Classifications

• • 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
  • 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
  • A61P25/18—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
  • A61P25/28—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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a novel compound having an antagonistic action on a group II metabotropic glutamate (mGlu) receptor or a pharmaceutically acceptable salt thereof, and a mood disorder (depressive disorder, bipolar) containing them as an active ingredient sexual disorder), anxiety disorder (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), schizophrenia, Alzheimer's disease, cognitive impairment
• the present invention relates to a preventive or therapeutic agent for diseases such as dementia, drug dependence, convulsions, tremors, pain, and sleep disorders.
• Glutamate is known as one of the major excitatory neurotransmitters that regulate higher-order functions such as memory and learning in the mammalian central nervous system.
• Glutamate receptors are ionotropic receptors (iGlu receptors) and G-protein coupled receptors (GPCRs), which are metabotropic receptors (metabolic glutamate receptors). ) are divided into two categories.
• iGlu receptor is based on its agonist specificity, N-methyl-D-aspartate (NMDA) receptor, ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropion There are three types of receptors: acid ( ⁇ -amino-3-hydroxy-5-methyl-4-isopropylpropionic acid (AMPA)) receptors and kainate receptors.
• NMDA N-methyl-D-aspartate
• AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isopropylpropionic acid
• the mGlu receptor has eight subtypes (mGlu1 to 8), and group I (mGlu1, mGlu5), group II (mGlu2, mGlu3) and group III (mGlu4) depend on the signal transduction system and pharmacological properties to be coupled. , MGlu6, mGlu7, mGlu8). Group II and Group III mGlu receptors are expressed primarily as autoreceptors or heteroreceptors at nerve endings, suppress adenylate cyclase through Gi proteins, and regulate specific K + or Ca 2+ channel activity. ing.
• Non-patent Document 1 the concentration of glutamate in cerebrospinal fluid and plasma in patients with mental disorders such as mood disorders, anxiety disorders, and schizophrenia has changed, suggesting abnormal glutamate neuronal function in mental disorders.
• Group II mGlu receptor antagonists exhibit antidepressant and anxiolytic effects in various animal models (Non-patent Document 1), so Group II mGlu receptor antagonists are novel. The possibility of becoming an antidepressant and anxiolytic is suggested. Furthermore, the efficacy as a cognitive function enhancer (dementia, Alzheimer's disease) of a group II mGlu receptor antagonist is also suggested (nonpatent literature 2).
• Patent Documents 1 to 5 Recently, compounds having group II mGlu receptor antagonistic activity have been reported in Patent Documents 1 to 5 and the like. However, these patent documents do not disclose or suggest any compound having a heteroaryl-pyrazole skeleton.
• the object of the present invention is to find a novel compound that antagonizes Group II mGlu receptor, mood disorder (depressive disorder, bipolar disorder, etc.), anxiety disorder (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, society) Anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, tremor, pain, and sleep disorders To provide a useful preventive or therapeutic agent.
• mood disorder depressive disorder, bipolar disorder, etc.
• anxiety disorder generalized anxiety disorder, panic disorder, obsessive compulsive disorder, society
• Anxiety disorder post-traumatic stress disorder, specific phobia, acute stress disorder, etc.
• schizophrenia Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, tremor, pain, and sleep disorders
• R 1 represents a C 1-6 alkyl group or a C 3-8 cycloalkyl group (wherein the C 1-6 alkyl group or C 3-8 cycloalkyl group may be substituted with 1 to 3 halogen atoms).
• R 2 represents a hydrogen atom or a C 1-6 alkyl group (wherein the C 1-6 alkyl group may be substituted with 1 to 3 halogen atoms); n represents an integer of 1 to 3, Y 1 represents a phenyl group or a heteroaryl group (wherein the phenyl group or heteroaryl group is a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group (wherein the C 1- A 6 alkyl group, a C 3-8 cycloalkyl group or a C 1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), 1 selected from the group consisting of a cyano group and a halogen atom It may be substituted with 3 substituents.
