WO2015152368A1 - Oxazolidinone et dérivés oxazinanone - Google Patents

Oxazolidinone et dérivés oxazinanone Download PDF

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WO2015152368A1
WO2015152368A1 PCT/JP2015/060450 JP2015060450W WO2015152368A1 WO 2015152368 A1 WO2015152368 A1 WO 2015152368A1 JP 2015060450 W JP2015060450 W JP 2015060450W WO 2015152368 A1 WO2015152368 A1 WO 2015152368A1
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methyl
oxa
diazaspiro
decan
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Japanese (ja)
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亮 鈴木
洋平 松田
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大正製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the present invention relates to a compound having an orexin (OX) receptor antagonistic action and a pharmaceutically acceptable salt thereof, and sleep disorders, depressions, anxiety disorders, panic disorders, schizophrenia, drug dependence containing them as active ingredients
  • OX orexin
  • the present invention relates to a therapeutic or prophylactic agent for diseases such as infectious diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive system diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, and hypertension.
  • Orexin is a neuropeptide spliced from preproorexin that is specifically expressed in the lateral hypothalamic area. So far, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are deeply involved in the regulation of sleep / wake patterns and the regulation of food intake. .
  • OX-A and OX-B act on the OX receptor.
  • the OX receptor has been cloned so far in two subtypes of OX1 and OX2 receptors, both of which are known to be 7-transmembrane G protein-coupled receptors that are mainly expressed in the brain. .
  • the OX1 receptor is specifically conjugated to Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).
  • the tissue distribution varies depending on the subtype of the OX receptor.
  • the OX1 receptor has a high density in the locus coeruleus, the origin of noradrenergic nerves, and the OX2 receptor in the nodule papillary nucleus, the origin of histamine neurons. (See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5). Expression of both the OX1 receptor and the OX2 receptor is observed in the raphe nucleus which is the origin nucleus of the serotonin nerve and the ventral tegmental area which is the origin nucleus of the dopamine nerve (see Non-Patent Document 3). Orexin neurons project to the brain stem and the monoamine nervous system in the hypothalamus and have an excitatory effect on those nerves.
  • OX2 receptors are also seen in the acetylcholine neurons of the brain stem involved in REM sleep control. It also affects the activity of these nerve nuclei (see Non-Patent Document 3 and Non-Patent Document 4).
  • Non-patent Documents 6 and 7 When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous movement is increased (see Non-patent Documents 6 and 7), the normal behavior is enhanced (see Non-Patent Document 7), and the awakening time is extended (non-patent documents). 6).
  • the effect of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8).
  • Patent Document 9 discloses compounds having various spiropiperidine skeletons, but do not disclose oxazolidinone and oxazinanone derivatives described in the present application.
  • OX receptor antagonistic compounds for example, compounds having various structures described in Non-Patent Document 11 are known as a review, but there is no disclosure of compounds having oxazolidinone and oxazinanone derivatives described in the present application.
  • the object of the present invention is to find a novel compound having an OX receptor antagonistic action, sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, feeding
  • the object is to provide a therapeutic or prophylactic agent for diseases such as disorders, headaches, migraines, pain, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, and hypertension. More specifically, it is to provide a novel compound exhibiting excellent pharmacokinetics and safety as well as excellent OX receptor antagonism.
  • Ring A is a heteroaryl group
  • the heteroaryl group is a C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a hydroxyl group, a halogen atom, a cyano group A phenyl group, a pyridyl group (which may be substituted with one or two groups selected from the group consisting of a pyrazolyl group) and a pyridyl group;
  • Ring B represents an aryl group or a heteroaryl group
  • 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,
  • R 2 and R 3 can be combined with adjacent carbon atoms to form a C 3-6 cycloalkane-1,1-diyl group
  • R 4 represents a hydrogen atom
  • the above formula (I) is converted to the following formula (II)
  • Ring A is a heteroaryl group
  • the heteroaryl group is a C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkyl group, a C 3-6 cycloalkyl group, a halogen atom, a cyano group, phenyl A group, a pyridyl group (which may be substituted with one or two groups selected from the group consisting of a pyrazolyl group).
