EP2318397A2 - Composé de sulfamide d'indole substituée, leur préparation et utilisation en tant que médicament - Google Patents

Composé de sulfamide d'indole substituée, leur préparation et utilisation en tant que médicament

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Publication number
EP2318397A2
EP2318397A2 EP09781294A EP09781294A EP2318397A2 EP 2318397 A2 EP2318397 A2 EP 2318397A2 EP 09781294 A EP09781294 A EP 09781294A EP 09781294 A EP09781294 A EP 09781294A EP 2318397 A2 EP2318397 A2 EP 2318397A2
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EP
European Patent Office
Prior art keywords
prophylaxis
treatment
indole
ethoxy
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09781294A
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German (de)
English (en)
Inventor
Matthias Beller
José Luis DIAZ-FERNANDEZ
Karolin Alex
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Esteve Pharmaceuticals SA
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Laboratorios del Dr Esteve SA
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Priority to EP09781294A priority Critical patent/EP2318397A2/fr
Publication of EP2318397A2 publication Critical patent/EP2318397A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to substituted indole sulfonamide compounds of general formula (I),
  • the superfamily of serotonin receptors includes 7 classes (5-HT 1 -S-HT 7 ) encompassing 14 human subclasses [D. Hoyer, et al., Neuropharmacology, 1997, 36, 419].
  • the 5-HT 6 receptor is the latest serotonin receptor identified by molecular cloning both in rats [F. J. Monsma, et al., MoI. Pharmacol., 1993, 43, 320; M. Ruat, et al., Biochem. Biophys. Res. Commun., 1993, 193, 268] and in humans [R. Kohen, et al., J. Neurochem., 1996, 66, 47].
  • Compounds with 5-HT 6 receptor affinity are useful for the treatment of various disorders of the Central Nervous System and of the gastrointestinal tract, such as irritable intestine syndrome. Compounds with 5- HT 6 receptor affinity are also useful in the treatment of anxiety, depression and cognitive memory disorders [M. Yoshioka, et al., Ann. NY Acad. ScL, 1998, 861, 244; A. Bourson, et al., Br. J. Pharmacol., 1998, 125, 1562; D. C. Rogers, et al., Br. J. Pharmacol. Suppl., 1999, 127, 22P; A. Bourson, et al., J. Pharmacol. Exp. Ther., 1995, 274, 173; AJ.
  • medicaments preferably in medicaments for the regulation of 5-HT 6 receptors, for cognitive enhancement, for the prophylaxis and/or treatment of food-intake related disorders, disorders of the central nervous system, disorders of the gastrointestinal tract, such as irritable intestine syndrome, anxiety, panic, depression, cognitive memory disorders, senile dementia disorders, such as Morbus Alzheimer, Morbus Parkinson and Morbus
  • Huntington schizophrenia, psychosis, infantile hyperkinesia, ADHD (attention deficit, hyperactivity disorders) and other 5-HT 6 mediated disorders particularly in mammals, including humans.
  • a medicament for cognitive enhancement for the prophylaxis and/or treatment of food ingestion (food intake) disorders, particularly for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type Il diabetes (Non-insulin Dependent Diabetes Mellitus), preferably type Il diabetes, which is caused by obesity, disorders of the central nervous system, disorders of the gastrointestinal tract, such as irritable intestine syndrome, anxiety, panic, depression, cognitive memory disorders, senile dementia disorders, such as Morbus Alzheimer, Morbus Parkinson and Morbus Huntington, schizophrenia, psychosis, infantile hyperkinesia, ADHD (attention deficit, hyperactivity disorders) and other 5-HT 6 mediated disorders particularly in mammals, including man.
