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  • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
  • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D213/82—Amides; Imides in position 3
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/84—Nitriles
  • C07D213/85—Nitriles in position 3
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

• the present invention may have an antagonism of N-methyl-D-aspartate (NMDA) receptor containing NR2B subunit, and may prevent depression, bipolar disorder, migraine, pain, peripheral symptoms of dementia or the like.
• NMDA N-methyl-D-aspartate
• the present invention relates to a heterocyclic compound expected to be useful as a therapeutic agent.
• the main excitatory neurotransmitter in the central nervous system such as the brain and spinal cord is glutamate, and its signal transduction is gamma-amino, which is an ion channel-coupled receptor N-methyl-D-aspartate (NMDA) receptor. It is performed by the -3-hydroxy-5-methyloxazole-4-propionic acid (AMPA)/kainic acid (KA) receptor and the metabotropic glutamate receptor.
• AMPA -3-hydroxy-5-methyloxazole-4-propionic acid
• KA kainic acid
• the NMDA receptor is highly permeable to cations such as calcium ions, and mediates excitatory neurotransmission by depolarizing nerve cells.
• the NMDA receptor is a receptor composed of a tetramer in which 2 to 3 subunits of NR1, NR2A, NR2B, NR2C, NR2D, NR3A and NR3B subunits are associated with each other, and is a receptor responsible for excitatory neurotransmission.
• the presence of the NR1 subunit is essential to have the function of.
• the NR1 subunit is contained in all functional NMDA receptors, it is widely distributed in the central nervous system, while the distribution and expression timing of the NR2 subunit differ from subunit to subunit. For example, the NR2A and NR2C subunits are detected only shortly before birth, whereas the NR2B and NR2D subunits are observed from early embryonic times. Further, for example, the NR2A subunit is widely distributed in the brain, whereas the NR2B subunit is localized in the forebrain region and the NR2C subunit is localized in the cerebellum (Non-Patent Document 1).
• the NMDA receptor containing the NR2B subunit targeted in the present invention is highly expressed in the cerebral cortex (particularly layers 2 to 3), hippocampus, amygdala, ventral nucleus of the thalamus, and olfactory bulb in the adult rodent brain. ing. In the spinal cord, it is limited to the dorsal horn of the spinal cord (particularly the second layer) (Non-patent Document 2). In a single cell, the NMDA receptor containing the NR2B subunit is most highly expressed in postsynaptic hypertrophy, and is also expressed in the extrasynaptic region (Non-Patent Document 3). This suggests that the NMDA receptor containing the NR2B subunit has a broad function in the brain and is effective in the prevention and treatment of central diseases.
• Patent Document 1 discloses the following compounds having an antibacterial action and useful as pesticides and the like.
• Patent Document 2 discloses the following compound which has a calcitonin gene-related peptide (CGPR) receptor antagonistic action and is useful for prevention/treatment of migraine, nervous system diseases and the like.
• CGPR calcitonin gene-related peptide
• Patent Document 3 discloses the following compound which has a CGPR receptor antagonistic action and is useful for prevention/treatment of migraine, nervous system diseases and the like.
• Patent Document 4 discloses the following compound having a cell growth inhibitory action and useful for the prevention/treatment of cancer (blood cancer, etc.) and the like.
• Patent Document 5 discloses the following compound having an FXa inhibitory action and useful for suppressing blood coagulation, preventing/treating thrombosis/embolism, and the like.
• Patent Document 6 discloses the following compound having an FXa inhibitory action and useful for antithrombosis and the like.
• Patent Document 7 discloses the following compound having a PPAR agonistic action and useful for improving insulin resistance, preventing and treating diabetes, X syndrome, inflammatory diseases of digestive organs and the like.
• Patent Document 8 discloses the following compounds having a PPAR ⁇ agonistic action and useful for the prevention/treatment of digestive system diseases (ulcerative colitis, Crohn's disease, pancreatitis, gastritis, etc.) and the like.
• Patent Document 9 discloses the following compound having an FXa inhibitory action and useful for antithrombosis and the like.
• Patent Document 10 discloses the following compound having a PPAR inhibitory action and useful for improving insulin resistance, preventing and treating diabetes, syndrome X and the like.
• Patent Document 11 discloses the following compounds having an inhibitor of gestation homolog (EZH) inhibitory action and useful for the prevention/treatment of cancer (including CNS) and the like.
• Patent Document 12 has the following NMDA receptor-specific negative allosteric modulator action containing an NR2B subunit, and is useful for the prevention/treatment of depression, bipolar disorder, migraine, pain, peripheral symptoms of dementia, etc. Compounds are disclosed.
• the object of the present invention is to have an antagonism of NMDA receptor containing NR2B subunit, and to be useful as a preventive or therapeutic agent for depression, bipolar disorder, migraine, pain, peripheral symptoms of dementia and the like. It is intended to provide an expected heterocyclic compound and a medicine containing the same.
• Ring A is (1) C 1-3 alkyl group, (2) C 1-3 haloalkyl group, (3) an optionally substituted cyclic group, (4) an optionally substituted C 1-6 alkoxy group, and (5) a 6-membered aromatic ring further substituted with 1 to 4 substituents selected from halogen atoms;
• R 1 and R 2 each independently represent a C 1-3 alkyl group optionally substituted with a hydrogen atom or a fluorine atom;
• R 3 is (1)
• R 4 is (1) a C 1-3 haloalkyl group, (2) represents a substituent selected from an optionally substituted C 3-7 cycloalkyl group and (3) an optionally substituted C 1-6 alkoxy group, Y represents a nitrogen atom or CR 6 , R 6 represents a hydrogen atom or a halogen atom, Z represents a hydrogen atom or a halogen atom. ), or (2)
• R 5 is (1) a C 1-3 haloalkyl group, (2) represents a substituent selected from an optionally substituted C 3-7 cycloalkyl group and (3) an optionally substituted C 1-6 alkoxy group, Ring B represents a thiophene ring which may be further substituted with one halogen atom. ) Is shown. ]
• the compound or its salt represented by this in this specification, it may abbreviate as "compound (I)").
• Ring A is (1) C 1-3 alkyl group, (2) C 3-10 cycloalkyl group, (3) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (4) a 6-membered aromatic ring further substituted with 1 to 2 substituents selected from halogen atoms.
• R 1 and R 2 are each a hydrogen atom;
• R 3 is (1)
• R 4 is a C 1-3 haloalkyl group or a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms
• Y is a nitrogen atom or CR 6
• R 6 is a hydrogen atom
• Z is a halogen atom or a hydrogen atom.
• R 5 is a C 1-3 haloalkyl group
• Ring B is a thiophene ring which may be further substituted with one halogen atom.
• [3] N-[(5-cyano-2-methoxypyridin-3-yl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide or a salt thereof.
• [4] N-[(3-Cyano-2-fluoro-6-methoxyphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide or a salt thereof.
• [5] A medicine containing the compound or salt thereof according to [1].
• the drug according to [5] which is an NMDA receptor antagonist containing an NR2B subunit.
• a method for antagonizing an NMDA receptor containing an NR2B subunit in a mammal which comprises administering an effective amount of the compound according to [1] or a salt thereof to the mammal.
• [10] Prevention of depression, bipolar disorder, migraine, pain, or peripheral symptoms of dementia in a mammal which comprises administering an effective amount of the compound according to [1] or a salt thereof to the mammal. Or treatment method.
• the present invention is expected to be useful as an agent for preventing or treating depression, bipolar disorder, migraine headache, pain, peripheral symptoms of dementia, etc., which may have an NMDA receptor antagonism including NR2B subunit.
• a heterocyclic compound and a pharmaceutical containing the same are provided.
• each substituent has the following definition.
• examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
• examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl.
• Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Fluoropentyl, hexyl and 6,6,6-trifluorohexyl are mentioned.
• examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and 3- Methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl can be mentioned.
• examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
• examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2. 2] octyl, bicyclo [3.2.1] octyl and adamantyl.
• the "optionally halogenated C 3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 3- And 10 cycloalkyl groups.
• examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• examples of the “C 3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
• examples of the “C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.
• examples of the “C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl.
• examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy.
• the "optionally halogenated C 1-6 alkoxy group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkoxy group is mentioned.
• Examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl.