  • Y represents the formula CH or a nitrogen atom
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 and R 3 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group
  • R 2 and R 3 can be combined with adjacent carbon atoms to form a cyclopropane-1,1-diyl group
  • R 4 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkyl group, or a C 3-6 cycloalkyl group
  • R 5 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkyl group, a halo C 1-6 alkoxy group, or a C 3-6 cycloalkyl group.
  • a pharmaceutically acceptable salt thereof according to (1) (3) Any one or a mixture of two or more selected from the following compound group described in (1) above and a pharmaceutically acceptable salt thereof: 4- (2,5-dimethylbenzyl) -8- (quinoxalin-2-yl) -1-oxa-4,8-diazaspiro [4.5] decan-3-one, 4- (2-fluorobenzyl) -8- (quinoxalin-2-yl) -1-oxa-4,8-diazaspiro [4.5] decan-3-one, 4- ⁇ [3- (Cyclopropyloxy) -6-
  • Decan-3-one 4- ⁇ [3- (Difluoromethoxy) -6-methylpyridin-2-yl] methyl ⁇ -8- (quinazolin-2-yl) -1-oxa-4,8-diazaspiro [4.5] decane-3 -on, 4- ⁇ [3- (Difluoromethoxy) -6-methylpyridin-2-yl] methyl ⁇ -8- (6,7-difluoroquinoxalin-2-yl) -1-oxa-4,8-diazaspiro [4.
  • oxazolidinone and oxazinanone derivatives of the present invention have an affinity for the OX receptor and antagonize the stimulation of the receptor by a physiological ligand.
  • halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl.
  • C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n- Butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-ethylpropoxy group, n-hexyloxy group, etc. Can be mentioned.
  • the “C 3-6 cycloalkyl group” means a cyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • the “C 3-6 cycloalkyloxy group” is a cyclic alkyloxy group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyloxy group and a cyclopentyloxy group.
  • C 3-6 cycloalkane-1,1-diyl means cycloalkane-1,1-diyl having 3 to 6 carbon atoms, cyclopropane-1,1-diyl, cyclobutane-1, Examples include 1-diyl, cyclopentane-1,1-diyl, and cyclohexane-1,1-diyl.
  • the “halo C 1-6 alkyl group” is an alkyl group having 1 to 6 carbon atoms substituted with 1 to 13 halogen atoms. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • halo C 1-6 alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with 1 to 13 halogen atoms.
  • the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • hydroxy C 1-6 alkyl group is an alkyl group having 1 to 6 carbon atoms having at least one hydroxy substituent, such as a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group. 1-hydroxy-1-methylethyl group, 3-hydroxypropyl group and the like.
  • the “aryl group” is a monocyclic to tetracyclic aromatic carbocyclic group composed of 6 to 18 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. It is done.
  • Heteroaryl group '' means a monocyclic or condensed cyclic aromatic heterocyclic group, for example, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, Pyrazolyl group, pyridonyl group, imidazolyl group, furyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, quinolyl group, isoquinolyl group, naphthyridinyl group , Quinoxalinyl group, quinazolinyl group, tetrahydrocinnolyl group, benzofuranyl group, benzothienyl group, indolyl group, benzo
  • the “6-membered heteroaryl group” means a 6-membered aromatic heterocyclic group, and examples thereof include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, and a pyrazinyl group.
  • “5-membered heteroaryl group” means a 5-membered aromatic heterocyclic group such as thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl Group, oxadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group and the like.
  • the “sleep disorder” in the present specification is a disorder at the time of falling asleep, a sleep continuation phase, or awakening, and examples thereof include insomnia. Examples of insomnia classification include sleep onset disorder, mid-wake awakening, early morning awakening, and deep sleep disorder.
  • “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and the acid used includes sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid. Salts with inorganic acids such as acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycol And salts with organic acids such as acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphthalene-2-sulfonic acid. Conversion from the educt to the salt can be performed by conventional methods.
  • Ring A is preferably a compound that is a pyridyl group, pyrimidinyl group, pyrazinyl group, quinoxalinyl group, or benzoxazolyl group, and more preferably a compound that is a pyrazinyl group or quinoxalinyl group.
