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WO2012099200A1 - Dérivé de pyrazole - Google Patents

Dérivé de pyrazole Download PDF

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Publication number
WO2012099200A1
WO2012099200A1 PCT/JP2012/051070 JP2012051070W WO2012099200A1 WO 2012099200 A1 WO2012099200 A1 WO 2012099200A1 JP 2012051070 W JP2012051070 W JP 2012051070W WO 2012099200 A1 WO2012099200 A1 WO 2012099200A1
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Prior art keywords
group
methyl
pyrazol
oxadiazol
trifluoromethyl
Prior art date
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Ceased
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PCT/JP2012/051070
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English (en)
Japanese (ja)
Inventor
誠治 増田
洋平 松田
一成 坂上
一豪 小西
洋樹 浦部
梨絵 下野
久美子 岡田
年男 中村
博 川元
幸祐 鹿沼
英明 天田
直樹 宮腰
修平 柏
彩 二村
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Publication of WO2012099200A1 publication Critical patent/WO2012099200A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P25/18—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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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 roughly divided.
  • 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.
  • R 1 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);
  • 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);
  • Ring A includes a phenyl group, a heteroaryl group, an indoline-2-one-5-yl group, an isoindoline-1-one-5-yl group, an isoindoline-1-one-6-yl group, a benzo [d] Represents an imidazol-2-one-5-yl group or a pyridonyl group; Ring A is an indoline-2-one-5-yl group, an isoindoline-1-one-5-yl group, an isoindoline-1-one-6-yl group or a benzo [d] imidazol-2--
  • the octan-6-yl group may be substituted with 1 to 2 halogen atoms. May be substituted with 1 to 3 substituents selected from the group consisting of ⁇ , A C 1-6 alkanoyl group, an oxetanyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group, Alternatively, R a and R b are formed together with a nitrogen atom to be bonded, and are a saturated or unsaturated 4- to 6-membered ring (here, which may further contain one or more nitrogen atom, oxygen atom or sulfur atom (wherein The saturated or unsaturated 4- to 6-membered ring may be substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, an oxo group and a hydroxyl group.
  • R a1 and R b1 are formed together with a nitrogen atom to which they are bonded, and are a saturated or unsaturated 4- to 6-membered ring that may contain one or more nitrogen atoms, oxygen atoms, or sulfur atoms, Or an unsaturated 4- to 6-membered ring may be substituted with 1 to 2 substituents selected from the group consisting of a C 1-6 alkyl group, an oxo group and a hydroxyl group.
  • R c represents a C 1-6 alkyl group, a hydroxyl group or a C 1-6 alkoxy group
  • R d represents a hydrogen atom or a C 1-6 alkyl group
  • R e represents a C 1-6 alkoxy group, an amino group, a mono-C 1-6 alkylamino group or a di-C 1-6 alkylamino group
  • R f and R g are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group
  • Y 1 represents — (CH 2 ) n —O— or — (CH 2 ) m —
  • n represents an integer of 1 to 6
  • m represents an integer of 0 to 6
  • Y 2 represents an aryl group or heteroaryl group (wherein the aryl group or heteroaryl group is a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group (wherein the C 1- A 6
  • R 1 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);
  • 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);
  • Ring A represents a phenyl group or a heteroaryl group,
  • R 3 represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group (wherein the C 1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
  • R 4 represents a C 1-6 alkyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkyl group or C 1-6 alkoxy group is substituted with —CONR a R b , —COR c or a cyano group).
  • R a and R b are the same or different and are each a hydrogen atom, a C 1-6 alkyl group, wherein the C 1-6 alkyl group is an amino group, a mono-C 1-6 alkylamino group, di-C 1 -6 may be substituted with 1 to 2 substituents selected from the group consisting of an alkylamino group and a hydroxyl group.
  • R a and R b are formed together with a nitrogen atom to be bonded to form a saturated or unsaturated 5- or 6-membered ring which may further contain one or more nitrogen atom, oxygen atom or sulfur atom.