  • type Il diabetes which is caused by obesity, disorders of the central nervous system, disorders of the gastrointestinal tract, such as irritable intestine syndrome, anxiety, panic, depression, cognitive memory disorders, senile dementia disorders, such as Morbus Alzheimer, Morbus
  • the present invention relates to an indole sulfonamide compound of general formula (I),
  • R 9 represents a hydrogen atom or a C M 0 alkyl radical optionally substituted with one or more substituents independently selected from Ci-C 6 alkyl, aryl, cyano, Ci-C 6 alkoxy and trifluoromethyl;
  • an halogen atom a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical; a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be bonded via a linear or branched alkylene, or an optionally at least mono-substituted aryl or heteroaryl radical, which may be bonded via a linear or branched alkylene group,
  • R 11 and R 12 independently from one another, each represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical; a saturated or unsaturated, optionally at least mono- substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be bonded via a linear or branched alkylene group; or an optionally at least mono-substituted aryl or heteroaryl radical, which may be bonded via a linear or branched alkylene group,
  • R 5 and R 6 independently from one another, each represents a hydrogen atom; or a linear or branched, saturated or unsaturated, unsubstituted or at least mono- substituted aliphatic radical;
  • R 5 and R 6 together with the bridging nitrogen atom form a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one additional heteroatom as ring member containing heterocycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
  • R 5 and R 6 together with the bridging nitrogen atom form an unsubstituted or at least mono-substituted, optionally at least one additional heteroatom as ring member containing heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted saturated, unsaturated or aromatic mono- or bicyclic ring system;
  • R 7 represents a linear or branched, saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical
  • alkinylene group which may be unsubstituted or substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -
  • R 13 represents a linear or branched, saturated or unsaturated C M 0 aliphatic radical
  • any of the substituent(s) represents or comprises a (hetero)cycloaliphatic radical, i.e. a cycloaliphatic radical or a heterocycloaliphatic, including a C 3 . 9 (hetero)cycloalkyl radical, i.e.
  • a C 3 - 9 cycloalkyl or a C 3 - 9 heterocycloalkyl radical or a C 4 - 9 (hetero)cycloalkenyl radical, i.e. a C 4 . 9 cycloalkenyl or a C 4 . 9 heterocycloalkenyl radical
  • said (hetero)cycloaliphatic radical, C 3 - 9 (hetero)cycloalkyl radical or C 4 - 9 (het- ero)cycloalkenyl is - if not defined otherwise - unsubstituted or optionally substituted with one or more substituents, preferably unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s).
  • d- 5 -alkyl may be linear or branched and whereby the cyclic part(s) of said substituent(s) are unsubstituted or optionally substituted by 1 , 2 or 3 substituent(s) independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, methoxy, eth- oxy, F, Cl, Br, -CN, -CF 3
  • any of the substituent(s) in any of the herein defined formulae represents or comprises a (hetero)cycloaliphatic radical, i.e. a cycloaliphatic or a heterocycloaliphatic radical, including a C 3 . 9 (hetero)cycloalkyl radical, i.e. a C 3 . 9 cycloalkyl radical or a C 3 . 9 heterocycloalkyl radical, or a C 4 - 9 (hetero)cycloalkenyl, i.e.
  • a C 4 - 9 cycloalkenyl or a C 4 -9 heterocycloalkenyl radical which contains one or more, preferably 1 , 2 or 3 heteroatom(s) as ring member(s), unless defined otherwise, each of these heteroatom(s) may preferably be selected independently from the group consisting of nitrogen, oxygen and sulfur.
  • any of the substituent(s) in any of the herein defined formulae represents or comprises a C 3 - 9 (hetero)cycloalkyl radical, i.e. a C 3 . 9 cycloalkyl or a C 3 . 9 heterocycloalkyl radical, or a C 4 . 9 (hetero)cycloalkenyl, i.e a C 4 . 9 cycloalkenyl or a C 4 . 9 heterocycloalkenyl radical, which contains optionally 1 or 2 additional heteroatom(s) as ring members), unless defined otherwise, each of these heteroatom(s) may preferably be se- lected independently from the group consisting of nitrogen, oxygen and sulfur.
  • (hetero)cycloaliphatic radicals i.e. cycloaliphatic or heterocycloaliphatic radicals
  • C 3 . 9 (hetero)cycloalkyl radicals i.e. C 3 . 9 cycloalkyl or C 3 . 9 heterocycloalkyl radicals or C 4 . 9 (hetero)cycloalkenyl radicals, i.e. C 4
  • heterocycloalkenyl radicals may preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, diazepanyl, azocanyl,
  • (hetero)cycloaliphatic radicals i.e. cycloaliphatic or heterocycloaliphatic radicals
  • C 3 - 9 (hetero)cycloalkyl radicals i.e. C 3 - 9 cycloalkyl or C 3 - 9 heterocycloalkyl radicals or C 4 .