• Examples include oxy and hexyloxy.
• examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
• examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
• the "optionally halogenated C 1-6 alkylthio group optionally" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkylthio group is mentioned.
• examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.
• examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Examples include dimethylpropanoyl, hexanoyl, and heptanoyl.
• the “optionally halogenated C 1-6 alkyl-carbonyl group” is, for example, C 1 optionally having 1 to 7, preferably 1 to 5 halogen atoms.
• -6 alkyl-carbonyl group can be mentioned.
• Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
• examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples include pentyloxycarbonyl and hexyloxycarbonyl.
• examples of the “C 6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
• examples of the “C 7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
• examples of the “5- to 14-membered aromatic heterocyclic carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
• examples of the “3- to 14-membered non-aromatic heterocyclic carbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.
• examples of the “mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.
• examples of the “mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
• examples of the “C 1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
• the "optionally halogenated C 1-6 alkylsulfonyl group” is, for example, C 1 -which may have 1 to 7, preferably 1 to 5 halogen atoms. 6 alkyl sulfonyl group is mentioned.
• examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.
• examples of the “C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
• examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and a substituted group.
• examples of the “hydrocarbon group” include, for example, a C 1-6 alkyl group, a C 2-6 alkenyl group, Examples thereof include a C 2-6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group and a C 7-16 aralkyl group.
• examples of the “hydrocarbon group which may be substituted” include a hydrocarbon group which may have a substituent selected from the following substituent group A.
• substituent Group A (1) halogen atom, (2) nitro group, (3) cyano group, (4) oxo group, (5) hydroxy group, (6) an optionally halogenated C 1-6 alkoxy group, (7) C 6-14 aryloxy group (eg, phenoxy, naphthoxy), (8) C 7-16 aralkyloxy group (eg, benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), (10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy), (11) C 1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy), (12) C 6-14 aryl-carbonyloxy group (
• heterocyclic group includes, as ring-constituting atoms, nitrogen atom, sulfur atom, and (I) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7-10 membered hetero bridged ring group, each containing 1 to 4 heteroatoms selected from oxygen atoms. ..
• examples of the “aromatic heterocyclic group” include, as ring-constituting atoms, a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms. And a 5 to 14-membered (preferably 5 to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms.
• aromatic heterocyclic group examples include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1
• a 5- to 6-membered monocyclic aromatic heterocyclic group such as 3,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyr
• non-aromatic heterocyclic group examples include, for example, nitrogen atoms, sulfur atoms and oxygen atoms other than carbon atoms as ring-constituting atoms.
• non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from Preferable examples of the “non-aromatic heterocyclic group” include aziridinyl, oxiranyl, thiyanyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, di
• preferred examples of the “7 to 10-membered heterobridged ring group” include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.
• examples of the “nitrogen-containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom.
• examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the above-mentioned substituent group A.
• the number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
• acyl group is, for example, 1 selected from “halogen atom, optionally halogenated C 1-6 alkoxy group, hydroxy group, nitro group, cyano group, amino group and carbamoyl group”.
• C 1-6 alkyl group C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aryl which may each have 3 to 3 substituents.
• Group C 7-16 aralkyl group, 5 to 14-membered aromatic heterocyclic group and 1 to 2 substituents selected from 3 to 14-membered non-aromatic heterocyclic group, respectively, formyl
• substituents selected from 3 to 14-membered non-aromatic heterocyclic group, respectively, formyl
• examples thereof include groups, carboxy groups, carbamoyl groups, thiocarbamoyl groups, sulfino groups, sulfo groups, sulfamoyl groups and phosphono groups.
• examples of the “acyl group” also include a hydrocarbon-sulfonyl group, a heterocycle-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocycle-sulfinyl group.
• the hydrocarbon-sulfonyl group means a sulfonyl group to which a hydrocarbon group is bound
• the heterocyclic-sulfonyl group means a sulfonyl group to which a heterocyclic group is bound
• the hydrocarbon-sulfinyl group means a hydrocarbon group
• the heterocyclic-sulfinyl group means a sulfinyl group to which a heterocyclic group is bonded.
• acyl group examples include formyl group, carboxy group, C 1-6 alkyl-carbonyl group, C 2-6 alkenyl-carbonyl group (eg, crotonoyl), C 3-10 cycloalkyl-carbonyl group ( Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl group, C 7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl , Naphthyloxycarbonyl
• the “optionally substituted amino group” is, for example, “a C 1-6 alkyl group, each of which may have 1 to 3 substituents selected from the substituent group A”. , C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Or a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 7-16 aralkyl-carbamoyl group, a C 1-6 alkylsulfonyl group
• the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6 alkyl)amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenylamino group (eg, diallylamino), mono- or di-C 3-10 cycloalkylamino group (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 arylamino group (eg, phenylamino), mono- or di-C 7-16 aralkylamino group (eg, benzylamino, dibenzylamino), Mono- or di-(optionally halogenated C 1-6 alkyl)-carbonylamino group (eg acetylamino,
• a 5- to 14-membered aromatic heterocyclic amino group eg, pyridylamino
• carbamoylamino group (mono- or di-C 1-6 alkyl-carbamoyl)amino group (eg, methylcarbamoylamino), (Mono- or di-C 7-16 aralkyl-carbamoyl)amino group (eg, benzylcarbamoylamino), C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino), C 6-14 arylsulfonyl Amino group (eg, phenylsulfonylamino), (C 1-6 alkyl)(C 1-6 alkyl-carbonyl)amino group (eg, N-acetyl-N-methylamino), (C 1-6 al
• examples of the “optionally substituted carbamoyl group” include, for example, “a C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A”. , C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5 to 14 membered aromatic heterocyclic carbonyl group, 3 to 14 membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5 to 14 membered aromatic heterocyclic group, carbamoyl Group, a mono- or di-C 1-6 alkyl-carbamoyl group and a mono- or di-C 7-16 aralkyl-carbamoyl group, which may have one or two substituents.
• Preferred examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (eg, diallylcarbamoyl ), a mono- or di-C 3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C 6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), a mono- or Di-C 7-16 aralkyl-carbamoyl group, mono- or di-C 1-6 alkyl-carbonyl-carbamoyl group (eg, acetylcarbamoyl, propionylcarbamoyl), mono-
• the “optionally substituted thiocarbamoyl group” is, for example, “C 1-6 alkyl optionally having 1 to 3 substituents selected from the substituent group A”.
• thiocarbamoyl group examples include a thiocarbamoyl group, a mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio).
• the “optionally substituted sulfamoyl group” is, for example, “a C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A”. , C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5 to 14 membered aromatic heterocyclic carbonyl group, 3 to 14 membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5 to 14 membered aromatic heterocyclic group, carbamoyl Group, a mono- or di-C 1-6 alkyl-carbamoyl group and a mono- or di-C 7-16 aralkyl-carbamoyl group, which may have one or two substituents”.
• Suitable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C 1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl Sulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 alkenyl-sulfamoyl group (eg, diallylsulfamoyl), mono- or di-C 3-10 cycloalkyl- Sulfamoyl group (eg, cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 aryl-sulfamoyl group (eg, phenylsulfamoyl), mono- or
• the “optionally substituted hydroxy group” is, for example, “a C 1-6 alkyl group which may each have 1 to 3 substituents selected from the substituent group A”. , C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5 to 14 membered aromatic heterocyclic carbonyl group, 3 to 14 membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5 to 14 membered aromatic heterocyclic group, carbamoyl Group, a substituent selected from a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 7-16 aralkyl-carbamoyl group, a C 1-6 alkylsulfon
• Preferred examples of the optionally substituted hydroxy group include a hydroxy group, a C 1-6 alkoxy group, a C 2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy.
• a C 3-10 cycloalkyloxy group eg, cyclohexyloxy
• a C 6-14 aryloxy group eg, phenoxy, naphthyloxy
• a C 7-16 aralkyloxy group eg, benzyloxy, phenethyloxy
• C 1-6 alkyl-carbonyloxy group eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
• C 6-14 aryl-carbonyloxy group eg, benzoyloxy
• C 7-16 aralkyl- Carbonyloxy group eg, benzylcarbonyloxy
• 5- to 14-membered aromatic heterocyclic carbonyloxy group eg, nicotinoyloxy
• 3- to 14-membered non-aromatic heterocyclic carbonyloxy group eg, piperidinylcarbonyloxy
• the "optionally substituted sulfanyl group” is, for example, "a C 1-6 alkyl group which may each have 1 to 3 substituents selected from the substituent group A. , C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group which may have a substituent selected from a 14-membered aromatic heterocyclic group and a halogenated sulfanyl group.
