WO2017209265A1 - Dérivé hétérocyclique bicyclique et composition pharmaceutique comprenant le dérivé hétérocyclique bicyclique - Google Patents

Dérivé hétérocyclique bicyclique et composition pharmaceutique comprenant le dérivé hétérocyclique bicyclique Download PDF

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WO2017209265A1
WO2017209265A1 PCT/JP2017/020532 JP2017020532W WO2017209265A1 WO 2017209265 A1 WO2017209265 A1 WO 2017209265A1 JP 2017020532 W JP2017020532 W JP 2017020532W WO 2017209265 A1 WO2017209265 A1 WO 2017209265A1
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substituted
unsubstituted
aromatic
aromatic heterocyclic
group
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Japanese (ja)
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佑介 市橋
宏美 工藤
尚武 小林
規之 黒瀬
徳文 中橋
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塩野義製薬株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • Adenosine triphosphate acts as an energy source and phosphorylation substrate inside the cell, while acting as an information transmitter outside the cell. It is known that ATP is released from cells by various stimuli such as cell damage, inflammation, noxious stimuli, reduction of blood oxygen concentration, and is released from nerve endings like other neurotransmitters. (Non-Patent Document 1). ATP released to the outside of the cell is responsible for various extracellular information transmission through the ATP receptor.
  • R 9a and R 9b are halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, the above (1A), (1), (1 ′), and (2 ) To (23), or a pharmaceutically acceptable salt thereof.
  • R 9a and R 9b are substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof Acceptable salt.
  • R 10a and R 10b are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy Substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted (1A), (1), (1 ′), which is a non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group, And the
  • Compounds according to the present invention has an inhibitory effect on P2X 7 receptors are useful as therapeutic and / or prophylactic agent for a disease or condition P2X 7 is involved.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • non-aromatic carbocycle means a monocyclic ring or two or more cyclic saturated hydrocarbon rings or cyclic non-aromatic unsaturated hydrocarbon rings.
  • the two or more non-aromatic carbocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more non-aromatic carbocycles.
  • the “non-aromatic carbocycle” includes a ring that is bridged as follows, or a spiro ring.
  • the monocyclic non-aromatic carbocycle preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • bicyclic aromatic heterocycle examples include indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, Benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine, etc.
  • aromatic heterocyclic group means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • the two or more non-aromatic heterocycles include those in which the ring in the above “non-aromatic carbocycle” is condensed with a single ring or two or more aromatic heterocycles.
  • the “non-aromatic heterocyclic ring” includes a ring that is bridged as follows, or a spiro ring.
  • the monocyclic non-aromatic heterocyclic ring is preferably 3 to 8 members, more preferably 5 or 6 members.
  • Examples include dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine, dioxolane, dioxazine, aziridine, dioxoline, oxepane, thio
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Alkylamino means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylamino, ethylamino, isopropylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Preferable embodiments of “alkylamino” include methylamino and ethylamino.
  • Alkenylamino means a group in which the above “alkenyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkenyl For example, ethylenylamino, propenylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkynylcarbamoyl means a group in which the above “alkynyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group.
  • alkynyl ethynylcarbamoyl, propynylcarbamoyl and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl”.
  • Alkynylsulfamoyl means a group in which the above “alkynyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group.
  • alkynyl ethynyl sulfamoyl, propynyl sulfamoyl, etc. are mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl”.
  • Alkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Preferable embodiments of “alkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
  • Alkynylcarbonylamino means a group in which the above “alkynylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkynylcarbonyl For example, ethynylcarbonylamino, propynylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Haloalkylcarbonyl means a group in which the above “haloalkyl” is bonded to a carbonyl group.
  • monofluoromethylcarbonyl, monofluoroethylcarbonyl, trifluoromethylcarbonyl, trichloromethylcarbonyl, trifluoroethylcarbonyl, trichloroethylcarbonyl and the like can be mentioned.
  • Preferable embodiments of “haloalkylcarbonyl” include trifluoromethylcarbonyl and trichloromethylcarbonyl.
