WO2001083487A1 - Derive de froindazole - Google Patents

Derive de froindazole Download PDF

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Publication number
WO2001083487A1
WO2001083487A1 PCT/JP2001/003556 JP0103556W WO0183487A1 WO 2001083487 A1 WO2001083487 A1 WO 2001083487A1 JP 0103556 W JP0103556 W JP 0103556W WO 0183487 A1 WO0183487 A1 WO 0183487A1
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Prior art keywords
alkyl
compound
formula
different
same
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PCT/JP2001/003556
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English (en)
Japanese (ja)
Inventor
Seiki Goto
Takumi Takahashi
Atsushi Nakamura
Akio Miyafuji
Kyoichi Maeno
Itsurou Shimada
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU52563/01A priority Critical patent/AU5256301A/en
Publication of WO2001083487A1 publication Critical patent/WO2001083487A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel Freindazole derivative having an aminoalkyl at the 1-position and an alkyl at the 7-position having high selectivity for 5-HT 2C receptor and excellent agonist activity, or a pharmaceutically acceptable product.
  • a salt thereof, and a pharmaceutical composition comprising the Freindazole derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, particularly a medicament for treating central nervous system diseases such as sexual dysfunction Composition.
  • the present invention relates to an industrial production method of the furindazole derivative or a pharmaceutically acceptable salt thereof, or an intermediate for producing the production method.
  • 5-HT 2C receptors are mainly distributed in the central nervous system and their role is poorly understood, but central nervous system disorders such as sexual dysfunction, anxiety, depression, and sleep disorders Invest. Drugs 2 (4) 317 (1993). Therefore, the 5-HT 2C receptor agonist is useful for preventing or treating the above diseases.
  • an indazole derivative (W098 / 56768) having an aminoalkyl at the 1-position and having an unsaturated heterocyclic ring fused thereto is disclosed.
  • These indazole derivatives are useful for treating central nervous system diseases, for example, sexual dysfunction such as impotence, anxiety, depression, and sleep disorders.
  • the compounds specifically described in W098 / 56768 also have an affinity for 5-HT 2A receptor, and there are concerns about side effects associated therewith, such as a blood pressure increasing effect. Therefore, there is a need for a drug having a low affinity for the 5-HT 2A receptor and a higher selectivity for the 5-HT 2C receptor.
  • W098 / 56768 has a production method, for example, in which an aminoalkyl having an asymmetric carbon at the 1-position is bonded (S) —2- (7-ethyl-1H-thieno [2 ', 3-glindazole- 1-yl) — 1-Methylethylamine is disclosed to be the following production method.
  • the present inventors have diligently searched for an indazole derivative having a fused heteroaromatic ring having high selectivity for 5-HT 2C receptor and excellent agonist activity.
  • a Freundazol derivative having an aminoalkyl at the 1-position and an alkyl at the 7-position represented by the following formula is represented by the general formula in W098 / 56768, but is not specifically described.
  • It is a novel compound that has remarkably low action on 5-HT 2A receptor, has high selectivity for 5-HT 2C receptor and excellent agonist activity, and is used as a drug for central nervous system diseases such as sexual dysfunction.
  • the present inventors have found that the present invention is useful as a therapeutic agent for the present invention and completed the present invention.
  • the present invention relates to a furoindazole derivative represented by the following formula (I) having an aminoalkyl at position 1 and an alkyl at position 7, or an optically active compound thereof, or a pharmaceutically acceptable salt thereof.