• Preferred examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6 alkylthio group, a C 2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 cycloalkylthio group (eg, cyclohexylthio), C 6-14 arylthio group (eg, phenylthio, naphthylthio), C 7-16 aralkylthio group (eg, benzylthio, phenethylthio), C 1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 aryl-carbonylthio group (eg, benzoylthio),
• the “optionally substituted silyl group” is, for example, “a C 1-6 alkyl group, each of which may have 1 to 3 substituents selected from the substituent group A”.
• Suitable examples of the optionally substituted silyl group include a tri-C 1-6 alkylsilyl group (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).
• examples of the “hydrocarbon ring” include C 6-14 aromatic hydrocarbon ring, C 3-10 cycloalkane and C 3-10 cycloalkene.
• examples of the “C 6-14 aromatic hydrocarbon ring” include benzene and naphthalene.
• examples of the “C 3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
• examples of the “C 3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
• examples of the “heterocycle” include aromatic heterocycles each containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms as ring-constituting atoms, A non-aromatic heterocycle is mentioned.
• the “aromatic heterocycle” is, for example, a 5 to 14-membered ring containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms as ring-constituting atoms ( Preferred is an aromatic heterocycle having 5 to 10 members).
• Preferred examples of the “aromatic heterocycle” include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiene.
• 5- to 6-membered monocyclic aromatic heterocycles such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, Imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3
• non-aromatic heterocycle is, for example, a 3 to 14-membered ring-containing atom, which contains 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom. (Preferably 4- to 10-membered) non-aromatic heterocycles are mentioned.
• non-aromatic heterocycle examples include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline.
• examples of the “C 1-3 alkyl group” include the above “C 1-6 alkyl group” having 1 to 3 carbon atoms.
• examples of the “C 1-3 haloalkyl group” include the above-mentioned “C 1-3 alkyl group” having 1 to 7, preferably 1 to 5 of the above “halogen atom”.
• examples of the “C 3-7 cycloalkyl group” include the above “C 3-10 cycloalkyl group” having 3 to 7 carbon atoms.
• examples of the “cyclic group” include the above-mentioned “C 3-10 cycloalkyl group”, “C 3-10 cycloalkenyl group”, “C 6-14 aryl group” and “heterocyclic group”. ..
• examples of the “6-membered aromatic ring” include a benzene ring and 6-membered aromatic rings described above.
• Ring A is (1) C 1-3 alkyl group, (2) C 1-3 haloalkyl group, (3) an optionally substituted cyclic group, (4) An optionally substituted C 1-6 alkoxy group, and (5) a 6-membered aromatic ring further substituted with 1 to 4 substituents selected from halogen atoms.
• a benzene ring and a pyridine ring are preferable.
• a C 3-10 cycloalkyl group eg, cyclopropyl
• the “cyclic group” may have 1 to 3 substituents selected from the substituent group A described above.
• a halogen atom eg, fluorine atom
• C 1-6 alkoxy group of the "optionally substituted C 1-6 alkoxy group” have the 1 to 3 substituents selected from Substituent Group A described above You may have.
• a halogen atom eg, fluorine atom
• Ring A is preferably (1) C 1-3 alkyl group (eg, methyl), (2) an optionally substituted cyclic group (eg, C 3-10 cycloalkyl group (eg, cyclopropyl)), (3) optionally substituted C 1-6 alkoxy group (eg, methoxy, ethoxy), and (4) halogen atom (eg, fluorine atom, bromine atom)
• cyclic group eg, C 3-10 cycloalkyl group (eg, cyclopropyl)
• C 1-6 alkoxy group eg, methoxy, ethoxy
• halogen atom eg, fluorine atom, bromine
• a 6-membered aromatic ring eg, benzene ring, pyridine ring
• 1 to 3 substituents selected from at least one of the substituents on the 6-membered aromatic ring is preferably located in the para position with respect to the cyano group on ring A.
• R 1 and R 2 each independently represent a C 1-3 alkyl group optionally substituted with a hydrogen atom or a fluorine atom.
• R 1 and R 2 are preferably each a hydrogen atom.
• R 3 is (1)
• R 4 is (1) a C 1-3 haloalkyl group, (2) represents a substituent selected from an optionally substituted C 3-7 cycloalkyl group and (3) an optionally substituted C 1-6 alkoxy group, Y represents a nitrogen atom or CR 6 , R 6 represents a hydrogen atom or a halogen atom, Z represents a hydrogen atom or a halogen atom. ), or (2)
• R 5 is (1) a C 1-3 haloalkyl group, (2) represents a substituent selected from an optionally substituted C 3-7 cycloalkyl group and (3) an optionally substituted C 1-6 alkoxy group, Ring B represents a thiophene ring which may be further substituted with one halogen atom. ) Is shown.
• C 3-7 cycloalkyl group in the "which may C 3-7 cycloalkyl group optionally substituted", have a 1 to 3 substituents selected from the aforementioned substituent group A You may have.
• a halogen atom eg, fluorine atom
• C 1-6 alkoxy group in the "optionally substituted C 1-6 alkoxy group” represented by R 4, have 1 to 3 substituents selected from the aforementioned substituent group A May be.
• a halogen atom eg, fluorine atom
• R 4 is preferably an optionally substituted C 1-6 alkoxy group (eg, methoxy), more preferably 1 to 3 halogen atoms (eg, fluorine atom).
• Another preferable embodiment of R 4 is a C 1-3 haloalkyl group (eg, trifluoromethyl) or a C 1-6 alkoxy group (which may be substituted with 1 to 3 halogen atoms (eg, fluorine atom) ( (Eg, methoxy).
• Y is preferably a nitrogen atom.
• R 6 is preferably a hydrogen atom.
• Z is preferably a halogen atom, and more preferably a fluorine atom.
• the “C 3-7 cycloalkyl group” in the “ optionally substituted C 3-7 cycloalkyl group” for R 5 has 1 to 3 substituents selected from the above-mentioned substituent group A. You may have. As such a “substituent”, a halogen atom (eg, fluorine atom) is preferable.
• R "C 1-6 alkoxy group” in the "optionally substituted C 1-6 alkoxy group” represented by 5, to 1 selected from substituent group A described above has a three substituents May be. As such a “substituent”, a halogen atom (eg, fluorine atom) is preferable.
• R 5 is preferably a C 1-3 haloalkyl group (eg, difluoromethyl, trifluoromethyl).
• Ring B is preferably a thiophene ring further substituted with one halogen atom (eg, fluorine atom).
• R 3 is preferably
• R 4 is a C 1-3 haloalkyl group (eg, trifluoromethyl) or an optionally substituted C 1-6 alkoxy group (eg, methoxy)
• Y is a nitrogen atom or CR 6
• R 6 is a hydrogen atom or a halogen atom (eg, a fluorine atom)
• Z is a hydrogen atom or a halogen atom (eg, a fluorine atom).
• R 4 is a C 1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), Y is a nitrogen atom, Z is a halogen atom (eg, fluorine atom).
• R 3 Another preferred embodiment of R 3 is
• R 4 is a C 1-3 haloalkyl group (eg, trifluoromethyl) or a C 1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom).
• Y is CR 6
• One of R 6 and Z is a halogen atom (eg, a fluorine atom), and the other is a hydrogen atom. ).
• Ring A is (1) C 1-3 alkyl group (eg, methyl), (2) an optionally substituted cyclic group (eg, C 3-10 cycloalkyl group (eg, cyclopropyl)), (3) optionally substituted C 1-6 alkoxy group (eg, methoxy, ethoxy), and (4) halogen atom (eg, fluorine atom, bromine atom)
• R 1 and R 2 are each a hydrogen atom;
• R 3 is (1)
• R 4 is a C 1-3 haloalkyl group (eg, trifluoromethyl) or an optionally substituted C 1-6 alkoxy group (eg, methoxy), Y is a nitrogen atom or CR 6 , R 6 is a hydrogen atom or a halogen atom (eg, a fluorine atom), Z is a hydrogen atom or a halogen atom (eg, fluorine atom) Is. ); or (2)
• R 5 is a C 1-3 haloalkyl group (eg, difluoromethyl, trifluoromethyl), Ring B is a thiophene ring which may be further substituted with one halogen atom (eg, fluorine). ) Is; Compound (I).