  • R 1 is preferably a compound that is a hydrogen atom or a methyl group.
  • R 2 and R 3 are preferably the same or different and are a hydrogen atom, a methyl group, or a compound in which R 2 and R 3 together with adjacent carbon atoms form cyclopropane-1,1-diyl.
  • R 4 is preferably a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or a halogen atom, and more preferably a methyl group or a cyclopropyl group.
  • R 5 is preferably a compound which is a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a C 3-6 cycloalkyl group, or a 1,2,3-triazolyl group, and is a difluoromethoxy group or 1,2 More preferred is a compound having a 1,3-triazolyl group.
  • a compound in which m is 0 is preferred.
  • the compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.
  • the compounds according to the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms and halogen atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
  • the compound according to the present invention can be administered orally or parenterally.
  • the dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
  • compositions containing the compounds of the invention are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
  • excipients eg crystalline cellulose, starch, lactose, mannitol
  • binders eg hydroxypropylcellulose
  • Polyvinylpyrrolidone lubricants
  • lubricants for example, magnesium stearate, talc
  • disintegrants for example, carboxymethyl cellulose calcium
  • carboxymethyl cellulose calcium for example, carboxymethyl cellulose calcium
  • a typical production method of the compound (I) of the present invention is shown in the following schemes A to H.
  • the following method is an illustration of the production method of the compound of the present invention, and is not limited thereto.
  • the compound may form a salt that does not hinder the reaction.
  • Pg is a general protecting group for amino groups such as J.F.W.McOmie, Protective Groups in Organic Chemistry, and T.W. Groups in Organic Synthesis etc., specifically benzyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, etc.
  • X 1 represents a halogen atom
  • X 2 represents a hydroxyl group
  • Step A-1 Compound (3) can be obtained by condensation and cyclization reaction of compound (1) and compound (2).
  • the reaction in Step A-1 can be carried out under the conditions in which an amide compound and a ketone are reacted in a solvent in the presence or absence of a base or acid and a dehydrating agent such as molecular sieve.
  • a base or acid such as molecular sieve.
  • the base used in this reaction include organic amines such as pyrrolidine, pyridine, triethylamine and diisopropylethylamine.
  • Acids used in this reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and bis (trifluoromethane) sulfonimide, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, Organic acids such as acetic acid can be mentioned.
  • Solvents used in this reaction include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, and aromatics such as toluene.
  • Step A-2 When Pg of the compound (3) is a group that is deprotected by hydrogenolysis such as a benzyl group or a benzyloxycarbonyl group, the compound (4) is converted into a metal catalyst such as palladium. It can deprotect by attaching
  • compound (3) is a group that can be deprotected with an acid such as a tert-butoxycarbonyl group
  • compound (4) is obtained by converting compound (3) into hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid. It can be obtained by reacting with an acid such as methanesulfonic acid.
  • an acid such as methanesulfonic acid.
  • Step A-3 Compound (6) can be obtained by aromatic nucleophilic substitution reaction of compound (4) and compound (5) or cross-coupling reaction using palladium.
  • the aromatic nucleophilic substitution reaction in Step A-3 can be carried out in a solvent in the presence or absence of a base.
  • the base used in this reaction include inorganic bases such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal lower alkoxides such as sodium ethoxide and tert-butoxypotassium, and organic such as triethylamine and diisopropylethylamine.
  • a base is a base.
  • Solvents used in this reaction include alcohol solvents such as methanol, ethanol and 1-butanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile. Examples thereof include polar solvents, halogen solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, water, and mixed solvents thereof.
  • This reaction can be carried out usually at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the cross-coupling reaction using palladium in Step A-3 is performed by reacting an aryl halide and an amine in a solvent in the presence of a palladium catalyst and a base, using a metal catalyst ligand as necessary.
  • a palladium catalyst used in this reaction include palladium acetate, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, and the ligand of the palladium catalyst includes triphenylphosphine, 4,5.
  • Solvents used in this reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, toluene
  • An aromatic hydrocarbon solvent such as water, water, or a mixed solvent thereof.