  • 9 (hetero)cycloalkenyl radicals i.e. C 4 .
  • 9 cycloalkenyl or C 4 - 9 heterocycloalkenyl radicals which are condensed with an unsubstituted or at least mono-substituted mono- or bicyclic ring system may preferably be selected from the group consisting of indolinyl, isoindolinyl, decahydronaphthyl, (1 ,2,3,4)-tetrahydroquinolinyl, (1 ,2,3,4)-tetrahydroisoquinolinyl, (1 ,2,3,4)-tetrahydronaphthyl, octahydro-cyclopenta[c]pyrrolyl, (1 ,3,4,7,9a)- hexahydro-2H-quinolizinyl, (1 ,2,3,5,6,8a)-hexahydro-indolizinyl, decahydroquinolinyl, dodecahydrocarbazolyl, 9H-carbazolyl, decahydroiso
  • Suitable saturated or unsaturated C 3 - 9 heterocycloalkyl and C 4 - 9 heterocycloalkenyl rings may preferably be selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, azepanyl, diazepanyl, azocanyl, (1 ,2,3,6)-tetrahydropyridinyl, (1 ,2,3,4)-tetrahydropyridinyl, (1 ,2,5,6)- tetrahydropyridinyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl and (5,6)- dihydro-4H-pyrimidinyl.
  • Suitable saturated or unsaturated C 3 . 9 heterocycloalkyl and C 4 . 9 heterocycloalkenyl rings which are condensed with an unsubstituted or at least mono-substituted mono- or bicyclic ring system may preferably be selected from the group consisting of indolinyl, isoindolinyl, (1 ,2,3,4)-tetrahydroquinolinyl, (1 ,2,3,4)- tetrahydroisoquinolinyl, octahydro-cyclopenta[c]pyrrolyl, decahydroquinolinyl, dodecahydrocarbazolyl, 9H-carbazolyl, decahydroisoquinolinyl, (2,3)-dihydro-1 H- cyclopenta[b]indolyl, [1 ,2,3,4]-tetrahydroquinazolinyl, [3,4]-dihydro-2H- benzo[1
  • any of the substituents in any of the herein defined formulae represents an alkylene group, including an Ci -6 alkylene group, an alkenylene group, including an C 2 - 6 alkenylene group or an alkinylene group, including an C 2 - 6 alkinylene group, said alkylene group, C 2 - 6 alkylene group, alkenylene group, C 2 - 6 alkenylene group, alkinylene group or C 2 .
  • 6 alkinylene group is unsubstituted or substituted with one or more substituents, preferably unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s).
  • Said substituent(s) may preferably be selected independently from the group consisting of -O-d-5-alkyl, -S-d-5-alkyl, -F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -NH(d-5-alkyl) and -N(d-5-alkyl) 2l whereby in each occurrence d -5 -alkyl may be linear or branched.
  • An alkenylene group comprises at least one carbon-carbon double bond
  • an alkinylene group comprises at least one carbon-carbon triple bond.
  • any of the substituents represents or comprises an aryl radical, including a 6- membered aryl radical such as phenyl or a 10-membered aryl radical such as naphthyl or a 14-membered aryl radical such as anthracenyl, said aryl radical is - if not defined otherwise - unsubstituted or substituted with one or more substituents, preferably unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s).
  • aryl radical including a 6- membered aryl radical such as phenyl or a 10-membered aryl radical such as naphthyl or a 14-membered aryl radical such as anthracenyl, said aryl radical is - if not defined otherwise - unsubstituted or substituted with one or more substituents, preferably unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s).
