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WO1998030548A1 - AGONISTES DU RECEPTEUR 5-HT2c ET DERIVES D'AMINOALKYLINDAZOLE - Google Patents

AGONISTES DU RECEPTEUR 5-HT2c ET DERIVES D'AMINOALKYLINDAZOLE Download PDF

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Publication number
WO1998030548A1
WO1998030548A1 PCT/JP1998/000071 JP9800071W WO9830548A1 WO 1998030548 A1 WO1998030548 A1 WO 1998030548A1 JP 9800071 W JP9800071 W JP 9800071W WO 9830548 A1 WO9830548 A1 WO 9830548A1
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WO
WIPO (PCT)
Prior art keywords
group
fluoro
indazo
indazole
added
Prior art date
Application number
PCT/JP1998/000071
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English (en)
Japanese (ja)
Inventor
Kyoichi Maeno
Hideki Kubota
Itsuro Shimada
Shuichi Sakamoto
Shin-Ichi Tsukamoto
Fumikazu Wanibuchi
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to JP53075298A priority Critical patent/JP3560986B2/ja
Priority to AU53432/98A priority patent/AU5343298A/en
Publication of WO1998030548A1 publication Critical patent/WO1998030548A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • the present invention relates to a 5-HT 2c receptor agonist comprising, as an active ingredient, an aminoalkylindazole derivative or a pharmaceutically acceptable salt thereof. Further regarding aminoalkyl indazoles derivative or a pharmaceutically acceptable salt thereof is a 5-HT 2 c receptor work for drugs. Background art
  • 5-HT 2 C receptor agonists are useful for the prevention or treatment of the above-mentioned diseases, and in particular, there is no effective treatment method that has been abandoned as a non-disease such as sexual dysfunction and sexual dysfunction. It is considered that it is also useful.
  • 5-HT 2 C receptor agonists For such 5-HT 2 C receptor agonists, several compounds have been known so far.
  • the compounds disclosed therein are only indole derivatives, tricyclic pial derivatives and tricyclic pyrazole derivatives.
  • the present inventors have, 5-HT 2 C receptor agonists result of intense study regarding, amino alkyl fin Dazo Ichiru derivative Shi pairs 5-HT 2 c receptor compared to Indoru derivatives mightier, affinity have sex, and completed also found present invention to have a selectivity for 5-HT 2 a and 5-HT receptors. Furthermore, it has been found that these aminoalkylindazole derivatives have high activity even in animal models. That is, the present invention relates to a medicament comprising, as an active ingredient, an aminoalkylindazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which has strong affinity and selectivity for 5-HT 2 C receptor.
  • an aminoalkylindazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof which has strong affinity and selectivity for 5-HT 2 C receptor.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof which is a therapeutic agent for central nervous system diseases such as sexual disorders, sexual dysfunction, anorexia dysfunction, anxiety, depression or sleep disorders, is used as an active ingredient.
  • the object of the present invention is to provide a drug comprising the compound (I) of the present invention, which is preferably a therapeutic agent for sexual dysfunction or sexual dysfunction, or a pharmaceutically acceptable salt thereof as an active ingredient. is there.
  • A may have a substituent having 2 to 6 carbon atoms, and may be a linear or branched alkylene group or cycloalkane
  • R 3 and R 4 are the same or different and are a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino Group, nitro group or cyano group)
  • the present invention provides a general compound having strong affinity and selectivity for 5-HT 2 C receptor as follows:
  • the aminoalkylindazole derivative AI represented by the formula (II) is a pharmaceutically acceptable salt thereof, or the compound (II) of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof. It is intended to provide a pharmaceutical composition comprising a carrier.
  • A may have a substituent having 2 to 6 carbon atoms t, linear or branched alkylene group or cycloalkane
  • R 1 and R 2 the same or different, and a hydrogen atom, a lower alkyl group or R 1 may combine with R 2 or A to form a nitrogen-containing saturated heterocycle
  • R 3 and R 4 are the same or different and are a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino Group, nitro group or cyano group, provided that when R 3 and R 4 are the same or different and are a hydrogen atom, a hydroxyl group, a lower alkoxy group, an amino group, a lower alkanoylamino group or a nitro group, R 1 is hydrogen Indicates the meaning of the atom)
  • Preferred compounds are the compounds (II) of the present invention wherein A is an ethylene or propylene group, and more preferably the compounds of the present invention wherein R 3 and R 4 are the same or different and are a hydrogen atom, a lower alkoxy group or a halogen atom.