• Ring A represents a phenyl group, a heteroaryl group or a pyridonyl group
• R 3 represents a hydrogen atom
• R 4 represents a C 1-6 alkyl group
• R 3 represents a hydrogen atom, a halogen atom, a C 1-6 alkoxy group or a C 1-6 alkyl group (wherein the C 1-6 alkoxy group or C 1-6 alkyl group is substituted with 1 to 3 halogen atoms) May be)
• R 4 is C 1-6 alkyl group ⁇ wherein the C 1-6 alkyl group is -NR a R b , -SO 2 R c , 1,2,4-triazol-3-yl group, A tetrazol-5-yl group or a tetrazol-5-yl-amino group (wherein the 1,2,4-triazol-3
• ⁇ Represents a 1,2,4-triazol-3-yl group or a tetrazol-5-yl group
• R a and R b are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, —COR c or —SO 2 R c ,
• R a and R b are formed together with a nitrogen atom to which they are bonded, and are a saturated or unsaturated 5- or 6-membered ring that may further contain one or more nitrogen atoms, oxygen atoms, or sulfur atoms ( Wherein the saturated or unsaturated 5- or 6-membered ring may be substituted with 1 to 2 substituents selected from a C 1-6 alkyl group and an oxo group.
• R c represents a hydroxy group, a C 1-6 alkoxy group, a C 1-6 alkyl group, an amino group, a mono-C 1-6 alkylamino group or a di-C 1-6 alkylamino group.
• n is 1,
• Y 1 is a phenyl group or a pyridyl group ⁇ wherein the phenyl group or pyridyl group is a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group (Wherein the C 1-6 alkyl group, C 3-8 cycloalkyl group or C 1-6 alkoxy group may be substituted with 1 to 3 halogen atoms), a cyano group and a halogen atom It may be substituted with 1 to 3 substituents selected from the group.
• R 4 is C 1-3 alkyl group ⁇ wherein the C 1-3 alkyl group is -NR a R b , -SO 2 R c , 1,2,4-triazol-3-yl group, A tetrazol-5-yl group or a tetrazol-5-yl-amino group (wherein the 1,2,4-triazol-3-yl group, tetrazol-5-yl group or tetrazol-5-yl group is 1 2 may be substituted with 2 methyl groups).
• R a and R b are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, —COR c or —SO 2 R c , Or R a and R b together with the nitrogen atom to which they are attached, Pyrrolidin-2-one-1-yl group, A piperidin-2-one-1-yl group, Morpholin-3-one-4-yl group, A pyridin-2-one-1-yl group, An imidazolidin-2-one-1-yl group, An oxazolidin-2-one-3-yl group, A pyrazol-1-yl group, 1,2,3-triazol-1-yl group, 1,2,3-triazol-2-yl group, 1,2,4-triazol-1-yl group, 1,2,4-triazol-5-one-4-yl group, Form a tetrazol-1-
• R c is a hydroxy group, a C 1-6 alkoxy group, a C 1-3 alkyl group, an amino group, a mono-C 1-3 alkylamino group or a di-C 1-3 alkylamino group, (5) the compound according to any one of the above or a pharmaceutically acceptable salt thereof, (7) A medicament comprising the compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient, (8) The pharmaceutical agent according to (7), wherein the active ingredient is a group II metabotropic glutamate receptor antagonist, and (9) the compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof It is a prophylactic or therapeutic agent for mood disorders, anxiety disorders, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, tremors, pain, or sleep disorders.
• the present compound and pharmaceutically acceptable salts thereof have been found to have strong group II mGlu receptor antagonistic activity.
• Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
• the “C 1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, Examples include hexyl group, isopropyl group, isobutyl group, tert-butyl group, sec-butyl group, isopentyl group, neopentyl group, tert-pentyl group, and 1,2-dimethylpropyl group.
• the “C 1-3 alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
• the “C 3-8 cycloalkyl group” is a cyclic cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group. Etc.
• the “C 1-6 alkoxy group” is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, or a pentyloxy group. Hexyloxy group, isopropoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1,2-dimethylpropoxy group and the like.
• the “mono-C 1-6 alkylamino group” is an amino group substituted with one C 1-6 alkyl group, and examples thereof include a methylamino group, an ethylamino group, a propylamino group, a butylamino group, Pentylamino group, hexylamino group, isopropylamino group, isobutylamino group, tert-butylamino group, sec-butylamino group, isopentylamino group, neopentylamino group, tert-pentylamino group, 1,2-dimethylpropyl An amino group etc. are mentioned.