  • C ⁇ s-alkyl may be linear or branched and whereby the cyclic part(s) of said substituent(s) are unsubstituted or optionally substituted by 1 , 2 or 3 substituent(s) independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, F, Cl, Br, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 and -NO 2
  • Preferred aryl radicals which may optionally be at least mono-substituted, are phenyl and naphthyl. If any of the substituents in any of the herein defined formulae represents or comprises a heteroaryl radical, including a monocyclic 5- or 6-membered heteroaryl radical or a bi- or tricyclic 8-, 9-, 10-, 1 1 -, 12-, 13- or 14- membered heteroaryl radical, said heteroaryl radical is - if not defined otherwise - unsubstituted or substituted by one or more substituents, preferably unsubstituted or optionally substituted with 1 , 2,
  • heteroatom(s), which are present as ring member(s) in the heteroaryl radical may, unless defined otherwise, independently be selected from the group consisting of nitrogen, oxygen and sulphur.
  • the heteroaryl radical comprises 1 , 2, 3 or 4 heteroatom(s).
  • Suitable bi- or tricyclic heteroaryl radicals may preferably be selected from the group consisting of indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, imidazo[2,1 -b]thiazolyl, 2H-chromenyl, indazolyl and quinazolinyl.
  • Suitable mono-, bi- or tricyclic heteroaryl radicals which are condensed with an un- substituted or at least mono-substituted saturated or unsaturated mono- or bicyclic ring system, may preferably be selected from the group consisting of (4,5,6,7)-tetra- hydro-1 H-indolyl, [1 ,3]-benzodioxolyl, [1 ,4]-benzodioxanyl, [1 ,2,3,4]-tetrahy- dronaphthyl, (2,3)-dihydro-1 H-cyclopenta[b]indolyl, [1 ,2,3,4]-tetrahydroquinolinyl,
  • Suitable monocyclic 5- or 6-membered heteroaryl radicals may preferably be selected from the group consisting of pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and pyranyl.
  • a mono- or bicyclic ring system according to the present invention - if not defined otherwise - means a mono- or bicyclic hydrocarbon ring system that may be saturated, unsaturated or aromatic. Each of its rings may show a different degree of saturation, i.e. it may be saturated, unsaturated or aromatic. Optionally each of the rings may contain one or more, preferably 1 , 2 or 3 heteroatom(s) as ring member(s), which may be independent from one another and which can preferably be selected from the group consisting of nitrogen, oxygen and sulphur.
  • the rings of the mono- or bicyclic ring system are preferably 5-, 6- or 7- membered. Examples of mono- and bicyclic rings are phenyl or naphtyl ring systems.
  • condensed means that a ring or ring system is attached to another ring or ring system, whereby the terms “annulated” or “annelated” are also used by those skilled in the art to designate this kind of attachment.
  • Such a mono- or bicyclic ring system is - if not defined otherwise - unsubstituted or substituted by one or more substituents, preferably unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s).
  • any of the substituents in any of the herein defined formulae represents a saturated or unsaturated aliphatic radical, i.e. an alkyl radical, including an Ci-i 0 alkyl radical; an alkenyl radical, including an C 2 -io alkenyl radical or an alkinyl radical, including an C 2 -io alkinyl radical; said aliphatic radical is - if not defined otherwise - unsubstituted or substituted with one or more substituents, preferably unsubstituted or optionally substituted with 1 , 2, 3, 4 or 5 substituent(s).
  • Said substituent(s) may preferably - if not defined otherwise - be selected independently from the group consisting of -O-d_ 5 -alkyl, -S-d_ 5 -alkyl, F, Cl, Br, I, -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -NH 2 , -NH(C 1 . 5 -alkyl) and -N(C 1 . 5 -alkyl) 2 , whereby in each occurrence C ⁇ s-alkyl may be linear or branched. More preferably said substituent(s) may preferably be selected independently from the group consisting of -0-CH 3 , -0-C 2 H 5 ,
  • An alkenyl radical comprises at least one carbon-carbon double bond
  • an alkinyl radical comprises at least one carbon-carbon triple bond
  • Suitable alkyl radicals which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neo-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • Suitable alkenyl radicals which may be substituted by one or more substituents, may preferably be selected from the group consisting of vinyl, 1 -propenyl, 2- propenyl, 1 -butenyl, 2-butenyl and 3-butenyl.
  • Suitable alkinyl radicals which may be substituted by one or more substituents, may preferably be selected from the group consisting of ethinyl, 1 -propinyl, 2-propinyl, 1 - butinyl, 2-butinyl and 3-butinyl.