  • R 3 and R 4 are the same or different and are a hydrogen atom, a lower alkoxy group or a halogen atom.
  • R 1 and R 2 are hydrogen atoms, and particularly preferably 2- (5,6-dichloro-1H-indazole-11-yl) ethylamine Or a pharmaceutically acceptable salt thereof;
  • S 6-fluoro-1H-indazole-11-yl) -11-methylethylamine or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention (1, II) will be described in detail.
  • 5-HT 2C receptor agonist is a compound that has an affinity for 5-HT 2C receptor and has an agonistic or antagonistic action.
  • the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.
  • linear or branched alkylene group having 2 to 6 carbon atoms examples include ethylene, trimethylene, propylene, tetramethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, Ethil Echire
  • “Cycloalkane” means a monocyclic hydrocarbon ring group having 3 to 8 ring atoms, and specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. And preferably pentane and pentane, and particularly preferably pentane.
  • lower alkyl group specifically, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl or isohexyl
  • hexyl group and the like can be mentioned, preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl or ethyl group, and particularly preferably a methyl group.
  • nitrogen-containing saturated heterocycle means a 3- to 8-membered nitrogen-containing saturated heterocycle, specifically, for example, aziridine, azetidine, pyrrolidine, piperidine, hexahydroazepine or octahydroazosine.
  • pyrrolidine and piperidine are particularly preferred, and particularly preferred is pyrrolidine.
  • halogen atom includes a fluorine, chlorine, bromine or iodine atom, and is preferably a fluorine or chlorine atom.
  • “Lower alkoxy group” means an oxy group substituted by the lower alkyl group.
  • Aryl lower alkoxy group means the above lower alkoxy group substituted by the aryl group.
  • aryl group means a carbon ring aryl group having 6 to 14 carbon atoms, specifically, for example, phenyl, trithyl, xylyl, biphenyl, naphthyl, anthryl or And a phenyl group.
  • a phenyl group is preferred.
  • the “mono- or di-lower alkylamino group” means an amino group in which the above lower alkyl group is substituted by 1 or 2 groups.
  • “Lower alkanoylamino” means a carbonylamino group substituted by the lower alkyl.
  • the substituent “may have a substituent” means the above-mentioned halogen atom or lower alkoxy group.
  • the compound (III) of the present invention may have an asymmetric carbon atom depending on the type of the group. Therefore, the compound (III) of the present invention includes a mixture of optical isomers and an isolated one.
  • the compound (III) of the present invention can form an acid addition salt.
  • the compounds of the present invention also include these salts.
  • Specific examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and the like.
  • Organic acid such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamic acid.
  • the compound (III) of the present invention or a pharmaceutically acceptable salt thereof may be isolated as various solvates such as hydrates and ethanolates, or as polymorphic substances thereof.
  • the compounds of the present invention also include various hydrates and solvates of the above-mentioned type.
  • the compound of the present invention represented by the general formula (II) can be synthesized, for example, by the following method, but the production method of the compound of the present invention is not limited thereto.
  • (iv) ⁇ ⁇ Middle, ⁇ . ( 4) is as described above, (D) is a straight chain or branched alkylene group having 6 carbons, and (E) is a halogen atom, a tosyloxy group or a mesyloxy group. And the like, or a group which can be easily converted to an amino group such as a cyano group, an azido group, a nitro group, an amino group protected with a commonly used protecting group, or a hydroxyl group.
  • D and E may combine to form a nitrogen-containing saturated ring.
  • the raw material (IV) of the compound of the present invention can be easily produced by subjecting the indazole derivative (III) to a conventional alkylation reaction.
  • a conventional alkylation reaction For example, an alkylation reaction using an alkyl halide, an alkyl tosylate, an alkyl mesylate or an epoxide derivative can be performed.
  • E is a hydroxyl group
  • esters of tosylic acid and mesylic acid can be easily produced by using a standard esterification reaction, and phthalimid derivatives can be easily produced by using Mitsunobu reaction or the like.
  • RR 2 , R 3 , R 4 and A are as described above, and X represents a leaving group such as a halogen atom, a tosyloxy group, a mesyloxy group, etc.
  • the compound (I, II) of the present invention can be produced by converting the compound represented by the general formula (IVa) into a corresponding amino compound.
  • This reaction can be carried out in the presence or absence of a suitable solvent, in the presence of a suitable base if necessary, under cooling or heating, or, if necessary, in a sealed reaction vessel.
  • the compounds (Ia, IIa) of the present invention can be produced by reducing the nitrile compound represented by the general formula (IVb) and converting it into the corresponding amino compound.