  • Haloalkylcarbamoyl means a group in which the above “haloalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include monofluoromethylcarbamoyl, monofluoroethylcarbamoyl, trifluoromethylcarbamoyl, trichloromethylcarbamoyl, trifluoroethylcarbamoyl, trichloroethylcarbamoyl and the like. Furthermore, the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl” or the above “haloalkyl”. Preferable embodiments of “haloalkylcarbamoyl” include trifluoromethylcarbamoyl and trichloromethylcarbamoyl.
  • Haloalkylcarbonylamino means a group in which the above “haloalkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • monofluoromethylcarbonylamino, monofluoroethylcarbonylamino, trifluoromethylcarbonylamino, trichloromethylcarbonylamino, trifluoroethylcarbonylamino, trichloroethylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl” or the above “haloalkyl”.
  • Preferable embodiments of “haloalkylcarbonylamino” include trifluoromethylcarbonylamino and trichloromethylcarbonylamino.
  • haloalkylsulfonylamino include trifluoromethylsulfonylamino and trichloromethylsulfonylamino.
  • “Aromatic carbocyclic oxy” means a group in which “aromatic carbocycle” is bonded to an oxygen atom.
  • “Aromatic carbocyclic amino” means a group in which the “aromatic carbocycle” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples thereof include phenylamino and naphthylamino.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • “Aromatic carbocyclic carbonyloxy” means a group in which the above “aromatic carbocyclic carbonyl” is bonded to an oxygen atom. For example, phenylcarbonyloxy, naphthylcarbonyloxy and the like can be mentioned.
  • non-aromatic carbocyclic sulfonyloxy means a group in which the above “non-aromatic carbocyclic sulfonyl” is bonded to an oxygen atom.
  • examples include cyclopropylsulfonyloxy, cyclohexylsulfonyloxy, cyclohexenylsulfonyloxy and the like.
  • non-aromatic carbocyclic carbamoyl means a group in which the “non-aromatic carbocyclic” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include cyclopropylcarbamoyl, cyclohexylcarbamoyl, cyclohexenylcarbamoyl and the like.
  • pyridyl sulfamoyl, oxazolyl sulfamoyl, etc. are mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced with the above “alkyl”.
  • the “aromatic heterocyclic carbonylamino” means a group in which the above “aromatic heterocyclic carbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • pyridylcarbonylamino, oxazolylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • the “aromatic heterocyclic sulfonylamino” means a group in which the above “aromatic heterocyclic sulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic oxycarbonylamino means a group in which the above “aromatic heterocyclic oxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
  • the “non-aromatic heterocyclic amino” means a group in which the “non-aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • piperidinylamino, tetrahydrofurylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Non-aromatic heterocyclic sulfanyl means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
  • Non-aromatic heterocyclic carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
  • non-aromatic heterocyclic oxysulfonyl means a group in which the “non-aromatic heterocyclic oxy” is bonded to a sulfonyl group.
  • piperidinyloxysulfonyl, tetrahydrofuryloxysulfonyl and the like can be mentioned.
  • the “non-aromatic heterocyclic carbamoyl” means a group in which the “non-aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group.
  • piperidinylcarbamoyl, tetrahydrofurylcarbamoyl and the like can be mentioned.
  • non-aromatic heterocyclic sulfamoyl means a group in which the “non-aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group.
  • non-aromatic heterocyclic sulfamoyl means a group in which the “non-aromatic heterocyclic ring” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group.
  • piperidinyl sulfamoyl, tetrahydrofuryl sulfamoyl and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced with the above “alkyl”.
  • non-aromatic heterocyclic oxycarbonylamino means a group in which the above “non-aromatic heterocyclic oxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • piperidinyloxycarbonylamino, tetrahydrofuryloxycarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl”.
  • Haloalkylamino means a group in which the above “haloalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples thereof include monofluoromethylamino, monofluoroethylamino, trifluoromethylamino, trichloromethylamino, trifluoroethylamino, trichloroethylamino and the like. Furthermore, the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl” or the above “haloalkyl”. Preferable embodiments of “haloalkylamino” include trifluoromethylamino and trichloromethylamino.
  • Haloalkylcarbonyl means a group in which the above “haloalkyl” is bonded to a carbonyl group.
  • monofluoromethylcarbonyl, monofluoroethylcarbonyl, trifluoromethylcarbonyl, trichloromethylcarbonyl, trifluoroethylcarbonyl, trichloroethylcarbonyl and the like can be mentioned.
