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WO2008146063A1 - Nouveaux dérivés de benzofurane utilisés en tant qu'inhibiteurs sélectifs du récepteur 5ht6 et procédé de préparation associé - Google Patents

Nouveaux dérivés de benzofurane utilisés en tant qu'inhibiteurs sélectifs du récepteur 5ht6 et procédé de préparation associé Download PDF

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Publication number
WO2008146063A1
WO2008146063A1 PCT/HU2008/000060 HU2008000060W WO2008146063A1 WO 2008146063 A1 WO2008146063 A1 WO 2008146063A1 HU 2008000060 W HU2008000060 W HU 2008000060W WO 2008146063 A1 WO2008146063 A1 WO 2008146063A1
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group
general formula
sulfonyl group
halogen atom
benzofuran
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PCT/HU2008/000060
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English (en)
Inventor
Endre RIVÓ
Ibolya Prauda
József Reiter
József Barkóczy
István Gacsályi
Hajnalka Kompagne
Nóra SZIRAY
Katalin Pallagi
András Egyed
Endre HEGEDÜS
György Lévay
László Gábor HÁRSING
Original Assignee
EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársagág
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Publication of WO2008146063A1 publication Critical patent/WO2008146063A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to new, selective 5HT 6 receptor inhibitors of general formula (I), pharmaceutical formulations containing the same as active ingredients and a process of the preparation thereof.
  • the new compounds are effective in the treatment of 5HT 6 receptor relating disorders, and for the treatment and/or prevention of the disorders of the central nervous system and cardiovascular system.
  • the invention relates to selective 5HT 6 receptor binding benzofuran derivatives of general formula (I),
  • Z represents a hydrogen atom, C 1 ⁇ acyl group, C 1-6 group alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionally substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10-camphor-sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and C 1-4 alkyl group, Y represents C 2 ⁇ alkylene group,
  • R 1 and R 2 represent, independently, a hydrogen atom, C 1 ⁇ alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or CM alkoxy group substituted 4-phenyl-piperazin-l-yl group; and/or their pharmaceutically suitable acid addition salts.
  • furan carboxylic amides have antidepressant properties [Yakugaku Zasshi 97 (5), 540 (1977); C.A., 87.
  • Tetrahydro-naphthoxy derivatives having hypotensive activity are known from published German patent application No. 22 35 597.
  • the chemical structure of the known compounds resembles to the benzofurane derivatives of general formula (I).
  • Patent Application No. US 2004/0224994 of the United States relates to benzofuran derivatives, some of them having a similar structure to the subject of the present invention.
  • the compounds are used as pesticides.
  • 5-HT 6 receptors are located in the central nervous system, in the cortex, in the nucleus caudatus, in the nucleus accumbens and in the hippocampus (Ward et al., 1995).
  • the receptor antagonists of 5-HT 6 receptors are responsible for the regulation of the neurotransmitter functions of the stimulating amino acids, dopamine and acethylkoline (Dawson and Nguyen, 2000). These neurotransmitters have an essential role in the regulation of the mood, and the maitenance of the memory and psychical activity.
  • the compounds of general formula (I) are selective inhibitors of the 5-HT 6 receptors.
  • This unique receptor profile allows the application of the compounds of the present invention in the disorders, arising from disorders of the central nervous system and/or medical disorders such as the disorders of the heart, cardiovascular system or the kidneys.
  • the aim of the present invention is to prepare novel benzofuran derivatives effective in the treatment of 5HT 6 receptor related disorders of the central nervous system and/or cardiovascular system.
  • Z represents a hydrogen atom, Ci -4 acyl group, Ci -6 alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionallly substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10- camphor-sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and C 1-4 alkyl group, Y represents C 2-6 alkylene group,
  • R 1 and R represent, independently, a hydrogen atom, C 1-4 alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or C 1-4 alkoxy group substituted 4-phenyl-piperazin-l-yl group; and/or their pharmaceutically suitable acid addition salts.
  • halogen atom is primarily fluoro, chloro, bromo or iodo atom, preferably chloro or bromo atom.