• the “mono-C 1-3 alkylamino group” is an amino group substituted with one C 1-3 alkyl group, and examples thereof include a methylamino group, an ethylamino group, a propylamino group, and an isopropylamino group. It is done.
• the “di-C 1-6 alkylamino group” is an amino group substituted by two independent C 1-6 alkyl groups, for example, a dimethylamino group, a diethylamino group, a dipropylamino group, dibutyl.
• Amino group dipentylamino group, dihexylamino group, diisopropylamino group, diisobutylamino group, di-tert-butylamino group, di-sec-butylamino group, di-isopentylamino group, di-neopentylamino group, di- -Tert-pentylamino group, di-1,2-dimethylpropylamino group, ethylmethylamino group, isopropylmethylamino group, isobutylisopropylamino group and the like.
• the “di-C 1-3 alkylamino group” is an amino group substituted with two independent C 1-3 alkyl groups, for example, dimethylamino group, diethylamino group, dipropylamino group, diisopropyl An amino group, an ethylmethylamino group, an isopropylmethylamino group, etc. are mentioned.
• Heteroaryl group '' means a monocyclic or fused-ring aromatic heterocyclic group, for example, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, Pyrazolyl group, imidazolyl group, furyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, quinolyl group , Isoquinolyl group, naphthyridinyl group, quinazolinyl group, benzofuranyl group, benzothienyl group, indolyl group, benzoxazolyl group, benzisoxazolyl group, 1H-in
• 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.
• C 1-6 alkylene means a divalent group formed by removing any one hydrogen atom from the above “C 1-6 alkyl group”.
• “Saturated or unsaturated 5- or 6-membered ring which is formed together with the nitrogen atom to which they are attached and may further contain one or more nitrogen, oxygen or sulfur atoms” means, for example, a pyrrolidino group, Piperidino group, piperazino group, morpholino group, thiomorpholino group, 1,2,3,6-tetrahydropyridin-1-yl group, imidazolidin-2-one-1-yl group, pyrrolidin-2-one-1-yl Group, piperidin-2-one-1-yl group, oxazolidin-2-one-3-yl group, morpholin-3-one-4-yl group, 1,2,4-triazol-5-one-4 -Yl group, pyridin-2-one-1-yl group, pyrazol-1-yl group, 1,2,3-triazol-1-yl group, 1,2,3-triazol-2-yl group, 1, 2,4-triazol-1-yl group Tetrazol
• Preferred forms of the compound of the present invention are as follows.
• R 1 is a C 1-3 alkyl group or a C 3-8 cycloalkyl group (wherein the C 1-3 alkyl group or C 3-8 cycloalkyl group may be substituted with 1 to 3 halogen atoms).
• Preferable R 2 is a hydrogen atom.
• Preferred n is 1.
• Y 1 is preferably a phenyl group or a pyridyl group (wherein the phenyl group or pyridyl group is a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group (wherein the C 1-6 The alkyl group, C 3-8 cycloalkyl group or C 1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), 1 to 3 selected from the group consisting of cyano groups and halogen atoms May be substituted with one substituent.
• Y 1 is more preferably a phenyl group or a pyridyl group (wherein the phenyl group or pyridyl group is a methyl group, a cyclopropyl group, a methoxy group (wherein the methyl group, cyclopropyl group, or methoxy group is 1 to 3 halogen atoms may be substituted.), Substituted with 1 to 3 substituents selected from the group consisting of a cyano group and a halogen atom.
• Preferred ring A is a phenyl group or a 6-membered heteroaryl group, and more preferred ring A is a phenyl group or a pyridyl group.
• Preferred R 3 is a hydrogen atom, a halogen atom or a methoxy group, and more preferred R 3 is a hydrogen atom.
• Preferred R 4 is C 1-3 alkyl group ⁇ wherein the C 1-3 alkyl group is -NR a R b , -SO 2 R c , 1,2,4-triazol-3-yl group, A tetrazol-5-yl group or a tetrazol-5-yl-amino group (wherein the 1,2,4-triazol-3-yl group, tetrazol-5-yl group or tetrazol-5-yl group is 1 2 may be substituted with 2 methyl groups).
