WO2016027757A1 - Nouveau dérivé de 2-aminobenzoyle - Google Patents

Nouveau dérivé de 2-aminobenzoyle Download PDF

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WO2016027757A1
WO2016027757A1 PCT/JP2015/073002 JP2015073002W WO2016027757A1 WO 2016027757 A1 WO2016027757 A1 WO 2016027757A1 JP 2015073002 W JP2015073002 W JP 2015073002W WO 2016027757 A1 WO2016027757 A1 WO 2016027757A1
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pharmaceutically acceptable
acceptable salt
compound
hydrogen atom
solvate
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PCT/JP2015/073002
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English (en)
Japanese (ja)
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健太郎 ▲高▼井
真吾 水嶋
昌一 島田
雪子 山本
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国立大学法人大阪大学
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Priority to JP2016544191A priority Critical patent/JP6664814B2/ja
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    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/4462—Non condensed piperidines, e.g. piperocaine only substituted in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

Definitions

  • the present invention relates to a novel 2-aminobenzoyl derivative and a salt thereof, and a therapeutic agent for mental illness, chronic pain or chronic pruritus comprising the compound as an active ingredient.
  • Patent Document 1 discloses that a compound represented by the following formula I regulates the production of kynurenine in the body and is useful for the treatment or prevention of central nervous system (CNS) diseases and the like.
  • CNS central nervous system
  • A is C 1-6 alkylene; R, R 1 and R 2 are independently hydrogen, alkyl, etc .; X is> C 1-6 alkylene,>C ⁇ O,> C ⁇ S or a single bond; Y is hydrogen, alkyl or the like.
  • the object of the present invention is to change the structure of metabolites present in the tryptophan metabolic pathway, so that depression, atypical depression, treatment-resistant depression, anxiety, bipolar disorder, obsessive compulsive disorder, post traumatic It is to provide a novel compound that exerts an effect on the treatment and / or prevention of mental disorders such as stress disorder (PTSD) and chronic pain symptoms such as fibromyalgia and chronic pruritus.
  • PTSD stress disorder
  • chronic pain symptoms such as fibromyalgia and chronic pruritus.
  • the present inventors have found that the compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter abbreviated as “the compound of the present invention” as necessary).
  • the compound of the present invention a novel compound having a different chemical structure from the compound described in Patent Document 1, and has been found to exhibit an excellent effect in the treatment and / or prevention of mental illness, chronic pain or chronic pruritus.
  • the invention has been completed.
  • this invention includes the following aspects in a certain side surface.
  • Formula (1) [Wherein Q represents the following formulas (2a) to (2c): (Wherein R 1 represents a hydrogen atom or a C 1-6 alkyl group; R 2 and R 3 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group; Alternatively, together with the carbon atom to which they are attached, a 3- to 8-membered cycloalkane ring may be formed; R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group; Alternatively, together with the nitrogen atom to which they are attached, a 3- to 8-membered cyclic amine may be formed; n represents 0, 1, 2, 3, 4, or 5;
  • R 4 and R 5 are both hydrogen atoms
  • R 2 represents a group represented by any one of C 2-6 alkyl group] Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • [5] The compound according to [1] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 2 is a hydrogen atom, and R 3 is a hydrogen atom or a C 1-6 alkyl group. Or a solvate.
  • [6] The compound according to any one of [1] or [5], wherein R 4 is a hydrogen atom or a C 1-6 alkyl group, and R 5 is a C 1-6 alkyl group. A pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • [7] The compound according to any one of [1], [5] or [6], wherein R 1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. .
  • a pharmaceutical comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.
  • Mental illness or chronic pain comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient Or a treatment for chronic pruritus.
  • the therapeutic agent according to [10] which is a therapeutic agent for mental illness.
  • the therapeutic agent according to [10] which is a therapeutic agent for chronic pain.
  • the therapeutic agent according to [10] which is a therapeutic agent for chronic pruritus.
  • the mental disease is depression, atypical depression, treatment-resistant depression, anxiety, bipolar disorder, obsessive compulsive disorder, or post-traumatic stress disorder (PTSD) [10] or [14 ] The therapeutic agent as described in any one of these.
  • the therapeutic agent according to any one of [10] or [14], wherein the chronic pain is fibromyalgia.
  • the chronic pruritus is caused by atopy, chronic kidney disease, psoriasis, psoriasis, lichen planus, scabies, contact dermatitis or insect stings, or any one of [10] or [14] Therapeutic agent.
  • a therapeutically effective amount of the compound according to any one of [1] to [8] or [14] or a pharmaceutically acceptable salt thereof is administered to a mammal in need of treatment.
  • a method for treating mental illness, chronic pain or chronic pruritus is administered to a mammal in need of treatment.
