-3-piperazin-1-phenyl) benzenesulfonamide, 3-Chloro-N - (4-methoxy-3-piperazin-1-phenyl) benzenesulfonamide, 5-chloronaphthalene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) amide, (4-methoxy-3-piperazine-1) 4-bromo-5-chlorothiophen-2-sulfonic acid amide, (4-methoxy-3-piperazin-1-ylphenyl) ami of 2, 5-dichlorothiophen-3-sulphonic acid, 4-Bromo-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, (4-methoxy-3-piperazin-1-ylphenyl) amide 5-Chloro-3-methylbenzo [b] thiophen-2-sulfonic acid, 5-chloro-2-methyl-benzo [b] thiophene-3-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) amide, ( 4-methoxy-3-piperazin-1-phenylphenyl) 1-methyl-1H-indole-2-sulfonic acid amide, benzofuran-2-sulfonic acid (4-methoxy-3-piperazin-1-phenyl) -amide, Naphthalene-2-suphonic acid (4-methoxy-3-piperazin-1-ylphenyl) -amide, 5-chloronaphthalene-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl) -amide, 4-Chloro-2, 5-Dimethyl-N- (4-methoxy-3-piperazin-1-phenyl) benzenesulfonamide, 3,4-Dichloro-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, 3-chloro -N- (4-methoxy-3-piperazin-2-ylphenyl) -4-methyl-benzenesulfonamide, 2-trifluoromethyl-N- (4-methoxy-3-p-piperazin-1-phenyl) -benzenesulfonamide, 4- Iodine-N- (4-methoxy-3-piperazin-1-ylphenyl) benzenesulfonamide, 4-tert-Butyl-N- (4-methoxy-3-piperazin-1-ylphenyl) ben Cisulfonamide, [7- (4-methylpiperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] naphthalene-1-suphonic acid amide, [7- (4-methyl-piperazin-1-yl) -2, 3 thiophene-2-sulphonic acid dihydrobenzofuran-5-ylide, [7- (4-methylpiperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] 5-chlorothiophen-2-sulfonic acid amide 5-pyridin-2-ylthiophene-2-sulfonic acid [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] -amide, [7- (4-methylpiperazine-1) -l) -2, 3-dihydrobenzofuran-5-yl] 2, 5-dichlorothiophen-3-sulfonic acid, [7- (4-methyl-piperazin-1-yl) -2, 3-dihydrobenzofuran-5-yl) ] 4-bromo-5-chlorothiophen-2-suphonic acid amide, [7- (4-methylpiperazin-1-yl) -2,3-dihydrobenzofuran-5-yl] 3-bromo-5-chlorothiophene acid amide 2-sulphonic acid, 4-chloro-2,5-dimethyl-N- [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl-benzenesulfonamide, [7- (4-methyl-piperazin-1-yl)] ) -2-, 3-dihydrobenzofuran-5-yl] 5-chloro-3-methylbenzo [b] thiophene-2-sulfonic acid, [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran] -5-ii] naphthalene-2-sulfonic acid amide, 3-Bromo-N- [7- (4-methyl-piperazin-1-yl) -2,3-hydrobenzofuran-5-yl] -benzenesulfonamide, 3,5-Dichloro -N- [7- (4-methyl-piperazin-1-yl) -2, 3-dihydrobenzofuran-5-yl] -benzenesulfonamide, 4-tert-Butyl-N- [7- (4-methyl-piperazin-1-yl) -2 , 3-dihydrobenzofuran-5-yl] benzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N- [7- (4-methyl-piperazin-1-yl) -2,3-dihydrobenzofuran-5-yl-benzenesulfonamide, 2, 5-Dibromo-3,6-difluoro-N- (7-methylpiperazin-1-yl-2, 3-dihydrobenzofuran-5-yl) benzenesulfonamide, 4-chloro-2,5-dimethyl-N- (7-piperazin- 1-yl-2, 3-dihydrobenzofuran-5-yl) benzenesulfonamide, [5- (4-cyclopropylmethyl-piperazin-1-yl) -4-methoxy-phenyl] -amide of 5-chloro-3-methylamide benzo [b] thiophene-2-sulphonic, [3- (4-benzyl-piperazin-1-yl) -4-methoxy-phenyl] -5-chloro-3-methyl-benzo [b] thiophene- 