  • This reaction is carried out in the presence or absence of a suitable inert solvent, preferably in tetrahydrofuran, if necessary, in the presence or absence of a suitable Lewis acid, using a suitable reducing agent, under cooling or heating. , Preferably at room temperature.
  • a suitable inert solvent preferably in tetrahydrofuran
  • a suitable reducing agent Preferably at room temperature.
  • the Lewis acid include aluminum chloride
  • examples of the reducing agent include a hydride complex such as lithium aluminum hydride.
  • This reaction can also be carried out by catalytic hydrogenation on a metal catalyst using a suitable solvent such as ethyl acetate, alcohol, tetrahydrofuran, dioxane, acetic acid or a mixture thereof.
  • a suitable solvent such as ethyl acetate, alcohol, tetrahydrofuran, dioxane, acetic acid or a mixture thereof.
  • RRR 4 and A are as described above, and Y represents a group that can be easily converted to an amino group such as an azido group, a nitro group, or an amino group protected with a commonly used protecting group.
  • a and Y may combine to form a nitrogen-containing saturated heterocycle.
  • the compounds (Ia, IIa) of the present invention can be produced by converting the compound represented by the general formula (IVc) to the corresponding amino compound.
  • this reduction reaction is carried out in the presence or absence of a suitable inert solvent, and if necessary, in the presence or absence of a suitable Lewis acid, by cooling or heating using a reducing agent.
  • a suitable inert solvent for example, ethyl acetate, alcohol, tetrahydrofuran, dioxane, acetic acid, water or The reaction can also be carried out by using catalytic hydrogenation on a metal catalyst using these mixtures or by using triphenylene.
  • the present reduction reaction can be carried out by catalytic hydrogenation on a metal catalyst using an appropriate solvent, for example, ethyl acetate, alcohol, tetrahydrofuran, dioxane, acetic acid or a mixture thereof.
  • an appropriate solvent for example, ethyl acetate, alcohol, tetrahydrofuran, dioxane, acetic acid or a mixture thereof.
  • the reaction can be carried out in the presence or absence of a suitable solvent, using a metal (eg, iron, tin) or the like, in the presence of an acid catalyst, and under cooling or heating.
  • Y represents an amino group protected by a commonly used protecting group
  • the amino group can be converted into an amino group by deprotection according to a conventional method.
  • the protecting group is a phthalimid group
  • a similar method described in Protecting Groups in Organic Synthesis, John Wiley & Sons, INC. Can be used. If the protecting group is a normal acyl group, it can be easily deprotected under acidic or basic conditions.
  • the compound (I, II) of the present invention can be produced by N-alkylating the compound represented by the general formula (Ia, IIa) produced by the second to fourth processes.
  • This reaction is carried out in the presence or absence of a suitable solvent, in the presence of a suitable alkylating agent, preferably a lower alkyl halide (eg, propyl iodide), and if necessary, a suitable base as a deoxidizing agent, and then cooling or heating.
  • a suitable alkylating agent preferably a lower alkyl halide (eg, propyl iodide)
  • a suitable base as a deoxidizing agent
  • a reductive alkylation reaction can also be performed as the present alkylation reaction.
  • a reducing agent such as a borohydride reagent (for example, sodium borohydride) is used, and if necessary, an acid catalyst, preferably a mineral acid or
  • an appropriate lower alkyl aldehyde eg, (Propanal) can be reacted.
  • the compound (I, II) of the present invention is obtained by reacting the compound represented by the general formula (V) with a hydrazine derivative (VI) to lead to a hydrazone (VII), and further converted to (VIII) by an intramolecular cyclization reaction. If necessary, it can be produced via desired functional group conversion.
  • the reaction for producing the hydrazone compound (VII) is carried out in the presence or absence of a suitable solvent, preferably in an alcohol, and, if necessary, in the presence or absence of a suitable acid or base, with a suitable substituted hydrazine (VI) (Eg, 2-hydrazinoethanol) under cooling or heating, preferably at room temperature.
  • a suitable solvent preferably in an alcohol
  • a suitable substituted hydrazine (VI) Eg, 2-hydrazinoethanol
  • the intramolecular cyclization reaction is carried out in the presence or absence of a suitable solvent, preferably in dimethylformamide, and, if necessary, in the presence or absence of a suitable acid or base (for example, in carbon dioxide lime).
  • a suitable solvent preferably in dimethylformamide
  • a suitable acid or base for example, in carbon dioxide lime
  • the reaction can be carried out at room temperature to 100 ° C. under cooling or heating.