  • RR 2 , R 4 and R 5 identical or different, 1 H or alkyl
  • R 3 alkyl
  • the compound (I) of the present invention is preferably the compound (I) of the present invention, wherein R 1 R 2 , R 4 and R 5 are the same or different and are 1 H, methyl or ethyl, more preferably R 3 is methyl, ethyl, propyl or isobutyl; R 1 R 2 and R 5 are the same or different and are 1 H, methyl or ethyl; R 4 is methyl and R 4 is substituted carbon;
  • the compound of the present invention (I) having a (S) configuration, and more preferably (S) -2- (7-ethyl-1 W-flow [2,3-g] indazolu-yl) ) 1-methylethylamine, (S) — 2— (7-ethyl-3—methyl-1 / ⁇ / —Flo [2,3-g] indazole—1-yl) (S) — 2— (3, 7—Jetil—1 H—F ⁇ [2,3-g] indazo 1
  • (S)-V-ethyl-2 _ (7-ethyl-1 H-flow [2,3-si indazol-1-ethyl])-1-methylethylamine, (S)-2-(4, 7—Jetyl—1H—Flo [2,3-g] indazole—11-yl) —1-Methylethylamine, (S) —2— (7-butyl—1 »—Flo [2,3 — G] indazo 1-yl) 1-methylethylamine or (S) — 2— (7-isopentyl— 1 H—f mouth [2,3—g] indazo 1—yl 1) -Methylethylamine or a pharmaceutically acceptable salt thereof, particularly preferably (S) -2- (7-ethyl-1W-furo [2,3-g] indazolone. 1-Methylethylamine or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (I) of the present invention or an optically active compound thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention is preferably a pharmaceutical composition for treating impotence.
  • the present inventors have conducted intensive studies on the industrial production method of the furoindazole derivative which is the compound (I) of the present invention, and as a result, have found the following production method.
  • the production method of the present invention is similar to the production method of the above-mentioned chenoindazole derivative (W098 / 56768). Solving industrial manufacturing problems.
  • a less expensive aminoalkylating agent can be used without using expensive (R) -propylene oxide, an azide compound which is difficult to handle, and lithium aluminum hydride.
  • the intermediates of the present invention and the compound of the present invention (I) can be obtained with high purity without performing silica gel column chromatography purification.
  • the following alcohol derivative (IV) obtained by reducing the following ketone derivative (III) can be dehydrated and aromatized by simply reacting it under acidic conditions without isolation and purification, and the compound of the present invention (
  • the production method of the following intermediate (V) of I) is a production method which has not been known for this type of compound, and can be carried out without using DDQ. Is the law.
  • the present invention also includes an industrial production method of the following compound (I) of the present invention.
  • the production method of the present invention comprises:
  • RR 2 , R 4 and R 5 same or different—H or alkyl
  • R 3 alkyl
  • R 6 protecting group for amino. The same applies hereinafter. )
  • the present invention also relates to the use of the following formula (11), (III), (IV), (V) or (VI) or a salt thereof as a production intermediate for the production of the compound (I) of the present invention. .
  • the present invention also provides a compound of the following formula (II, (IV) or (V) or a compound thereof useful as an intermediate for producing the compound (I) of the present invention, which is useful as a medicament, particularly as a therapeutic agent for central nervous system diseases such as sexual dysfunction.
  • the intermediate (III), (IV) or (V.) of the present invention can be produced by the following production method or the method shown in the Examples, and the intermediate (III) of the present invention can be produced.
  • Compound (I) of the present invention can be produced from (IV), (IV) or (V).
  • the intermediate (111), (IV) or (V) according to the present invention is preferably such that R 3 is methyl, ethyl, propyl or isobutyl, and R 1 and R 2 are the same or different and 1 H,
  • the intermediate (11 1), (IV) or (V) of the present invention which is methyl or ethyl, and particularly preferably the present invention wherein R 3 is methyl and R 1 and R 2 are —H. It is a production intermediate (111), (IV) or (V).
  • the present invention also provides the following formula (VI) or a salt thereof, which is useful as an intermediate for the production of the compound (I) of the present invention, which is useful as a medicament, particularly as a therapeutic agent for central nervous system diseases such as sexual dysfunction.
  • the intermediate (VI) of the present invention can be produced, and the compound (I) of the present invention can be produced from the intermediate (VI) of the present invention by the following production methods or the methods described in Examples.