  • Examples of the base used in this reaction include potassium carbonate, cesium carbonate, tert-butoxy sodium, lithium hexamethyldisilazide and the like. This reaction can usually be carried out at 0 ° C to 150 ° C.
  • Step A-4 When X 2 of the compound (7) is a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, the compound (Ia) of the present invention is converted to the compound (6) It can be obtained by nucleophilic substitution reaction of compound (7).
  • the nucleophilic substitution reaction in Step A-4 can be carried out in a solvent in the presence of a base.
  • Examples of the base used in this reaction include inorganic bases such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, and lower alkoxides of alkali metals or alkaline earth metals such as sodium ethoxide and potassium tert-butoxide.
  • Examples of the solvent used in this reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, Examples thereof include halogen solvents such as dichloromethane and chloroform, dimethyl sulfoxide, water, and mixed solvents thereof.
  • This reaction can be carried out usually at around ⁇ 80 ° C. to the boiling point of the solvent, preferably at 0 ° C. to 60 ° C.
  • X 2 of the compound (7) is a hydroxyl group
  • the compound (Ia) of the present invention can be obtained by Mitsunobu reaction between the compound (6) and the compound (7).
  • the Mitsunobu reaction in step A-4 can be carried out in a solvent in the presence of an organic phosphorus compound and an azo compound or in the presence of a phosphorus ylide reagent.
  • Examples of the organic phosphorus compound used in this reaction include triphenylphosphine and tributylphosphine, and examples of the azo compound include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and ditert-butyl azodicarboxylate.
  • Examples of the phosphorus ylide reagent include cyanomethyltributylphosphorane.
  • Solvents used in this reaction include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, halogen solvents such as dichloromethane and chloroform, toluene And the like, and proceeds under temperature conditions from 0 ° C. to the boiling point of the solvent.
  • ether solvents such as tetrahydrofuran and 1,4-dioxane
  • aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile
  • halogen solvents such as dichloromethane and chloroform
  • toluene And the like proceeds under temperature conditions from 0 ° C. to the boiling point of the solvent.
  • the compound (Ia) of the present invention can also be produced by the method shown in Scheme B as an alternative method.
  • Step B-1 The compound (9) can be obtained by an aromatic nucleophilic substitution reaction of the compound (5) and the compound (8).
  • the reaction in Step B-1 can be performed according to the same reaction conditions as in Step A-3.
  • Step B-2 Compound (6) can be obtained by condensation and cyclization reaction of Compound (2) and Compound (9).
  • the reaction in step B-2 can be carried out according to the same reaction conditions as in step A-1.
  • Step B-3 When X 2 of the compound (7) is a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, the compound (Ia) of the present invention is converted to the compound (6) It can be obtained by nucleophilic substitution reaction of compound (7).
  • X 2 of the compound (7) is a hydroxyl group
  • the compound (Ia) of the present invention can be obtained by Mitsunobu reaction between the compound (6) and the compound (7).
  • the nucleophilic substitution reaction and Mitsunobu reaction in Step B-3 can be performed according to the same reaction conditions as in Step A-4.
  • the compound (Ia) of the present invention can also be produced by the method shown in Scheme C as an alternative method.
  • Step C-1 When X 2 of the compound (7) is a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, the compound (10) is converted into the compound (3) and the compound (7). Can be obtained by the nucleophilic substitution reaction.
  • X 2 in the compound (7) is a hydroxy group
  • compound (10) can be obtained by Mitsunobu reaction of the compound (3) with the compound (7).
  • Step C-1 The nucleophilic substitution reaction and Mitsunobu reaction in Step C-1 can be performed according to the same reaction conditions as in Step A-4.
  • Step C-2 Compound (11) can be obtained by deprotection of Pg in compound (10). The reaction in Step C-2 can be performed according to the same reaction conditions as in Step A-2.
  • Step C-3 The compound (Ia) of the present invention can be obtained by an aromatic nucleophilic substitution reaction of the compound (5) and the compound (11) or a cross-coupling reaction using palladium. The reaction in Step C-3 can be performed according to the same reaction conditions as in Step A-3.