  • a C M acyl group represents acetyl, propionyl, or butyryl, preferably acetyl group.
  • a C ⁇ alkylsulfonyl group represents methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, .fee-butyl-, pentyl- or hexylsulfonyl-, preferably isopropylsulfonyl group.
  • a phenylsulfonyl group substituted with one or more halogen atoms represents o-, m-, or ⁇ -chloro-phenyl, 2,3-dichloro-phenyl-, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl-, 2,6-dichloro-phenyl, 3,5-dichloro-phenyl-, preferably 2,5- dichloro-phenyl sulfonyl group.
  • a naphthyl-sulfonyl group optionally substituted with halogen atom represents 1-naphtyl, 2-naphthyl-, l-chloro-2-naphthyl-, 2-chloro-l-naphthyl-, 3-chloro-l-naphthyl-, 4-chloro-l-naphthyl-, 5-chloro-l-naphthyl- l-bromo-2- naphthyl-, 2-bromo-l-naphthyl-, 3-bromo-l-naphthyl-, 4-bromo-l-naphthyl-, 5- bromo-1 -naphthyl-sulfonyl-, preferably 1-naphthyl, 2-naphthyl, 4-chloro-l- naphthyl, 5-chloro-l -nap
  • a benzofuranyl-sulfonyl group, substituted with a halogen atom and C 1-4 alkyl group represents 5-chloro-3-methyl-benzofuran-2-, 5-chloro-3-ethyl- benzofuran-2-, 5-chloro-3-propyl-benzofuran-2-, 5-chloro-3-isopropyl- benzofuran-2-, 5-chloro-3-butyl-benzofuran-2-sulfonyl, preferably 5-chloro-3- methyl-benzofuran-2 -sulfonyl group.
  • a C 1-6 alkylene group represents ethylene, propylene, butylene, pentylene, hexylene, ethylene-, propylene-, butylene, pentylene, or hexylene group, preferably ethylene or propylene group.
  • a CM alkyl-group represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, preferably methyl or ethyl group.
  • a 4-phenyl-piperazine-l-yl group substituted with one or more halogen atoms, trifluoromethyl group or C 1-4 alkoxy group represents 4-(2-chloro- phenyl)-piperazin-l-yl, 4-(3-chloro-phenyl)-piperazin-l-yl, 4-(4-chloro-phenyl)- piperazin- 1 -yl, 4-(2-bromo-phenyl)-piperazin- 1 -yl, 4-(3 -bromo-phenyl)- piperazin- 1 -yl, 4-(4-bromo-phenyl)-piperazin- 1 -yl, 4-(2-trifluoro-methyl- phenyl)-piperazin- 1 -yl, 4-(3-trifluoro-methyl-phenyl)-piperazin- 1 -yl, 4-(4- trifluoro-methyl-phenyl)-piperazin- 1 -
  • a preferred subgroup of selective 5HT 6 receptor binding benzofuran derivatives of the invention consists of the benzofuran derivatives of general formula (I)
  • Z represents a hydrogen atom, C 1-2 acyl group, C 1-3 group alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionally substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10-camphor-sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and Ci -2 alkyl group, Y represents C 2 . 3 alkylene group,
  • R 1 and R 2 represent, independently, a hydrogen atom, C 1-2 alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or Cj- 4 alkoxy group substituted 4-phenyl-piperazin-l-yl group; and/or their pharmaceutically suitable acid addition salts.
  • the especially preferred benzofuran derivatives of general formula (I) are the following:
  • Hal represents a halogen atom
  • Z represent as defined in claims 1 and 2 or with an acid anhydride of general formula (X)
  • a further subject of our invention is a process for the preparation of compounds of general formula (VII) wherein a. the compound of formula (II)
  • a further subject of our invention are new compounds of general formula (IV), (V), (VII), (VIII), (XIII), (XIV) and (XV).
  • the invention also relates to all possible isomer, tautomer, or crystalline forms of the compounds.
  • reaction of compound of formula (II) with a compound of general formula (III) is carried out in water, or in aqueous alcoholic media, preferably in water in the presence of a phase transfer catalyst, preferably a tetraalkyl ammonium halogen, more preferably triethylbenzylammonium chloride and a base, preferably alkali metal hydroxide, more preferably sodium hydroxide.