  • the treatment method according to [21] wherein the mental illness is depression, atypical depression, treatment-resistant depression, anxiety, bipolar disorder, obsessive compulsive disorder, or PTSD.
  • the compounds of the present invention can be used for depression, atypical depression, treatment-resistant depression, anxiety, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD) and other psychiatric disorders as well as fibromyalgia. It is useful as a therapeutic and / or prophylactic agent for chronic pain symptoms and chronic pruritus.
  • FIG. 1 shows the results of a forced mouse swimming test in a group administered with kynuramine (Kynx), imipramine (Imi), kynurenine (Kyn) and 4-hydroxyquinoline (4-HQ).
  • FIG. 2 shows the results of a forced mouse swimming test in the Example 1 compound administration group.
  • FIG. 3A shows the test results for measuring the amount of inhibition of extracellular serotonin uptake in the groups administered with Kynx, serotonin (5-HT), Kyn, and Example compounds.
  • FIG. 3B shows the test results for measuring the amount of inhibition of extracellular serotonin uptake in the groups administered with Kynx, serotonin (5-HT), Kyn, and Example compounds.
  • FIG. 1 shows the results of a forced mouse swimming test in a group administered with kynuramine (Kynx), imipramine (Imi), kynurenine (Kyn) and 4-hydroxyquinoline (4-HQ).
  • FIG. 2 shows the results of a forced mouse swimming test
  • FIG. 4 shows the results of measurement of intracellular serotonin release amount in the groups administered with Kynx, 5-HT, Kyn and Example compounds.
  • FIG. 5A shows the MAO-A inhibitory activity measurement test results for the Kynx, 5-HT and Kyn administration groups.
  • FIG. 5B shows the MAO-B inhibitory activity measurement test results for the groups administered with Kynx, 5-HT and Kyn.
  • FIG. 6A shows the MAO-A inhibitory activity measurement test results for the groups administered with Kynx, 5-HT and Example compounds.
  • FIG. 6B shows MAO-B inhibitory activity measurement test results for the groups administered with Kynx, 5-HT, and Example compounds.
  • FIG. 7 shows the in-vivo serotonin release amount measurement test results of Example 1 compound administration group.
  • FIG. 8 shows the results of the in vivo vivo serotonin release amount measurement test in the Kynx administration group.
  • FIG. 9 shows the neurogenesis evaluation results in the hippocampal dentate gyrus of the group administered with Kynx and Example 1.
  • FIG. 10 shows the neurogenesis evaluation results in the hippocampal dentate gyrus of the group administered with Kynx and Example 1.
  • FIG. 11 shows the in vitro operability test results of the human 5-HT3A receptor in the group administered with Kynx and Example 1.
  • FIG. 12 shows the in vitro operability test results of human type 5-HT3A receptors in the groups administered with Kynx and the Example compounds.
  • FIG. 13 shows the results of a chronic pain stress test in the Kynx administration group.
  • C 1-6 alkyl is synonymous with a linear or branched alkyl group having 1 to 6 carbon atoms.
  • group means a monovalent group.
  • alkyl group means a monovalent saturated hydrocarbon group.
  • group may be omitted.
  • description of each group also applies when the group is a part of another group or a substituent.
  • C 1-6 alkyl group means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is a “C 1-4 alkyl group”. Specific examples of “C 1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • Examples of the “cycloalkane ring” in which R 2 and R 3 may form a 3- to 8-membered cycloalkane ring together with the carbon atom to which they are bonded include, for example, cyclopropane A ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and the like.
  • “3- to 8-membered cyclic amine” means a 3- to 8-membered saturated or unsaturated cyclic amine.
  • Examples of the “cyclic amine” in which R 4 and R 5 may be combined with the nitrogen atom to which they are bonded to form a 3- to 8-membered cyclic amine include, for example, an aziridine ring, azetidine Ring, pyrrolidine ring, piperidine ring, azepane ring, azocan ring and the like.
  • R 4 and R 5 are “may form a 3- to 8-membered cyclic amine together with the nitrogen atom to which they are bonded” is represented by the following formula: Groups and the like.
  • Group represented by formula (2b) examples thereof include an aziridin-2-ylmethyl group, an azetidin-2-ylmethyl group, a pyrrolidin-2-ylmethyl group, and a piperidin-2-ylmethyl group.
  • a pyrrolidin-2-ylmethyl group is preferable.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (1) include salts with inorganic acids or organic acids.
  • Specific examples of the salt with an inorganic acid include hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like.
  • Specific examples of salts with organic acids include, for example, formate, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, ascorbate, fumarate, maleate, Examples thereof include citrate, malonate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate.
  • the compound represented by the formula (1) or the pharmaceutically acceptable salt may exist in the form of a hydrate and / or a solvate, a solvent such as these hydrates or ethanol solvates. Japanese products are also included in the compounds of the present invention. Further, the compounds of the present invention include all forms of crystal forms.