  • R 6 represents a hydrogen atom or a C 1-6 alkyl group
  • R 7 represents a cycloalkyl group or a 6-membered heteroaryl group
  • X 3 represents a halogen atom or a trifluoromethanesulfonyloxy group
  • Y represents formula CH or a nitrogen atom
  • M 1 represents boronic acid, boronic ester, trifluoroborate, or trialkyltin, and other symbols are as defined above.
  • Step D-1 When X 2 of the compound (12) is a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, the compound (13) is converted into the compound (6) and the compound (12). Can be obtained by the nucleophilic substitution reaction.
  • X 2 of the compound (12) is a hydroxy group
  • compound (13) can be obtained by Mitsunobu reaction of the compound (6) and the compound (12).
  • the nucleophilic substitution reaction and Mitsunobu reaction in Step D-1 can be performed according to the same reaction conditions as in Step A-4.
  • Step D-2 The compound (Ib) of the present invention can be obtained by Suzuki coupling reaction or Stille coupling reaction of the compound (13) and the compound (14).
  • the Suzuki coupling reaction includes an alcohol solvent such as methanol and ethanol, an ether solvent such as tetrahydrofuran and 1,4-dioxane, an aprotic polar solvent such as N, N-dimethylformamide and acetonitrile, toluene. It can be obtained by reacting with an organoboron compound in the presence of a palladium catalyst and optionally a ligand in an aromatic hydrocarbon solvent such as water, water, or a mixed solvent thereof.
  • Examples of the palladium catalyst used in this reaction include palladium acetate, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, and the ligand used in this reaction includes triphenylphosphine, 4 , 5-bis (diphenylphosphino) -9,9-dimethylxanthene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2-dicyclohexylphosphino-2 ′-(N, N— Dimethylamino) biphenyl, 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (XPhos) and the like.
  • triphenylphosphine 4
  • Step D-2 is carried out by using an aprotic polar solvent such as N, N-dimethylformamide or acetonitrile, an aromatic hydrocarbon solvent such as toluene, or an ether system such as tetrahydrofuran or 1,4-dioxane. It can be obtained by reacting with an organotin compound in a solvent or a mixed solvent thereof in the presence of a palladium catalyst and optionally a ligand.
  • an aprotic polar solvent such as N, N-dimethylformamide or acetonitrile
  • aromatic hydrocarbon solvent such as toluene
  • ether system such as tetrahydrofuran or 1,4-dioxane.
  • Examples of the palladium catalyst used in this reaction include palladium acetate, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, and the ligand used in this reaction includes triphenylphosphine, triphenylphosphine. (O-Tolyl) phosphine, tri (2-furyl) phosphine and the like.
  • Step E-1 When X 2 of the compound (15) is a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, the compound (16) is converted into the compound (6) and the compound (15). Can be obtained by the nucleophilic substitution reaction.
  • Step E-2 The compound (Ic) of the present invention can be obtained by reacting the compound (16) with an organometallic reagent such as the compound (17).
  • the reaction in Step E-2 is carried out by using an aprotic polar solvent such as N, N-dimethylformamide or acetonitrile, an aromatic hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran or 1,4-dioxane, or the like.
  • the compound (17) represents an organometallic reagent, and examples thereof include a Grignard reagent such as R 9 MgCl, an organolithium reagent such as R 9 Li, and the like. This reaction can usually be carried out at around ⁇ 80 ° C. to around the boiling point of the solvent.
  • Step F-1 When X 2 of compound (18) is a halogen atom, methanesulfonyloxy group, p-toluenesulfonyloxy group or trifluoromethanesulfonyloxy group, compound (19) is compound (6) and compound (18). Can be obtained by the nucleophilic substitution reaction. When X 2 of the compound (18) is a hydroxy group, compound (19) can be obtained by Mitsunobu reaction of the compound (6) with the compound (18). The nucleophilic substitution reaction and Mitsunobu reaction in Step F-1 can be performed according to the same reaction conditions as in Step A-4.
  • Step F-2 The compound (Id) of the present invention can be obtained by deprotecting the compound (19).
