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WO2015087993A1 - Oxazolidine et dérivés d'oxazinane - Google Patents

Oxazolidine et dérivés d'oxazinane Download PDF

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Publication number
WO2015087993A1
WO2015087993A1 PCT/JP2014/082935 JP2014082935W WO2015087993A1 WO 2015087993 A1 WO2015087993 A1 WO 2015087993A1 JP 2014082935 W JP2014082935 W JP 2014082935W WO 2015087993 A1 WO2015087993 A1 WO 2015087993A1
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methyl
methanone
oxazinan
amino
pyridin
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PCT/JP2014/082935
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Japanese (ja)
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亮 鈴木
正人 阿部
有也 尾形
一豪 小西
信隆 服部
彩 二村
洋平 松田
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大正製薬株式会社
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Publication of WO2015087993A1 publication Critical patent/WO2015087993A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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

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 N-heteroaryl or O-heteroaryl derivatives, but there is no disclosure of compounds having an oxazolidine and oxazinane skeleton 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 article, but there is no disclosure of compounds having oxazolidine and oxazinane skeletons 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.
  • R 4 represents a hydrogen atom or a C 1-6 alkyl group when Y is the formula NR N1 or an oxygen atom, or a hydroxymethyl group when Y is pyrazole;
  • R 2 represents a triazolyl group, a pyrimidinyl group, or a C 1-6 alkoxy group,
  • R 3 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with a C 1-6 alkoxy group), a halo C 1-6 alkyl group, A C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a C 1-6 alkylsulfonyl group, or the formula CONHR N 2 ,
  • R 4 represents a hydrogen atom or a C 1-6 alkyl group when Y is the formula NR N1 or an oxygen atom, or
  • Y is the formula NR N1 or an oxygen atom, The compound or a pharmaceutically acceptable salt thereof according to (1), wherein R 1 is a hydrogen atom or a C 1-6 alkyl group.
  • R 2 is a triazolyl group or a pyrimidinyl group, m is 1, The compound or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein n is 2.
  • a medicament comprising the compound according to any one of (1) to (4) above or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the oxazolidinone and oxazinane derivative of the present invention have an affinity for the OX receptor and an antagonistic action against 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, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -Butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl group and the like can be mentioned.
  • C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Examples thereof include sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-ethylpropoxy, n-hexyloxy group and the like.
  • Examples of the “C 3-6 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • C 1-6 alkylsulfonyl group means a sulfonyl group substituted with the above “C 1-6 alkyl group”, and includes methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl.
  • halo C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, and the preferred number of substitution of halogen atoms is 1 to 3.
  • halo C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with a halogen atom, and the preferred number of substitution of halogen atoms is 1 to 3.
  • Examples thereof include a fluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group.
  • Heteroaromatic ring means a 6-membered heteroaromatic ring composed of one or more nitrogen atoms and 1 to 5 carbon atoms, and examples thereof include pyridine, pyrazine, pyrimidine, pyridazine 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.
  • X is preferably a nitrogen atom or a compound of the formula CH.
  • Y represents an oxygen atom or the compound is of formula NR N1 is preferably the compound is of formula NR N1 is more preferable.
  • the compound of formula NR N1 is preferably a hydrogen atom or a methyl group.
  • R 1 is preferably a compound having a C 1-6 alkyl group, and more preferably a compound having a methyl group.
  • R 2 is preferably a compound which is a triazolyl group or a pyrimidinyl group, more preferably a 1,2,3-triazol-2-yl group or a pyrimidin-2-yl group.
  • R 3 is preferably a halo C 1-6 alkyl group or a halo C 1-6 alkoxy group, more preferably a trifluoromethyl group or a difluoromethoxy group.
  • R 4 is preferably a compound that is a hydrogen atom or a methyl group.
  • m is preferably a compound of 1, and n is preferably a compound of 2.
  • A is preferably a compound that is pyridine, pyrazine, pyrimidine, or pyridazine, more preferably pyridine or pyrimidine.
  • this invention compound forms a hydrate or a solvate, they are also contained in the scope of the present invention.
  • pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.
  • 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.
  • These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose).
  • the compound of the present invention can be orally or parenterally administered to an adult patient at a dosage of 0.001 to 500 mg once or several times a day.