  • Preferable embodiments of “haloalkylcarbonyl” include trifluoromethylcarbonyl and trichloromethylcarbonyl.
  • Haloalkylsulfonyl means a group in which the above “haloalkyl” is bonded to a sulfonyl group.
  • monofluoromethylsulfonyl, monofluoroethylsulfonyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, trifluoroethylsulfonyl, trichloroethylsulfonyl and the like can be mentioned.
  • Preferable embodiments of “haloalkylsulfonyl” include trifluoromethylsulfonyl and trichloromethylsulfonyl.
  • Haloalkylcarbamoyl means a group in which the above “haloalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include monofluoromethylcarbamoyl, monofluoroethylcarbamoyl, trifluoromethylcarbamoyl, trichloromethylcarbamoyl, trifluoroethylcarbamoyl, trichloroethylcarbamoyl and the like. Furthermore, the other hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above “alkyl” or the above “haloalkyl”. Preferable embodiments of “haloalkylcarbamoyl” include trifluoromethylcarbamoyl and trichloromethylcarbamoyl.
  • haloalkylsulfamoyl include trifluoromethylsulfamoyl and trichloromethylsulfamoyl.
  • Haloalkylcarbonylamino means a group in which the above “haloalkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • monofluoromethylcarbonylamino, monofluoroethylcarbonylamino, trifluoromethylcarbonylamino, trichloromethylcarbonylamino, trifluoroethylcarbonylamino, trichloroethylcarbonylamino and the like can be mentioned.
  • the other hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl” or the above “haloalkyl”.
  • Preferable embodiments of “haloalkylcarbonylamino” include trifluoromethylcarbonylamino and trichloromethylcarbonylamino.
  • Haloalkylsulfonylamino means a group in which the above “haloalkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • monofluoromethylsulfonylamino, monofluoroethylsulfonylamino, trifluoromethylsulfonylamino, trichloromethylsulfonylamino, trifluoroethylsulfonylamino, trichloroethylsulfonylamino and the like can be mentioned.
  • haloalkylsulfonylamino include trifluoromethylsulfonylamino and trichloromethylsulfonylamino.
  • alkylsulfonyl alkylcarbonylamino optionally substituted with one or more groups selected from substituent group C2, alkylsulfonylamino optionally substituted with one or more groups selected from substituent group C2 From alkylcarbamoyl optionally substituted with one or more groups selected from group C2, alkylsulfamoyl optionally substituted with one or more groups selected from substituent group C2, from substituent group C2 Alkylcarbonyloxy optionally substituted with one or more selected groups, alkyloxycarbonyl optionally substituted with one or more groups selected from substituent group C2, 1 selected from substituent group C2 Alkylsulfonyloxy optionally substituted with one or more of the above groups, Al optionally substituted with one or more groups selected from Substituent Group C2 Ruoxysulfonyl, an aromatic carbocyclic group which may be substituted with one or more groups selected from substituent group E, and a non-substituted group which is
  • the carbon atom at any position may be bonded to one or more groups selected from the substituent group B.
  • Substituent group B alkyl optionally substituted by one or more groups selected from halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, formyl, imino, hydroxyimino, cyanoimino, substituent group D Oxy, alkylamino optionally substituted with one or more groups selected from substituent group D, alkylsulfanyl optionally substituted with one or more groups selected from substituent group D, substituent group D 1 selected from alkylimino optionally substituted with one or more groups selected from the above, alkyloxyimino optionally substituted with one or more groups selected from the substituent group D, 1 selected from substituent group D Alkylcarbonyl which may be substituted with the above groups, and alkylsulfonyl which may be substituted with one or more groups selected from Substi
  • Aromatic carbocyclic sulfonyloxy optionally substituted with a group
  • Non-aromatic carbocyclic sulfonyloxy optionally substituted with one or more groups selected from Substituent Group E, selected from Substituent Group E
  • An aromatic heterocyclic sulfonyloxy which may be substituted with one or more groups
  • a non-aromatic heterocyclic sulfonyloxy which may be substituted with one or more groups selected from substituent group E.