  • R c represents a hydroxyl group or a C 1-6 alkoxy group
  • Y 1 represents — (CH 2 ) n —O— or — (CH 2 ) m —
  • n represents an integer of 1 to 6
  • m represents an integer of 0 to 6
  • Y 2 represents an aryl group or heteroaryl group (wherein the aryl group or heteroaryl group is a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group (wherein the C 1- A 6 alkyl group, a C 3-6 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.
  • Y 3 represents a 5-membered heteroarylene] Or a pharmaceutically acceptable salt thereof according to (1),
  • 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, 1,2-dimethylpropyl group and the like.
  • 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 “di-C 1-6 alkylamino group” is an amino group substituted with two independent C 1-6 alkyl groups, such as a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutyl group.
  • 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 “C 1-6 alkanoyl group” is a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, A valeryl group, a hexanoyl group, a pivaloyl group, etc. are mentioned.
  • the “aryl group” is a monocyclic to tetracyclic aromatic carbocyclic group composed of 6 to 18 carbon atoms, such as a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a tetracenyl group. And pyrenyl group.
  • 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.
  • the “5-membered heteroaryl group” means a 5-membered aromatic heterocyclic group such as thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, furyl group, oxazolyl group, isoxazolyl group.
  • C 3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms, and means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • 5-membered heteroarylene means a divalent group formed by removing any one hydrogen atom from the above-mentioned “5-membered heteroaryl group”.
  • “Saturated or unsaturated 5- or 6-membered ring which is formed together with the nitrogen atom to be bonded and may further contain one or more nitrogen atom, oxygen atom or sulfur atom” means, for example, pyrrolidino group, piperidino group A piperazino group, a morpholino group, a thiomorpholino group, a 1,2,3,6-tetrahydropyridin-1-yl group, and the like.
  • “Saturated or unsaturated 4- to 6-membered ring which is formed together with the nitrogen atom to be bonded and may further contain one or more nitrogen atom, oxygen atom or sulfur atom” means, for example, an azetidino group, a pyrrolidino group And piperidino group, piperazino group, morpholino group, thiomorpholino group, 1,2,3,6-tetrahydropyridin-1-yl group and the like.
  • C 1-6 alkylene means a divalent group formed by removing any one hydrogen atom from the above “C 1-6 alkyl group”.
  • C 1-6 oxyalkylene means a divalent group formed by removing any one hydrogen atom from the “C 1-6 alkoxy group”.
  • R 1 is preferably a hydrogen atom or a C 1-6 alkyl group, more preferably a C 1-6 alkyl group. Particularly preferred R 1 is a methyl group.
  • R 2 is a hydrogen atom.
  • Preferred ring A is a phenyl group or a 6-membered heteroaryl group, more preferably a phenyl group or a pyridyl group.
  • R 3 is preferably a hydrogen atom, a halogen atom or a C 1-6 alkyl group (wherein the C 1-6 alkyl group may be substituted with 1 to 3 halogen atoms), more preferably a hydrogen atom.
  • R 4 is a C 1-3 alkyl group, a C 1-3 alkoxy group (wherein the C 1-3 alkyl group or C 1-3 alkoxy group is substituted with —CONR a R b , or a hydroxyl group. ), —CONR a R b , —NR d COR e or —NR d SO 2 R e (wherein R a , R b , R c , R d and R e are as defined above).
  • Preferred Y 1 is —CH 2 —O—.
  • Y 2 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 3-6 cycloalkyl group, a C 1-6 alkoxy group (wherein the C 1-6 The alkyl group, C 3-6 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 a cyano group and a halogen atom May be substituted with one substituent.
  • Preferred Y 3 is any of the structures shown in formula [II]
  • R 1 is 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);
  • R 2 is 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);
  • Ring A is a phenyl group or a 6-membered heteroaryl group,
  • R 3 is a hydrogen atom, a halogen atom or a C 1-6 alkyl group (wherein the C 1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
  • R 4 represents a C 1-6 alkyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkyl group or C 1-6 alkoxy group is substituted with —CONR a R b , —COR c or a cyano group).
  • R a and R b are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group (wherein the C 1-6 alkyl group is an amino group, a mono-C 1-6 alkylamino group, di-C 1 -6 may be substituted with 1 to 2 substituents selected from the group consisting of an alkylamino group and a hydroxyl group.) Or a 4-6 membered cyclic ether group, Or, R a and R b are formed together with the nitrogen atom to which they are bonded to form a saturated or unsaturated 5- or 6-membered ring which may further contain one or more nitrogen, oxygen or sulfur atoms.