  • the dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
  • Scheme A Representative schemes for producing the compound (I) of the present invention are shown in the following schemes A to G.
  • 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.
  • X 1 represents a hydroxyl group or a halogen atom
  • X 2 represents a halogen atom or a trifluoromethanesulfonyloxy group
  • R 5 represents a C 1-6 alkoxy group
  • R 6 represents a triazolyl group
  • C 1- 6 represents an alkoxy group, and other symbols are as defined above.
  • Step A-1 Compound (2) can be obtained from Compound (1).
  • the reaction in Step A-1 is carried out by using a hydroalcoholic solvent such as hydrous methanol or hydrous ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, a halogen solvent such as dichloromethane or chloroform, a ketone solvent such as acetone, water or the like.
  • the reaction can be carried out under the condition of reacting with an acid such as hydrochloric acid, trifluoroacetic acid, or p-toluenesulfonic acid. This reaction can be carried out at 0 ° C to 80 ° C.
  • Step A-2 Compound (4) can be obtained by condensation and cyclization reaction of compound (2) and compound (3).
  • the reaction in Step A-2 can be carried out in the presence or absence of a base, molecular sieve, dehydrated agent such as anhydrous copper sulfate, or the like, in a solvent, under the conditions for reacting the amine compound or its hydrochloride with an aldehyde.
  • a base such as pyridine, triethylamine and diisopropylethylamine
  • inorganic bases such as sodium hydroxide, potassium hydroxide and sodium bicarbonate
  • acetates such as sodium acetate and potassium acetate.
  • 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.
  • 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
  • aromatics such as toluene.
  • Step A-3 Compound (6) can be obtained by a condensation reaction of compound (4) and compound (5).
  • the reaction in Step A-3 can be carried out by a general method for amidation of carboxylic acid.
  • a method of reacting (4) after introducing carboxylic acid to a carboxylic acid halide such as carboxylic acid chloride or carboxylic acid bromide a method of reacting carboxylic acid with (4) in the presence of a dehydrating condensing agent, and the like. All of these reactions can be carried out in a solvent in the presence or absence of a base.
  • Examples of the halogenating agent used in this reaction include thionyl chloride, oxalyl chloride, phosphorus oxychloride and phosphorus oxybromide.
  • Examples of the dehydrating condensing agent used in this reaction include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride, [O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate], propanephosphonic acid anhydride, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) 4-methylmorpholinium Examples include chloride, dicyclohexylcarbodiimide, diphenylphosphonyl azide, carbonyldiimidazole and the like, and an activator such as 1-hydroxybenzotriazole or hydroxysuccinimide can be used as necessary.
  • 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 toluene.
  • An aromatic hydrocarbon solvent, ethyl acetate, or a mixed solvent thereof can be used.
  • Examples of the base used in this reaction include organic amines such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate and sodium bicarbonate. This reaction can be carried out usually at 0 ° C. to 150 ° C., preferably 0 ° C. to 80 ° C.
  • Step A-4 Compound (7) can be obtained from compound (6).
  • the reaction in Step A-4 is an alcohol solvent such as methanol or ethanol, an ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, a halogen solvent such as dichloromethane or chloroform, ethyl acetate, water or a mixed solvent thereof.
  • the reaction can be carried out under the condition of reacting with an acid such as hydrochloric acid or trifluoroacetic acid or a base such as triethylamine, diisopropylethylamine, sodium hydroxide or sodium hydrogencarbonate, or hydrazine. This reaction can be performed at 0 ° C. to 100 ° C.
  • Step A-5 Compound (Ia) of the present invention can be obtained by aromatic nucleophilic substitution reaction of compound (7) and compound (8) or cross-coupling reaction using palladium.
  • the aromatic nucleophilic substitution reaction in Step A-5 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 and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, dichloromethane , Halogen solvents such as chloroform, aromatic hydrocarbon solvents such as toluene, water, or a mixed solvent 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-5 can be obtained by reacting an aryl halide and an amine in a solvent in the presence of a palladium catalyst and a base.
  • 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 and acetonitrile, and aromatics such as toluene.
  • 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 B-1 Compound (10) can be obtained by aromatic nucleophilic substitution reaction of compound (8) and compound (9) or cross-coupling reaction using palladium.