  • substituents of “substituted or unsubstituted alkyl” and “substituted or unsubstituted alkylcarbonyl” in R 7a include, for example, halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, substituent group D Alkyloxy optionally substituted with one or more groups selected from: alkylamino optionally substituted with one or more groups selected from substituent group D, one or more selected from substituent group D An alkylsulfanyl which may be substituted with a group of the above, an alkylcarbonyl which may be substituted with one or more groups selected from the substituent group D, and a substituent which is substituted with one or more groups selected from the substituent group D An alkylsulfonylamino which may be substituted with one or more groups selected from substituent group D, Alkylsulfonylamino optionally substituted with one or
  • Substituted or unsubstituted alkyl at R 6, "substituted or unsubstituted alkenyl", “substituted or unsubstituted alkynyl", “substituted or unsubstituted alkyloxy", “substituted or unsubstituted alkenyloxy", And the substituent of “substituted or unsubstituted alkynyloxy” is, for example, substituted with one or more groups selected from halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, and substituent group D Alkyloxy which may be substituted, alkylamino which may be substituted with one or more groups selected from substituent group D, alkylsulfanyl which may be substituted with one or more groups selected from substituent group D, Alkylcarbonyl optionally substituted with one or more groups selected from Substituent Group
  • Substituted or unsubstituted alkyl substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyl” in R 9a and R 9b Oxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkyl Amino, substituted or unsubstituted alkenylamino, substituted or unsubstituted alkynylamino, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or un
  • substituents of “carbonylamino”, “substituted or unsubstituted alkenyloxycarbonylamino”, and “substituted or unsubstituted alkynyloxycarbonylamino” include, for example, halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, Cyano, alkyloxy optionally substituted with one or more groups selected from substituent group D, alkylamino optionally substituted with one or more groups selected from substituent group D, substituent group D An alkylsulfanyl optionally substituted with one or more groups selected from the above, an alkylcarbonyl optionally substituted with one or more groups selected from the substituent group D, one or more selected from the substituent group D An alkylsulfonyl which may be substituted with one or more groups, and one or more groups selected from Substituent Group D Alkylcarbonylamino which may be substituted
  • (D) A compound described in the following (d-1) or (d-2) or a pharmaceutically acceptable salt thereof.
  • D-1) A compound represented by the formula (I) and any one of the above (a) to (c), wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof.
  • D-2) A compound represented by the formula (I) and any one of the above (a) to (c), wherein n is 1, or a pharmaceutically acceptable salt thereof.
  • (I) A compound according to any one of the following (i-1) to (i-3) or a pharmaceutically acceptable salt thereof: (I-1) The compound represented by the formula (I) and any one of the above (a) to (h) or a pharmaceutically acceptable salt thereof, wherein R 2d is a hydrogen atom, halogen, or substituted or unsubstituted alkyl. Salt. (I-2) A compound represented by formula (I) and any one of the above (a) to (h) or a pharmaceutically acceptable salt thereof, wherein R 2d is a hydrogen atom or halogen. (I-3) The compound represented by formula (I) and any one of the above (a) to (h) or a pharmaceutically acceptable salt thereof, wherein R 2d is a hydrogen atom.
  • (J) A compound according to the following (j-1) or a pharmaceutically acceptable salt thereof.
  • (J-1) A compound represented by the formula (I) and any one of the above (a) to (i) or a pharmaceutically acceptable salt thereof, wherein Y 1 is O.
  • (M) The compound according to any one of the following (m-1) to (m-17) or a pharmaceutically acceptable salt thereof.
  • (M-1) R 1 is a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 3- to 6-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5- to 6-membered aromatic
  • R 1 is Wherein R 12a and R 13a are each independently halogen; R 12b , R 12c , and R 13b are substituted with one or more groups selected from halogen, alkyl optionally substituted with one or more groups selected from substituent group D, or substituent group D A compound represented by formula (I) and any one of the above (a) to (l), or a pharmaceutically acceptable salt thereof.
  • R 12b , R 12c and R 13b each independently represent halogen or alkyl optionally substituted with one or more groups selected from substituent group D (m- 12) or a pharmaceutically acceptable salt thereof.
  • N The compound according to any one of the following (n-1) to (n-34) or a pharmaceutically acceptable salt thereof.
  • N-1 The compound according to formula (I) and any one of the above (a) to (m), wherein Z 1 is N, or a pharmaceutically acceptable salt thereof.