  • the (VIII) thus obtained can be produced, if necessary, by converting it to the compound (1, II) of the present invention by a method similar to Production Methods 1 to 5.
  • the salt of the compound of the present invention (I, II) can also be produced by subjecting the salt to a conventional salt-forming operation.
  • the compound of the present invention (1, II) thus produced is isolated and purified as a salt, a hydrate, a solvate, or a polymorphic substance of the compound as free. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, reconstituted products, and valley chromatography.
  • Various isomers can be separated by selecting an appropriate starting compound or by utilizing a difference in physical properties between the isomers.
  • the optical isomers can be sterically selected by selecting an appropriate raw material or by a racemic resolution method of a racemic compound (for example, a method of optically resolving a diastereomer salt with a general optically active acid or base). It can lead to scientifically pure isomers.
  • the compound of the present invention has a strong affinity and selectivity for 5-HT 2C receptor and is also effective in animal models, so that it can be used in central nervous system diseases such as sexual disorders, sexual dysfunction, and appetite regulation. It is useful for treating disorders, anxiety, depression, sleep disorders, etc.
  • 5-HT 2 c and 5 -HT 2 A receptor were performed by [3 H] 5- HT binding assay according to the method of 191-196 (1992).
  • Rat penile erection-inducing action 5-—The ability to induce penile erection by HT 2 C receptor stimulation is known (Berendsen & Broekkamp, Eur. J. Pharmacol., 135, 179-184 (1987) ). The test compound was administered to the rat. Immediately after the administration, the number of penile erections for 30 minutes was measured and compared with the minimum effective dose at which a statistically significant response was observed. Table 2 shows the results. Table 2 Animal model using rat
  • the indazole derivative of the present invention is an animal compared to the indole derivative of EP 655440.
  • the model showed a much higher activity of 10 times or more.
  • the compound of the present invention is effective in animal models using rats, and is therefore useful for treating central nervous system diseases such as sexual dysfunction or sexual dysfunction.
  • compositions containing one or more of the compound (I, 11) of the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, etc. as an active ingredient are usually used.
  • the clinical dose of the compound of the present invention (I, II) for humans is appropriately determined according to the individual case in consideration of the patient's symptoms, body weight, age, sex, administration route, and the like. Normally, per adult, 10 mg to 100 mg per day, preferably in the range of 50 mg to 200 ⁇ ⁇ orally once or several times a day, or adult Per person Or from 1 mg to 500 mg, preferably 5 mg to 100 mg per day, administered intravenously once to several times a day, or 1 hour to 24 hours a day It is administered intravenously over a period of time.
  • a smaller amount of t or less than the above dose may be sufficient.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. Mixed with magnesium aluminate metasilicate.
  • the composition may contain, in a conventional manner, additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stabilizers such as lactose.
  • a solubilizing agent such as glutamate or aspartic acid may be contained.
  • Tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or with a gastric or enteric film, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified Contains water and ethanol.
  • the composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweeteners, flavors, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injections and saline.
  • water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). is there.
  • Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. .
  • Reference Example 20 (6-Methoxy Iff-Indazo-1-ru) Acetonitrile
  • Reference Example 21 2- (6-Fluoro-1H-Indazo-1-ru) Propionnitrile
  • Example 1 Under an argon stream, 0.30 g of lithium aluminum hydride was suspended in 0 ml of tetrahydrofuran, and 0.97 g of aluminum chloride was added thereto under ice-cooling, followed by stirring for 15 minutes. To this suspension, a tetrahydrofuran solution (5 ml) of 1.28 g of (4-fluoro-1H-indazo-1-yl) acetonitrile was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. . Methanol was added to the reaction solution, and the excess reagent was separated by ft.
  • Example 7 2- (5-nitro-1 1 / -1-indazole-1-yl) ethylamine hydrochloride
  • Raw material (5-nitro-1 indazole-1-yl) acetonitrile
  • Example 8 2- (5-Chloro-1-indazo-1-yl) ethylamine hydrochloride
  • Raw material (5-chloro-1-H-indazol-1-inole) acetonitrile
  • Example 9 2- (5-Bromo-1 ⁇ -indazo 1-l-inole) ethylamine hydrochloride
  • Raw material (5-bromo-1 1-indazo 1-l 1-inole) acetonitrile
  • Example 11 1 2 (5-bromo-6-fluoro-1H-indazo-1-ru-1-yl) ethylamine hydrochloride
  • Example 14 2- (5-butyl-1H-indazole-1-inole) Ethylamine hydrochloride
  • Raw material (5-butyl-1H-indazo-1-ru-1-yl) acetate
  • Methanesulfonic acid 2- (5-fluoro-1 ⁇ -indazole-1-yl) ethyl
  • a mixture of U.2 g and getylamine 2.O ml was placed in a 10 mj sealed vessel and stirred at room temperature for 16 hours.