  • R c is a hydroxyl group or a C 1-6 alkoxy group
  • Y 1 is —CH 2 —O—
  • Y 2 is a phenyl group or a pyridyl group (wherein the phenyl group or pyridyl group is a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkyl is Group, a C 3-6 cycloalkyl group or a C 1-6 alkoxy group may be substituted with 1 to 3 halogen atoms.), 1 to 3 selected from the group consisting of a cyano group and a halogen atom It may be substituted with a substituent.
  • Y 3 is a 5-membered heteroarylene.
  • 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 their salts. 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, etc
  • 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 and phosphoric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
  • 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 [II] 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.
  • the compound [II] of the present invention is obtained by subjecting the compound (1) in which R 5 is a hydrogen atom to an amidation reaction known to those skilled in the art in an inert solvent, followed by the subsequent intramolecular cyclization reaction. ⁇ See Comprehensive Organic Transformations Second Edition 1999, 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 is, 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.
  • Step 2 Compound (4) can be produced by an amidation reaction known to those skilled in the art of Compound (1) and Compound (3) in which R 5 is a hydrogen atom in an inert solvent ⁇ Comprehensive Organic Transformations Second Edition (see John Wiley & Sons, INC., 1999) ⁇ .
  • R 5 is a hydrogen atom in an inert solvent
  • the compound (1) and the compound (3) 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 is, 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)
  • Step 3 The compound [I-II] of the present invention can be produced by an intramolecular cyclization reaction of the compound (4) in an inert solvent.
  • an activator such as tosyl chloride, thionyl chloride, phosphoryl chloride, Burgess Reagent ⁇ Methyl-N- (triethylammoniumsulfonyl) carbamate ⁇ can be used. ⁇ See Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, INC. ⁇ .
  • compound (4) can be produced by the following method.
  • R 6 is an amino group such as methoxymethyl group, trimethylsilylethoxymethyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, acetyl group, benzyl group, trityl group, methanesulfonyl group, benzenesulfonyl group, p-toluenesulfonyl group, etc.
  • Protective group ⁇ see Protective Groups in Organic Synthesis 4th Edition, John Wiley & Sons, INC. ⁇ Or hydrogen atom.
  • Step 4 Compound (6) can be produced from Compound (1) and Compound (5) wherein R 5 is a hydrogen atom by the same method as in Step 2 in ⁇ Scheme 2>.
  • R 6 is an amino-protecting group
  • compound (6) can be prepared by various organic synthesis methods known to those skilled in the art for protecting group R 6 ⁇ Protective Groups in Organic Synthesis). 4th edition, see John Wiley & Sons, Inc. ⁇ .
  • compound (6) is produced by a condensation reaction known to those skilled in the art of compound (1) in which R 5 is a protecting group for a carboxy group and compound (5) in which R 6 is a hydrogen atom in an inert solvent.
  • Step 5 Compound (4) can be produced from compound (6) and compound (7) by the same method as in Step 2 in ⁇ Scheme 2>.
  • the compound (7) 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 6 Compound [I-IV] of the present invention can be produced from compound [I-III] of the present invention and compound (8) by the same method as in Step 2 in ⁇ Scheme 2>.
  • 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.
  • Step 7 The compound [IV] of the present invention is produced by a reductive amination reaction known to those skilled in the art of the compound (8) and the compound (9) in the presence of an acid and a reducing agent in an inert solvent. ⁇ Comprehensive Organic Transformations Second Edition 1999, see John Wiley & Sons, INC. ⁇ .
  • the compound (8) and the compound (9) 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.
  • the acid herein include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid.
  • the reducing agent used in the reductive amination reaction is a reagent capable of reducing an imino group to convert it to an amino group.
  • sodium borohydride, sodium triacetoxyborohydride, cyanoborohydride Sodium, borane, borane-pyridine, borane-picoline and the like can be mentioned.