  • R 10 represents an heteroaryl radical, which is a 8- or 9- membered aromatic bicyclic system, having from 1 to 3 heteroatoms independently selected from nitrogen and sulphur atoms, more preferred are benzothiadiazole, benzothiophene, imidazothiazole and benzothiophene bicyclic systems, and optionally, said bicyclic systems are substituted with one or more halogen atoms, preferably chloro, and/or with a linear saturated aliphatic radical, preferably methyl.
  • R 1 , R 3 , and R 4 are hydrogen.
  • R 7 is a saturated aliphatic radical; more preferably methyl.
  • R 13 is preferably a branched saturated C M 0 aliphatic radical, more preferably t-butyl.
  • R 5 and R 6 independent from one another, each represents a hydrogen atom; or a linear or branched, saturated or unsaturated, unsubstituted or at least mono- substituted aliphatic radical; more preferably R 5 and R 6 are the same, i.e. a saturated C M 0 alkyl radical, most preferably ethyl.
  • the invention relates to a process for the preparation of an indole sulphonamide compound of general formula (I), wherein at least one compound of formula 3 or 4
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the meaning as defined above, with the proviso that at least one of R 1 , R 2 , R 3 , R 4 is -NHR 9 in compound of formula 3, or -NH 2 in compound of formula 4, is reacted with at least one compound of general formula (II),
  • R 10 has the respective meaning as defined above and X represents a leaving group preferably selected from the group consisting of Cl and Br, optionally in the presence of at least one base, preferably in the presence of at least one inorganic base selected from the group consisting of alkali metal hydroxides or carbonates or in the presence of at least one organic base selected from the group consisting of triethylamine or pyridine, at temperatures from 0 Q C to room temperature and with reaction time from 5 minutes to 24 hours to yield at least one compound of general formula (I),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the meaning as defined above, with the proviso that at least one of R 1 , R 2 , R 3 , R 4 is -N(R 9 )SO 2 R 10 .
  • the aforementioned reaction is carried out in an organic solvent, preferably an alkyl ether, more preferably diethyl ether, a cycloalkyl ether, more preferablly tetrahidrofurane or dioxane, an halogenated organic hydrocarbon, more preferably methylene chloride or chloroform, an alcohol, more preferably methanol or ethanol, an aprotic dipolar solvent, more preferably acetonitrile, pyridine or dimethylformamide.
  • an organic solvent preferably an alkyl ether, more preferably diethyl ether, a cycloalkyl ether, more preferablly tetrahidrofurane or dioxane, an halogenated organic hydrocarbon, more preferably methylene chloride or chloroform, an alcohol, more preferably methanol or ethanol, an aprotic dipolar solvent, more preferably acetonitrile, pyridine or dimethylformamide.
  • R 1 , R 2 , R 3 , R 4 , R 7 and R 8 have the meaning as defined above, with the proviso that at least one of R 1 , R 2 , R 3 , R 4 is Br, with a desilylating agent as TBAF at room temperature in a reaction medium, such as THF, followed by condensation with at least one compound of general formula (III)
  • R 5 and R 6 have the meaning as defined above, and X represents a leaving group preferably selected from the group consisting of Cl and Br, at temperatures from 25 to 100 Q C with reaction time from 3 to 12 hours, to yield at least one compound of formula 2
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , R 7 and R 8 have the meaning as defined above;
  • a compound of formula (I) wherein R 8 is a radical as above defined, different from hydrogen may be deprotected to yield the corresponding compound of formula (I) wherein R 8 is hydrogen according to known method in the art.
  • the receptor-ligand affinity increases additionally with a free NH-group in position 1 .
  • inventors have deprotected compound 5g and 5h to the biologically more active indole derivatives 6a and 6b which are obtained in very good yields up to 88 % (Table 1 ).
  • the compounds of general formula (I), given above may be purified and/or isolated according to methods well known to those skilled in the art.
  • the compounds of general formula (I) may be isolated by evaporating the reaction medium, addition of water and adjusting the pH value to obtain the compound in form of a solid that can be isolated by filtration, or by extraction with a solvent that is not miscible with water such as chloroform and purification by chromatography or recrystallisation from a suitable solvent.