  • a phase transfer catalyst preferably a tetraalkyl ammonium halogen, more preferably triethylbenzylammonium chloride and a base, preferably alkali metal hydroxide, more preferably sodium hydroxide.
  • the product can be obtained by a method known in itself, preferably the product is dissolved in a water-immiscible solvent, the phases are separated, the organic phase is washed with water, dried and evaporated.
  • ⁇ -hydroxyalkoxy benzofuran derivatives ⁇ i gcuciai formula (IV) to a ⁇ -haloalkoxy derivative of general formula (V) is carried out with a known halogenizing agent, preferably with a phosphor-trihalogenide, more preferably with phosphor-tribromide in the presence of an indifferent solution in relation of the present reaction, preferably with an aromatic or halogenated solvent, more preferably in toluene, or dichloromethane, between a temperature of 0 C 0 and room temperature, preferably between 0 C 0 and 10 C 0 , more preferably between 0 and 5 C 0 .
  • a known halogenizing agent preferably with a phosphor-trihalogenide, more preferably with phosphor-tribromide in the presence of an indifferent solution in relation of the present reaction, preferably with an aromatic or halogenated solvent, more preferably in toluene, or dichloromethane, between a temperature of
  • the product can be obtained by a method known in itself, for example after evaporating the solutions with chromathography or the residue is dissolved in a water immiscible solvent, preferably with a halogenated solvent, more preferably in dichloromethane, and the solvent is washed with water, dried and evaporated. When required the evaporated residue is purified with chromathography.
  • the reaction of ⁇ -haloalkoxy derivatives of general formula (V) with the amine derivatives of general formula (VI) is carried out in the presence of an indifferent solution in relation of the present reaction, in water or alcohol, in halogenated solvents, or in a mixture thereof.
  • the media is water, a mixture of water and dichloromethane and methanol, or a mixture of water and isopropanol, when required the reaction is carried out in the presence of a phase transfer catalyst and a base.
  • phase transfer catalyst a tertiary ammonium salt, preferably a trimethylbenzylammonium chloride can be used.
  • As a base an alkali metal hydroxide, preferably sodium hydroxide is used.
  • the reaction is performed at a temperature between 10 C 0 and 50 C 0 , preferably between 15 C 0 and 30 C 0 , more preferably at room temperature.
  • the obtained ⁇ - monoaminoalkoxy, or ⁇ -dialkylaminoalkoxy derivatives general formula (VII) can be separated by a method known in itself, usually, after removing the organic solvents, the product is dissolved in a water immiscible solvent, the solution is washed with water, dried, and evaporated until dry.
  • the reduction of ⁇ -monoaminoalkoxy, or ⁇ -dialkylamino-alkoxy derivatives of general formula (VII) to an aniline derivative of general formula (VIII) is carried out by hydrogenation or by a reduction with hydrazine hydrate, in the presence of an indifferent solution in relation of the present reaction, preferably in alcohol, more preferably in methanol, or in ethanol.
  • the reaction is performed in the presence of palladium (5 - 10 %) or plauuum/ L. ⁇ UUUII ⁇ uupi (5 - 10 %).
  • the product is separated after filtering the catalyst, by evaporation until dry or by washing the crystalline product with ether.
  • the reaction of aniline derivatives of general formula (VIII) is performed with an acyl or sulfonyl-halogenide of general formula (IX), or an acid anhydride of general formula (X).
  • compounds of general formula (I) are obtained.
  • the reaction is carried out in the presence of an indifferent solution in relation of the present reaction, preferably in a halogenated solvent, more preferably in dichloromethane in the presence of pyridine, at a temperature between 0 and 40 C 0 , preferably at room temperature.
  • the product is separated by adding to the reaction mixture water, or aqueous sodium hydrogencarbonate (10 %) and the phases are separated, the organic is washed with water, dried, then evaporated.
  • the obtained crystals are washed with ether and when required can be purified with chromathography.