  • the reaction solution was concentrated under reduced pressure, and the obtained residue was made basic by adding a 1N aqueous solution of sodium hydroxide, and then extracted with chloroform.
  • the combined organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate.
  • Example 3 9 5_Fluoro-11- (2-piperidine-1-1-ylethyl) -Iff-Indazole hydrochloride
  • Methanesulfonic acid 2 (5-Fluoro-1 fi-Indazo-1-ru 1-yl) Ethyl and piperidine
  • Example 42 Dissolve 0.20 g of tert-butyl canolebamic acid in 20 ml of ethanol, and add 4N ethyl acetate solution of hydrochloric acid acetate (1 Om). The mixture was stirred at room temperature for 19 hours. The resulting crystals were collected by filtration and then recrystallized from ethanol to obtain 0.15 g of 2- (5-amino-indazo-1-yl) ethylamine hydrochloride.
  • 6-Fluoro 1- (1-benzo-1-pyrrolidine) was synthesized in the same manner as in Reference Example 1, using 6-fluorindazole and 1-benzoylpyrrolidine-13-yl methanesulfonate as starting materials. Dissolve 0.38 g of 1H-indazole in 10 ml of acetic acid, add 5 ml of 6 N hydrochloric acid, heat to reflux for 6 hours, and remove the solvent under reduced pressure. Distilled off. After adding saturated aqueous ammonia, the solvent was again distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. This was dissolved in ethanol, and 67 mg of fumaric acid was added, followed by stirring for 10 minutes.
  • the mixture was stirred for 6 days under a hydrogen atmosphere at 3 atm.
  • the solvent was distilled off under reduced pressure, and the residue was purified by silica gel gel chromatography. This was dissolved in ethanol, an ethanol solution of fumaric acid was added and the mixture was stirred, and then the solvent was distilled off under reduced pressure.
  • the obtained crystals were washed with ethanol to obtain 0.04 g of (S) -2- (6-hydroxy-1H-indazole-11-yl) -1-methylethylamine fumarate.
  • ⁇ R nuclear magnetic resonance scan Bae spectrum (unless otherwise specified MSO- d 6, TMS internal standard)

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Abstract

L'invention concerne des médicaments contenant comme principe actif des dérivés d'aminoalkylindazole de la formule générale (I), ou leurs sels pharmaceutiquement acceptables, qui présentent une grande affinité et sélectivité pour les récepteurs 5-HT2c et conviennent pour le traitement d'affections du système nerveux central (troubles sexuels, insuffisances génitales, troubles de régulation de l'appétit, anxiété, dépression, troubles du sommeil). Dans ladite formule (I), A est alkylène C2-6 linéaire ou ramifié éventuellement substitué ou cycloalcane; R1 et R2 sont identiques ou différents et sont, chacun, hydrogène ou alkyle inférieur, ou peuvent former ensemble, avec A, un composé hétérocyclique saturé contenant de l'azote; R3 et R4 sont identiques ou différents et sont, chacun, hydrogène, alkyle inférieur, halogéno, hydroxy, alcoxy inférieur, alcoxy inférieur substitué par aryle, amino, mono ou bi(alkyle inférieur)amino, alcanoylamino inférieur, nitro ou cyano.