  • the compounds of the present invention may have at least one asymmetric carbon atom. Accordingly, the compound of the present invention includes not only the racemic form of the compound represented by the formula (1) but also optically active forms of these compounds. When the compound represented by the formula (1) has two or more asymmetric carbon atoms, stereoisomerism may occur. Accordingly, the compounds of the present invention include stereoisomers of these compounds, mixtures thereof and isolated ones.
  • a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the formula (1) into 2 H (D) is also included in the compound represented by the formula (1). .
  • the present invention also includes a prodrug of the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the prodrugs are functional derivatives of the compounds of the present invention that can be readily converted into the required compound in vivo.
  • chronic pain examples include fibromyalgia.
  • chronic pruritus is caused by, for example, atopy, chronic kidney disease, psoriasis, psoriasis, lichen planus, scabies, contact dermatitis or insect stings. Chronic pruritus has the same onset mechanism as chronic pain in that it passes through C fibers from the periphery, and both chronic pruritus and chronic pain are considered to be included in the CNS hypersensitivity syndrome.
  • Phenylethylamine is taken up by the dopamine transporter, actively releases intracellular dopamine to the outside of the cell, and has an action of suppressing the degradation of dopamine as a MAO inhibitor, but it is very easy to decompose into MAO and difficult to use. It is.
  • Amphetamine and methamphetamine are compounds obtained by partially modifying the structure of phenylethylamine, and have the characteristics that phenylethylamine is not easily decomposed into MAO by becoming a competitive MAO inhibitor without losing its affinity with MAO.
  • the compound of the present invention includes a compound obtained by partially modifying the structure of kynuramine (Kynx) based on this synthetic strategy while maintaining its characteristics.
  • the compound represented by the formula (1) of the present invention is produced, for example, by the following production method.
  • the compound used by the following manufacturing method may form the salt in the range which does not interfere with reaction.
  • Manufacturing method 1 The compound represented by the formula (1-2a), (1-2b) or (1-2c) or a salt thereof is produced, for example, by the method shown below.
  • X represents a bromine atom or an iodine atom
  • Boc represents a tert-butoxycarbonyl group
  • n, R 1 , R 2 , R 3 and R 4 have the same meanings as the above [1].
  • Step 1 Production Steps of Compounds (7-1), (7-2) and (7-3) Compounds (7-1), (7-2) and (7-3) are obtained from Compound (3). Produced by conversion to a nucleating agent followed by reaction with an aldehyde. This step is performed, for example, by the method described in Angew. Chem. Int. Ed., 2002, 41, 1610-1611, or a method analogous thereto.
  • Step 2 Production Step of Compounds (8-1), (8-2) and (8-3) Compounds (8-1), (8-2) and (8-3) were obtained in Step 1. It is produced by oxidizing the hydroxyl group of a compound to a carbonyl group. Examples of the oxidation method include Swern oxidation and oxidation in the presence of Dess-Martin periodinane.
  • Step 3 Production Step of Compounds (9-1), (9-2) and (9-3) Compounds (9-1), (9-2) and (9-3) were obtained in Step 2. It is produced by reducing the nitro group of a compound to an amino group. This step is performed, for example, by mixing and stirring the compound obtained in Step 2 in a solvent such as methanol or ethanol in the presence of a metal catalyst such as palladium-carbon or rhodium-carbon in a hydrogen atmosphere. This step is usually performed at 0 to 100 ° C. within a range of 0.5 to 24 hours.
  • Step 4 Compound (1-2a), (1-2b) and (1-2c 1) of the manufacturing process the compound (1-2a), and (1-2b) (1-2c 1) is obtained in step 3
  • Step 3 Prepared by deprotecting the Boc group on the nitrogen atom of the resulting compound.
  • This step is carried out, for example, by reacting the compound obtained in Step 3 in the presence of an acid such as hydrochloric acid or trifluoroacetic acid without solvent or in a solvent such as dichloromethane or chloroform.
  • This step is usually performed at 0 to 100 ° C. within a range of 0.5 to 24 hours.
  • Step 5 Production Step of Compound (1-2c)
  • Compound (1-2c) is produced by introducing R 5 into compound (1-2c 1 ) obtained in Step 4.
  • Examples of the method for introducing R 5 include reductive amination reaction and alkylation reaction.
  • acetic acid is added as necessary in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, and mixed and stirred in a solvent such as tetrahydrofuran, chloroform, or dichloromethane. It is carried out by doing. This step is usually performed at 0 ° C. to 120 ° C. for 0.5 to 24 hours.
  • the alkylation reaction is carried out by mixing and stirring in a solvent such as tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, or dimethyl sulfoxide in the presence of a base such as potassium carbonate, cesium carbonate, or sodium hydride. Is done. This step is usually performed at 0 ° C. to 120 ° C. for 0.5 to 24 hours.