  • the reaction of 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol, compound of formula (II) is carried out with an ⁇ , ⁇ -dihalogen derivative of general formula (XI) in the presence of aqueous alkali metal hydroxide, preferably sodium hydroxide and in the presence of a tertiary ammonium halogenide, preferably triethylbenzylammonium chloride catalyst.
  • aqueous alkali metal hydroxide preferably sodium hydroxide
  • a tertiary ammonium halogenide preferably triethylbenzylammonium chloride catalyst.
  • the obtained ⁇ -haloalkoxy derivative of general formula (V) can be separated after cooling the reaction mixture by an extraction with a water immiscible organic solvent, preferably with ether, and thereafter the organic solvent is washed, dried, then evaporated.
  • reaction of 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol of formula (II) with an aminoalkyl halogenide of general formula (XII) is carried out in absolute alcohol, preferably in absolute ethanol, in the presence of sodium ethylate, under boiling the reaction mixture.
  • the ⁇ - monoaminoalkoxy, or ⁇ -dialkylaminoalkoxy derivative of general formula (VII) in the aqueous phase is isolated by calibrating the pH of the solution to 12, then extracting with a water immiscible organic solvent, preferably with dichloromethane, drying and evaporating.
  • ⁇ - monoaminoalkoxy, or ⁇ -dialkylaminoalkoxy derivative of general formula (VII) can be separated according to the above, by dividing the pro ⁇ uci oeiween waicr and a water immiscible solvent, preferably dichloromethane, then washing the solvent with water, drying and evaporating.
  • a water immiscible solvent preferably dichloromethane
  • the reduction of aromatic nitro group of the hydroxyalkoxy benzofuran derivatives of general formula (IV) is carried out by hydrogenation of a hydroxy-aniline derivative of general formula (XIII) in an alkanol, preferably in methanol, in the presence of a palladium/carbon (5-10 %) or platinum/carbon (5-10 %), preferably platinum/carbon catalyst.
  • a palladium/carbon preferably in methanol
  • platinum/carbon preferably platinum/carbon catalyst
  • the reaction of hydroxy-aniline derivative of general formula (XIII) and an acyl, or sulfonyl halogenide of general formula (DC), or an acid anhydride of general formula (X) can be obtained the hydroxyalkoxy acid amides of general formula (XIV) in the presence of an indifferent solution in relation of the present reaction, preferably a halogenated solvent, more preferably in dichloromethane, in the presence of pyridine at a temperature between 0 and 40 C 0 , preferably at room temperature.
  • the product can be separated from the reaction mixture by dividing with water, or with aqueous sodium hydrogencarbonate (10 %) then separating the phases and washing the organic phase with an aqueous solvent, drying and evaporating the product.
  • the obtained crystals are washed with ether and when required can be purified with chromathography.
  • a know halogenating agent preferably with a phosphor-trihalogenide, more preferably phosphor-tribromide in the presence of an indifferent solution in relation of the present reaction, preferably an aromatic, or halogenated solvent, more preferably in toluene, or in dichloromethane, at 0 C 0 and room temperature, preferably at a temperature between 0 and 10 C 0 , more preferably between 0 and 5 C 0 .
  • the product can be obtained by a method known in itself, for example after evaporating the solvent purified by chromathography, or dissolving the residue in a water immiscible solvent, preferably in a halogenated solvent, more preferably in dichloromethane, and washing the solution with water and drying and evaporating the product.
  • a water immiscible solvent preferably in a halogenated solvent, more preferably in dichloromethane
  • halo-alkoxy acid amides of general formula (XV) with an amine of general formula (VI) is carried out in the presence of an indifferent solution in relation of the present reaction, preferably in a halogenated solvent, more preferably in dichloromethane, in the presence of a tertiary amine, preferably triethylamine at room temperature.
  • the obtained compound of general formula (I) can be separated from the reaction mixture by evaporating the mixture, dividing the residue between water and a water immiscible solvent, preferably dichloromethane then separating the phases and washing the organic phase with water drying and evaporating the product. When required the product can be purified with chromathography.
  • a further subject of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof and one or more pharmaceutically applicable diluent, excipient and/or inert carrier.