PCT/JP1998/000071 1997-01-13 1998-01-12 AGONISTES DU RECEPTEUR 5-HT2c ET DERIVES D'AMINOALKYLINDAZOLE WO1998030548A1 (fr)

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JP53075298A JP3560986B2 (ja) 1997-01-13 1998-01-12 ５―ｈｔ２ｃ受容体作用薬及びアミノアルキルインダゾール誘導体
AU53432/98A AU5343298A (en) 1997-01-13 1998-01-12 5-ht2c receptor agonists and aminoalkylindazole derivatives

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JP398097 1997-01-13
JP9/3980 1997-01-13

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Cited By (42)

* Cited by examiner, † Cited by third party
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WO2000012502A1 (fr) * 1998-09-01 2000-03-09 Vernalis Research Limited Pyrrololoquinolines destinees au traitement de l'obesite
WO2000012482A3 (fr) * 1998-09-01 2000-05-25 Cerebrus Pharm Ltd Composes chimiques iii
WO2000012481A3 (fr) * 1998-09-01 2000-06-08 Cerebrus Pharm Ltd Composes chimiques iv
WO2000038677A1 (fr) * 1998-12-23 2000-07-06 Allelix Biopharmaceuticals Inc. Derives indole et indolizidine permettant de traiter les migraines
EP1023898A1 (fr) * 1999-01-26 2000-08-02 Adir Et Compagnie Cyano-indoles en tant qu' inhibiteurs de recapture de sérotonine et ligands du récepteur 5-HT2c
WO2000017170A3 (fr) * 1998-09-23 2000-08-03 Cerebrus Pharm Ltd Composes chimiques viii
WO2001012603A1 (fr) * 1999-08-11 2001-02-22 Vernalis Research Limited Derives d'indole, procede de leur preparation, compositions pharmaceutiques renfermant ceux-ci et leur application medicinale
WO2001070207A3 (fr) * 2000-03-17 2002-05-10 Alcon Universal Ltd Agonistes de 5ht2 permettant de commander la pression intra-oculaire elevee et de traiter le glaucome
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
US6410858B1 (en) 1999-12-17 2002-06-25 Shinko Electric Industries Co. Ltd. Multilayered wiring board, a production process for, and semiconductor device using, the same
US6479534B1 (en) 2000-10-16 2002-11-12 Hoffmann La Roche Indoline derivatives and method of treating obesity
WO2002098862A1 (fr) * 2001-06-01 2002-12-12 Alcon, Inc. Procedes de fabrication d'indazoles
WO2002098861A1 (fr) * 2001-06-01 2002-12-12 Alcon, Inc. Procedes de fabrication de 1-(2-aminopropyl)-6-hydroxyindazole
US6509357B1 (en) 2001-01-23 2003-01-21 Wyeth 1-aryl or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
US6583134B2 (en) 2000-03-06 2003-06-24 Hoffman-La Roche Inc. Aza- indolyl derivatives for treating obesity
US6593330B2 (en) 2000-11-20 2003-07-15 Biovitrum Compounds and their use
US6610685B2 (en) 2000-12-27 2003-08-26 Hoffmann-La Roche Inc. Fused indole derivatives
US6664286B1 (en) 1998-09-18 2003-12-16 Alcon Manufacturing, Ltd. Serotonergic 5ht2 agonists for treating glaucoma
WO2004000830A1 (fr) 2002-06-19 2003-12-31 Biovitrum Ab Nouveaux composes, leur utilisation et leur preparation
WO2003057213A3 (fr) * 2001-12-28 2004-02-19 Bayer Pharmaceuticals Corp Composes derives de cyclohexano- et cycloheptapyrazole destines au traitement des maladies associees au recepteur 5-ht2c
WO2004058725A1 (fr) * 2002-12-23 2004-07-15 Alcon, Inc. 1-alkyl-3-aminoindazoles
US6881749B2 (en) 2001-06-01 2005-04-19 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma
US6927233B1 (en) 2000-03-17 2005-08-09 Alcon, Inc. 5ht2 agonists for controlling IOP and treating glaucoma
US6956036B1 (en) 2000-03-17 2005-10-18 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
US6962939B1 (en) 1999-08-11 2005-11-08 Vernalis Research Limited Condensed indoline derivatives and their use as 5HT, in particular 5HT2C, receptor ligands
US6998489B2 (en) 2001-06-01 2006-02-14 Alcon, Inc. Methods of making indazoles
US7005443B1 (en) 2000-03-17 2006-02-28 Alcon, Inc. 5-Hydroxy indazole derivatives for treating glaucoma
US7022707B2 (en) 2000-12-15 2006-04-04 Hoffman-La Roche Inc. Piperazine derivatives
WO2006052189A1 (fr) * 2004-11-11 2006-05-18 Astrazeneca Ab Derives de nitro indazole
US7049307B2 (en) 2003-12-23 2006-05-23 Abbott Laboratories Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor
WO2007029629A1 (fr) * 2005-09-06 2007-03-15 Shionogi & Co., Ltd. Dérivé d’acide indolécarboxylate ayant une activité à effet antagoniste du récepteur pgd2