  • a solvent such as tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, or dimethyl sulfoxide.
  • Compound (1-2c 2 ) can also be produced by the method shown below.
  • Boc represents a tert-butoxycarbonyl group
  • R 2 and R 4 have the same meanings as the above [1].
  • Step 1 Production Step of Compound (11)
  • Compound (11) is produced by subjecting compound (10) to reductive amination conditions.
  • a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, acetic acid or the like is added as necessary, and in a solvent such as tetrahydrofuran, chloroform, or dichloromethane. It is carried out by mixing and stirring.
  • This step is usually performed at 0 ° C. to 120 ° C. for 0.5 to 24 hours.
  • Step 2 Production Step of Compound (12)
  • Compound (12) is produced by protecting the amino group of compound (11) with a Boc group. This step is carried out, for example, by mixing and stirring in a solvent such as tetrahydrofuran, chloroform, or dichloromethane in the presence of (Boc) 2 O and triethylamine or diisopropylethylamine. This step is usually performed at 0 ° C. to 120 ° C. for 0.5 to 24 hours.
  • Step 3-5 Production process of Compound (1-2c 2) (1-2c 2) is produced by a method similar to that described in Step 2-4 of the Preparation Process 1 from the compound (12) .
  • the compound (1) obtained by the production method shown above is isolated and purified according to conventional methods such as extraction, column chromatography, recrystallization and reprecipitation.
  • As the extraction solvent diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene or the like is used.
  • Purification by column chromatography uses silica gel, alumina or the like that has been subjected to acidic, basic, or various chemical treatments, and examples of developing solvents include hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, acetonitrile.
  • Water, methanol / water, etc. can be used.
  • the optical isomer of the compound of the present invention can be obtained as a racemate or as an optically active substance when an optically active starting material or intermediate is used. If necessary, at the appropriate stage of the production method, the corresponding raw material, intermediate or final product is physically separated by a known separation method such as a method using an optically active column or a fractional crystallization method. Can be resolved into their optical enantiomers either chemically or chemically. Specifically, for example, in the diastereomeric method, two diastereomers are formed from a racemate using an optically active resolving agent, or a diastereomeric salt is formed. Since these different diastereomers generally have different physical properties, they can be resolved by a known method such as fractional crystallization.
  • the pharmaceutically acceptable salt of compound (1) includes, for example, compound (1) having sufficient basicity or acidity to form a salt in a solvent such as water, methanol, ethanol, and acetone, and pharmaceutically It can be produced by mixing an acceptable acid or base.
  • the compounds of the present invention include depression, atypical depression, treatment-resistant depression, anxiety, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD) and other psychiatric disorders such as fibromyalgia It is preferably used as a therapeutic and / or prophylactic agent for chronic pain or chronic pruritus caused by atopy, chronic kidney disease, psoriasis, psoriasis, lichen planus, scabies, contact dermatitis or insect stings.
  • the usefulness of the compound of the present invention as a pharmaceutical product is proved by a pharmacological test capable of confirming pharmacological action; a pharmacokinetic test capable of confirming pharmacokinetics; a safety test capable of confirming safety, for example, by the following test. .
  • These tests can generally be performed in mice, rats, dogs, and monkeys. Moreover, it can implement under awakening or anesthesia as needed.
  • Examples of the pharmacological test include an in vitro test for confirming the action of a compound on a serotonin transporter, and an in vivo test for confirming an antidepressant action and an anxiolytic action.
  • Specific examples of the in vitro test include a serotonin release amount measurement test.
  • Specific in vivo tests include, for example, forced swimming test, reserpine-induced hypothermia test, tail suspension test, learning helplessness test, ball-filling behavior test, elevated cross maze test, light-dark box test, olfactory bulb extraction-induced excessive exercise amount Examples include tests.
  • Examples of the pharmacokinetic test include a blood concentration evaluation test, a brain migration evaluation test, a P-glycoprotein substrate recognition test, a drug interaction test, a drug metabolic pathway identification test, and a dansyl glutathione addition test.
  • preferred compounds of the present invention can exhibit high brain migration.
  • safety tests include blood pressure and heart rate measurement tests, electrocardiogram measurement tests, general symptom observations, general toxicity tests, in addition to in vitro tests such as hERG inhibition tests, cytotoxicity tests, and Ames.
  • the compound in the present invention can be administered as a preparation having an appropriate dosage form by oral administration or parenteral administration.
  • the dosage form include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and haptics.
  • the preparation is produced by a known method using a pharmaceutically acceptable additive.
  • Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes and the like can be used.
  • lactose lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, stearin
  • examples include magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
  • the compound of the present invention or a salt thereof can be administered to a patient suffering from a mental illness.