• R a and R b are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, —COR c or —SO 2 R c , Or R a and R b together with the nitrogen atom to which they are attached, Pyrrolidin-2-one-1-yl group, A piperidin-2-one-1-yl group, Morpholin-3-one-4-yl group, A pyridin-2-one-1-yl group, An imidazolidin-2-one-1-yl group, An oxazolidin-2-one-3-yl group, A pyrazol-1-yl group, 1,2,3-triazol-1-yl group, 1,2,3-triazol-2-yl group, 1,2,4-triazol-1-yl group, 1,2,4-triazol-5-one-4-yl group, Form a tetrazol-1
• the compound of the present invention may have stereoisomers such as tautomers and geometric isomers, and optical isomers, and the present invention includes these isomers. Also included are various hydrates, solvates and polymorphic substances of the inventive compounds and salts thereof. Furthermore, the compound [I] of the present invention may be labeled with an isotope (eg, D, 3 H, 13 C, 14 C, 15 N, 31 P, 32 P, 35 S, 18 F, 125 I, etc.). Good.
• an isotope eg, D, 3 H, 13 C, 14 C, 15 N, 31 P, 32 P, 35 S, 18 F, 125 I, etc.
• the pharmaceutically acceptable salt means a pharmaceutically acceptable salt.
• the compound [I] or a pharmaceutically acceptable salt of the present invention can be formulated according to a method known per se as it is or together with a pharmaceutically acceptable carrier.
• pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as pharmaceutical materials, such as excipients in solid formulations (eg, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silica Acid), lubricant (eg, magnesium stearate, calcium stearate, talc, colloidal silica), binder (eg, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl) Pyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), disintegrants (eg starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose Sodium, carboxymethyl starch sodium, low
• preservatives for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
• antioxidants for example, sulfites, Ascorbic acid and the like
• colorants for example, sweeteners, adsorbents, wetting agents and the like
• the compound [I] or pharmaceutically acceptable salt of the present invention can be administered orally or parenterally (for example, intravenous, topical, rectal administration, etc.).
• the dosage form includes, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, powders, troches, capsules (including soft capsules), liquids, injections (for example, subcutaneous injections, intravenous injections) Injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, nasal preparations, transdermal preparations, ointments, creams, etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.) ), Sustained-release agents (eg, sustained-release microcapsules, etc.), pellets, infusions, etc., all of which can be produced by conventional formulation techniques (eg, the method described in the 15th revised Japanese Pharmacopoeia). it
• the compound [I] of the present invention or a pharmaceutically acceptable salt is appropriately selected depending on the administration subject, administration route, disease, patient age, weight and symptoms. For example, when treating an adult patient, the dose is 1 to 2000 mg / day, and this amount is administered once or divided into several times a day.
• Group II mGlu receptor antagonist When Group II mGlu receptor antagonist is used as an active pharmaceutical ingredient, it is not intended for use only in humans, but in other animals other than humans (cats, dogs, cows, chickens, fish, etc.) Can also be used.
• the compound of the present invention and a pharmaceutically acceptable salt thereof can be synthesized, for example, by the method shown below, but the production method of the compound of the present invention is not limited thereto.
• “Inert solvent” means, for example, aromatic solvents such as benzene, toluene, xylene, pyridine; hydrocarbon solvents such as hexane, pentane, cyclohexane; dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.
• Halogenated hydrocarbon solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane; ester solvents such as ethyl acetate and ethyl formate; methanol, ethanol, isopropyl alcohol, tert- Alcohol solvents such as butyl alcohol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; amide solvents such as N, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylacetamide; sulfos such as dimethyl sulfoxide Sid solvents; acetonitrile, nitriles and water, such as propionitrile, and also these homogeneous and heterogeneous mixed solvents.
• inert solvents are appropriately selected according to various reaction conditions known to those skilled in the art.
• Examples of the “base” include hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or alkaline earth Lower metal alkoxides; alkyl lithiums such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, Beauty hydroxide Alkali metal or alkaline earth metal hydroxides such as sodium carbonate; alkaline metal or alkaline earth metal carbonates such as sodium carbon
• Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and ammonium chloride, organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid, and Lewis acids such as aluminum chloride and zinc bromide. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
• inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and ammonium chloride
• organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid
• Lewis acids such as aluminum chloride and zinc bromide.
• rings A, R 1 , R 2 , R 3 , R 4 , Y 1 and n are as defined above.