  • the intermediate (VI) of the present invention is preferably the intermediate (VI) of the present invention wherein RR 2 , R 4 and R 5 are the same or different and are 1 H, methyl or ethyl, and more preferably, R 3 is methyl, ethyl, propyl or isobutyl; R 1 R 2 and R 5 are the same or different and are 1 H, methyl or ethyl; RS is tert-butoxycarbonyl; R 4 is methyl And the configuration of the carbon substituted by R 4 is the intermediate (VI) of the present invention in which the configuration is ( ⁇ configuration). Particularly preferably, R 3 and R 4 are methyl, and RR 2 and R 5 is —H, R 6 is ⁇ er ⁇ -butoxycarbonyl, and the configuration of the carbon substituted with R 4 is the intermediate (VI) of the present invention.
  • Alkyl means a linear or branched carbon chain having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , Isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, heptyl, nonyl, decyl, etc., preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and more preferably Is methyl or ethyl, particularly preferably methyl.
  • amino protecting group means an amino protecting group that can be used industrially, and includes, for example, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzyl or P-toluenesulfonyl. And preferably tert-butoxycarbonyl.
  • the compound (I) of the present invention may have an asymmetric carbon atom depending on the type of the substituent. is there. Therefore, the compound (I) of the present invention includes a mixture of optical isomers and an isolated one.
  • the compound (I) of the present invention can form a salt with an acid.
  • Such salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid Organic acid such as maleic 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.
  • it is succinic acid.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be isolated as various solvates such as hydrates and ethanol solvates, or as crystalline polymorphs thereof.
  • the compound of the present invention (or a pharmaceutically acceptable salt thereof) also includes various hydrates, solvates and polymorphic substances.
  • the compound (I) of the present invention also includes all compounds that are metabolized in vivo and converted into the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, so-called prodrugs.
  • Examples of the group that forms a prodrug of the compound (I) of the present invention include those described in Prog. Med. 5: 2157-1161 (1985), and Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. Groups described in Designs 163-198. Specifically, it is a group which can be converted back into the primary or secondary amine of the compound (I) of the present invention by hydrolysis, solvolysis or under physiological conditions. Monoalkyl, monoNH—C (0) —O—alkyl, —NH—C (O) —NH—alkyl or —NH—CH, -0-C (O) —alkyl.
  • the intermediate (II), (III), (IV), (V) or (VI) of the present invention which is a useful intermediate for the production method of the present invention, is obtained by subjecting it to a usual salt-forming treatment.
  • Lithic acid addition salts can be produced.
  • Such salts include, for example, acid addition salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid and the like.
  • the compound (I) of the present invention can be produced industrially by the following production method of the present invention. 1st step
  • Compound (II) or a salt thereof can be produced by acylating compound (II).
  • the reaction is carried out by reacting the compound (II) with an excess of an appropriate acylating agent and an acid, such as acetic acid, propinoic acid or butyric acid, the acid chloride, the acid bromide or the acid anhydride as the acylating agent.
  • an acid such as acetic acid, propinoic acid or butyric acid, the acid chloride, the acid bromide or the acid anhydride
  • acetic anhydride and methanesulfonic acid with respect to I).
  • the reaction solvent include acetic acid, acetic anhydride, acetate nitrile or ethers such as diisopropyl ether, tetrahydrofuran or dioxane, and preferably acetic acid or no solvent.
  • the reaction temperature is from cooling to heating, preferably from room temperature to heating.
  • the reaction product is followed by the addition of alcohols such as methanol, ethanol or 2-propanol or water, preferably 2-propanol, optionally with a suitable base such as sodium hydroxide, potassium hydroxide.
  • the reaction is carried out at room temperature or under heating in the presence of calcium, sodium carbonate, potassium carbonate, sodium ethoxide or sodium methoxide.
  • Compound (II) can be produced by a known method (Heterocycles, 22, 2313, 1984; W098 / 56768).
  • the compound (IV) can be produced by reducing the ketone group of the compound (II or a salt thereof.
  • the reaction is carried out by using a suitable reducing agent such as sodium borohydride, sodium triethoxy borohydride, diisobutylaluminum.
  • a suitable reducing agent such as sodium borohydride, sodium triethoxy borohydride, diisobutylaluminum.