  • the deprotection reaction in step F-2 can be carried out in a solvent in the presence of a base.
  • the base used in this reaction include inorganic bases such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, and alkali metal or alkaline earth metal lower alkoxides such as sodium ethoxide and potassium tert-butoxide.
  • solvent used in this reaction examples include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, and dichloromethane. , Halogen-based solvents such as chloroform, dimethyl sulfoxide, water, or a mixed solvent thereof.
  • This reaction can be carried out usually under a temperature condition of 0 ° C. to around the boiling point of the solvent, preferably 20 ° C. to 80 ° C.
  • Step G-1 When X 2 of the compound (20) is a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, the compound (21) is converted into the compound (6) and the compound (20). Can be obtained by the nucleophilic substitution reaction.
  • X 2 of the compound (20) is a hydroxy group
  • compound (21) can be obtained by Mitsunobu reaction of the compound (6) with the compound (20).
  • the nucleophilic substitution reaction and Mitsunobu reaction in Step G-1 can be performed according to the same reaction conditions as in Step A-4.
  • Step G-2 The compound (Ie) of the present invention can be obtained by deprotecting the compound (21).
  • the reaction in Step G-2 can be performed according to the same reaction conditions as in Step F-2.
  • Step H-1 Compound (23) can be obtained by aromatic nucleophilic substitution reaction of compound (11) and compound (22) or cross-coupling reaction using palladium. The reaction in Step H-1 can be performed according to the same reaction conditions as in Step A-3.
  • Step H-2 The compound (If) of the present invention can be obtained by Suzuki coupling reaction or Stille coupling reaction of the compound (23) and the compound (24). The reaction in Step H-2 can be performed according to the same reaction conditions as in Step D-2.
  • KP-Sil when purified using column chromatography is Biotage's SNAPPartridge KP-Sil, “HP-Sil” is Biotage ’s SNAPPartrige HP-Sil, “SNAP Ultra”. ”For Biotage SNAPPartridge SNAP Ultra,“ KP-NH ”for Biotage SNAPPartridge KP-NH,“ Grace ”for Grace Revelis Silica Flash Cartridge, and“ GraceNH ”for GraceNH YMC YMC-DispoPackAT NH2 is used for NH It was.
  • Biotage's ISOLUTE Phase Separator was used for “ISOLUTE Phase Separator” in the post-processing operations of the following Reference Examples and Examples.
  • LCMS liquid chromatography mass spectrum
  • MS measuring instrument Shimadzu LCMS-2010EV or micromass Platform LC
  • Triethylamine (1.5 ml, 10 ml) was added to a solution of 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (2.0 g, 9.84 mmol) in THF (10 ml) under ice-cooling. 0.8 mmol) and ethyl chloroformate (1.0 ml, 10.8 mmol) were added, and the mixture was stirred for 1 hour. Thereafter, an aqueous solution (10 ml) of sodium borohydride (0.75 g, 19.7 mmol) was slowly added dropwise and stirred at room temperature for 13 hours.
  • Methyl 6-methyl-3- (3-methyl-1,2,4-oxadiazol-5-yl) pyridine-2-carboxylate (0.35 g, 1.49 mmol) obtained in Reference Example 4 in THF
  • calcium chloride (0.17 g, 1.49 mmol) was added at room temperature to completely dissolve it.
  • sodium borohydride (0.11 g, 2.98 mmol) and stirred overnight. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, and the mixture was extracted with chloroform.
  • Reference Examples 8 to 12 were obtained in the same manner as Reference Example 7.
  • Table 1 shows the structural formula, compound name, and MS data of the obtained compound.
  • 3,4-Dihydro-2H-pyran was added to a solution of [3- (benzyloxy) -6-methylpyridin-2-yl] methanol (8.4 g, 36.6 mmol) obtained in Reference Example 8 in chloroform (105 ml). (8.3 ml, 91.6 mmol), 10-camphorsulfonic acid (8.5 g, 36.6 mmol) was added, and the mixture was heated to reflux for 6 hours. Further, 3,4-dihydro-2H-pyran (1.7 ml, 18.3 mmol) and 10-camphorsulfonic acid (1.7 g, 7.33 mmol) were added, and the mixture was heated to reflux for 4 hours.