US7208494B2 (en) 2003-06-26 2007-04-24 Hoffmann-La Roche Inc. 5HT2c receptor agonists
US7271180B2 (en) 2001-01-23 2007-09-18 Wyeth 1-Aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
US7507732B2 (en) 2005-03-31 2009-03-24 Pfizer Inc. Cyclopentapyridine and tetrahydroquinoline derivatives
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
EP2277513A2 (fr) 2003-04-25 2011-01-26 Pfizer Inc. Traitement de l'incontinence avec des 5ht2c agonistes
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
WO2015066344A1 (fr) 2013-11-01 2015-05-07 Arena Pharmaceuticals, Inc. Agonistes du récepteur 5-ht2c et compositions et procédés d'utilisation
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale
WO2024044848A1 (fr) * 2022-08-29 2024-03-07 Mindset Pharma Inc. Dérivés d'indazole en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés

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Cited By (66)

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Publication number Priority date Publication date Assignee Title
WO2000012502A1 (fr) * 1998-09-01 2000-03-09 Vernalis Research Limited Pyrrololoquinolines destinees au traitement de l'obesite
WO2000012482A3 (fr) * 1998-09-01 2000-05-25 Cerebrus Pharm Ltd Composes chimiques iii
WO2000012481A3 (fr) * 1998-09-01 2000-06-08 Cerebrus Pharm Ltd Composes chimiques iv
US6365598B1 (en) 1998-09-01 2002-04-02 Vernalis Research Limited Pyrroloquinolines for treatment of obesity
US6664286B1 (en) 1998-09-18 2003-12-16 Alcon Manufacturing, Ltd. Serotonergic 5ht2 agonists for treating glaucoma
WO2000017170A3 (fr) * 1998-09-23 2000-08-03 Cerebrus Pharm Ltd Composes chimiques viii
WO2000038677A1 (fr) * 1998-12-23 2000-07-06 Allelix Biopharmaceuticals Inc. Derives indole et indolizidine permettant de traiter les migraines
EP1023898A1 (fr) * 1999-01-26 2000-08-02 Adir Et Compagnie Cyano-indoles en tant qu' inhibiteurs de recapture de sérotonine et ligands du récepteur 5-HT2c
US7323473B2 (en) 1999-08-11 2008-01-29 Vernalis Research Limited Condensed indoline derivatives and their use as 5-HT, in particular 5-HT2C, receptor ligands
US6962939B1 (en) 1999-08-11 2005-11-08 Vernalis Research Limited Condensed indoline derivatives and their use as 5HT, in particular 5HT2C, receptor ligands
US6706750B1 (en) 1999-08-11 2004-03-16 Vernalis Research Limited Indole derivatives process for their preparation, pharmaceutical compositions containing them and their medicinal application
US7323486B2 (en) 1999-08-11 2008-01-29 Vernalis Research Limited Condensed indoline derivatives and their use as 5HT, in particular 5HT2C, receptor ligands
WO2001012603A1 (fr) * 1999-08-11 2001-02-22 Vernalis Research Limited Derives d'indole, procede de leur preparation, compositions pharmaceutiques renfermant ceux-ci et leur application medicinale
US7323487B2 (en) 1999-08-11 2008-01-29 Vernalis Research Limited Condensed indoline derivatives and their use as 5HT, in particular 5HT2C, receptor ligands
US7173056B2 (en) 1999-08-11 2007-02-06 Vernalis Research Limited Condensed indoline derivatives and their use as 5HT, in particular 5HT2C, receptor ligands
US7166632B2 (en) 1999-08-11 2007-01-23 Vernalis Research Limited Condensed indoline derivatives and their use as 5HT, in particular 5HT2C, receptor ligands
US7166613B2 (en) 1999-08-11 2007-01-23 Vernalis Research Limited Condensed indoline derivatives and their use as 5HT, in particular 5HT2c, receptor ligands
US6410858B1 (en) 1999-12-17 2002-06-25 Shinko Electric Industries Co. Ltd. Multilayered wiring board, a production process for, and semiconductor device using, the same
US6583134B2 (en) 2000-03-06 2003-06-24 Hoffman-La Roche Inc. Aza- indolyl derivatives for treating obesity
WO2001070207A3 (fr) * 2000-03-17 2002-05-10 Alcon Universal Ltd Agonistes de 5ht2 permettant de commander la pression intra-oculaire elevee et de traiter le glaucome
AU2001216071B2 (en) * 2000-03-17 2004-12-02 Alcon, Inc. 5HT2 agonists for controlling IOP and treating glaucoma
US7005443B1 (en) 2000-03-17 2006-02-28 Alcon, Inc. 5-Hydroxy indazole derivatives for treating glaucoma