  • the reaction can be performed using hydride, borane, platinum (IV) oxide, hydrogen in the presence of palladium-carbon, or the like, preferably using an equivalent to excess amount of sodium borohydride.
  • Alcohols such as methanol, ethanol or 2-propanol; aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diisopropyl ether, tetrahydrofuran or dioxane; water; and the like.
  • the reaction temperature is preferably from cooling to room temperature.
  • a salt of the compound (III) is used in the reaction, an equivalent amount of a suitable base, for example, sodium ethoxide, sodium methoxide, sodium hydroxide, or hydroxide is used.
  • the reaction may be carried out after neutralization with potassium, sodium carbonate or potassium carbonate, preferably sodium ureaoxide or sodium hydroxide. It can also be used for the next reaction.
  • the compound (V) or a salt thereof can be produced by subjecting the compound (IV) to dehydration and aromatization under acidic conditions.
  • the reaction can be carried out using an equivalent to excess amount of a suitable acid, for example, hydrochloric acid, acetic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, or the like, relative to compound (IV).
  • a suitable acid for example, hydrochloric acid, acetic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, or the like
  • an equivalent amount of hydrochloric acid is used.
  • the reaction solvent include alcohols such as methanol, ethanol and 2-propanol, aromatic hydrocarbons such as benzene, toluene and xylene, water and acetic acid, and preferably ethanol.
  • the reaction temperature is from room temperature to under heating, preferably Or under heating reflux
  • the compound (VI) can be produced by a condensation reaction between the compound (V) or a salt thereof and an amino-protected aminoalkylating agent.
  • amino-protected amino alkylating agents include, for example, (S)-(1-methyl-2-tosyl-kisechil) rubamic acid i "ert-butyl ester, (S)-(1-methyl-2-mesyl-kisechil) ) Potassium tertiary butyl ester, (S)-(1-Methyl-12-butyl bromide) Potassium tertiary butyl ester or (S) — (1-Methyl-2- cisyl) Acid benzyl ester, etc., and preferably (S)-(1-methyl-2-tosylkisechyl) terfamine terf-butyl ester The reaction is equivalent to compound (V) or a salt thereof.
  • reaction can be carried out using an excess amount of a suitable base, for example, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium ⁇ -butoxide.
  • a suitable base for example, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium ⁇ -butoxide.
  • the reaction can be carried out using 2 equivalents of cesium carbonate with respect to the compound (V)
  • the reaction solvent include aromatic hydrocarbons such as benzene, toluene and xylene, acetone and 2-butynone.
  • ketones such as diisopropyl ether, tetrahydrofuran, or dioxane
  • alcohols such as methanol, ethanol, or 2-propanol
  • the reaction temperature is from cooling to heating, and preferably from room temperature to heating. It can also be used for the reaction.
  • Compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be produced by deprotecting the amino of compound (VI).
  • the reaction can be performed using a known method (Theodora. Greene and Peter G. Ulluts, Protective Groups in Organic Synthesis, John Wiley & Sons, INC., 199L) or a method similar thereto, and preferably vinegar.
  • the reaction can be carried out at an ice-cooled temperature to room temperature by using an excess amount of hydrochloric acid with respect to compound (VI) in an ethyl acetate solvent.
  • the reaction product is subsequently neutralized with a suitable base in a solvent such as water or alcohols, preferably in an aqueous solution of potassium carbonate, under cooling to room temperature, preferably under ice cooling to room temperature.
  • a suitable base such as water or alcohols, preferably in an aqueous solution of potassium carbonate, under cooling to room temperature, preferably under ice cooling to room temperature.
  • the compound (I) of the present invention can be obtained.
  • the compound (I) of the present invention thus produced is isolated as it is or as a pharmaceutically acceptable salt thereof.
  • the salt of the compound (I) of the present invention can be produced by subjecting the compound (I) of the present invention, which is a free base, to a usual salt-forming reaction.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is isolated and purified as a hydrate, solvate, or polymorphic substance thereof. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, and recrystallization.