  • Step 8 Compound [I-VII] of the present invention can be produced by a hydration reaction known to those skilled in the art of Compound [I-VI] of the present invention ⁇ Comprehensive Organic Transformations Second Edition (Comprehensive Organic Transformations Second Edition) See 1999 John Wiley & Sons, INC. ⁇ .
  • a compound in which compound (1) is represented by formula (1-1) or formula (1-2) can be produced by the following method.
  • R 10 , R 10 ′ and R 10 ′′ are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkyl Group, a C 3-6 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 9 Compound (1-1) can be produced by Mitsunobu reaction of compound (10) and compound (11) in an inert solvent.
  • the compound (10) and the compound (11) 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.
  • 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.
  • Step 10 Compound (1-2) is compound (10) and Compound (12) 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.
  • a base in the presence or absence of a palladium catalyst
  • a palladium catalyst ligand in the presence or absence of a palladium catalyst ligand.
  • 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 (10) is represented by formula (10-1) can be produced by the following method.
  • Step 11 Compound (14) can be produced by reacting compound (13) with N, N-dimethylformamide or the like in the presence of a base in an inert solvent.
  • Compound (13) 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 12 Compound (10-1) can be produced by reacting compound (14) 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 13 Compound (16) is appropriately combined with Compound (15) 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.
  • a cyanating agent As the compound (15), 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.
  • suitable cyanating agents include, for example, zinc cyanide, copper cyanide, potassium cyanide or sodium cyanide.
  • Step 14 Compound (2) can be produced by addition reaction of compound (16) with hydroxyamine or a salt thereof in an inert solvent in the presence or absence of a base.
  • compound (16) synthesized from the compound (15) 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.
  • compound (3) can be produced by the following method.
  • Step 15 Compound (3) can be produced from compound (17) and compound (5) by the same method as in Step 4 in ⁇ Scheme 3>.
  • the compound (17) and the compound (5) a commercially available compound, a known compound or a compound synthesized from a known compound by using various organic synthesis methods 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
  • Ethyl 5- (hydroxymethyl) -1-methyl-1H-pyrazole-4-carboxylate Ethyl 5-formyl-1-methyl-1H-pyrazole-4-carboxylate Diisopropylamine (27 1.6 g) in tetrahydrofuran (400 mL) was added dropwise n-butyllithium (105 mL, 2.60 M hexane solution) under ice bath cooling, and the mixture was stirred for 1 hour.
  • reaction mixture was cooled to ⁇ 78 ° C., a solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (20.0 g) in tetrahydrofuran (100 mL) was added dropwise, and the mixture was stirred for 2 hr.
  • N, N-dimethylformamide (79.7 g) was added dropwise to the reaction solution at ⁇ 78 ° C., and the mixture was stirred for 1 hour, and then 2M aqueous hydrogen chloride solution was added.
  • the reaction mixture was acidified with 5M aqueous hydrogen chloride solution and extracted three times with ethyl acetate.
  • reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure.
  • HATU Tetramethyluronium hexafluorophosphoric acid
  • Example 2 Using the same method as in Example 1, the compounds of Examples 2 to 14 listed in Table 1-1 to Table 1-3 were obtained.
  • Example 2 4- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4 -Oxadiazol-3-yl ⁇ benzamide
  • Example 3 3- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4- Yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide
  • Example 4 2- (3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] Oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ phenyl) acetamide
  • Example 5 6- [5- (1-Methyl-5- ⁇ [4- (tri Fluor
  • Example 16 Using the same method as in Example 15, the compounds of Example 16 to Example 31 described in Tables 2-1 to 2-3 were obtained.
  • Example 16 4- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3-yl] Benzoic acid
  • Example 17 3- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3- yl] benzoic acid
  • example 18 2- ⁇ 4- [5- (1-methyl-5 - ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) -1,2,4 -Oxadiazol-3-yl] phenyl ⁇ acetamide
  • Example 19 ⁇ 4- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) -1
  • Example 33 Using the same method as in Example 32, the compounds of Example 33 to Example 41 described in Table 3-1 to Table 3-2 were obtained.