• Ring A is (1) C 1-3 alkyl group (eg, methyl), (2) C 3-10 cycloalkyl group (eg, cyclopropyl), (3) C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom), and (4) halogen atom (eg, fluorine atom, bromine).
• a 6-membered aromatic ring eg, benzene ring, pyridine ring
• R 1 and R 2 are each a hydrogen atom
• R 3 is (1)
• R 4 is a C 1-3 haloalkyl group (eg, trifluoromethyl) or a C 1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom).
• Y is a nitrogen atom or CR 6
• R 6 is a hydrogen atom
• Z is a hydrogen atom or a halogen atom (eg, a fluorine atom).
• R 5 is a C 1-3 haloalkyl group (eg, difluoromethyl, trifluoromethyl), Ring B is a thiophene ring which may be further substituted with one halogen atom (eg, fluorine). ) Is; Compound (I).
• R 4 is a C 1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), Y is a nitrogen atom, Z is a halogen atom (eg, fluorine atom). ) Is; [Compound I-2] above.
• R 4 is a C 1-3 haloalkyl group (eg, trifluoromethyl) or a C 1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom).
• Y is CR 6
• R 6 is a hydrogen atom
• Z is a hydrogen atom or a halogen atom (eg, a fluorine atom).
• Ring A is (1) a C 1-6 alkoxy group (eg, methoxy), and (2) a benzene ring or a pyridine ring further substituted with 1 or 2 substituents selected from a fluorine atom; R 1 and R 2 are each a hydrogen atom; R 3 is (1)
• R 4 is a C 1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), Y is a nitrogen atom, Z is a fluorine atom. ) Is; Compound (I).
• Specific examples of the compound (I) include the compounds of Examples 1 to 30 described later.
• the salt of the compound represented by the formula (I) is preferably a pharmacologically acceptable salt, and examples of such a salt include salts with an inorganic base, salts with an organic base and inorganic acids. Examples thereof include salts, salts with organic acids, and salts with basic or acidic amino acids.
• salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; ammonium salts.
• Suitable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, Examples thereof include salts with dicyclohexylamine and N,N-dibenzylethylenediamine.
• salts with inorganic acids include salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid and phosphoric acid.
• salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid. , A salt of p-toluenesulfonic acid.
• salts with basic amino acids include salts with arginine, lysine and ornithine.
• salts with acidic amino acids include salts with aspartic acid and glutamic acid.
• the compound (I) may be used as a prodrug.
• the prodrug of compound (I) is a compound which is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, a compound (I) which is enzymatically oxidized, reduced or hydrolyzed. And a compound which is converted to the compound (I) by being hydrolyzed by gastric acid or the like.
• a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated eg, amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo- 1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated compounds
• a compound in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated eg, hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated
• Alanylated or dimethylaminomethylcarbonylated compound Compound (I) having
• the prodrug of compound (I) is a compound which is changed to compound (I) under physiological conditions as described in Hirokawa Shoten 1990 "Development of Pharmaceuticals” Vol. 7, Molecular Design, pages 163 to 198. May be
• the prodrug may form a salt, and examples of such a salt include those exemplified as the salt of the compound represented by the above formula (I).
• the compound (I) may be labeled with an isotope (eg, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) and the like.
• Compound (I) labeled or substituted with an isotope can be used as, for example, a tracer (PET tracer) used in Positron Emission Tomography (PET), and can be useful in fields such as medical diagnosis. ..
• PET tracer Positron Emission Tomography
• the compound (I) may be a hydrate, a non-hydrate, a non-solvate or a solvate.
• a deuterium converter obtained by converting 1 H into 2 H(D) is also included in the compound (I).
• compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt.
• co-crystal or co-crystal salt means two or more unique at room temperature each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability).
• the co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.
• the compound (I) or a prodrug thereof may be used as it is or in a mixture with a pharmacologically acceptable carrier or the like to prepare a pharmaceutical composition (in the present specification, " It may be abbreviated as "medicament of the present invention"), whereby various diseases described below are applied to mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey). It can be used as a preventive or therapeutic agent.
• various organic or inorganic carrier substances conventionally used as a formulation material can be used, and an excipient, a lubricant, a binder, a disintegrant in a solid formulation; a solvent in a liquid formulation, a dissolution agent It may be added as an auxiliary agent, a suspending agent, an isotonicity agent, a buffering agent, a soothing agent and the like. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents, sweeteners and the like can be used.
• excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light
• excipients include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.
• Suitable examples of lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.
• binder examples include pregelatinized starch, sucrose, gelatin, acacia, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxy.
• examples include propylmethyl cellulose and polyvinylpyrrolidone.
• Suitable examples of disintegrating agents include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
• Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil.
• solubilizing agent examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate.
• solubilizing agent examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate.
• the suspending agent include stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, and other surfactants; polyvinyl alcohol, polyvinylpyrrolidone. , Hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose; polysorbates and polyoxyethylene hydrogenated castor oil.
• Suitable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
• buffer solutions of phosphate, acetate, carbonate, citrate and the like Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
• a preferred example of the soothing agent is benzyl alcohol.
• preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
• antioxidant include sulfite and ascorbate.
• colorants include water-soluble food tar dyes (eg, food red Nos. 2 and 3, food yellows No. 4 and 5, food blue Nos. 1 and 2, etc.), water-insoluble lake dyes. (Eg, the aluminum salt of the water-soluble edible tar pigment) and natural pigments (eg, ⁇ -carotene, chlorophyll, red iron oxide).
• water-soluble food tar dyes eg, food red Nos. 2 and 3, food yellows No. 4 and 5, food blue Nos. 1 and 2, etc.
• water-insoluble lake dyes eg, the aluminum salt of the water-soluble edible tar pigment
• natural pigments eg, ⁇ -carotene, chlorophyll, red iron oxide
• sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
• the pharmaceutical dosage form of the present invention includes, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, Oral preparations (including microcapsules), troches, syrups, solutions, emulsions, suspensions, aerosols, films (eg, orally disintegrating films, oral mucosa sticking films); and injections (eg, Subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip, external preparation (eg, transdermal preparation, ointment, lotion, patch), suppository (eg, rectal) Suppositories, vaginal suppositories), pellets, nasal agents, pulmonary agents (inhalants), and parenteral agents such as eye drops.
• tablets including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
• pills including sugar-co
• the compound of the present invention and the medicament of the present invention are orally or parenterally (eg, intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, vaginal, abdominal cavity). Internal, intratumoral, proximal to tumor, etc. and direct to the lesion).
• compositions may be controlled release preparations (eg, sustained release microcapsules) such as immediate release preparations or sustained release preparations.
• the drug of the present invention can be produced by a method conventionally used in the field of formulation technology, for example, the method described in the Japanese Pharmacopoeia.
• the content of the compound of the present invention in the medicament of the present invention varies depending on the dosage form, dose of the compound of the present invention and the like, but may be, for example, about 0.1 to 100% by weight.
• coating When manufacturing an oral preparation, coating may be carried out, if necessary, for the purpose of taste masking, enteric coating or sustainability.
• coating bases used for coating include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases.
• Sucrose is used as the sugar coating base, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, and carnauba wax may be used in combination.
• water-soluble film coating base examples include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name) ], synthetic polymers such as polyvinylpyrrolidone; and polysaccharides such as pullulan.
• cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose
• synthetic polymers such as polyvinylpyrrolidone
• polysaccharides such as pullulan.
• enteric film coating bases include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ], acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)] and methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as shellac.
• cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
• methacrylic acid copolymer L Eudragit L (trade name)
• acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)]
• sustained-release film coating base examples include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] and the like acrylic acid-based polymers.
• cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] and the like acrylic acid-based polymers.
• the above-mentioned coating base may be used as a mixture of two or more kinds thereof at an appropriate ratio. Further, at the time of coating, a light shielding agent such as titanium oxide or iron sesquioxide may be used.