  • the reaction in step B-1 can be carried out according to the same reaction conditions as in step A-5.
  • Step B-2 Compound (11) can be obtained from compound (10).
  • the reaction in Step B-2 can be performed according to the same reaction conditions as in Step A-1.
  • Step B-3 The compound (12) can be obtained by condensation and cyclization reaction of the compound (11) and the compound (3).
  • the reaction in Step B-3 can be performed according to the same reaction conditions as in Step A-2.
  • Step B-4 The compound (Ia) of the present invention can be obtained by a condensation reaction of the compound (12) and the compound (5).
  • the reaction in Step B-4 can be performed according to the same reaction conditions as in Step A-3.
  • Scheme C
  • Step C-1 Compound (14) can be obtained by condensation and cyclization reaction of Compound (13) and Compound (3).
  • the reaction in step C-1 can be carried out according to the same reaction conditions as in step A-2.
  • Step C-2 Compound (15) can be obtained by condensation reaction of Compound (14) and Compound (5).
  • the reaction in Step C-2 can be performed according to the same reaction conditions as in Step A-3.
  • Step C-3 Compound (16) can be obtained by ester reduction reaction of Compound (15).
  • the reaction in Step C-3 is carried out in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene, or a mixed solvent thereof, lithium aluminum hydride.
  • the reaction can be carried out under the condition of reacting with a reducing agent such as diisobutylaluminum hydride, sodium borohydride or lithium borohydride. This reaction can be carried out at ⁇ 80 ° C. to 150 ° C., preferably 0 ° C. to 25 ° C.
  • Step C-4 The compound (17) can be obtained by oxidation reaction of the hydroxyl group of the compound (16).
  • the reaction in Step C-4 is carried out in a halogen-based solvent such as dichloromethane or chloroform, dimethyl sulfoxide or acetonitrile, a desvalent reagent, a hypervalent iodine compound such as 2-iodoxybenzoic acid, pyridinium chlorochromate, pyridinium dichromate, etc.
  • the reaction can be carried out under the condition of reacting with an oxidizing agent such as chromate, tetrapropylammonium perruthenate, manganese dioxide. This reaction can be carried out at 0 ° C. to 150 ° C., preferably 25 ° C. to 80 ° C.
  • Step C-5 The compound (Ia) of the present invention can be obtained by a reductive amination reaction between the compound (17) and the compound (18).
  • the reaction in Step C-5 can be carried out using a reducing agent in the presence or absence of an acid or a base.
  • the reducing agent used in this reaction include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.
  • the acid used in this reaction include acetic acid and hydrochloric acid.
  • Examples of the base used in this reaction include triethylamine.
  • 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, water, and the like.
  • the mixed solvent is mentioned.
  • the reaction can be carried out under a temperature condition from about ⁇ 80 ° C. to the boiling point of the solvent.
  • Step D-1 The compound (2) can be obtained from the compound (1).
  • the reaction in Step D-1 can be carried out according to the same reaction conditions as in Step A-1.
  • Step D-2 Compound (4) can be obtained by condensation and cyclization reaction of compound (2) and compound (3).
  • the reaction in Step D-2 can be performed according to the same reaction conditions as in Step A-2.
  • Step D-3 The compound (20) can be obtained by a condensation reaction of the compound (4) and the compound (19).
  • the reaction in Step D-3 can be performed according to the same reaction conditions as in Step A-3.
  • Step D-4 The compound (22) can be obtained by a Stille coupling reaction of the compound (20) and the compound (21).
  • the reaction in Step D-4 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 a mixture thereof. It can be obtained by reacting with an organotin compound in a solvent in the presence of a palladium catalyst.
  • Step D-5 Compound (23) can be obtained from compound (22).
  • the reaction in Step D-5 can be performed according to the same reaction conditions as in Step A-4.
  • Step D-6 The compound (Ib) of the present invention can be obtained by aromatic nucleophilic substitution reaction of compound (23) and compound (8) or cross-coupling reaction using palladium.
  • the reaction in Step D-6 can be performed according to the same reaction conditions as in Step A-5.
  • Scheme E
  • Step E-1 The compound (Ic) of the present invention can be obtained by reacting the compound (24) with the compound (25).