  • Example 33 tert-butyl 3- [5- (1-methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) -1,2,4-oxadiazol-3 -Yl] benzoate
  • Example 34 4- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) -1,2,4-oxadiazol -3-yl] benzamide
  • Example 35 3- [5- (5- ⁇ [(5-Fluoropyridin-2-yl) oxy] methyl ⁇ -1-methyl-1H-pyrazol-4-yl) -1,2 , 4-Oxadiazol-3-yl] benzamide
  • Example 36 4- [5- (5- ⁇ [(5-Fluoropyridin-2-yl) oxy] methyl ⁇ -1-methyl-1H-pyrazol-4-yl) -1,2,4
  • Example 45 Using the same method as in Example 44, the compounds of Example 45 to Example 49 listed in Table 4 were obtained.
  • Example 45 2- ⁇ 3- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl) -1,3,4-oxadiazol-2 -Yl] phenyl ⁇ acetamide
  • Example 46 4- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,3,4-oxadiazol-2-yl ⁇ benzamide
  • Example 47 3- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol-4-yl ) -1,3,4-oxadiazol-2-yl] benzamide
  • Example 48 4- [5- (1-Methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazol
  • Example 20 Using the same procedure as in Example 50, ⁇ 3- [5- (1-methyl-5- ⁇ [4- (trifluoromethyl) phenoxy] methyl ⁇ -1H-pyrazole-4 obtained in Example 20 was used. -Il) -1,2,4-oxadiazol-3-yl] phenyl ⁇ acetic acid (43 mg) and methylamine (70 ⁇ L, 2M tetrahydrofuran solution) gave the title compound (34 mg) as a colorless solid.
  • Example 53 3-Fluoro-4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1 , 2,4-oxadiazol-3-yl ⁇ benzamide
  • Example 54 2- (2-Bromo-4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] Oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ phenyl) acetamide
  • Example 55 N- (2-hydroxyethyl) -3- ⁇ 5- [1-methyl -5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide
  • Example 56 2
  • Example 50 Using the same method as in Example 50, the compounds of Examples 129 to 175 described in Table 6-1 to Table 6-8 were obtained.
  • N- (2,2-dimethoxyethyl) -3- (N′-hydroxycarbamimidoyl) benzamide (846 mg) obtained in Production Example 5 was added to the reaction solution, and the mixture was stirred at 120 ° C. for 10 hours.
  • the reaction mixture was allowed to cool to room temperature, ISOLUTE HM-N was added, and the mixture was concentrated under reduced pressure.
  • Example 177 and Example 178 were obtained using the same method as in Example 176.
  • Example 179 N- ⁇ 2-[(3S) -3-fluoropyrrolidin-1-yl] ethyl ⁇ -3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridine-2 -Yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide N- (2,2-dimethoxyethyl) -3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy obtained in Example 176-1) ⁇ Methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide (52 mg) in tetrahydrofuran (1.0 mL) and p-toluenesulfonic acid monohydrate (8.4 mg) was added, and the mixture was stirred at room temperature for 19 hours.
  • Example 180 In the same manner as in Example 179, the compounds of Example 180 to Example 187 described in Table 7-1 to Table 7-2 were obtained.
  • Example 180 N- [2- (azetidin-1-yl) ethyl] -3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇ benzamide
  • Example 181 N- [2- (3,3-difluoroazetidin-1-yl) ethyl] -3- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4-oxadiazol-3-yl ⁇
  • Example 182 N- [2- (3-Fluoroazetidin-1-yl) ethyl] -3- ⁇ 5- [1-methyl-5-( ⁇ [5- (triflu
  • Example 188 N-acetyl-2- (4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl ] -1,2,4-oxadiazol-3-yl ⁇ phenyl) acetamide 2- (4- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl obtained in Example 1 ] -1,2,4-oxadiazol-3-yl ⁇ phenyl) acetamide (100 mg), acetic anhydride (67 ⁇ L) and pyridine (2.0 mL) were stirred at 85 ° C.
  • Example 189 (4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2, 4-oxadiazol-3-yl ⁇ phenyl) acetonitrile 2- (4- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl obtained in Example 1 ] To a solution of 1,2,4-oxadiazol-3-yl ⁇ phenyl) acetamide (100 mg) in pyridine (2.0 mL) under ice-cooling, phosphorus oxychloride (40 ⁇ L) was added at room temperature.