  • compositions of the present invention comprise a therapeutically effective dose of one or more compounds of general formula (I) and/or pharmaceutically suitable acid additional salts thereof and one or more pharmaceutically applicable diluent, excipient and/or inert carrier.
  • compositions containing compounds of general formula (I) and/or pharmaceutically suitable acid additional salts thereof are suitable for peroral, parenteral (including subcutaneous, intramuscular and intravenous mode of administration), buccal, sublingual, nasal or rectal administration or for local treatment, and can be solid or liquid.
  • the solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and optionally comprise binding agents such as gelatine, sorbitol, poly(vinyl-pyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly (ethyleneglycol), silica etc.; werang agents sucn as sodium laurylsulfate etc. as the carrier.
  • binding agents such as gelatine, sorbitol, poly(vinyl-pyrrolidone) etc.
  • filling agents such as lactose, glucose, starch, calcium phosphate etc.
  • auxiliary substances for tabletting such as magnesium stearate, talc, poly (ethyleneglycol), silica etc.
  • werang agents sucn as sodium laurylsulfate etc. as the carrier may be powders, capsules, tablets
  • the liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and may comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
  • suspending agents such as gelatine, carboxymethylcellulose etc.
  • emulsifiers such as sorbitane monooleate etc.
  • solvents such as water, oils, glycerol, propyleneglycol, ethanol etc.
  • preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
  • Typical parenteral compositions consising of a solution or suspension of the compound of formula (I) and/or and/or pharmaceutically suitable acid additional salts thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions of the present invention for nasal administration containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in a single or multidose quantities in sterile form is a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fluorochlorohydrocarbon.
  • the aerosol dosages form can also take the form af a pump-atomiser.
  • compositions of the present invention containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof are suitable for buccal or sublingual administration including tamets, lozenges ana pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine, glycerine etc.
  • compositions of the present invention containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • compositions of the present invention containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof for transdermal administration include ointments, gels and patches.
  • compositions of the invention are prepared by admixing a selective 5HT 6 receptor binding benzofuran derivative of general formula (I) or a pharmaceutically suitable acid addition salt thereof to one or more carrier (s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se.
  • Useful methods are known from the literature, e. g. Remington's Pharmaceutical Sciences.
  • compositions of the invention contain, in general, 0.1 to 95.0 per cent by mass of a benzofuran derivative of formula (I) or a pharmaceutically suitable acid addition salt thereof.
  • the amount of the active ingredient mixed with the suitable carrier, wich is for one administration can be different depending on the treated recipient or the route of administration.
  • the typical dosege for adult patients is 0,1-20 mg of a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof, which can be administered once or portions.
  • the actual dose depends on many factors for example: the age, sex, weight or general health condition of the patient etc.
  • a further subject of the invention use of a pharmaceutical composmon comprising as active ingredient a therapeutically effective dose of one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts for the treatment and prevention of 5HT 6 receptor relating disorders of the central nervous system and/or cardiovascular disorders.
  • the invention relates to the use of one or more compounds of general formula (I) as defined above and/or pharmaceutically suitable acid additional salts thereof, in the manufacture of a medicament for the prevention and/or treatment of 5HT 6 receptor relating disorders of the central nervous system and/or cardiovascular disorders.
  • our invention relates to a method of treatment, administering for a patient suffering from 5HT 6 receptor relating disorders, especially disorders of the central nervous system and/or cardiovascular disorders a non-toxic dose of one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof.
  • the compounds of the invention namely compounds of general formula (I) are selective 5-HT 6 -receptor antagonists.
  • This unique receptor profile makes possible the use of the compounds in the treatment of such diseases, which have in the background disorders of the central nervous system and/or some other internal disorders, such as problems of the heart-circulatory system, or diseases of the kidney.
  • the compounds of the invention are well suited for the prevention and/or treatment of the following disorders of the mental and cardiovascular system such as depression, the different types of anxiety (such as Generalized Anxiety Disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia), schisofrenia, schisoaffective disorder, different mood disorders, psychosomatic disorders (for example hypertonia, stomach ulcer etc.), catastrophes of the brain, cell death oh a defined area of the central nervous system, mental disorders caused by the cell deaths of the brain (pi.: Alzheimer disease, stroke, dementias etc.), disorders of the circadian rhythm and sleep disorders.