• R 5 is a protecting group of a carboxy group such as a methyl group, an ethyl group, a tert-butyl group, or a benzyl group ⁇ Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons (John Wiley & Sons) Sons, INC.) ⁇ Or hydrogen atom.
• Step 1: Compound [I] of the present invention is a condensation reaction known to those skilled in the art of compound (1) and compound (2) in which R 5 is a protecting group for a carboxy group in an inert solvent in the presence of a base, followed by a molecule.
• the compound [I] of the present invention is produced by an intramolecular cyclization reaction after an amidation reaction known to those skilled in the art of the compound (1) and the compound (2) in which R 5 is a hydrogen atom in an inert solvent. ⁇ Comprehensive Organic Transformations Second Edition 1999, see John Wiley & Sons, INC. ⁇ .
• the compound (1) and the compound (2) a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis techniques known to those skilled in the art can be used.
• the amidation reaction means, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluro in an inert solvent in the presence or absence of a base.
• Nium hexafluorophosphoric acid (HATU) O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphoric acid (HBTU)
• the amidation reaction using the condensing agent additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary.
• the intramolecular cyclization reaction is, for example, a cyclization reaction of an amide compound using an acid or a base as necessary under heating or non-heating conditions in an inert solvent.
• rings A, R 1 , R 2 , R 3 , Y 1 and n are as defined above.
• R 6 represents a bond or C 1-6 alkylene
• Y 2 represents a nitrogen atom or the formula CH
• P 1 represents an acetyl group, a methanesulfonyl group, a p-methoxyphenylsulfonyl group, a p-toluenesulfonyl group, a benzyloxy group Protective group of nitrogen atom on triazole or tetrazole ring such as carbonyl group, t-butyloxycarbonyl group, benzyl group, p-methoxybenzyl group, trityl group ⁇ Protective Groups in Organic Synthesis No.
• Step 2 The compound [II] of the present invention is prepared by subjecting the protecting group P 1 of the compound (3) to various organic synthesis methods known to those skilled in the art ⁇ Protective Groups in Organic Synthesis in an inert solvent ⁇ Protective Groups in Organic Synthesis]. Synthesis), 4th edition, see John Wiley & Sons, INC. ⁇ .
• the compound (3) a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis methods known to those skilled in the art can be used.
• Step 3 The compound [I-II] of the present invention can be produced by a cyclization reaction known to those skilled in the art of the compound (4) and the compound (5) in an inert solvent in the presence or absence of an acid.
• the compound (4) and the compound (5) a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis methods known to those skilled in the art can be used.
• Step 4 The compounds [I-III] and [I-IV] of the present invention are subjected to an alkylation reaction known to those skilled in the art with the compound [I-II] of the present invention in an inert solvent in the presence or absence of a base. Can be manufactured.
• the alkylating agent used in the alkylation reaction include methyl iodide, ethyl iodide, propyl iodide, and trimethylsilyldiazomethane.
• compound (1) and compound (1-1) can be produced by the following method.
• R 9 , R 9 ′ and R 9 ′′ are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkyl Group, a C 3-8 cycloalkyl group or a C 1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), A cyano group and a halogen atom, and X 1 represents a chlorine atom, bromine An atom, an iodine atom, or a fluorine atom is shown.
• Step 5 Compound (1) can be produced by Mitsunobu reaction of compound (6) and compound (7) in an inert solvent.
• the compound (6) and the compound (7) a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis techniques known to those skilled in the art can be used.
• Mitsunobu reaction is, for example, a method using an organic phosphorus compound such as triphenylphosphine or tributylphosphine and an azo compound such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, ditertbutyl azodicarboxylate, or cyanomethyltributylphosphorane. (See Chem. Rev.
• Step 6 Compound (1-1) is compound (6) and Compound (8) in an inert solvent in the presence of a base, in the presence or absence of a palladium catalyst, in the presence or absence of a palladium catalyst ligand. ⁇ See Comprehensive Organic Transformations Second Edition 1999, John Wiley & Sons, INC. ⁇ .
• the compound (6) and the compound (8) a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis methods known to those skilled in the art can be used.
• Examples of the base here include sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, lithium hydride, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide.
• Examples of the palladium catalyst include palladium acetate (II), dichlorobistriphenylphosphine palladium (II), dichlorobisacetonitrile palladium (II), tetrakistriphenylphosphine palladium (0), and the like.