  • an optical isomer can be obtained 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 with a general optically active acid). It can lead to stereochemically pure isomers.
  • the compound (I) of the present invention is a novel compound not specifically described in W098 / 56768, which has excellent agonist activity for 5-HT 2 C receptor, and has 5-HT 2A receptor activity. It showed over 90 times higher selectivity to the body. Furthermore, it has a penile erection evoking effect in rats, and is useful for treating central nervous system diseases, for example, sexual dysfunction such as impotence, anxiety, depression and sleep disorders.
  • compositions containing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared using tablets, excipients and other additives commonly used in the preparation of tablets, tablets and tablets. It is prepared into powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc., and is administered orally (including sublingually) or parenterally.
  • the clinical dose of the compound (I) of the present invention to humans is appropriately determined depending on the individual case in consideration of the symptoms, body weight, age, sex, administration route and the like of the patient to which the compound is applied. It is orally administered once to several times a day in the range of 10 mg to 100 mg, preferably 50 mg to 200 mg per person, or 1 adult per day. 1 mg to 500 mg per day, preferably 5 mg to 100 mg 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.
  • the dosage varies under various conditions, so that a smaller amount may be sufficient in some cases.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, dextrose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrole. Ridone is mixed with magnesium aluminate metasilicate.
  • the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stable materials such as lactose.
  • tablets or pills may be coated with sugar such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose or a gastric or enteric film.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents, For example, it contains purified water and ethanol.
  • This composition f may contain, in addition to the inert diluent, solubilizing agents, solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweeteners, flavoring agents, 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 physiological saline.
  • water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as crude oil, alcohols such as ethanol, polysorbate 80 (trade name), and the like.
  • Such compositions further include additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. But it is good.
  • the compound (I) of the present invention which is useful for central nervous system diseases such as sexual dysfunction, is industrially advantageously produced by the production method of the present invention as compared with the production method described in W098 / 56768.
  • the compound (V) can be prepared by using a less expensive aminoalkyliylide without using expensive (R) -propylene oxide, difficult-to-handle azide compound and lithium aluminum hydride. Aminoalkyl can be easily introduced at the first position.
  • each of the intermediates and the compound of the present invention ( ⁇ ) can be obtained with high purity without purification by chromatography in any of the steps. Not using Holm.
  • the alcohol derivative (IV) obtained by reducing the ketone derivative (III) is dehydrated and aromatized by simply reacting it under acidic conditions without isolation and purification, and the compound of the present invention (I)
  • the production method for obtaining the intermediate (V) is a production method that has not been known for this kind of compound, and is a highly useful production method because it can be carried out without using DDQ.
  • the production method of the present invention has solved the problems in the conventional industrial production, and can now industrially produce the compound (I) of the present invention for the first time.
  • the organic layer was washed successively with aqueous sodium bicarbonate (8.3 kg of sodium bicarbonate / 90 L of water) and brine (24 kg of sodium chloride / 74 L of water).
  • the organic layer was concentrated under reduced pressure to give 6,7-dihydrobenzofuran-1,4 having a purity of 98.4%. ⁇ ;) 24.8 kg of a toluene solution was obtained. .
  • 5-Hydroxymethylidene-6,7-dihydrobenzofuran-1 4 5H 1 30.1 kg of toluene 60 L, ethanol 190 L, 80.35% hydrazine monohydrate The product (12.6 kg) was added, and the mixture was stirred at 45 ° C or lower for 22 hours. To the solution obtained by concentrating the reaction solution under reduced pressure, 180 L of water was added with stirring, followed by cooling. The precipitated crystals were collected by filtration and dried to obtain brownish crystals having a purity of 99.0%.
  • the obtained crystals were dissolved in 25 ml of methanol, 13.3 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 15 minutes. After adding 40 ml of water and stirring for 1 hour under ice-cooling, the crystals were filtered, washed with water and dried to obtain 5.26 g of 7-ethyl-1H-furo [2,3-g] indazole.