• the compound of the present invention has antagonism of NMDA receptor containing NR2B subunit.
• the antagonism of the NMDA receptor containing the NR2B subunit is confirmed, for example, by the inhibitory effect of the activation of the receptor (for example, intracellular calcium ion (Ca 2+ ) influx by glutamate).
• the NMDA receptor containing the NR2B subunit contains one NR2B subunit, and further contains three subunits of 2 or 3 kinds selected from NR1, NR2A, NR2B, NR2C, NR2D, NR3A and NR3B. It is a receptor composed of four subunits.
• the NMDA receptor containing an NR2B subunit is preferably a heterodimer of NR1 and NR2B, and four heterodimers of one subunit selected from NR2A, NR2B, NR2C and NR2D and a heterodimer of NR1. It is a receptor composed of subunits.
• the NMDA receptor containing the NR2B subunit is more preferably a receptor composed of four subunits consisting of two sets of heterodimers of NR1 and NR2B.
• the compound of the present invention has low toxicity (eg, cardiotoxicity, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, lung toxicity, carcinogenicity) and side effects (eg, psychotomimetic side effect). It can be used as a preventive or therapeutic agent for various diseases or a diagnostic agent for mammals.
• the compound of the present invention has low mutagenicity in the Ames test (Ames test) and is expected to have low hERG (human Ether-a-go-go Related Gene) inhibitory action.
• the compound of the present invention is expected to be excellent in stability against conjugation metabolism due to less extracorporeal excretion via the BCRP (Breath Cancer Resistance Protein) transporter.
• the compound of the present invention can be used as a prophylactic or therapeutic agent for central and peripheral diseases.
• the compound of the present invention is, for example, (1) Mental disorders [eg, major depression (including intractable major depression, treatment-resistant depression), minor depressive disorder, bipolar depression, recurrent depression, postpartum depression, stress disorder] , Major depressive disorder with psychosis (including delusional disorder and schizophrenia), manic or mixed mood episodes, hypomanic mood episodes, depressive episodes with atypical features, depressive episodes with depressive features , Depressive episodes with tonic features, Depressive episodes after stroke (abbreviated as "depression” in the present specification), dysthymia, affective disorder (seasonal affective disorder, etc.) , Delirium, peripheral dementia symptoms (psychiatric symptoms or behavior abnormalities), anxiety, generalized anxiety disorder, anxiety syndrome, mood disorder, mood circulation disorder, premenstrual dysphoric disorder, panic disorder, phobia, social phobia, Social anxiety disorder, obsessive-compulsive disorder, post-traumatic
• the compound of the present invention is useful for preventing or treating depression (including major depression, intractable major depression, treatment-resistant depression, etc.), bipolar disorder, migraine, pain, or peripheral symptoms of dementia. possible.
• Major depression and bipolar disorder are both classified as mood disorders, and are a disease that presents with depression or depression and mania over a long period of time.
• ketamine, an NMDA receptor antagonist rapidly and persistently improves depressive symptoms associated with major depression and bipolar disorder [Therapeutic Advances in Psycho Pharmacology (Ther. Adv. Psychopharmacol.) Vol. 4, pp. 75-99, 2014].
• CP-101 and 606 which are NMDA receptor antagonists containing NR2B subunit, significantly improves treatment-resistant depressive symptoms [Journal of Clinical Psychopharmacology ( J. Clin. Psychopharmacol.) 28, 631-637, 2008]. Therefore, the compound of the present invention is promising as a prophylactic or therapeutic drug for treatment-resistant depression.
• ⁇ Migraine is a chronic, paroxysmal, primary headache.
• the onset mechanism is unknown, but it is thought to occur in association with abnormalities in central nervous system processing and abnormalities in the trigeminal vascular system.
• attention has been paid to the cortical spreading depletion phenomenon.
• CP-101, 606 and Ro25-6981 which are NMDA receptor antagonists containing the NR2B subunit, caused the occurrence frequency and depth of the spread inhibition of cortex. It has been reported to be suppressed [The Journal of Pharmacology and Experimental Therapeutics (J. Pharmacol. Exp. Ther.) 321, 564-572, 2007]. Therefore, the compound of the present invention is promising as a prophylactic or therapeutic drug for migraine.
• Pain is classified into acute pain that lasts for a relatively short period of time and chronic pain that persists or relapses for 3 months or more, persists for 1 month or more after recovery of acute tissue damage, or is accompanied by unhealed lesions.
• the NMDA receptor containing the NR2B subunit is highly expressed in the dorsal horn of the spinal cord, which plays an important role in pain reception, and it has been suggested that its function control can control pain.
• the pain threshold is increased by a genetic modification that causes a functional decline of the NR2B subunit [European Journal of Neuroscience (Eur. J. Neurosci.) 32, 798-810, 2010.
• the compound of the present invention is promising as a drug for preventing or treating pain.
• Dementia is a chronic, general, and usually irreversible cognitive decline. Although the quality of life of patients is significantly reduced due to cognitive decline, peripheral symptoms of dementia (psychological symptoms or behavioral abnormalities) are also considered to be a major factor in the deterioration of quality of life of patients and their caregivers. ing. Although no effective therapeutic intervention for peripheral dementia has been established, it has been reported that administration of memantine, an NMDA receptor antagonist, partially improves peripheral dementia [The Annuls of Pharma]. Cotherapy (Ann. Pharmacother.) Volume 42, pages 32-38, 2007].
• NMDA receptors containing NR2B subunits are widely distributed in the brain excluding the cerebellum, but peripheral dementia symptoms have been reported to be associated with white matter abnormalities in brain regions excluding the cerebellum [Journal of the Neurological Sciences (J. Neurol. Sci.) 337, 162-166, 2014]. Therefore, the compound of the present invention is promising as a preventive or therapeutic drug for peripheral symptoms of dementia.
• the dose of the compound of the present invention may vary depending on the administration subject, administration route, target disease, symptom and the like.
• a single dose is usually about 0.01 to 100 mg. /Kg body weight, preferably 0.1 to 50 mg/kg body weight, more preferably 0.5 to 20 mg/kg body weight, and this amount can be administered once to three times a day.
• the compound of the present invention can be used in combination with other active ingredients (hereinafter abbreviated as concomitant drug).
• concomitant drug include the following. Acetylcholinesterase inhibitors (eg donepezil, rivastigmine, galantamine, zanapezil), nootropics (eg memantine), ⁇ -amyloid protein production, secretion, accumulation, aggregation and/or deposition inhibitors, ⁇ -secretase inhibitors (eg, 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6- (4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4
• Parkinson's disease therapeutic agent [(eg, dopamine receptor agonist (eg, L-dopa, bromocriptine, pergolide, talipexol, pramipexole, cabergoline, amantadine) , Monoamine oxidase (MAO) inhibitors (eg deprenyl, sergiline (selegiline), remasemide, riluzole), anticholinergics (eg trihexif) Enidil, biperiden), COMT inhibitors (eg, entacapone)], amyotrophic lateral sclerosis therapeutic agents (eg, riluzole, etc., neurotrophic factors), therapeutic agents for abnormal behavior, wandering, etc.
• dopamine receptor agonist eg, L-dopa, bromocriptine, pergolide, talipexol, pramipexole, cabergoline, amantadine
• MAO Monoamine oxida
• dementia progression Eg, sedatives, anxiolytics, apoptosis inhibitors (eg, CPI-1189, IDN-6556, CEP-1347), neural differentiation/regeneration promoters (eg, leteprinim, xaliproden; SR-57746-A) , SB-216763, Y-128, VX-853, prostide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro -1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1- Benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofur
• the concomitant drug may be used in combination of two or more kinds at an appropriate ratio.
• the compound of the present invention when it is applied to each of the above diseases, it can be used in combination with a biologic (eg, antibody drug, nucleic acid or nucleic acid derivative, aptamer drug, vaccine formulation), and also with a gene therapy method or the like. It is also possible to use in combination, or in combination with a therapeutic method in the psychiatric field where no drug is used.
• Therapeutic methods in the psychiatric area that do not use drugs include modified electroconvulsive therapy, deep brain stimulation therapy, repeated transcranial magnetic stimulation therapy, and psychotherapy including cognitive behavior therapy.