• Examples of the ligand include rac-2- (di-t-butylphosphino) -1,1′-binaphthyl, triphenylphosphine, tributylphosphine, 2,2-bis (diphenylphosphino) -1,1-binaphthyl.
• BINAP 2- (di-tert-butylphosphino) biphenyl, 1,1′-bis (diphenylphosphino) ferrocene (dppf), 1,3-bis (diphenylphosphino) propane (dppp), etc. It is done.
• a compound in which compound (6) is represented by formula (6-1) can be produced by the following method.
• Step 7 Compound (10) can be produced by subjecting compound (9) to a formylation reaction using N, N-dimethylformamide or the like in the presence of a base in an inert solvent.
• Compound (9) may be a commercially available compound, a known compound, or a compound synthesized from a commercially available compound or a known compound using various organic synthesis methods known to those skilled in the art.
• Step 8 Compound (6-1) can be produced by reacting compound (10) with a reducing agent in an inert solvent. ⁇ See Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, INC. ⁇ .
• the reducing agent is a reagent that can reduce a formyl group and convert it into a hydroxyl group.
• a reagent that can reduce a formyl group and convert it into a hydroxyl group.
• compound (2) can be produced by the following method.
• Step 9 Compound (12) is appropriately combined with Compound (11) in an inert solvent in the presence or absence of a base, in the presence or absence of a palladium catalyst, in the presence or absence of a palladium catalyst ligand. It can be produced by reaction with a cyanating agent.
• Compound (11) may be a commercially available compound, a known compound or a compound synthesized from a commercially available compound or a known compound using various organic synthesis methods known to those skilled in the art.
• suitable cyanating agents include, for example, zinc cyanide, copper cyanide, potassium cyanide or sodium cyanide.
• Step 10 Compound (2) can be produced by addition reaction of compound (12) and hydroxyamine or a salt thereof in an inert solvent in the presence or absence of a base.
• compound (12) synthesized from the compound (11) a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis techniques known to those skilled in the art can be used.
• Biotage (registered trademark) SNAP cartridge KP-NH manufactured by Biotage was used for “NH silica gel cartridge” when purified using column chromatography, and Biotage was manufactured for “silica gel cartridge”.
• Biotage (registered trademark) SNAPCartridge KP-Sil and HP-Sil Biotage (registered trademark) SNAPCartridge KP-Sil and HP-Sil
• Silica gel 60 N is silica gel 60 N manufactured by Kanto Chemical Co.
• Chromatolex NH Chromatrex (registered trademark) NH manufactured by Fuji Silysia Chemical Ltd.
• NMR nuclear magnetic resonance
• reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure.
• the organic layer was passed through a phase separator (manufactured by Biotage Corp.), water was removed, and the mixture was concentrated under reduced pressure.
• cesium carbonate (10.4 g) and N, N-dimethylformamide (25 mL), 1H-tetrazole (1.79 g) was added little by little under ice-cooling, and the mixture was stirred at room temperature for 13 hours. Stir.
• the reaction mixture was diluted with ethyl acetate (250 mL) and washed successively with water (50 mL) -saturated brine (100 mL) and saturated brine (150 mL ⁇ 2).
• ISOLUTE HM-N was added to the organic layer and concentrated under reduced pressure.
• the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (0.5 mL) and methanol (1.0 mL) were added to the residue, and then concentrated under reduced pressure.
• Example 4 Using the same method as in Example 3, the compounds of Example 4 to Example 152 described in Table 1-1 to Table 1-25 were obtained.