  • the compounds of the present invention in the treatment of hypertonia are effective.
  • Receptors are from different region of the brain of Wistar-rats with a body weight of 20-200 g.
  • 5-HT 6 receptors are human cloned receptors.
  • the protein content of the membrane preparations was defined according to the method of Lowry (1951). The following table contains the basic data of the receptor binding:
  • the compounds of general formula (I) have selective binding affinity to the central 5-HT 6 receptors, but do not show strong considerable affinity to the different central 5-HT subtype receptors.
  • the reaction mixture is stirred for 5 hours, then after standing the solution for one night, next day the solution is stirred for 6 hours at room temperature, then it is left standing for another night in refrigerator.
  • the catalyst is filtered, washed with ethanol, then the solution is evaporated until dry in vacuum. Thus, 7.1 g (96.8 %) yellow, oily product are obtained, which is directly suitable for use in the next steps.
  • the obtained mixture is divided with water (30 ml), the phases are separated, the organic phase is extracted with water (2 x 30 ml), dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. To the residue ether is added, the precipitated crystals are filtered, and washed with ether. Thus, 6.0 g (59.6 %) of the title product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 3.6 g (35.8 %) of the pure crystalline product are obtained, which is directly suitable for use in the next steps.
  • Example 31 l-Naphthalenesulfonyl-N-[7-(3-diethylamino-propoxy)-2,3-dihydro-2,2- dimethyl-benzofuran-5-yl]-amide
  • l-naphthalenesulfonyl-N-[7-(3-bromo-propoxy)-2,3-dihydro- 2,2-dimethyl-benzofuran-5-yl]-amide 3.4 g, 0.0069 mol
  • dichloromethane 13 ml
  • triethylamine 1.9 ml, 1.39 g, 0.0138 mol
  • diethylamine 1.4 ml, 1.0 g, 0.0138 mol
  • reaction mixture is divided with a solution of sodium hydrogencarbonate (10 ml, 10 %), the phases are separated, the organic phase washed with water (20 ml), dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. The residue is suspended with ether, filtered, washed with ether. Thus, 1.25 g (59.3 %) crystalline, title product are obtained, which has a melting point 129-131 C 0 , after recrystallization with acetonitrile.
  • reaction mixture is divided with a sodium hydrogencarbonate solution (30 ml, 10 %), the phases are separated, the organic phase is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • a sodium hydrogencarbonate solution (30 ml, 10 %)
  • the phases are separated, the organic phase is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • 1.83 g (78.1 %) oily product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate.
  • the suitable fractions are evaporated and thus, 0.74 g (31.6 %) crystalline pure product, melting point: 64-66 C 0 , which is directly suitable for biological experiments.
  • the reaction mixture is stirred at 0 C°-on for 5 hours, then it is left to warm itself and is stirred at this temperature for a further 20 hours.
  • the obtained reaction mixture is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (30 ml), the solution is extracted sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • the residue is 1.40 g (30.5 %) crystalline product after crystallization with acetonitrile. After recrystallization with acetonitrile 1.19 g (25.9 %) of the product are obtained. Melting point: 104-109 C 0 .
  • the obtained product is directly suitable for biological experiments.
  • reaction mixture is stirred for 3 hours at 0 C 0 , it is left to warm itself and is stirred at this temperature for a further 2 hours.
  • the obtained reaction mixture is left to stand for 2 days and evaporated until dry in vacuum, the residue is dissolved in dichloromethane (30 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. To the oily residue ether is added and a crystalline product is obtained, which is filtered and washed with ether.
  • the reaction mixture is stirred for 4 hours at 0 C 0 , then it is left to warm itself at room temperature and it is left to stand for 2 days.
  • the obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (20 ml) the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • the oily residue is dissolved in dichloromethane (10 ml), hydrochloric acidic isopropanol (2.0 ml, 25 %) is added to the solution, then evaporated until dry again. To the residue ether is added and the obtained crystalline product is filtered and washed with ether.