US6956036B1 (en) 2000-03-17 2005-10-18 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
US6927233B1 (en) 2000-03-17 2005-08-09 Alcon, Inc. 5ht2 agonists for controlling IOP and treating glaucoma
US6479534B1 (en) 2000-10-16 2002-11-12 Hoffmann La Roche Indoline derivatives and method of treating obesity
US6593330B2 (en) 2000-11-20 2003-07-15 Biovitrum Compounds and their use
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
US7247633B2 (en) 2000-11-20 2007-07-24 Biovitrum Ab Pyrimidine compounds and their use
US7022707B2 (en) 2000-12-15 2006-04-04 Hoffman-La Roche Inc. Piperazine derivatives
US6610685B2 (en) 2000-12-27 2003-08-26 Hoffmann-La Roche Inc. Fused indole derivatives
US6919354B2 (en) 2001-01-23 2005-07-19 Wyeth 1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
US7541358B2 (en) 2001-01-23 2009-06-02 Wyeth 1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
US6710069B2 (en) 2001-01-23 2004-03-23 Wyeth 1-aryl- or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
US7271180B2 (en) 2001-01-23 2007-09-18 Wyeth 1-Aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
US6509357B1 (en) 2001-01-23 2003-01-21 Wyeth 1-aryl or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
WO2002098861A1 (fr) * 2001-06-01 2002-12-12 Alcon, Inc. Procedes de fabrication de 1-(2-aminopropyl)-6-hydroxyindazole
WO2002098862A1 (fr) * 2001-06-01 2002-12-12 Alcon, Inc. Procedes de fabrication d'indazoles
AU2002310224B9 (en) * 2001-06-01 2002-12-16 Alcon, Inc. Methods of making indazoles
AU2002310224B2 (en) * 2001-06-01 2007-06-07 Alcon, Inc. Methods of making indazoles
US6998489B2 (en) 2001-06-01 2006-02-14 Alcon, Inc. Methods of making indazoles
US6881749B2 (en) 2001-06-01 2005-04-19 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma
WO2003057213A3 (fr) * 2001-12-28 2004-02-19 Bayer Pharmaceuticals Corp Composes derives de cyclohexano- et cycloheptapyrazole destines au traitement des maladies associees au recepteur 5-ht2c
WO2004000830A1 (fr) 2002-06-19 2003-12-31 Biovitrum Ab Nouveaux composes, leur utilisation et leur preparation
US7799930B2 (en) 2002-12-23 2010-09-21 Alcon, Inc. 1-alkyl-3-aminoindazoles
WO2004058725A1 (fr) * 2002-12-23 2004-07-15 Alcon, Inc. 1-alkyl-3-aminoindazoles
CN100361977C (zh) * 2002-12-23 2008-01-16 爱尔康公司 1-烷基-3-氨基吲唑
EP2277513A2 (fr) 2003-04-25 2011-01-26 Pfizer Inc. Traitement de l'incontinence avec des 5ht2c agonistes
US7208494B2 (en) 2003-06-26 2007-04-24 Hoffmann-La Roche Inc. 5HT2c receptor agonists
US7049307B2 (en) 2003-12-23 2006-05-23 Abbott Laboratories Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor
EP2400300A1 (fr) 2004-08-25 2011-12-28 Takeda Pharmaceutical Company Limited Procédé de sélection d'agents préventifs/remèdes pour l'incontinence de stress
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
WO2006052189A1 (fr) * 2004-11-11 2006-05-18 Astrazeneca Ab Derives de nitro indazole
US7507732B2 (en) 2005-03-31 2009-03-24 Pfizer Inc. Cyclopentapyridine and tetrahydroquinoline derivatives
US8143285B2 (en) 2005-09-06 2012-03-27 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
WO2007029629A1 (fr) * 2005-09-06 2007-03-15 Shionogi & Co., Ltd. Dérivé d’acide indolécarboxylate ayant une activité à effet antagoniste du récepteur pgd2
JP5147401B2 (ja) * 2005-09-06 2013-02-20 塩野義製薬株式会社 Ｐｇｄ２受容体アンタゴニスト活性を有するインドールカルボン酸誘導体
US8623903B2 (en) 2005-09-06 2014-01-07 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
EP2727585A1 (fr) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited Méthode de dépistage in-vivo
EP2742936A1 (fr) 2006-05-16 2014-06-18 Takeda Pharmaceutical Company Limited Composé hétérocyclique condensé et son utilisation
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2789338A2 (fr) 2007-11-15 2014-10-15 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
WO2015066344A1 (fr) 2013-11-01 2015-05-07 Arena Pharmaceuticals, Inc. Agonistes du récepteur 5-ht2c et compositions et procédés d'utilisation
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale
WO2024044848A1 (fr) * 2022-08-29 2024-03-07 Mindset Pharma Inc. Dérivés d'indazole en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés

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