• Example 4 2-[(1-Methyl-4- ⁇ 3- [4- (1H-tetrazol-5-yl) phenyl] -1,2,4-oxadiazol-5-yl ⁇ -1H-pyrazol-5- Yl) methoxy] -5- (trifluoromethyl) pyridine
• Example 5 2-[(1-Methyl-4- ⁇ 3- [3- (1H-tetrazol-5-yl) phenyl] -1,2,4- Oxadiazol-5-yl ⁇ -1H-pyrazol-5-yl) methoxy] -5- (trifluoromethyl) pyridine
• Example 6 2- ⁇ [1-Methyl-4- (3- ⁇ 4-[(5-methyl -1H-tetrazol-1-yl) methyl] phenyl ⁇ -1,2,4-oxadiazol-5-yl) -1H-pyrazol-5-yl] methoxy ⁇ -5- (trifluoromethyl) pyr
• Example 31 5-Fluoro-2-[(1-methyl-4- ⁇ 3- [4- (2H-tetrazol-2-ylmethyl) phenyl] -1,2,4-oxadiazol-5-yl ⁇ -1H- Pyrazol-5-yl) methoxy] pyridine
• Example 32 5-Fluoro-2-[(1-methyl-4- ⁇ 3- [3- (1H-tetrazol-1-ylmethyl) phenyl] -1,2,4- Oxadiazol-5-yl ⁇ -1H-pyrazol-5-yl) methoxy] pyridine
• Example 33 5-Fluoro-2-[(1-methyl-4- ⁇ 3- [3- (2H-tetrazol-2-ylmethyl)] Phenyl] -1,2,4-oxadiazol-5-yl ⁇ -1H-pyrazol-5-yl) methoxy] pyridine
• Example 34 6-Methyl-1- (3- ⁇ 5- [1-methyl
• Example 61 5-chloro-2-[(1-methyl-4- ⁇ 3- [4- (1H-tetrazol-1-ylmethyl) phenyl] -1,2,4-oxadiazol-5-yl ⁇ -1H- Pyrazol-5-yl) methoxy] pyridine
• Example 62 1- (3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H— Pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ benzyl) imidazolidin-2-one
• Example 63 5-Cyclopropyl-2-[(1-methyl-4- ⁇ 3- [3 -(1H-tetrazol-1-ylmethyl) phenyl] -1,2,4-oxadiazol-5-yl ⁇ -1H-pyrazol-5-yl) methoxy] pyridine
• Example 64 2-methoxy-4-
• Example 91 5-Fluoro-2-[(4- ⁇ 3- [3-fluoro-4- (1H-tetrazol-1-ylmethyl) phenyl] -1,2,4-oxadiazol-5-yl ⁇ -1- Methyl-1H-pyrazol-5-yl) methoxy] pyridine
• Example 92 2-[(4- ⁇ 3- [2-methoxy-5- (1H-tetrazol-1-ylmethyl) phenyl] -1,2,4- Oxadiazol-5-yl ⁇ -1-methyl-1H-pyrazol-5-yl) methoxy] -5- (trifluoromethyl) pyridine
• Example 93 2-Methyl-6-[(1-methyl-4- ⁇ 3- [3- (1H-tetrazol-1-ylmethyl) phenyl] -1,2,4-oxadiazol-5-yl ⁇ -1H-pyrazol-5-yl) methoxy] pyridine
• Example 94 4-
• Example 121 2-Chloro-4-[(1-methyl-4- ⁇ 3- [6- (1H-tetrazol-1-ylmethyl) pyridin-2-yl] -1,2,4-oxadiazol-5-yl ⁇ -1H-pyrazol-5-yl) methoxy] pyridine
• Example 122 4- [5- (1-Ethyl-5- ⁇ [(5-fluoropyridin-2-yl) oxy] methyl ⁇ -1H-pyrazol-4 -Yl) -1,2,4-oxadiazol-3-yl] -2- (1H-tetrazol-1-ylmethyl) pyridine
• Example 123 4- (5- ⁇ 1-methyl-5-[(pyridin-2- Yloxy) methyl] -1H-pyrazol-4-yl ⁇ -1,2,4-oxadiazol-3-yl) -2- (1H-tetrazol-1-ylmethyl) pyridine
• Example 124 2-chloro-4-[
• Example 153 In the same reaction as in Example 153, the title compound (14 mg) which is a structural isomer of Example 153 was obtained as a colorless solid.
• 1H NMR 600 MHz, CHLOROFORM-d
• N′-hydroxy-2-oxo-1,2-dihydropyridine-3-carboximidamide 2-oxo-1,2-dihydropyridine-3-carbonitrile (1.00 g), 50% hydroxyamine aqueous solution ( 600 ⁇ L) and ethanol (10 mL) were heated to reflux for 3 hours. The precipitate was collected by filtration to give the title compound (1.06 g) as a light brown solid.
• N'-hydroxy-2-oxo-1,2-dihydropyridine-3-carboximidamide (184 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and at 110 ° C for 17 hours.