  • the dose and frequency of administration vary depending on symptoms, age, body weight, dosage form, etc., but when administered orally, it is usually in the range of about 1 to about 500 mg per day for adults, preferably about 5
  • the range of about 100 mg can be administered in one or several divided doses.
  • the range of about 0.1 to about 300 mg, preferably about 1 to about 100 mg can be administered once or divided into several times.
  • LC-MS was measured using various conditions shown in Table 1 below.
  • the retention time (R.T.) represents the time when the mass spectrum peak appears in the LC-MS measurement.
  • tert-butyl 3-formylazetidine-1-carboxylate (409 mg, 2.21 mmol) in THF (3 mL) was added, and the mixture was stirred for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then anhydrous sodium sulfate. After filtration through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (521 mg, 84%).
  • Example 1 (2-Aminophenyl) (azetidin-3-yl) methanone TFA (1 mL) was added to a chloroform solution (6 mL) of the compound of Reference Example 3 (270 mg, 0.98 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by amino silica gel column chromatography to obtain the title compound (65 mg, 39%).
  • Example 2 (2-Aminophenyl) -3- (methylamino) propan-1-one hydrochloride
  • a chloroform solution (2 mL) of tert-butyl [3- (2-aminophenyl) -3-oxopropyl] (methyl) carbamate (137 mg, 0.49 mmol) obtained in the same manner as in Reference Examples 1 to 3, 4 mol / L Hydrochloric acid / dioxane (1 mL) was added, and the mixture was stirred for 30 minutes in an ice bath.
  • the reaction mixture was concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with acetone, and dried under reduced pressure to give the title compound (74 mg, 60%).
  • Example 2 In the same manner as in Example 1, the compound of Example 4 was obtained. In addition, the compounds of Examples 3 and 5 were obtained in the same manner as in Example 2.
  • Example 6 2-Aminophenyl) -3- (methylamino) butan-1-one
  • the title compound was obtained by treating the compound of Reference Example 4 in the same manner as in Reference Example 2, Reference Example 3 and Example 1.
  • Example 7 3-Amino-1- (2-aminophenyl) butan-1-one
  • the same reaction was performed using ammonium acetate instead of methylamine hydrochloride, and then the same treatment as in Reference Example 2, Reference Example 3, and Example 1 was performed to obtain the title compound.
  • Test Example 1 Mouse tail suspension test The compound of the present invention or physiological saline was intraperitoneally administered to 6-week-old male Slc: ICR mice. After 30 minutes, a hooking tape was applied to the tail of the mouse, the mouse was hooked to a measuring device, and the immobility time was measured for 6 minutes. For the measurement and analysis, a tail suspension experimental apparatus (manufactured by Brain Science Idea) was used. The immobility time of 6 minutes was treated statistically by expressing the inhibition rate (%) as a numerical value of 0 to 100 based on the immobility time of the physiological saline solution administration group. The compound of Example 1 significantly suppressed the immobility time of mice (see Table 3). From this result, the compound of the present invention is expected to be used as an antidepressant.
  • Test Example 2 Mouse reserpine-induced hypothermia test 6-week-old male Slc: ICR mice were treated with reserpine (Daiichi Sankyo Co., Ltd., Apopron Injection 1 mg, 2 mg / kg) and physiological saline or the present invention. The compound was administered intraperitoneally. Rectal temperature was measured before drug administration and 3 hours after administration. Statistical treatment was performed by expressing the inhibition rate (%) as a numerical value of 0 to 100 on the basis of the decrease in rectal temperature 3 hours after administration relative to the rectal temperature before drug administration in the physiological saline administration group. The compound of Example 1 significantly suppressed the decrease in rectal temperature of mice (see Table 4).
  • Test Example 3 Mouse Brain Transfer Test
  • the compound of the present invention was intraperitoneally administered to a 5-week-old mouse in a physiological saline solution, and blood and brain were collected 30 minutes after the administration.
  • the collected blood was centrifuged at 3000 rpm ⁇ 10 minutes using a cooling centrifuge set at 4 ° C. to obtain plasma.
  • the collected brain was homogenized with 4 times the amount of phosphate buffered saline to prepare a brain homogenate. Plasma and brain homogenates were measured by LC / MS / MS, and brain migration was evaluated based on the concentration ratios obtained.
  • the compound of Example 1 showed high brain migration (see Table 5).
  • Test Example 4 Mouse forced swimming test
  • Example compounds, Kynx, Kyn, 4-HQ or vehicle were intraperitoneally administered to 7-week-old male C57BL / 6J mice, and after 30 minutes, floated in water at a diameter of 16 cm, a depth of 10 cm and 25 ° C.
  • the immobility time in minutes was measured. Based on the immobility time of the vehicle-administered group, the immobility time was significantly decreased in the group administered with Kynx 3 mg / kg and the Example compound 3 or 10 mg / kg (FIGS. 1 and 2). From this result, the compound of the present invention is expected to be used as an antidepressant.