5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [4-hydroxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide, [4-benzyl] -3 - (4-methyl-piperazin-1-yl) -phenyl] - 5-c-acid amide paro-3-methyl benzo [b] thiophen-2-sulfonic acid, [4-ethoxy-3- (4-methyl-piperazin-1-yl) -phenyl] -amide of 5-chloro-3-methyl-benzo [b] thiophen-2-sulfonic5-Chloro-3-methyl benzo [b] thiophene-2-sulphonic acid [4-isopropoxy-3- (4-methyl-p1perazin-1-yl) -phenyl] -amide, [4-methoxy] 5- (Chloro-3-methyl-benzo [b] thiophen-2-sulphonic acid, 3- [1-methyl-piperazin-3-yloxy] -phenyl] -amide, [2-bromo-5- (4-methylpiperazine Naphthalene-2-sulfonic acid-1-phenyl] -amide, [5-chloro-3-methyl-benzo [4-chloro-3- (4-methyl-piperazin-1-yl) -phenyl] -amide] b] thiophene-2-sulphonic, [4-bromo-3- (4-methyl-piperazin-1-yl) -phenyl] -amide-2-naphthalene-2-ylphosphonic acid, [3- (2-dimethylamino-ethoxy) -4-iodophenyl] 5-Chloro-3-methylbenzo [b] thiophene-2-sulfonic acid amide, [1- (2-dimethylaminoethyl) -2,3-dihydro-lH-indol-6-yl] -amide chloro-3-methylbenzo [b] thiophene-2-sulfonyl, 1- (5-chloro-3-methyl-benzo [b] thiophen-2-sulfonyl) -6- (4-methyl-piperazin-1-yl) -2, 3-dihydro-1 H-indole, 1- (5-chloro-3-methyl-benzo [b] thiophen-2-sulfonyl) -5-methoxy-6- (4-methyl-piperazin-1-yl) -2,3 -dihydro-1 H-indole, 5-chloro-3-methylbenzo [b] thiofo [4-methoxy-2-methyl-3- (4-methylpiperazin-1-yl) phenyl] amide en-2-sulfonic acid, [2- (2-hydroxyethyl) -4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] 5-chloro-3-methyl-benzo [b] thiophen-2-sulfonic acid amide , 1- (5-Chloro-3-methylbenzo [b] thiophen-2-sulfonyl) -5-methoxy-4- (4-methyl-piperazin-1-yl) -2,3-dihydro-1H-indole hydrochloride, [3-methoxy-4- (4-methyl-piperazin-1-yl) -pheni] 5-chloro-3-methyl-benzo [b] thiophen-2-sulfonic acid, 4-Bromo-N- [4-methoxy-3-] (1-methyl-1, 2,3,6-tetrahydropyridin-4-yl) phenyl] benzenesulfonamide, [4-methoxy-3- (1-methyl-1, 2,3,6-tetrahydropyridin-4-yl); l) phenyl] amide of 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid, 5-chloro- [4-methoxy-3- (1-methyl-piperidin-4-yl) -phenyl] -amide; 3-Methylbenzo [b] thiophene-2-sulfonic acid, [3- (4-methylpiperazin-1-yl) phenyl] naphthalene-2-sulfonic acid amide, 2,3,4-trichloro-N- (4-methoxy-3-) piperazin-1-phenyl) benzenesulfonamide, 3,3-Dichloro-N- (4-methoxy-3-piperazin-1-yl-phenyl) benzenesulfonamide, 3-chloro-2-methyl-N- (4-methoxy- 3-piperazin-1-yl-phenyl) benzenesulfonamide, 4-chloro-N- (4-methoxy-3-piperazin-1-yl-phenyl) benzenesulfone Mide, 5-bromo-thiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-yl-phenyl) -amide, 2,3-Dichloro-N- [4-methyl-piperazin-1-yl] -phenyl] -benzenesulfonamide, 1- (5-chloro-3-methylbenzo [b] thiophen-2-sulfonyl) -5-phenyl-6-piperazin-1-yl-2,3-dihydro-1 H-indole, 5-chloro- 1- (5-chloro-3-methylbenzo [b] thiophen-2-sulfonyl) -6-piperazin-1-yl-2,3-dihydro-1 H-indole, 1- (5-chloro-3-methylbenzo [ b] thiophen-2-sulfonyl) -7-piperazin-1-yl-1, 2,3,4-tetrahydroquinoline, [4-methyl-3- (4-methylpiperazin-1-yl) phenyl] -amide of 5-acid Chloro-3-methylbenzo [b] thiophene-2-sulfonic acid, [4-methoxy-3- (-methylpyrrolidin-2-ylmethoxy) phenol] -amide of (S) -5-chloro-3-acid methylbenzo [b] thiophene-2-sulfonic acid, and pharmaceutically acceptable salts thereof.