• the compound of the present invention is used for various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, and blood vessel regeneration, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells), and artificial organs utilizing tissue engineering ( (Eg, artificial blood vessel, cardiomyocyte sheet).
• organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, and blood vessel regeneration, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells), and artificial organs utilizing tissue engineering (Eg, artificial blood vessel, cardiomyocyte sheet).
• the dose can be reduced as compared with the case where the compound of the present invention or the concomitant drug is administered alone.
• a drug to be used in combination with the compound of the present invention can be selected according to the symptom of the patient (mild, severe, etc.), (3) The treatment period can be set longer by selecting a concomitant drug having a different mechanism of action from the compound of the present invention.
• the therapeutic effect can be sustained.
• excellent effects such as a synergistic effect can be obtained.
• the combined use of the compound of the present invention and the concomitant drug is referred to as the “combination agent of the present invention”.
• the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof are simultaneously administered to an administration subject (
• the compound of the present invention and the concomitant drug may be administered in a single preparation or in separate preparations), or may be administered with a time lag. In the case of administration with a time lag, the compound of the present invention and the concomitant drug may be administered in any order.
• the compound of the present invention may be administered after the concomitant drug is continuously administered for a certain period of time.
• the dose of the concomitant drug may be similar to the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
• the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
• the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
• the raw materials and reagents used in each step of the following production methods, and the obtained compounds may form salts.
• Examples of such salts include the same salts as the above-mentioned salts of the compound of the present invention.
• the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se.
• the compound obtained in each step is a salt, it can be converted to a free form or other desired salt by a method known per se.
• the compound obtained in each step can be used as the reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step can be concentrated from the reaction mixture according to a conventional method. It can be isolated and/or purified by a separation means such as crystallization, recrystallization, distillation, solvent extraction, fractional distillation and chromatography.
• the commercially available product can be used as it is.
• the reaction time may differ depending on the reagent and solvent to be used, but unless otherwise specified, it is generally 1 minute to 48 hours, preferably 10 minutes to 8 hours.
• the reaction temperature may differ depending on the reagent or solvent to be used, but unless otherwise specified, it is usually ⁇ 78° C. to 300° C., preferably ⁇ 78° C. to 150° C.
• the pressure may differ depending on the reagent or solvent to be used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.
• a Microwave synthesizer such as Initiator manufactured by Biotage may be used.
• the reaction temperature may vary depending on the reagents and solvents used, but unless otherwise specified, it is generally room temperature to 300°C, preferably 50°C to 250°C.
• the reaction time may vary depending on the reagents and solvents to be used, but unless otherwise specified, it is generally 1 minute to 48 hours, preferably 1 minute to 8 hours.
• a reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate, unless otherwise specified.
• the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate.
• the reagent also serves as the reaction solvent, the amount of the solvent used is the reagent.
• these reactions are carried out without solvent or by dissolving or suspending in a suitable solvent.
• the solvent include the solvents described in the examples or the following.
• Alcohols methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.
• Ethers diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.
• Aromatic hydrocarbons chlorobenzene, toluene, xylene, etc.
• Saturated hydrocarbons cyclohexane, hexane, etc.
• Amides N,N-dimethylformamide, N-methylpyrrolidone, etc.
• Halogenated hydrocarbons dichloromethane, carbon tetrachloride, etc.
• Nitriles acetonitrile, etc.
• Sulfoxides dimethyl sulfoxide, etc.
• Aromatic organic bases such as
• Inorganic bases sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate, etc.
• Organic bases triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]- 7-undecene, imidazole, piperidine, etc.
• metal alkoxides sodium ethoxide, potassium tert-butoxide, etc.
• Alkali metal hydrides sodium hydride, etc.
• Metal amides sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.
• Organic lithiums n-butyl lithium, etc.
• an acid or acidic catalyst is used in the reaction of each step, for example, the acid or acidic catalyst shown below, or the acid or acidic catalyst described in the examples is used.
• Inorganic acids hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.
• Organic acids acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.
• Lewis acid boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.
• reaction in each step is a method known per se, for example, 5th Edition Experimental Chemistry Course, 13 to 19 volumes (edited by the Chemical Society of Japan); New Experimental Chemistry Course, 14 to 15 volumes (Japan. Chemical Society Edition); Fine Organic Chemistry Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Revised Organic Personal Name Reaction: Mechanism and Points (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII ( . John Wiley & Sons Inc); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li al., OXFORD UNIVERSITY publication); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol.
• the protection or deprotection reaction of the functional group can be carried out by a method known per se, for example, “Protective Groups in Organic Synthesis, 4th Ed.” published by Wiley-Interscience, 2007 (Theodora W. Greene, W. Peter G. et al. Author); The method described in 2004, “Protecting Groups 3rd Ed.” (PJ Kocienski), etc., or the method described in Examples.
• protective groups for hydroxyl groups such as alcohols and phenolic hydroxyl groups
• ether type protective groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether
• carboxylic ester type protective groups such as acetic acid ester.
• a sulfonic acid ester type protecting group such as methanesulfonic acid ester
• a carbonic acid ester type protecting group such as tert-butyl carbonate.
• the carbonyl-protecting group for aldehyde include acetal-type protecting groups such as dimethylacetal; and cyclic acetal-type protecting groups such as 1,3-dioxane.
• Examples of the protecting group for the carbonyl group of the ketone include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; N,N-dimethyl. Examples thereof include hydrazone-type protecting groups such as hydrazone. Examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the thiol protecting group include ether type protecting groups such as benzyl thioether; ester type protecting groups such as thioacetic acid ester, thiocarbonate and thiocarbamate.
• Examples of the protective group for an amino group or an aromatic heterocycle such as imidazole, pyrrole or indole include carbamate type protective groups such as benzyl carbamate; amide type protective groups such as acetamide; alkylamines such as N-triphenylmethylamine.
• Type protecting groups, sulfonamide type protecting groups such as methanesulfonamide and the like include carbamate type protective groups such as benzyl carbamate; amide type protective groups such as acetamide; alkylamines such as N-triphenylmethylamine.
• Type protecting groups, sulfonamide type protecting groups such as methanesulfonamide and the like.
• the protecting group can be removed by a method known per se, for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide). , Trimethylsilyl bromide), a reduction method, or the like.
• a method known per se for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide). , Trimethylsilyl bromide), a reduction method, or the like.
• the reducing agent used is lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride.
• Metal hydrides such as triacetoxyborohydride tetramethylammonium; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like.
• a catalyst such as palladium-carbon or Lindlar catalyst.
• peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butylhydroperoxide; tetrabutylammonium perchlorate, etc.
• Perchlorates chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese dioxide, peroxides Reagents having manganese such as potassium manganate; Leads such as lead tetraacetate; Pyridinium chlorochromate (PCC), Pyridinium dichromate (PDC), Reagents having chromium such as Jones reagent; N-bromosuccinimide (NBS) And the like; oxygen; ozone; sulfur trioxide/pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.
• PCC Pyridinium chlorochromate
• PDC Pyridinium dichromate
• Reagents having chromium such as Jones reagent
• the radical initiator used is an azo compound such as azobisisobutyronitrile (AIBN); 4-4′-azobis-4-cyanopentanoic acid (ACPA) Water-soluble radical initiators such as; triethylboron in the presence of air or oxygen; and benzoyl peroxide.
• AIBN azobisisobutyronitrile
• ACPA 4-4′-azobis-4-cyanopentanoic acid
• Water-soluble radical initiators such as; triethylboron in the presence of air or oxygen; and benzoyl peroxide.
• the radical reaction agent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane and samarium iodide.
• examples of the Wittig reagent used include alkylidenephosphoranes.
• the alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.
• the reagents used include phosphonoacetic acid esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organolithiums. Can be mentioned.
• the reagent used is a combination of a Lewis acid and an acid chloride, or a Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.)
• a Lewis acid and an alkylating agent eg, alkyl halides, alcohols, olefins, etc.
• an organic acid or an inorganic acid can be used instead of the Lewis acid
• an acid anhydride such as acetic anhydride can be used instead of the acid chloride.
• a nucleophile eg, amines, imidazole, etc.
• a base eg, organic bases, etc.