  • Test Example 5 Test for measurement of extracellular serotonin uptake inhibition amount
  • the inhibitory action of extracellular serotonin uptake by the compound of the present invention can be evaluated.
  • Uses a medium in which human embryonic kidney (HEK) cells, in which 1 ⁇ 10 5 cells of human serotonin transporter are constantly expressed, are cultivated for 48 days on a 48-well plate coated with poly-D-lysine (PDL) and cultured for 1 day did.
  • Example compounds, Kynx, 5-HT, Kyn or buffer were administered extracellularly and incubated for 10 minutes.
  • Test Example 6 Serotonin release amount measurement test
  • Unlabeled 5-HT was added to 0.1 ⁇ Ci of [ 3 H] 5-HT per well to give a final concentration of 30 ⁇ M of 5-HT. This was administered extracellularly and incubated for 20 minutes to incorporate [ 3 H] 5-HT into the cells. After washing the extracellular fluid, 300 ⁇ M of the example compound, Kynx, 5-HT, Kyn or buffer was administered extracellularly and incubated for 5 minutes.
  • Test Example 7 Monoamine oxidase (MAO) inhibitory activity measurement test
  • MAO Monoamine oxidase
  • [ 14 C] 5-HT (0.1 ⁇ Ci) was incubated with 6 ⁇ g / ml MAO-A for 30 minutes in the presence of the Example compound, Kynx, 5-HT, Kyn or buffer. Thereafter, the mixture was mixed with a solution of toluene-ethyl acetate (1: 1, v / v), and the deaminated compound separated into the organic layer was measured with a liquid scintillation counter to measure MAO inhibitory activity of the compound ( FIG. 5AB).
  • the inhibitory activity of the test compound against human MAOA (manufactured by promega) and human MAOB (manufactured by BD Bioscience) was measured using MAO-Glo TM Assay (manufactured by promega).
  • the reaction was carried out in a 96-well plate, and the luminescence of each well was measured with Luminoscan Ascent (manufactured by Thermo Labsystems).
  • the MAO activity of the test compound was calculated as a relative value with the luminescence value upon solvent treatment being 100% (FIG. 6AB). From these results, MAOX inhibitory activity was observed in Kynx and the example compounds, suggesting that the compounds of the present invention inhibit the degradation of serotonin.
  • Kynx and Example compounds are taken up into cells via the serotonin transporter, they are considered to be serotonin neuron-specific MAO inhibitors, and therapeutic and / or preventive agents for atypical depression with few side effects. Expected to be a medicine.
  • Test Example 8 Test for measuring serotonin release amount in vivo
  • a dialysis probe was immobilized on the right prefrontal cortex (A + 1.9 mm, L -0.5 mm, V -0.8 mm, from bregma and skull) of 7 week-old male C57BL / 6J mice under anesthesia, and Ringer's solution (147.2 mM) NaCl, 4.0 mM KCl, and 2.2 mM CaCl 2 ) were refluxed at a rate of 1 ⁇ l / min, and Example Compound or Kynx was administered intraperitoneally at 3 mg / kg.
  • Test Example 9 Evaluation of neurogenesis in the hippocampal dentate gyrus
  • neurogenesis in the hippocampus by the compound of the present invention can be evaluated.
  • Example compounds, Kynx, Kyn, 4-HQ or vehicle were intraperitoneally administered to 7-week-old male C57BL / 6J mice, and BrdU 100 mg / kg was intraperitoneally administered 2 hours later.
  • the brain was removed by reflux fixation with 0.1 M PBS solution containing% PFA. Thereafter, the removed brain was sliced to 20 ⁇ m, washed with 0.1 M PBS solution, permeated into 2 M HCl and borate buffer, and immunostained with BrdU and doublecortin.
  • the number of BrdU positive cells and doublecortin positive cells was measured with a microscope. Compared with the vehicle control group, the number of BrdU positive cells was significantly increased in the group administered with Kynx and the Example compound (FIG. 9). Furthermore, an increase in the number of co-localized cells of BrdU and doublecortin was observed (FIG. 10). From this result, it was shown that the increase of hippocampal neurogenesis which takes 3 weeks or more by SSRI administration etc. is caused in a short period of one day with the compound of the present invention. It is expected that the compounds of the present invention can be used as immediate-acting antidepressants.
  • Test Example 10 In vitro agonistic test of human type 5-HT3A receptor
  • the agonist activity of the compound of the present invention to serotonin 3 receptor can be evaluated.
  • 0.05 ng of human serotonin 3 receptor cRNA was injected into Xenopus laevis oocytes, and agonist activity of serotonin 3 receptor of example compounds and Kynx was measured by the two-electrode voltage clamp method (FIG. 11).