11. A compound according to any of claims 1 to 9, which is 5-chloro-3-methylbenzo [b] thiophen-2 (4-methoxy-3-piperazin-1-phenylphenyl) amide hydrochloride. -sulfonic.
12. A compound according to any of claims 1 to 11, for use in therapy.
13. A compound according to any of claims 1 to 11, for use in therapy, in which the useful activity performed pro-antagonism of 5-HT6 receptors.
14. A compound according to any of claims 1 to 11, for use in the treatment of schizophrenia, Alzheimer's disease and / or depression.
15. A pharmaceutical composition comprising a compound according to any of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.
16. A process for the preparation of a compound of formula (I) or a salt thereof: (0 where: P is phenyl, naphthyl, or bicyclic heterocyclic ring or is a 5- to 7-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur; A is a single bond, a group of alkylene of C? -6 or an alkenylene group of C?? 6; R1 is halogen, C? -6 alkyl optionally substituted by one or more halogen atoms, C? 6 cycloaicil, C? -6 alkyl, C-6 alkoxy, OCF 3, hydroxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, C 1-6 alkoxy of Ci-β alkoxy, C 1-6 alkanoyl, acyl, nitro, amino, C? -6 alkylamino or C-? -6 dialkylamino, cyano or R1 is phenyl, naphthyl, or bicyclic heterocyclic ring or is a 5- to 7-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, n is 0, 1, 2,3,4,5, or 6, R 2 is hydrogen, C 1 -C 6 alkyl or arylalkyl of C 1 - R 3 is a group R 5 or together with R 5 forms a group ( CH2) 2O or (CH2) 3O or R3 binds to R2 pair to form a group (CH2) 2 or (CH2) 3; R4 is X (CH2) p-R6 where X is a single bond, CH2, O, NH or N-C6 alkyl -6 and p is 0 to 6 and R6 is an optionally substituted 5- to 7-membered heterocyclic ring containing from 1 to 3 heteroatoms selected from nitrogen, sulfur, or oxygen, or R6 is NR7R8 where R7 and R8 are independent of hydrogen, C1-6alkyl, or arylalkyl. H.H; and R5 is hydrogen, halogen, C-? 6 alkyl, C3-6 cycloalkyl. CO - C 1-6 alkyl, C? 6 alkoxy) hydroxy, C? -6 hydroxyalkyl, C? -6 hiroxyalkoxy, C? -6 alkoxy, C? -6 alkoxy, C 1-6 alkanoyl 6, nitro, trifluoromethyl, cyano or aryl, which process comprises coupling a compound of formula (II): (ll) wherein R1, n, P, and A are as defined in formula (I) or protected derivatives thereof and L is an leaving group with a compound of formula (III): (III) wherein R2, R3, R4 and R5 are as defined in formula (I) or protected derivatives thereof and optionally hereafter: removing any of the protecting groups, forming a pharmaceutically acceptable salt.
MXPA/A/1999/005900A 1996-12-19 1999-06-21 Sulphonamide derivatives, process for their preparation, and their use as medicaments MXPA99005900A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9626377.7 1996-12-19
GB9700901.3 1997-01-17
GB9722757.3 1997-10-27

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MXPA99005900A true MXPA99005900A (en) 2000-01-01

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