  • Az oily residue (2.5 g) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The suitable fractions are united then evaporated until dry. Thus, 1.1 g (46.3 %) of the crystalline product are obtained, which has a melting point: 61-65 C 0 . The obtained product is directly suitable for biological experiments.
  • the reaction mixture is divided with aqueous sodium hydrogen carbonate solution (30 ml, 10 %), the phases are separated, the organic phase washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum.
  • aqueous sodium hydrogen carbonate solution (30 ml, 10 %)
  • the phases are separated, the organic phase washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum.
  • To the oily residue ether is added and the obtained crystalline product is filtered and washed with ether.
  • 1.9 g (55.0 %) crystalline product are obtained, which has a melting point of 249-253 C 0 , after recrystallization with methanol and adding to the hot solution hydrochloric acid (3 ml, 25 w/w%).
  • the obtained product is directly suitable for biological experiments.
  • the reaction mixture is divided with aqueous sodium hydrogen carbonate solution (30 ml, 10 %), the phases are separated, the organic phase washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. To the oily residue ether is added and the obtained crystalline product is filtered and washed with ether. Thus, 1.0 g (33.7 %) crystalline pure product are obtained, melting point: 170-173 C 0 . The obtained product is directly suitable for biological experiments.
  • the reaction mixture is stirred at 0 C 0 for 5 hours, then it is left to warm itself at room temperature and it is left to stand for 20 hours.
  • the obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (30 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • the crystalline residue is suspended with ether, filtered, washed with ether.
  • 2.08 g (44.8 %) of the product are obtained, which has a melting point of 133-134 C 0 after recrystallization with acetonitrile.
  • the obtained product is directly suitable for biological experiments.
  • the reaction mixture is stirred at 0 C 0 for 5 hours, then it is left to warm itself at room temperature and it is left to stand for 20 hours.
  • the obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (20 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • the oily residue (1.32 g, 50.8 % ) is subjected to chromatography on a column filled with Kieselgel 60 using as eluent a mixture of cyclohexane - ethylacetate in different ratios. The residue is suspended with ether, then filtered.
  • the reaction mixture is stirred at 0 C 0 for 5 hours, then it is left to warm itself at room temperature and left to stand for 16 hours.
  • the obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (20 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • the oily residue (2.0 g, 66.9 % ) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The residue is suspended with ether, then filtered.
  • the reaction mixture is stirred at 0 C 0 for 5 hours, then it is left to warm itself at room temperature and left to stand for 18 hours.
  • the obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (20 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • the oily residue (2.5 g) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The suitable fractions are united then evaporated until dry.
  • the reaction mixture is stirred at 0 C 0 for 5 hours, then it is left to warm itself at room temperature and left to stand for 28 hours.
  • the obtained solution is extracted with sodium hydroxide (30 ml, 10 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • the oily residue (2.29 g) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The suitable fractions are united then evaporated until dry.
  • the residue is suspended with ether, then filtered.
  • the reaction mixture is stirred at 0 C 0 for 5 hours, then it is left to warm itself at room temperature and it is left to stand for 48 hours.
  • the obtained solution is extracted with sodium hydroxide (30 ml, 10 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum.
  • the oily residue (2.68 g) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The suitable fractions are united then evaporated until dry.
  • the residue is suspended with ether, then filtered.

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Abstract

L'invention concerne de nouveaux dérivés sélectifs de benzofurane se liant au récepteur 5HT6, de formule générale (I) dans laquelle Z représente un atome d'hydrogène, un groupe acyle C1-4, un groupe alkyle sulfonyle C1-6, un groupe phényle sulfonyle substitué par au moins un atome d'halogène; ou un groupe naphtyle sulfonyle facultativement substitué par un atome d'halogène, un groupe tétrahydro naphtyle sulfonyle, un groupe (lS)(+)-10-camphor-sulfonyle, un groupe (lR)(-)-10-camphor-sulfonyle ou un groupe benzofuranyle sulfonyle, substitué par un atome d'halogène et un groupe alkyle C1-4, Y représente un groupe alkylène C2-6, R1 et R2 représentent indépendamment un atome d'hydrogène, un groupe alkyle C1-4, un groupe benzyle ou, associés à au moins un atome d'halogène, un groupe trifluorométhyle ou un groupe alcoxy C1-4 substitué par un groupe 4-phényl-pipérazine-l-yle; et/ou leurs sels d'addition acides pharmaceutiquement acceptables, ainsi qu'un procédé de production de ces composés, des compositions pharmaceutiques les contenant et leur utilisation dans le traitement et/ou la prévention des troubles du système nerveux central et du système cardiovasculaire.