  • Human 5-HT3A receptor and apoaequorin were transiently expressed in HEK293 cells, and the operability was evaluated using the amount of calcium flowing into the cells by ligand stimulation as an index.
  • Transiently expressed cells were seeded at 4000 cells / well in a 384 well plate and cultured for 16-22 hours. After returning the plate to room temperature, coelenterazine (final concentration: 1 ⁇ M) was added and allowed to stand at room temperature for 2 hours. Thereafter, 5-HT or a test compound was added, and the amount of luminescence of the cells was measured with FDSS7000 (manufactured by Hamamatsu Photonics). 5-HT and the test compound were dissolved in DMSO (final concentration 0.1%) and diluted with buffer (Hanks, 20 mM HEPES, 0.1% BSA).
  • the 5-HT3A receptor operability (E-max) of the test compound was calculated as a relative value with the luminescence value during 5-HT (10 ⁇ M) treatment as 100% (FIG. 12). This result suggests that the serotonin 3 receptor is activated by the compound of the present invention.
  • the antidepressant effect caused by exercise occurs through the serotonin 3 receptor, and the increase in hippocampal neurogenesis that takes 3 weeks or more with SSRI administration, etc., can be induced in a short period of 1 day with an agonist of serotonin 3 receptor
  • the present inventors have reported. Since serotonin 3 receptor agonists can be used as immediate-acting antidepressants, it is expected that Kynx and the example compounds can also be used as immediate-acting antidepressants.
  • the serotonin 3 receptor agonist since the serotonin 3 receptor agonist has a different point of action from SSRI, it is a novel therapeutic and / or prophylactic agent for psychiatric disorders such as treatment-resistant depression, anxiety, bipolar disorder, and obsessive-compulsive disorder. Is expected to be used. Furthermore, since serotonin 3 receptor is essential for eliminating fear memory, the compound of the present invention, which is a serotonin 3 receptor agonist, is expected to be used as a therapeutic and / or prophylactic agent for post-traumatic stress disorder (PTSD) and the like. .
  • PTSD post-traumatic stress disorder
  • Test Example 11 Chronic pain stress test
  • the effect of the compound of the present invention on chronic pain can be evaluated.
  • Six-week-old male C57BL / 6J mice were alternately placed in an environment of 4 ° C. and 24 ° C. to create fibromyalgia model mice (FM model mice).
  • 8 model mice 30 minutes before entering the environment, Kynx 3 mg / kg or vehicle was administered intraperitoneally, and the mechanical stimulation threshold was measured by the Von Frey test.
  • the threshold decreased in the FM model was recovered in the Kynx administration group (FIG. 13). From this result, it is expected that the compound of the present invention can be used as a prophylactic and / or therapeutic agent effective for chronic pain symptoms such as fibromyalgia and chronic pruritus.
  • the compounds of the present invention may be used for depression, atypical depression, treatment-resistant depression, anxiety, bipolar disorder, obsessive compulsive disorder, PTSD and other chronic illnesses such as fibromyalgia and chronic It is useful as a therapeutic and / or prophylactic agent for pruritus.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Le problème abordé par cette invention est de pourvoir à un nouveau composé pour produire un effet sur un médicament destiné à traiter et/ou à prévenir les maladies mentales, telles que la dépression, la dépression atypique, la dépression résistant aux traitements, la névrose d'angoisse, les troubles bipolaires, un trouble obsessionnel compulsif, et le PTSD, des symptômes de douleur chronique tels que la fibromyalgie, et le prurit chronique, cet effet étant dû à la conversion d'un produit à structure métabolique qui est présent dans la voie métabolique du tryptophane. La solution selon l'invention porte sur un composé représenté par la formule (1) ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate ou un solvate du composé ou du sel, et son utilisation en médecine. [Dans la formule, Q représente les formules (2a) à (2c) suivantes (où R1 est un atome d'hydrogène, et autre ; R2 et R3 sont identiques ou différents et sont choisis parmi un atome d'hydrogène, et autre, ou ensemble avec les atomes de carbone auxquels ils sont liés, ils forment éventuellement un cycle cycloalcane de 3 à 8 chaînons ; R4 et R5 sont identiques ou différents et sont choisis parmi un atome d'hydrogène, et autre, ou ensemble avec les atomes d'azote ils sont liés, ils forment éventuellement une amine cyclique ; et n est 0, 1, 2, 3, 4 ou 5)].