  • the protection of sensitive or reactive groups may be necessary and/or desirable. This can be performed by using conventional protective groups like those described in Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T.W. Greene & P. G. M. Wuts and Protective Groups in Organic Chemistry, John Wiley & sons, 1991 .
  • the respective parts of the description is hereby incorporated by reference and forms part of the disclosure.
  • the protective groups may be eliminated when convenient by means well-known to those skilled in the art.
  • substituted indole sulfonamide compounds of general formula (I) are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents.
  • the substituted indole sulfonamide compounds of general formula (I), and in each case stereoisomers thereof may be obtained in form of a corresponding salt according to methods well known to those skilled in the art, e.g. by reacting said compound with at least one inorganic and/or organic acid, preferably in a suitable reaction medium.
  • Suitable reaction media include, for example, any of the ones given above.
  • Suitable inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, phosphoric acid, oxalic acid, sulfuric acid, nitric acid
  • suitable organic acids include but are not limited to citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.
  • salt is to be understood as meaning any form of the substituted indole sulfonamide compounds in which they assume an ionic form or are charged and are coupled with a counter-ion (a cation or anion) or are in solution.
  • a counter-ion a cation or anion
  • physiologically acceptable salt is understood in particular, in the context of this invention, as salt (as defined above) formed either with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals - or with at least one, preferably inorganic, cation which are physiologically tolerated - especially if used on humans and/or mammals.
  • physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, hydrobromide, monohydrobromide, monohydrochloride or hydrochloride, methiodide, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, hippuric acid picric acid and/or aspartic acid.
  • physiologically tolerated salts of particular bases are salts of alkali metals and alkaline earth metals and with NH 4 .
  • Solvates, preferably hydrates, of the substituted indole sulfonamide compounds of general formula (I), and in each case of corresponding stereoisomers may also be obtained by standard procedures known to those skilled in the art.
  • solvate is to be understood as meaning any form of the substituted indole sulfonamide compounds in which they have attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.
  • prodrug according to this invention is to be understood in its broadest sense encompassing those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides.
  • the invention relates to new intermediate compounds of the following formulae 3 and 4 which are useful in the preparation of an indole sulphonamide compound of general formula (I) ,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the meaning as defined above, with the proviso that at least one of R 1 , R 2 , R 3 , R 4 is -NHR 9 in compound of formula 3, or -NH 2 in compound of formula 4, and wherein R 9 has the meaning as defined above.
  • Benzyl-[3-(2-diethylamino-ethoxy)-1 ,2-dimethyl-1 H-indol-5-yl]-amine (3a) Benzyl-[1 -benzyl-3-(2-diethylamino-ethoxy)-2-methyl-1 H-indol-5-yl]-amine (3b) 5-Benzylamino-3-(2-diethylamino-ethoxy)-2-methyl-indole-1 -carboxylic acid tert- butyl ester (3c)
  • the invention is directed to a medicament which comprises at least a one indole sulphonamide compound of general formula (I), optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixture ratio, or a salt, preferably a physiologically acceptable salt, or a prodrug, or a corresponding solvate and at least a pharmaceutical acceptable carrier, adjuvant or vehicle.
  • a salt preferably a physiologically acceptable salt, or a prodrug, or a corresponding solvate
  • Said medicament is particularly suitable for 5-HT 6 receptor regulation and therefore for the treatment and/or prophylaxis of diseases or disorders that are at least partially mediated via 5-HT 6 receptors.
  • said medicament is suitable for the prophylaxis and/or treatment of food intake disorders, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, for the prophylaxis and/or treatment of bulimia, for the prophylaxis and/or treatment of anorexia, for the prophylaxis and/or treatment of cachexia, for the prophylaxis and/or treatment of type Il diabetes (non-insulin dependent diabetes mellitus); for the prophylaxis and/or treatment of cognitive disorders, preferably memory disorders; or for improvement of cognition (for cognitive enhancement).