  • the reaction in Step E-1 can be carried out using a phosphonium salt in a solvent in the presence of a base.
  • the phosphonium salt used in this reaction include bromotris (pyrrolidino) phosphonium hexafluorophosphate, bromotris (dimethylamino) phosphonium hexafluorophosphate, and the like.
  • Examples of the base used in this reaction include diisopropylethylamine and triethylamine.
  • Solvents used in this reaction include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide, halogen solvents such as dichloromethane and chloroform, or those solvents.
  • ether solvents such as tetrahydrofuran and 1,4-dioxane
  • aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide
  • halogen solvents such as dichloromethane and chloroform
  • Step F-1 Compound (27) can be obtained by aromatic nucleophilic substitution reaction of compound (26) and compound (8) or cross-coupling reaction using palladium.
  • the reaction in Step F-1 can be carried out according to the same reaction conditions as in Step A-5.
  • Step F-2 The compound (28) can be obtained from the compound (27).
  • the reaction in Step F-2 can be performed according to the same reaction conditions as in Step A-1.
  • Step F-3 Compound (29) can be obtained by the condensation and cyclization reaction of compound (28) and compound (3). The reaction in Step F-3 can be performed according to the same reaction conditions as in Step A-2.
  • Step F-4 The compound (Id) of the present invention can be obtained by a condensation reaction of the compound (29) and the compound (5). The reaction in Step F-4 can be performed according to the same reaction conditions as in Step A-3.
  • Scheme G
  • X 4 represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group
  • R 7 represents a C 1-6 alkyl group, and other symbols are as defined above. is there.
  • Step G-1 The compound (Ie) of the present invention can be obtained by an alkylation reaction of the compound (30).
  • the reaction in step G-1 can be carried out by a general alkylation method.
  • 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 and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, dichloromethane , Halogen solvents such as chloroform, aromatic hydrocarbon solvents such as toluene, water, or a mixed solvent thereof.
  • This reaction can be carried out usually at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • 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“ Grace NH ”for GraceNH .
  • Biotage's ISOLUTE Phase Separator was used as the “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
  • Condition 4 Measuring machine: Agilent 1100 Agilent Column: CHIRALPAK AD-3 (Daicel, 4.6mm * 250mm)
  • Trifluoroacetic acid (3.37 ml, 45.6 mmol) was added to a solution of phthalimidoacetaldehyde diethyl acetal (2.0 g, 7.60 mmol) in chloroform (40 ml), and the mixture was stirred at room temperature for 15 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the extracted organic layer was washed with brine, passed through a phase separator, and the solvent was distilled off under reduced pressure to obtain N- (2-oxoethyl) phthalimide (1.41 g).
  • molecular sieve 4A (5.0 g) was added to a solution of 2-aminoethanol (0.44 ml, 7.40 mmol) in chloroform (30 ml), and the mixture was stirred at room temperature for 30 minutes. N- (2-oxoethyl) phthalimide (1.40 g, 7.40 mmol) obtained previously was added thereto and stirred at room temperature for 15 hours.
  • the molecular sieve 4A was separated by filtration through Celite (registered trademark), and the solvent was distilled off under reduced pressure to obtain a colorless oil.
  • Reference Example 14-2 The compound was designated as Reference Example 14-2.
  • Reference Example 14-1 MS (ESI pos.) M / z: 444 [M + H] + colorless solid, 0.18 g
  • Reference Example 14-2 MS (ESI pos.) M / z: 444 [M + H] + colorless solid, 0.16 g
  • Reference Examples 16 to 22 were obtained in the same manner as Reference Example 15.
  • Table 2 shows the structural formula, compound name, and MS data of the obtained compound.
  • Reference Examples 25 to 28 were obtained in the same manner as Reference Example 24.
  • Table 3 shows the structural formula, compound name, and MS data of the obtained compound.
  • Examples 2 to 16 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 4-1 to 4-2.
  • Examples 18 to 25 were obtained in the same manner as in Example 17.
  • Table 5 shows the structural formula, compound name, and LCMS data of the obtained compound.
  • Examples 27 to 34 were obtained in the same manner as in Example 26.
  • Table 6 shows the structural formula, compound name, and LCMS data of the obtained compound.