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019004292A1 (fr) * 2017-06-28 2019-01-03 国立大学法人大阪大学 Traitement de la douleur avec un agoniste de récepteur de la sérotonine-3

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3789072A (en) * 1970-04-22 1974-01-29 Squibb & Sons Inc Carboxamides
US4093734A (en) * 1975-11-03 1978-06-06 Boehringer Ingelheim Gmbh Amino-benzoic acid amides
JPH06510023A (ja) * 1991-04-18 1994-11-10 ユニバーシティ　オブ　ジョージア　リサーチ　ファウンデーション，インコーポレイテッド キヌレニナーゼの阻害剤
WO1997015550A1 (fr) * 1995-10-20 1997-05-01 Pharmacia & Upjohn S.P.A. Derives de l'acide benzoylpropionique substitues par fluoro
JPH10503525A (ja) * 1995-01-09 1998-03-31 チョン クン ダン コーポレイション カンプトテシン誘導体及びその製造方法
JP2002536434A (ja) * 1999-02-10 2002-10-29 イーライ・リリー・アンド・カンパニー ５−ｈｔ１ｆアゴニスト
JP2007518673A (ja) * 2003-06-26 2007-07-12 ニューリム ファーマシューティカルズ（１９９１）リミテッド ２−アミノベンゾイル誘導体
JP2008546651A (ja) * 2005-06-14 2008-12-25 メルク フロスト カナダ リミテツド モノアミンオキシダーゼａ及びｂの可逆的阻害剤
JP2010505816A (ja) * 2006-10-03 2010-02-25 ヌリム・ファーマスーティカルズ・（１９９１）・リミテッド 治療薬剤としての置換アリール−インドール化合物とそのキヌレニン／キヌラミン様代謝産物
WO2013151707A1 (fr) * 2012-04-05 2013-10-10 Chdi Foundation, Inc. Inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques, et procédés d'utilisation de ceux-ci

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3789072A (en) * 1970-04-22 1974-01-29 Squibb & Sons Inc Carboxamides
US4093734A (en) * 1975-11-03 1978-06-06 Boehringer Ingelheim Gmbh Amino-benzoic acid amides
JPH06510023A (ja) * 1991-04-18 1994-11-10 ユニバーシティ　オブ　ジョージア　リサーチ　ファウンデーション，インコーポレイテッド キヌレニナーゼの阻害剤
JPH10503525A (ja) * 1995-01-09 1998-03-31 チョン クン ダン コーポレイション カンプトテシン誘導体及びその製造方法
WO1997015550A1 (fr) * 1995-10-20 1997-05-01 Pharmacia & Upjohn S.P.A. Derives de l'acide benzoylpropionique substitues par fluoro
JP2002536434A (ja) * 1999-02-10 2002-10-29 イーライ・リリー・アンド・カンパニー ５−ｈｔ１ｆアゴニスト
JP2007518673A (ja) * 2003-06-26 2007-07-12 ニューリム ファーマシューティカルズ（１９９１）リミテッド ２−アミノベンゾイル誘導体
JP2008546651A (ja) * 2005-06-14 2008-12-25 メルク フロスト カナダ リミテツド モノアミンオキシダーゼａ及びｂの可逆的阻害剤
JP2010505816A (ja) * 2006-10-03 2010-02-25 ヌリム・ファーマスーティカルズ・（１９９１）・リミテッド 治療薬剤としての置換アリール−インドール化合物とそのキヌレニン／キヌラミン様代謝産物
WO2013151707A1 (fr) * 2012-04-05 2013-10-10 Chdi Foundation, Inc. Inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques, et procédés d'utilisation de ceux-ci

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BACK W., ARCHIV DER PHARMAZIE, vol. 303, no. 6, 1970, pages 465 - 470, ISSN: 0376-0367 *
MAKINO K. ET AL., SCIENCE, vol. 120, 1954, pages 544 - 545, ISSN: 0036-8075 *
MUELLER P. ET AL., ARCH. PHARM. ( WEINHEIM, vol. 316, no. 8, 1983, pages 707 - 712, ISSN: 0365-6233 *
PERTZ H. ET AL., PHARM.ACTA HELV., vol. 63, no. 4-5, 1988, pages 128 - 131, ISSN: 0031-6865 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019004292A1 (fr) * 2017-06-28 2019-01-03 国立大学法人大阪大学 Traitement de la douleur avec un agoniste de récepteur de la sérotonine-3
CN111050800A (zh) * 2017-06-28 2020-04-21 国立大学法人大阪大学 血清素3受体激动剂对疼痛的治疗
JPWO2019004292A1 (ja) * 2017-06-28 2020-04-30 国立大学法人大阪大学 セロトニン３受容体アゴニストによる疼痛の治療
EP3646886A4 (fr) * 2017-06-28 2020-05-06 Osaka University Traitement de la douleur avec un agoniste de récepteur de la sérotonine-3
JP7090344B2 (ja) 2017-06-28 2022-06-24 国立大学法人大阪大学 セロトニン３受容体アゴニストによる疼痛の治療
US11446290B2 (en) 2017-06-28 2022-09-20 Osaka University Treatment of pain with serotonin-3 receptor agonist

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