• the reaction solution was allowed to cool to room temperature, water was added, and the precipitate was collected by filtration. This was recrystallized from ethyl acetate-methanol to give the title compound (185 mg) as a colorless solid.
• Example 158 1- (4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl ⁇ phenyl) methanamine
• Example 160 (3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl ⁇ phenyl) methanesulfonamide
• N N of 1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazole-4-carboxylic acid (85 mg) obtained in Production Example 8
• dimethylformamide 1.0 mL
• 1,1′-carbonyldiimidazole 55 mg
• N'-hydroxy-3- (sulfamoylmethyl) benzenecarboximidamide 65 mg obtained in Production Example 11 was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and at 110 ° C. for 20 hours.
• the reaction solution was allowed to cool to room temperature, water was added, and the precipitate was collected by filtration.
• Example 161 to Example 164 listed in Table 2 were obtained.
• Example 161 1- (4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl ⁇ phenyl) methanesulfonamide
• Example 162 (4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl ) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ phenyl) methanesulfonic acid
• Example 163 N-methyl-1- (4- ⁇ 5- [1-methyl-5- ( ⁇ [5- (Trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ phenyl) methanesul
• Test example 1 Preparation of crude membrane fraction of CHO cells stably expressing human metabotropic glutamate receptor (mGlu2)
• CHO cells stably expressing human mGlu2 receptor were mixed with Dulbecco's modified Eagle medium containing 10% dialyzed fetal bovine serum [1% proline, 50 units / mL penicillin, 50 ⁇ g / mL streptomycin, 400 ⁇ g / mL Hygromycin B, 2 mM L-glutamine (for use) Added)] and cultured at 37 ° C. under 5% CO 2 .
• Confluent cells were washed twice with PBS ( ⁇ ), detached with a cell scraper, and centrifuged at 4 ° C.
• the obtained precipitate was suspended in 20 mM HEPES buffer (pH 7.4), the suspension was homogenized with a Teflon (registered trademark) homogenizer, and then centrifuged at 4 ° C., 48,000 ⁇ g for 20 minutes. By getting sunk again. Further, the obtained precipitate was centrifugally washed twice and then homogenized with the above buffer solution to obtain a crude membrane fraction. The obtained crude membrane fraction was stored at ⁇ 80 ° C.
• reaction solution was suction filtered onto a Whatman GF / C filter pre-soaked in 20 mM HEPES buffer (pH 7.4), and the filter was ice-cooled 20 mM HEPES buffer (pH 7.4). Washed 3 times with 300 ⁇ L. A scintillation cocktail was added to the obtained filter, and membrane-bound radioactivity was measured with a liquid scintillation counter.
• the amount of [ 35 S] GTP ⁇ S binding when the above reaction was performed in the absence of glutamic acid was defined as non-specific binding, and the difference from the amount of [ 35 S] GTP ⁇ S binding obtained in the presence of glutamic acid was defined as specific binding.
• Inhibition curves were obtained from the specific binding inhibition rates at various concentrations of each Example compound using nonlinear analysis.
• the concentration (IC 50 value) of each Example compound at which the specific [ 35 S] GTP ⁇ S binding amount was suppressed by 50% was calculated from the inhibition curve.
• the IC 50 value of the compound of the present invention was 10 ⁇ M or less.
• a compound having an IC 50 value of 0.1 ⁇ M or less is represented by A
• a compound having 0.1 ⁇ M to 1 ⁇ M is represented by B
• a compound having 1 ⁇ M to 10 ⁇ M is represented by C.
• Table 4 illustrating an IC 50 value in Table 4.
• the compound of the present invention has an antagonistic action on Group II mGlu receptor, and is a preventive and therapeutic agent for diseases related to Group II mGlu receptor, specifically, mood disorder (depressive disorder, bipolar) Disorders), anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), schizophrenia, Alzheimer's disease, cognitive impairment, It can be used as a preventive or therapeutic agent for dementia, drug dependence, convulsions, tremors, pain, sleep disorders and the like.
• mood disorder depressive disorder, bipolar
• anxiety disorders generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.
• schizophrenia Alzheimer's disease, cognitive impairment
• It can be used as a preventive or therapeutic agent for dementia, drug dependence, convulsions, tremors, pain, sleep disorders and the like.

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