  • Examples 37 to 42 were obtained in the same manner as in Example 36.
  • Table 7 shows the structural formula, compound name, and LCMS data of the obtained compound.
  • Example 43-1 and Example 43-2 [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] [2-( ⁇ [5- (trifluoromethyl) pyridine- 2-yl] amino ⁇ methyl) -1,3-oxazinan-3-yl] methanone
  • Example 43-1 LCMS retention time 1.03 min. MS (ESI pos.) M / z: 447 [M + H] + colorless solid, 0.003 g Example 43-2 LCMS retention time 1.03 min. MS (ESI pos.) M / z: 447 [M + H] + colorless solid, 0.003 g
  • Examples 44 to 55 were obtained in the same manner as in Example 43.
  • the structural formulas, compound names, LCMS data, and racemic analysis data of the obtained compounds are shown in Tables 8-1 to 8-2.
  • Example 56-1 and Example 56-2 [5-Methyl-2- (pyrimidin-2-yl) phenyl] [2-( ⁇ [5- (trifluoromethyl) pyrimidin-2-yl] amino ⁇ methyl) -1,3-oxazinan-3-yl] methanone
  • reaction solution is filtered to remove potassium carbonate, and the filtrate is purified by HPLC and then purified by column chromatography (Grace NH, hexane-EtOAc system) and (Grace OH, hexane-EtOAc system) ( ⁇ ).
  • column chromatography Gram NH, hexane-EtOAc system
  • Gram OH hexane-EtOAc system
  • Examples 57 to 60 were obtained in the same manner as in Example 56.
  • Table 9 shows the structural formula, compound name, LCMS data, and racemic analysis data of the obtained compound.
  • Example 61-1 and Example 61-2 (2-Ethoxy-5-methylphenyl) [2-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] amino ⁇ methyl) -1,3-oxazinane -3-yl] methanone
  • Example 62 was obtained in a similar manner to Example 61.
  • Table 10 shows the structural formula, compound name, LCMS data, and racemic analysis data of the obtained compound.
  • Examples 65 to 67 were obtained in the same manner as in Example 64.
  • Table 11 shows the structural formula, compound name, and LCMS data of the obtained compound.
  • Example 69-1 Example 69-2 (2- ⁇ [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5- (Hydroxymethyl) -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone
  • Example 69-1, relative retention The compound having a long time (Rt 2 7.92 min) was determined as Example 69-2.
  • Example 69-1 LCMS retention time 0.74 min.
  • Example 69-2 LCMS retention time 0.74 min.
  • 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 an 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

Un composé représenté par la formule (I) ou son sel pharmaceutiquement acceptable est un composé nouveau ou son sel pharmaceutiquement acceptable qui présente une activité antagoniste sur les récepteurs d'orexine (OX) et est par conséquent utile dans le traitement ou la prévention de maladies notamment les troubles du sommeil, la dépression, les troubles anxieux, le trouble panique, la schizophrénie, la toxicomanie, la maladie d'Alzheimer, la maladie de Parkinson, la chorée de Huntington, les troubles de l'alimentation, le mal de tête, la migraine, la douleur, les maladies des organes digestifs, l'épilepsie, les inflammations, les maladies liées au système immunitaire, les maladies liées à l'incrétion et l'hypertension.
PCT/JP2014/082935 2013-12-13 2014-12-12 Oxazolidine et dérivés d'oxazinane WO2015087993A1 (fr)

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WO2017057717A1 (fr) * 2015-10-02 2017-04-06 大正製薬株式会社 Dérivé hétéroaromatique
CN110869368A (zh) * 2017-07-13 2020-03-06 大正制药株式会社 （2s）-2-［（1h-吡唑-1-基）甲基］-1,3-噁嗪烷衍生物的制备方法

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CN110869368A (zh) * 2017-07-13 2020-03-06 大正制药株式会社 （2s）-2-［（1h-吡唑-1-基）甲基］-1,3-噁嗪烷衍生物的制备方法
CN110869368B (zh) * 2017-07-13 2023-03-28 大正制药株式会社 （2s）-2-［（1h-吡唑-1-基）甲基］-1,3-噁嗪烷衍生物的制备方法

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