  • Example 190 2- [4- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl ⁇ -2-oxopyridin-1 (2H) -yl] acetamide 1) 4- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl ⁇ pyridin-2 (1H) -one 1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H- obtained in Preparation Example 4 To a solution of pyrazole-4-carboxylic acid (100 mg) in N, N-dimethylformamide (2.0 mL) was added 1,1
  • N'-hydroxy-2-oxo-1,2-dihydropyridine-4-carboximidamide (62 mg) obtained in Production Example 5 was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and at 110 ° C. for 14 hours. did.
  • the reaction solution was allowed to cool to room temperature, water was added, and the precipitated crystals were collected by filtration. This afford the title compound recrystallized from ethyl acetate (74 mg) as a colorless solid.
  • Example 191 2- [5- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4 -Oxadiazol-3-yl ⁇ -2-oxopyridin-1 (2H) -yl] acetamide Using a method similar to that in Example 190, the title compound was obtained as a colorless solid.
  • Example 192 N- (3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl ⁇ phenyl) sulfuric diamide 1) 3- ⁇ 5- [1-Methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1,2,4- Oxadiazol-3-yl ⁇ aniline 1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazole-4-carboxylic acid obtained in Production Example 4 To a solution of 800 mg) in N, N-dimethylformamide (3.0 mL) was added 1,1′-carbonyldiimidazole (517 mg) at room temperature and stirred for 30 minutes.
  • Triethylamine (319 ⁇ L) and 3- ⁇ 5- [1-methyl-5-( ⁇ [5- (trifluoromethyl) pyridin-2-yl] oxy ⁇ methyl) -1H-pyrazol-4-yl] -1, 2,4-oxadiazol-3-yl ⁇ aniline 159 mg was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 21 hours.
  • a saturated aqueous sodium hydrogen carbonate solution (1.6 mL) and water (1.6 mL) were added to the reaction solution, and the two layers were separated.
  • the organic layer was passed through a phase separator (manufactured by Biotage Corp.), water was removed, and the mixture was concentrated under reduced pressure. Chloroform was added to the residue, trifluoroacetic acid (3.2 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and chloroform (6.4 mL), saturated aqueous sodium hydrogen carbonate solution (3.2 mL), water (6.4 mL) and methanol (3.2 mL) were added to the residue. After separating the two layers, the aqueous layer was extracted with a mixed solvent of chloroform (3.2 mL) -methanol (1.6 mL).
  • 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 resulting precipitate was washed twice by centrifugation 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.
  • 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
  • a compound having 10 ⁇ M or more is represented by D.
  • IC 50 values are exemplified in Table 9.
  • 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 disorders (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 disorders 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.

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  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
  • Addiction (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur un composé représenté par la formule [I] [dans laquelle R1 représente un groupe alkyle ou similaire ; R² représente un atome d'hydrogène similaire ; le noyau A représente un groupe phényle ou similaire ; R3 représente un atome d'hydrogène ou similaire ; R4 représente -CONRaRb ou similaire ; Ra et Rb représentent chacun indépendamment un atome d'hydrogène ou similaire ; Y1 représente -(CH2)n-O- ou -(CH2)m- ; n représente un nombre entier de 1 à 6 ; m représente un nombre entier de 0 à 6 ; Y² représente un groupe hétéroaryle ou similaire ; et Y3 représente un hétéroarylène à cinq chaînons] ou un sel pharmaceutiquement acceptable de celui-ci, qui est un nouveau composé ayant une activité d'antagoniste sur les récepteurs métabotropiques du glutamate (mGlu) du groupe II ou un sel pharmaceutiquement acceptable de celui-ci et qui est approprié pour un agent prophylactique ou thérapeutique pour des maladies dont les troubles de l'humeur (les troubles dépressifs, les troubles bipolaires, etc.), les troubles anxieux (les troubles anxieux généralisés, les troubles paniques, les troubles obsessionnels-compulsifs, les troubles d'anxiété sociale, les troubles de stress post-traumatique, une phobie spécifique, les troubles de stress aigus, etc.), la schizophrénie, la maladie d'Alzheimer, un dysfonctionnement cognitif, la démence, la pharmacodépendance, les convulsions, les tremblements, la douleur et les troubles du sommeil qui contient le composé ou le sel pharmaceutiquement acceptable de celui-ci comme principe actif.