  • Triethylamine was added to a solution of 6-methyl-2-[(tetrahydro-2H-pyran-2-yloxy) methyl] pyridin-3-ol (1.0 g, 4.48 mmol) obtained in Reference Example 17 in chloroform (10 ml). (0.68 ml, 6.72 mmol) and trifluoromethanesulfonic anhydride (0.90 ml, 5.37 mmol) were added, followed by stirring at room temperature for 3 days. Water and chloroform were added to the reaction solution, and the organic layer was separated. The separated organic layer was washed with a saturated aqueous sodium chloride solution, passed through a phase separator, and the solvent was distilled off under reduced pressure.
  • Reference Examples 44 to 53 were obtained in the same manner as Reference Example 43.
  • Table 2 shows the structural formula, compound name, and MS data of the obtained compound.
  • Reference Examples 57 to 61 were obtained in the same manner as Reference Example 56.
  • Table 3 shows the structural formula, compound name, and MS data of the obtained compound.
  • Reference Examples 63 to 65 were obtained in the same manner as Reference Example 62.
  • Table 4 shows the structural formula, compound name, and MS data of the obtained compound.
  • Reference Examples 67 to 68 were obtained in the same manner as Reference Example 66.
  • Table 5 shows the structural formula, compound name, and MS data of the obtained compound.
  • Examples 2 to 23 were obtained in the same manner as in Example 1.
  • the structural formulas, compound names, and LCMS data of the obtained compounds are shown in Tables 6-1 to 6-3.
  • Examples 25 to 34 were obtained in the same manner as in Example 24.
  • the structural formulas, compound names, and LCMS data of the obtained compounds are shown in Tables 7-1 to 7-2.
  • Examples 36 to 59 were obtained in the same manner as in Example 35.
  • the structural formulas, compound names, and LCMS data of the obtained compounds are shown in Tables 8-1 to 8-3.
  • Example 60 4- ⁇ [3- (Difluoromethoxy) -6-methylpyridin-2-yl] methyl ⁇ -8- (quinazolin-2-yl) -1-oxa-4,8-diazaspiro [4.5] Decan-3-on
  • Examples 61 to 84 were obtained in the same manner as in Example 60.
  • the structural formulas, compound names and LCMS data of the obtained compounds are shown in Tables 9-1 to 9-3.
  • Examples 86 to 89 were obtained in the same manner as in Example 85.
  • Table 10 shows the structural formula, compound name, and LCMS data of the obtained compound.
  • Example 90 4- ⁇ [3- (difluoromethoxy) -6-methylpyridin-2-yl] methyl ⁇ -8- [2- (trifluoromethyl) pyrimidin-5-yl] -1-oxa-4,8 -Diazaspiro [4.5] decan-3-one
  • Examples 91 to 98 were obtained in the same manner as in Example 90.
  • Table 11 shows the structural formula, compound name, and LCMS data of the obtained compound.
  • Example 103 4- ⁇ [3- (2-hydroxypropan-2-yl) -6-methylpyridin-2-yl] methyl ⁇ -8- (quinoxalin-2-yl) -1-oxa-4,8- Diazaspiro [4.5] decan-3-one
  • Example 104 4- ⁇ [3- (difluoromethoxy) -6-methylpyridin-2-yl] methyl ⁇ -8- (5-phenylpyrimidin-2-yl) -1-oxa-4,8-diazaspiro [4 .5] Decan-3-one
  • Test example (measurement of orexin antagonistic activity)
  • the antagonistic activity of the test compound against human orexin type 1 receptor (hOX1R) and orexin type 2 receptor (hOX2R) is described in the literature (Toshikata Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001). The method was modified. Chinese hamster ovary (CHO) cells forcibly expressing hOX1R and hOX2R were seeded in each well of a 96-well Black clear bottom plate (Nunc) at 24,000 cells, 0.1 mM MEM non-essential amino acids, 0.