• a base used to generate a carbanion when a nucleophilic addition reaction with a carbanion, a nucleophilic 1,4-addition reaction with a carbanion (Michael addition reaction), or a nucleophilic substitution reaction with a carbanion is performed in each step.
• Examples thereof include organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.
• Grignard reagents include aryl magnesium halides such as phenyl magnesium bromide; alkyl magnesium halides such as methyl magnesium bromide.
• the Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with magnesium metal using ether or tetrahydrofuran as a solvent.
• the reagents include an active methylene compound (eg, malonic acid, diethyl malonate, malononitrile, etc.) sandwiched between two electron-withdrawing groups and a base (eg, organic bases, Metal alkoxides and inorganic bases) are used.
• an active methylene compound eg, malonic acid, diethyl malonate, malononitrile, etc.
• a base eg, organic bases, Metal alkoxides and inorganic bases
• phosphoryl chloride and an amide derivative are used as reagents.
• examples of the azidating agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide and the like.
• DPPA diphenylphosphoryl azide
• DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
• examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen and formic acid.
• examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone.
• examples of amines used include ammonia; primary amines such as methylamine; secondary amines such as dimethylamine.
• the reagents include azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and phosphines such as triphenylphosphine, tributylphosphine, etc. Is used.
• azodicarboxylic acid esters eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.
• phosphines such as triphenylphosphine, tributylphosphine, etc. Is used.
• the reagents used are acyl halides such as acid chlorides and bromides; acid anhydrides, active ester bodies, and sulfate ester bodies. Examples include activated carboxylic acids.
• carboxylic acid activator examples include carbodiimide-based condensing agents such as N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (WSC ⁇ HCl); 4-(4,6-dimethoxy-1) ,3,5-Triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM) and other triazine-based condensing agents; 1,1-carbonyldiimidazole (CDI) and other carbonic acid esters -Based condensing agents; diphenylphosphoric acid azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukoyama reagent); thionyl chloride; chloroformic acid Lower alkyl haloformates such as ethyl; O-
• an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu) or dimethylaminopyridine (DMAP) may be further added to the reaction.
• HOBt 1-hydroxybenzotriazole
• HOSu N-hydroxysuccinimide
• DMAP dimethylaminopyridine
• the metal catalyst used is palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethyl).
• Palladium compounds such as phosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride; tetrakis(triphenylphosphine)nickel(0 ) Etc.; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds.
• a base may be added to the reaction, and examples of such a base include inorganic bases.
• diphosphorus pentasulfide is typically used as the thiocarbonylating agent.
• 2,4-bis(4-methoxyphenyl) is used.
• -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawson's reagent) and other reagents having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure May be used.
• the halogenating agent used is N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, or the like.
• NBS N-bromosuccinimide
• NCS N-chlorosuccinimide
• bromine sulfuryl chloride
• the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.
• the halogenating agent used is an acid halide of hydrohalic acid and an inorganic acid, specifically, in chlorination, hydrochloric acid, thionyl chloride, oxy
• bromination such as phosphorus chloride, 48% hydrobromic acid and the like can be mentioned.
• a method of obtaining an alkyl halide from alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used.
• a method of synthesizing an alkyl halide by a two-step reaction such as reaction with lithium bromide, lithium chloride or sodium iodide after conversion of alcohol to sulfonate may be used.
• reagents used include alkyl halides such as ethyl bromoacetate; phosphites such as triethylphosphite and tri(isopropyl)phosphite.
• examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride.
• an acid or base is used as the reagent when carrying out the hydrolysis reaction.
• formic acid, triethylsilane, or the like may be added in order to reductively trap the tert-butyl cation produced as a by-product.
• examples of the dehydrating agent used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina and polyphosphoric acid.
• Compound (I) can be produced from compound (1) according to the following production step A or a method analogous thereto. [Manufacturing process A]
• R a is a hydrogen atom, a C 1-6 alkoxy group, or a C 1-3 alkyl group optionally substituted with a fluorine atom
• X a is a halogen atom
• ring A, R 1 , R 2 and R 3 have the same meaning as described above.
• the compound (2) can be produced by subjecting the compound (1) to a cyanation reaction.
• the cyanating reagent to be used include zinc cyanide and the like, and examples of the metal catalyst to be used include tetrakis(triphenylphosphine)palladium(0) and the like.
• the compound (3) can be produced by subjecting the compound (2) to a nucleophilic addition reaction or a reduction reaction with a carbanion.
• the reagent used for the nucleophilic addition reaction include an organolithium reagent and a Grignard reagent (organomagnesium halide).
• Compound (4) can be produced by subjecting compound (3) to an azidation reaction.
• Compound (5) can be produced by subjecting compound (4) to a reduction reaction.
• compound (5) can be produced by subjecting compound (4) to a reduction reaction, and then passing through a protecting group introduction and deprotection reaction.
• protecting group include a tert-butoxycarbonyl group.
• Compound (I) can be produced by subjecting compound (5) to an amidation reaction with compound (6).
• compound (I) can be produced from compound (7) according to the following production step B or a method analogous thereto. [Manufacturing process B]
• R b is a hydrogen atom, a C 1-6 alkoxy group or a C 1-3 alkyl group optionally substituted with a fluorine atom
• X b is a halogen atom
• ring A, R 1 , R 2 and R 3 have the same meaning as described above.
• the compound (8) can be produced by subjecting the compound (7) to a nucleophilic addition reaction or a reduction reaction with a carbanion.
• Compound (9) can be produced by subjecting compound (8) to an azidation reaction.
• Compound (10) can be produced by subjecting compound (9) to a reduction reaction.
• compound (10) can be produced by subjecting compound (9) to a reduction reaction, and then passing through a protecting group introduction and deprotection reaction.
• Compound (11) can be produced by subjecting compound (10) to an amidation reaction with compound (6).
• Compound (I) can be produced by subjecting compound (11) to a cyanation reaction.
• Each process of manufacturing process B can be performed by the same method as each process of manufacturing process A.
• the functional group in the molecule can be converted to the target functional group by combining chemical reactions known per se.
• the chemical reaction include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, urea reaction, hydrolysis reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection reaction and the like. Can be mentioned.
• the compound (I) obtained by the above production method can be isolated and purified by known means, for example, solvent extraction, pH conversion of solution, phase transfer, crystallization, recrystallization, and chromatography.
• the compound (I) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, these are also contained as the compound (I), and they are each synthesized by a known synthesis method or separation method. Can be obtained as a single item.
• the optical isomer resolved from the compound is also included in the compound (I).
• the optical isomer can be produced by a method known per se.
• the compound (I) may be crystalline.
• the crystal of compound (I) (hereinafter, may be abbreviated as the crystal of the present invention) can be produced by applying crystallization method known per se to compound (I) to crystallize.
• the crystal of the present invention has excellent physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), manifestation of drug efficacy) and is useful as a medicine. Is expected to be.
• ACD/SpecManager (trade name) software or the like was used.
• a peak having a very gentle proton peak such as a hydroxyl group or an amino group may not be described.
• MS was measured by LC/MS.
• the ionization method the ESI method or the APCI method was used.
• the data show the actual measured value (found).
• a molecular ion peak is observed, but it may be observed as a fragment ion.
• salt the molecular ion peak or fragment ion peak of the free form is usually observed.
• the elemental analysis value (Anal.) is shown as a calculated value (Calcd) and an actual measurement value (Found).
• Example 1 N-[(2-Bromo-5-cyanophenyl)methyl]-3-fluoro-4-(trifluoromethoxy)benzamide A) 3-(azidomethyl)-4-bromobenzonitrile 4-bromo-3-(hydroxymethyl)benzonitrile (3.42 g) in a mixture of DBU (4.86 ml) and THF (35 ml), DPPA (6.94 mL) Was added at 0° C. and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
• Example 7 N-[(5-cyano-2-methoxyphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide A) N-[(5-bromo-2-methoxyphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide 6-(difluoromethoxy)-5-fluoronicotinic acid (1.04 g) A mixture of DMF (10 ml), (5-bromo-2-methoxyphenyl)methanamine (1.08 g), TEA (1.39 ml) and HATU (2.85 g) was stirred at room temperature for 1 hour.