PCT/JP2012/051070 2011-01-21 2012-01-19 Dérivé de pyrazole Ceased WO2012099200A1 (fr)

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WO2013111796A1 (fr) * 2012-01-25 2013-08-01 大正製薬株式会社 Dérivé de pyrazole n-substitué
EP3000814A1 (fr) 2014-09-26 2016-03-30 Domain Therapeutics Pyrazoloquinazolinones et pyrroloquinazolinones substitués en tant que modulateurs allostériques des récepteurs métabotropiques du glutamate du groupe II
WO2016141258A1 (fr) * 2015-03-04 2016-09-09 Medivation Technologies, Inc. Inhibiteurs des protéines de liaison à l'elément de régulation des stérols (srebp)
US10183015B2 (en) 2015-03-04 2019-01-22 Medivation Technologies Llc Heterocyclic compounds and methods of use

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WO2007039439A1 (fr) * 2005-09-27 2007-04-12 F.Hoffmann-La Roche Ag Oxadiazolylpyrazolopyrimidines en tant qu'antagonistes de mglur2
WO2007110337A1 (fr) * 2006-03-29 2007-10-04 F. Hoffmann-La Roche Ag Derives de pyridine et de pyrimidine en tant qu'antagonistes de mglur2
WO2008119689A1 (fr) * 2007-04-02 2008-10-09 F. Hoffmann-La Roche Ag Dérivés de pyridine et de pyrimidine comme antagonistes de mglur2
WO2009078432A1 (fr) * 2007-12-18 2009-06-25 Taisho Pharmaceutical Co., Ltd. Composé 1-alkyl-4-amino-1h-pyrazole-3-carboxamide
WO2010142628A1 (fr) * 2009-06-08 2010-12-16 Merck Serono S.A. Dérivés pyrazoles oxadiazoles en tant qu'agonistes de s1p1
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WO2005040110A1 (fr) * 2003-10-08 2005-05-06 Eli Lilly And Company Composes de pyrrole et pyrazole presentant un effet potentiateur sur les recepteurs du glutamate
WO2007039439A1 (fr) * 2005-09-27 2007-04-12 F.Hoffmann-La Roche Ag Oxadiazolylpyrazolopyrimidines en tant qu'antagonistes de mglur2
WO2007110337A1 (fr) * 2006-03-29 2007-10-04 F. Hoffmann-La Roche Ag Derives de pyridine et de pyrimidine en tant qu'antagonistes de mglur2
WO2008119689A1 (fr) * 2007-04-02 2008-10-09 F. Hoffmann-La Roche Ag Dérivés de pyridine et de pyrimidine comme antagonistes de mglur2
WO2009078432A1 (fr) * 2007-12-18 2009-06-25 Taisho Pharmaceutical Co., Ltd. Composé 1-alkyl-4-amino-1h-pyrazole-3-carboxamide
WO2010142628A1 (fr) * 2009-06-08 2010-12-16 Merck Serono S.A. Dérivés pyrazoles oxadiazoles en tant qu'agonistes de s1p1
WO2012020820A1 (fr) * 2010-08-11 2012-02-16 大正製薬株式会社 Dérivé d'hétéroaryl pyrazole

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013111796A1 (fr) * 2012-01-25 2013-08-01 大正製薬株式会社 Dérivé de pyrazole n-substitué
EP3000814A1 (fr) 2014-09-26 2016-03-30 Domain Therapeutics Pyrazoloquinazolinones et pyrroloquinazolinones substitués en tant que modulateurs allostériques des récepteurs métabotropiques du glutamate du groupe II
WO2016141258A1 (fr) * 2015-03-04 2016-09-09 Medivation Technologies, Inc. Inhibiteurs des protéines de liaison à l'elément de régulation des stérols (srebp)
US10183015B2 (en) 2015-03-04 2019-01-22 Medivation Technologies Llc Heterocyclic compounds and methods of use
US10189826B2 (en) 2015-03-04 2019-01-29 Medivation Technologies Llc Heterocyclic compounds and methods of use

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TW201245187A (en) 2012-11-16

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