  • the organic layer was concentrated under reduced pressure, to a solution of the remaining 180 L of ethanol, 5.7 kg of succinic acid was added with stirring, and the mixture was cooled.
  • the precipitated crystals were collected by filtration to obtain crude crystals.
  • 180 L of ethanol and 3.5 L of water were added.
  • the mixture was heated to around the reflux temperature with stirring to dissolve the crude crystals.
  • the mixture was filtered with ethanol 9.2 and washed with 0.18 L of water.
  • the filtrate was cooled with stirring.
  • the precipitated crystals were collected by filtration and dried to give a yellow-brown crystal (S) with a purity of 99.5%.
  • Example 6 The compounds of Examples 6 to 12 were obtained in the same manner as in Examples 1, 4 and 5.
  • Example 6 (S) —2— (7-ethyl-3—methyl-1H—furo [2,3-g] indazolu-1-yl) —1-methylethylethylamine hydrochloride
  • Example 7 (S) -2- (3-, 7-Jetyl-1H-furo [2,3-g] indazol-vinyl) 1-methylethylethylamine hydrochloride
  • Example 8 (S) -1-methyl-2- (7-propyl-1H-furo [2,3-g] indazole-1-yl) ethylamine hydrochloride
  • Example 11 1 (S) —2— (7-butyl—1H—F. [2,3—g] indazolu-1-yl) 1-1-methylethylamine hydrochloride
  • a P-hydrolysis assay was performed using CH0 cells expressing human 5-HT 2C and 5-HT 2A receptors. EC 5 . Values were calculated by non-linear regression analysis. Table 3 shows the results.
  • Target compound Example 1 of W098 / 56768 1 ((5) — 2— (1 ⁇ —furo [2, 3 g] indazole—1 yl) 1—1—Methylethylamine hydrochloride)
  • the agonist activity of the compound of the present invention was 1.5 times higher than that of the target compound, and the selectivity was 93 times higher than that of the target compound, which was 93 times higher than that of the target compound.
  • the compound of Example 5 showed strong activity with a minimum effective dose of 0.3 mg / kg, po.

Abstract

L'invention concerne un dérivé de froindazole correspondant à la formule (I), qui est un aminoalkyle en première position et un alkyle en septième position, ou un de leurs sels acceptables sur le plan pharmaceutique. Le dérivé présente une sélectivité élevée pour des récepteurs 5-HT2c et une excellente activité agonistique. (Dans ladite formule, R?1, R2, R4, et R5¿ représentent chacun un hydrogène ou un alkyle, et R3 représente un alkyle.) L'invention concerne également une composition médicinale comprenant le dérivé froindazole ou un sel et un support acceptables sur le plan pharmaceutique, notamment une composition médicinale destinée au traitement des maladies du système nerveux central, telles que des troubles des fonctions sexuelles. L'invention concerne enfin un procédé de production industrielle de dérivé de froindazole ou de sel acceptable sur le plan pharmaceutique, et un intermédiaire s'utilisant dans ce procédé. (I)
PCT/JP2001/003556 2000-04-28 2001-04-25 Derive de froindazole WO2001083487A1 (fr)

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AU52563/01A AU5256301A (en) 2000-04-28 2001-04-25 Froindazole derivative

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JP2000129854 2000-04-28
JP2000-129854 2000-04-28

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Cited By (14)

* Cited by examiner, † Cited by third party
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WO2003057213A2 (fr) * 2001-12-28 2003-07-17 Bayer Pharmaceuticals Corporation Composes derives de cyclohexano- et cycloheptapyrazole destines au traitement des maladies associees au recepteur 5-ht2c
EP1392292A2 (fr) * 2001-06-01 2004-03-03 Alcon, Inc. Pyranoindazoles et leur utilisation dans le traitement du glaucome