PCT/HU2008/000060 2007-05-30 2008-05-30 Nouveaux dérivés de benzofurane utilisés en tant qu'inhibiteurs sélectifs du récepteur 5ht6 et procédé de préparation associé WO2008146063A1 (fr)

Applications Claiming Priority (2)

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HUP0700378 2007-05-30
HU0700378A HU230761B1 (hu) 2007-05-30 2007-05-30 Új, szelektív 5HT6-receptorgátló benzofurán-származékok és eljárás előállításukra

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9840482B2 (en) 2014-04-19 2017-12-12 Sunshine Lake Pharma Co., Ltd. Sulfonamide derivatives and pharmaceutical applications thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986002550A1 (fr) * 1984-10-23 1986-05-09 Rorer International (Overseas) Inc. Ethers et thioethers heterocycliques de benzo-oxy bicyclique servant d'antagonistes du recepteur d'h2
WO1996028437A1 (fr) * 1995-03-10 1996-09-19 Hoechst Marion Roussel, Inc. Nouveau procede de preparation de derives du 2,3-dihydro-benzofuranol
WO1999058527A2 (fr) * 1998-05-14 1999-11-18 EGIS Gyógyszergyár Rt. Derives de benzofuranne, composition pharmaceutique renfermant ces derives et procede de preparation du principe actif
US20030153599A1 (en) * 2001-10-04 2003-08-14 Wyeth Chroman and benzofuran derivatives as 5-hydroxytryptamine-6 ligands
WO2005058858A1 (fr) * 2003-12-19 2005-06-30 Biovitrum Ab Nouveaux derives de benzofurane, pouvant etre utilises dans la prophylaxie ou le traitement des affections associees au recepteur de 5-ht6

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986002550A1 (fr) * 1984-10-23 1986-05-09 Rorer International (Overseas) Inc. Ethers et thioethers heterocycliques de benzo-oxy bicyclique servant d'antagonistes du recepteur d'h2
WO1996028437A1 (fr) * 1995-03-10 1996-09-19 Hoechst Marion Roussel, Inc. Nouveau procede de preparation de derives du 2,3-dihydro-benzofuranol
WO1999058527A2 (fr) * 1998-05-14 1999-11-18 EGIS Gyógyszergyár Rt. Derives de benzofuranne, composition pharmaceutique renfermant ces derives et procede de preparation du principe actif
US20030153599A1 (en) * 2001-10-04 2003-08-14 Wyeth Chroman and benzofuran derivatives as 5-hydroxytryptamine-6 ligands
WO2005058858A1 (fr) * 2003-12-19 2005-06-30 Biovitrum Ab Nouveaux derives de benzofurane, pouvant etre utilises dans la prophylaxie ou le traitement des affections associees au recepteur de 5-ht6

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. HOLENZ, P.J. PAUWELS, J.L. DÌAZ, R. MERCÈ, X. CODONY, H. BUSCHMANN: "Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents", DRUG DISCOVERY TODAY, vol. 11, no. 7/8, April 2006 (2006-04-01), pages 283 - 299, XP002499921 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9840482B2 (en) 2014-04-19 2017-12-12 Sunshine Lake Pharma Co., Ltd. Sulfonamide derivatives and pharmaceutical applications thereof

Also Published As

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HUP0700378A3 (en) 2013-06-28
HUP0700378A2 (en) 2011-03-28
HU230761B1 (hu) 2018-03-28
HU0700378D0 (en) 2007-07-30

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