• Example 9 N-[(5-cyano-2-methoxypyridin-3-yl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide A) 5-formyl-6-methoxypyridine-3-carbonitrile 5-bromo-2-methoxynicotinaldehyde (1.70 g), Pd(PPh 3 ) 4 (0.909 g), zinc cyanide (1.386 g) and DMF ( 14 ml) of the mixture was subjected to microwave irradiation at 110° C. for 1 hour. The same reaction was run once again (total 2 batches).
• Example 12 N-[(5-cyano-2-fluorophenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide A) 3-(azidomethyl)-4-fluorobenzonitrile 4-fluoro-3-(hydroxymethyl)benzonitrile (0.507 g) and THF (6 ml) in a mixture, DBU (0.758 ml) and DPPA (0.865 mL) was added at 0°C. The mixture was stirred at room temperature for 5 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.533 g).
• Example 16 N-[(5-cyano-2-methoxypyridin-3-yl)methyl]-5-(trifluoromethyl)thiophene-2-carboxamide 5-(trifluoromethylthiophene)-2-carboxylic acid (0.105 g)
• Example 17 N-[(3-cyano-2-fluoro-6-methoxyphenyl)methyl]-6-(difluoromethoxy)-5-fluoropyridine-3-carboxamide
• 2-Fluoro-3-formyl-4-methoxybenzonitrile To a mixture of diisopropylamine (11.1 ml) and THF (100 ml), add 1.6 M butyllithium-hexane solution (45.5 ml) at -78 °C over 10 minutes. The mixture was stirred at 0 °C for 20 minutes. After cooling the mixture to -78°C, 2-fluoro-4-methoxybenzonitrile (10.0 g) was added. The mixture was stirred at ⁇ 78° C.
• Example compounds are shown in the table below. MS in the table indicates a measured value.
• the compounds of Examples 2 to 6, 8, 10, 11, 13 to 15, and 18 to 30 in the following table were produced according to the methods shown in the above Examples or methods analogous thereto.
• Test example 1 NR2B Ca 2+ influx assay
• “composed of 4 subunits consisting of 2 sets of heterodimers of NR1 and NR2B” Human fetal kidney cells expressing "NMDA receptor", specifically, human glutamate ionotropic receptor NMDA type subunit 1 (GRIN1) and human glutamate ionotropic receptor 29E, which expresses NMDA type 3 receptor cells (HB2G2R), and a human Glutamate ionotropic receptor 29E, 2HB2R subunit, and a human Glutamate ionotropic receptor.
• the body activation inhibitory effect was measured.
• HEK293 cells expressing GRIN1 and GRIN2B were purchased from ChanTest (Human NMDA (NR1/NR2B) Receptor-expressing, stable replicating cell line (HEK293) Catalog No. CT6121).
• NMDA receptor activation intracellular calcium ion (Ca 2+ ) influx caused by binding of glycine and glutamic acid to NR1 and NR2B was used.
• HEK293 cells expressing GRIN1 and GRIN2B were placed in a cell culture flask with 10% FBS (fetal bovine serum, Ausgene), 100 units/mL penicillin, 100 ⁇ g/mL streptomycin, 500 ⁇ g/mL neomycin, 100 ⁇ g/mL Zeocin (Invitrogen). (Registered trademark), DMEM/F-12 (Cosmobio, 10-092-CM) medium supplemented with 5 ⁇ g/mL blasticidin was used to culture in an incubator (37° C., 5% CO 2 ).
• FBS fetal bovine serum, Ausgene
• penicillin 100 ⁇ g/mL streptomycin
• 500 ⁇ g/mL neomycin 100 ⁇ g/mL Zeocin (Invitrogen).
• DMEM/F-12 Cosmobio, 10-092-CM
• the cells were detached from the flask with trypsin, and seeding medium (10% FBS, 100 units/mL penicillin, 100 ⁇ g/mL streptomycin-containing DMEM (Invitrogen, 31053) was added so that the cells had 8 ⁇ 10 5 cells/mL. 25 ⁇ L per well was suspended in a 384-well plate (Falcon, 356663) at 20,000 cells/well, and cultured overnight in an incubator.
• seeding medium (10% FBS, 100 units/mL penicillin, 100 ⁇ g/mL streptomycin-containing DMEM (Invitrogen, 31053) was added so that the cells had 8 ⁇ 10 5 cells/mL.
• 25 ⁇ L per well was suspended in a 384-well plate (Falcon, 356663) at 20,000 cells/well, and cultured overnight in an incubator.
• tetracycline (Wako Pure Chemical Industries, Ltd., 209-16561) was diluted to 2 ⁇ g/mL in a seeding medium, 25 ⁇ L/well was added to a cell seeded plate, and the plate was cultured in an incubator for 2 hours. .. Then, the medium was removed, and the wells were washed with 50 ⁇ L/well of assay buffer (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl 2 , 10 mM HEPES (pH 7.2), 10 mM Glucose, 0.1% BSA).
• assay buffer 137 mM NaCl, 4 mM KCl, 1.8 mM CaCl 2
• 10 mM HEPES pH 7.2
• 10 mM Glucose 0.1% BSA
• loading buffer 2.5 ⁇ M Fluo-4AM, 2 mM Amaranth, 1 mM Tartrazine was added to the assay buffer
• the compound of the present invention suppressed intracellular calcium ion (Ca 2+ ) influx at the NMDA receptor containing the NR2B subunit. That is, it was confirmed that the compound of the present invention has an antagonistic action on the NMDA receptor containing the NR2B subunit.
• Test example 2 In vivo [ 3 H]MK-801 binding test
• a compound that binds to the opening of NMDA receptor MK-801 ((5R,10S)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene) labeled with tritium ([ 3 H] A binding test was performed using MK-801).
• Sprague Dawley rats (body weight 180-260 g) were orally administered (po) with the example compound (1 mg/kg/2 mL, 0.5% MC water) or vehicle (kg/2 mL, 0.5% MC water), and then kept constant.
• [ 3 H]MK-801 (20 ⁇ Ci/kg/mL, Muromachi Kikai) was administered into the tail vein 10 hours later (around the time when the maximum blood concentration was reached), and 10 minutes later, it was euthanized by decapitation and the craniotomy was performed. , The hippocampus was collected.
• tissue weight (30 mL per 1 g of tissue) of ice-cold 20 mM Hepes (pH7.5, Hampton Research) was added to the collected hippocampus, and the mixture was homogenized for 10 seconds with a homogenizer (Microtech Nition). 600 ⁇ L of the homogenate was added to a manifold filtration system (Millipore) set with a GF/B Whatman glass filter (GE Healthcare) that had been treated with 0.5% polyethyleneimine (Fuji Film Wako Pure Chemical Industries) in advance, and suction filtration was performed. did.
• the filter was washed 4 times with 5 mL of ice-cold physiological saline (Otsuka Pharmaceutical Co., Ltd.) and then placed in a scintillation vial, 10 mL of liquid scintillator A (Fuji Film Wako Pure Chemical Industries, Ltd.) was added, and a liquid scintillation counter (ALOKA).
• LSC-6100 liquid scintillator A
• the value was corrected by the dose of [ 3 H]MK-801, and this value was expressed in the hippocampal tissue of each individual.
• the ratio was [ 3 H]MK-801 binding to the receptor.
• the binding rate of [ 3 H]MK-801 in the vehicle administration group was set to 100%, and an excess amount of MK-801 maleate (2 mg/kg/2 mL, 0.5% MC water) was subcutaneously administered.
• the binding rate of [ 3 H]MK-801 in the treated group was set to 0%.
• Formulation Example 1 (production of capsules) 1) Compound of Example 1 30 mg 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 60 mg in total Mix 1), 2), 3) and 4) and fill into gelatin capsules.
• Formulation example 2 (production of tablets) 1) 30 g of the compound of Example 1 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethyl cellulose calcium 44 g 5) Magnesium stearate 1 g 1000 tablets total 140 g The whole amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried in vacuum and then sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and the mixture is compressed with a tableting machine. In this way, 1000 tablets each containing 30 mg of the compound of Example 1 are obtained.
• the compound of the present invention may have an antagonism of NMDA receptor containing NR2B subunit and is expected to be useful as a preventive or therapeutic agent for depression, bipolar disorder, migraine, pain, peripheral symptoms of dementia and the like. To be done.

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