  • food intake disorders preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, for the prophylaxis and/or treatment of bulimia, for the prophylaxis and/or treatment of anorexia, for the prophylaxis and/or treatment of cachexia, for the prophylaxi
  • said medicament is suitable for the prophylaxis and/or treatment of gastrointestinal disorders, preferably irritable colon syndrome; for the prophylaxis and/or treatment of disorders of the central nervous system; for the prophylaxis and/or treatment of anxiety; for the prophylaxis and/or treatment panic attacks; for the prophylaxis and/or treatment of depression; for the prophylaxis and/or treatment of bipolar disorders; for the prophylaxis and/or treatment of senile dementia; for the prophylaxis and/or treatment of psychosis; for the prophylaxis and/or treatment neurodegenerative disorders; preferably selected from the group consisting of Morbus Alzheimer, Morbus Parkinson, Morbus Huntington and Multiple Sclerosis; for the prophylaxis and/or treatment of schizophrenia or for the prophylaxis and/or treatment hyperactivity disorder (ADHD, attention deficit, hyperactivity disorder).
  • ADHD attention deficit, hyperactivity disorder
  • the medicament obtained according to the present invention is particularly suitable for the administration to mammals, including man.
  • the drug can preferably be administered to all age groups, namely, children, adolescents and adults.
  • Another aspect of the present invention is the use of at least one indole sulfonamide compound of general formula (I) , optionally in form of one of its stereoisomers, preferably enantiomers or diasteromers, a racemate or in form of a mixture of at least two stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a corresponding solvate, for the manufacture of a drug for regulating the 5-HT 6 receptor, for the prophylaxis and/or treatment of food intake disorders, preferably for the regulation of appetite, for the maintenance, increase or reduction of body weight, for the prophylaxis and/or treatment of obesity, for the prophylaxis and/or treatment of bulimia, for the prophylaxis and/or treatment of anorexia, for the prophylaxis and/or treatment of cachexia, for the prophylaxis and/or treatment of type Il diabetes (non-insulin dependent diabetes
  • Any medicament according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults.
  • the medicament can be produced by standard procedures known to those skilled in the art, e.g. from the table of contents of "Pharmaceutics: The Science of Dosage Forms", Second Edition, Aulton, M. E. (ED. Churchill Livingstone, Edinburgh (2002); “Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan J. C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modern
  • composition of the medicament may vary depending on the route of administration.
  • the medicament of the present invention may, for example, be administered par- enterally in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional pharmaceutical excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions.
  • These medicaments may for example be injected intramuscularly, intraperitoneal ⁇ , or intravenously.
  • Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form.
  • These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the compositions may take any convenient form, such as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.
  • the multiparticulate forms, such as pellets or granules may e.g. be filled into a capsule, compressed into tablets or suspended in a suitable liquid.
  • Suitable controlled release formulations, materials and methods for their preparation are known from the prior art, e.g. from the table of contents of "Modified-Release Drug Delivery Technology", Rathbone, MJ. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Release Technology”, Wise, D. L. (Ed.), Marcel Dekker, Inc. New York, (2000); "Controlled Drug Delivery", VoI, I, Basic Concepts, Bruck, S. D. (Ed.), CRD Press Inc., Boca Raton (1983) y de Takada, K.
  • Medicaments according to the present invention may also comprise an enteric coating, so that their dissolution is dependent on pH-value. Due to said coating the medicament can pass the stomach undissolved and the respective indole sulfonamide compound is liberated in the intestinal tract.
  • the enteric coating is soluble at a pH value of 5 to 7.5. Suitable materials and methods for the preparation are known from the prior art.
  • the medicaments according to the present invention may contain 1 -60 % by weight of one or more substituted indole sulfonamide compounds as defined herein and 40-99 % by weight of one or more auxiliary substances (additives).
  • liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents.
  • Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
  • compositions of the present invention may also be administered topically or via a suppository.
  • the daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.
  • the daily dosage for humans may preferably be in the range from 0.01 to 4000 mg, preferably 0.1 to 2000 mg, more preferably 0.5 to 1000 of active substance to be administered during one or several intakes per day.
  • Step 1 In a round bottomed flask under an argon atmosphere (4- bromophenyl)hydrazine (0.09 mol), te/t-butyldimethylsilyloxy-2-propyne (0.07 mol) and ZnCI 2 (0.09 mmol) were dissolved in 50 mL THF. The reaction mixture was heated to 100 0 C under reflux for 24 h.