  • CHO Chinese hamster ovary
  • the cells were cultured in Ham's F-12 medium (Invitrogen) containing 5 mg / ml G418, 10% fetal calf serum for 16 hours under conditions of 37 ° C. and 5% CO 2 .
  • an assay buffer containing 25 ⁇ M Fluo-3AM ester (Dojin) (25 mM HEPES (Dojin), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5 mM probenecid, 100 ⁇ L of 200 ⁇ g / ml Amaranth (above Sigma-Aldrich), pH 7.4) was added and incubated for 60 minutes at 37 ° C., 5% CO 2 .
  • test compound was dissolved in dimethyl sulfoxide to 10 mM, diluted with assay buffer, 150 ⁇ L was added, and the mixture was incubated for 30 minutes.
  • Peptide substituted with 2 amino acids of human orexin-A ligand (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2 (Peptide Institute) is a final concentration of 500 pM for hOX1R and hOX2R The reaction was started by diluting with an assay buffer to 1 nM and adding 50 ⁇ L of this ligand solution.
  • the fluorescence value of each well was measured for 3 minutes every second using a Functional Drug Screening System (FDSS; manufactured by Hamamatsu Photonics), and the antagonistic activity was determined using the maximum fluorescence value as an index of intracellular Ca 2+ concentration.
  • the antagonistic activity of the test compound was calculated by setting the fluorescence value of the well to which only the dilution buffer was added to 100% and the fluorescence value of the well to which the buffer solution containing no ligand and compound was added to 0%.
  • the 50% inhibitory concentration (IC 50 value) was determined from the fluorescence value upon addition.
  • the IC 50 values of the compounds of the present invention are shown in Table 12.
  • the compound of the present invention was shown to have OX receptor antagonistic action. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof is a disease modulated by OX receptor antagonism, such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease , Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc. .
  • OX receptor antagonism such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease , Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc.

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Abstract

L'invention concerne un nouveau composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de ce dernier. Le composé ou le sel pharmaceutiquement acceptable de ce dernier fait preuve d'une action antagoniste vis-à-vis du récepteur de l'oréxine (OX), et est par conséquent utile pour le traitement ou la prévention d'états médicaux tels que les troubles du sommeil, la dépression, les troubles de l'anxiété, les troubles de panique, la schizophrénie, la dépendance médicamenteuse, la maladie d'Alzheimer, la maladie de Parkinson, la chorée de Huntington, les troubles de l'alimentation, les céphalées, les migraines, la douleur, les maladies des organes digestifs, l'épilepsie, l'inflammation, les maladies immunologiques, les maladies liées au système endocrinien, et l'hypertension.
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CN111263764A (zh) * 2017-10-17 2020-06-09 埃斯蒂文制药股份有限公司 (r)-9-(2,5-二氟苯乙基)-4-乙基-2-甲基-1-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮的盐
US10689398B2 (en) 2015-10-23 2020-06-23 Esteve Pharmaceuticals, S.A. OXA-Diazaspiro compounds having activity against pain
US10703765B2 (en) 2014-06-02 2020-07-07 Esteve Pharmaceuticals, S.A. Alkyl and aryl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain
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US11059828B2 (en) 2009-10-23 2021-07-13 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators
USRE48841E1 (en) 2009-10-23 2021-12-07 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
US11667644B2 (en) 2009-10-23 2023-06-06 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
US10703765B2 (en) 2014-06-02 2020-07-07 Esteve Pharmaceuticals, S.A. Alkyl and aryl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain
US10196383B2 (en) 2015-07-17 2019-02-05 Sunshine Lake Pharma Co., Ltd. Substituted quinazoline compounds and preparation and uses thereof
US10689398B2 (en) 2015-10-23 2020-06-23 Esteve Pharmaceuticals, S.A. OXA-Diazaspiro compounds having activity against pain
US10828302B2 (en) 2016-03-10 2020-11-10 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US11241432B2 (en) 2016-03-10 2022-02-08 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
CN111263764A (zh) * 2017-10-17 2020-06-09 埃斯蒂文制药股份有限公司 (r)-9-(2,5-二氟苯乙基)-4-乙基-2-甲基-1-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮的盐

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