WO2005053688A1 (fr) * 2003-11-26 2005-06-16 Alcon, Inc. Furo[2,3-g] indazoles substitues destines au traitement du glaucome
WO2005058911A2 (fr) * 2003-12-15 2005-06-30 Alcon, Inc. [1,4]oxazino[2,3-g]indazoles substitues pour traiter le glaucome
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
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
WO2021122415A1 (fr) 2019-12-19 2021-06-24 Bayer Aktiengesellschaft Dérivés furoindazole
WO2022179940A1 (fr) 2021-02-23 2022-09-01 Bayer Aktiengesellschaft Dérivés de furoindazole utilisés en tant qu'antagonistes de gpr84
WO2022229061A1 (fr) 2021-04-29 2022-11-03 Bayer Aktiengesellschaft Dérivés de furoindazole utilisés comme antagonistes ou inhibiteurs de gpr84

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US3880867A (en) * 1974-02-05 1975-04-29 Squibb & Sons Inc Derivatives of furo(2,3-d)pyrazolo(3,4-b)pyridines
EP0655440A2 (fr) * 1993-10-22 1995-05-31 F. Hoffmann-La Roche Ag 1-Aminoéthylindoles
EP0990650A1 (fr) * 1997-06-13 2000-04-05 Yamanouchi Pharmaceutical Co. Ltd. Derives tricycliques de pyrrole ou de pyrazole

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US3880867A (en) * 1974-02-05 1975-04-29 Squibb & Sons Inc Derivatives of furo(2,3-d)pyrazolo(3,4-b)pyridines
EP0655440A2 (fr) * 1993-10-22 1995-05-31 F. Hoffmann-La Roche Ag 1-Aminoéthylindoles
EP0990650A1 (fr) * 1997-06-13 2000-04-05 Yamanouchi Pharmaceutical Co. Ltd. Derives tricycliques de pyrrole ou de pyrazole

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1392292A2 (fr) * 2001-06-01 2004-03-03 Alcon, Inc. Pyranoindazoles et leur utilisation dans le traitement du glaucome
EP1392292A4 (fr) * 2001-06-01 2004-08-11 Alcon Inc Pyranoindazoles et leur utilisation dans le traitement du glaucome
US6881749B2 (en) 2001-06-01 2005-04-19 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma
WO2003057213A2 (fr) * 2001-12-28 2003-07-17 Bayer Pharmaceuticals Corporation Composes derives de cyclohexano- et cycloheptapyrazole destines au traitement des maladies associees au recepteur 5-ht2c
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
EP2277513A2 (fr) 2003-04-25 2011-01-26 Pfizer Inc. Traitement de l'incontinence avec des 5ht2c agonistes
WO2005053688A1 (fr) * 2003-11-26 2005-06-16 Alcon, Inc. Furo[2,3-g] indazoles substitues destines au traitement du glaucome
US7476687B2 (en) 2003-11-26 2009-01-13 Alcon, Inc. Substituted furo[2,3-g]indazoles for the treatment of glaucoma
WO2005058911A2 (fr) * 2003-12-15 2005-06-30 Alcon, Inc. [1,4]oxazino[2,3-g]indazoles substitues pour traiter le glaucome
US7268131B2 (en) 2003-12-15 2007-09-11 Alcon, Inc. Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma
US6989445B2 (en) 2003-12-15 2006-01-24 Alcon, Inc. Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma
WO2005058911A3 (fr) * 2003-12-15 2005-08-25 Alcon Inc [1,4]oxazino[2,3-g]indazoles substitues pour traiter le glaucome
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
EP2742936A1 (fr) 2006-05-16 2014-06-18 Takeda Pharmaceutical Company Limited Composé hétérocyclique condensé et son utilisation
EP2727585A1 (fr) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited Méthode de dépistage in-vivo
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et 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
WO2021122415A1 (fr) 2019-12-19 2021-06-24 Bayer Aktiengesellschaft Dérivés furoindazole
WO2022179940A1 (fr) 2021-02-23 2022-09-01 Bayer Aktiengesellschaft Dérivés de furoindazole utilisés en tant qu'antagonistes de gpr84
WO2022229061A1 (fr) 2021-04-29 2022-11-03 Bayer Aktiengesellschaft Dérivés de furoindazole utilisés comme antagonistes ou inhibiteurs de gpr84

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