  • Step 2 In a round bottomed flask under an argon atmosphere 5-bromo-3-(te/t-butyl- dimethyl-silanyloxy)-2-methyl-1 /-/-indole 1 a (10 mmol), di-te/t-butyl-dicarbonate (12 mmol) and DMAP (0.35 mmol) were dissolved in dry THF and stirred over night at room temperature.
  • Step 3 In a round bottomed flask 5-bromo-3-(te/t-butyl-dimethyl-silanyloxy)-2- methyl-indole-1 -carboxylic acid te/t-butyl ester 1 b (3.4 mmol) and tetrabutylammoniumfluoride (TBAF) (4.1 mmol) were dissolved in dry THF and stirred for 10 min at room temperature. After Na 2 CO 3 (6.8 mmol) was added, the reaction mixture was stirred for further 10 min at room temperature. Finally (2- chloro-ethyl)-diethyl-amine (6.8 mmol) was added and the solution was heated up to 45 °C for 4 h. After removal of the solvent the residue was cleaned by column chromatography (eluent CH 2 CI 2 /ethanol 20:1 ). The isolated product obtained as pale yellow oil with a yield of 68 %.
  • TBAF tetrabutylammoniumflu
  • the pressure tube was fitted with a Teflon cap and heated up to 100 °C for 20 h. After removal of the solvent in vacuo, the corresponding indole product was isolated as oil by column chromatography (eluent: ethyl acetate gradient 0-20% in heptane with 1 -2% triethylamine).
  • FTIR FTIR (ATR): 3416, 3062, 3028, 2969, 2927, 2872, 2810, 1720, 1470, 1452, 1367, 1330, 1275, 1221, 1168, 1129, 1062,734,697 cm 1 .
  • FTIR (neat): 3442, 3093, 3060, 2965, 2929, 2871, 2809, 2725, 1732, 1471, 1353, 1272, 1256, 1225, 1208, 1162, 1070, 1021, 970, 853, 831, 754, 730, 622, 604, 593 cm 1 .

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Abstract

La présente invention concerne des composés d'indole-sulfonamides de formule générale (I), leur méthode de préparation, un médicament comprenant ces composés et leur utilisation pour la préparation de médicaments destinés à la régulation du récepteur 5-HT6 ainsi qu'au traitement de troubles associés.
EP09781294A 2008-08-01 2009-07-30 Composé de sulfamide d'indole substituée, leur préparation et utilisation en tant que médicament Withdrawn EP2318397A2 (fr)

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EP09781294A EP2318397A2 (fr) 2008-08-01 2009-07-30 Composé de sulfamide d'indole substituée, leur préparation et utilisation en tant que médicament

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EP08380238A EP2149573A1 (fr) 2008-08-01 2008-08-01 Composé de sulfamide d'indole substituée, leur préparation et utilisation en tant que médicament
PCT/EP2009/059876 WO2010012806A2 (fr) 2008-08-01 2009-07-30 Composés d'indole-sulfonamides substitués, leur préparation et leur utilisation comme médicaments
EP09781294A EP2318397A2 (fr) 2008-08-01 2009-07-30 Composé de sulfamide d'indole substituée, leur préparation et utilisation en tant que médicament

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ATE157361T1 (de) * 1990-10-15 1997-09-15 Pfizer Indolderivate
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EP1626715B1 (fr) * 2003-05-09 2008-09-10 Laboratorios Del Dr. Esteve, S.A. Utilisation de derives sulfamides pour la fabrication d'un medicament pour la prophylaxie et/ou le traitement de troubles d'ingestion des aliments
ES2222832B1 (es) * 2003-07-30 2006-02-16 Laboratorios Del Dr. Esteve, S.A. Derivados de 6-indolilsulfonamidas, su preparacion y su aplicacion como medicamentos.
EP1632491A1 (fr) * 2004-08-30 2006-03-08 Laboratorios Del Dr. Esteve, S.A. composes indole substitues et leur utilisation comme modulateurs du recepteur 5-ht6

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