  • N-2) The compound according to formula (I) and any one of the above (a) to (m), or a pharmaceutically acceptable salt thereof, wherein Z 1 is C (R 4 ).
  • N-3) A compound represented by formula (I), any one of the above (a) to (c), (n-1) and (n-2) or a pharmaceutically acceptable salt thereof.
  • N-4) The compound represented by the above (n-3) or a pharmaceutically acceptable salt thereof, wherein the broken line indicates the presence of a bond.
  • N-5) The compound represented by the above (n-3) or a pharmaceutically acceptable salt thereof, wherein the broken line indicates the absence of a bond.
  • N-6 Shown in any one of (n-1) to (n-5) above, wherein ring Q is a 6-membered aromatic carbocycle, 5-membered aromatic heterocycle, or 6-membered aromatic heterocycle Or a pharmaceutically acceptable salt thereof.
  • N-7) The compound represented by any one of the above (n-1) to (n-5), wherein the ring Q is a 5-membered aromatic heterocycle or a 6-membered aromatic heterocycle, or a pharmaceutical thereof Acceptable salt.
  • N-8) any one of (n-1) to (n-5) above, wherein ring Q is imidazole, thiazole, oxazole, pyrazole, pyrrole, thiophene, pyridine, pyridazine, pyrimidine, or pyrazine A compound, or a pharmaceutically acceptable salt thereof.
  • N-12 The compound represented by any one of the above (n-1) to (n-5), wherein ring Q is thiazole, oxazole, pyrazole, pyrrole, thiophene, pyridine, pyridazine, pyrimidine, or pyrazine, Or a pharmaceutically acceptable salt thereof.
  • N-13 The compound represented by any one of the above (n-1) to (n-5), or a pharmaceutically acceptable salt thereof, wherein the ring Q is thiazole, pyrrole, pyridine, or pyrazine.
  • N-16 The compound represented by formula (I) and any one of the above (a) to (m), or a pharmaceutically acceptable salt thereof.
  • N-17 The compound represented by formula (I) and any one of the above (a) to (m), or a pharmaceutically acceptable salt thereof.
  • N-18 The compound represented by formula (I) and any one of the above (a) to (m), or a pharmaceutically acceptable salt thereof.
  • N-19 The compound represented by formula (I) and any one of the above (a) to (m), or a pharmaceutically acceptable salt thereof.
  • N-26 A compound represented by the formula (I), any of the above (a) to (m), (n-1) and (n-2) or a pharmaceutically acceptable salt thereof.
  • N-27 A compound represented by the formula (I), any of the above (a) to (m), (n-1) and (n-2) or a pharmaceutically acceptable salt thereof.
  • N-28 A compound represented by the formula (I), any of the above (a) to (m), (n-1) and (n-2) or a pharmaceutically acceptable salt thereof.
  • N-29 The compound according to any one of the above (n-26) to (n-28) or a pharmaceutically acceptable salt thereof, wherein ring Q is a 5-membered aromatic heterocycle.
  • each R 5 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, or A compound represented by formula (I), which is a substituted or unsubstituted aromatic heterocyclic group, and any one of the above (a) to (n) or a pharmaceutically acceptable salt thereof.
  • R 5 is each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aromatic carbocyclic group A compound represented by formula (I) and any one of the above (a) to (n) or a pharmaceutically acceptable salt thereof.
  • R 5 is each independently halogen; Alkyl substituted with one or more groups selected from halogen, hydroxy, cyano, formyl, alkyloxyimino and aromatic carbocyclic groups; unsubstituted alkyl; An unsubstituted alkenyl; an unsubstituted alkynyl; or an unsubstituted aromatic carbocyclic group, a compound represented by formula (I) and any of the above (a) to (n) or a pharmaceutically acceptable salt thereof Salt.
  • R 9a and R 9b are each independently halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl Substituted, unsubstituted alkylamino, substituted or unsubstituted alken
  • R 10a and R 10b are each independently halogen, hydroxy, amino, carbamoyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or Unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted Alkylamino, substituted or unsubstituted alkenylamino, substituted or unsubstituted alkynylamino, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl,
  • R 10a and R 10b are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or Unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocycl
  • R 10a and R 10b are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or un
  • R 10a and R 10b are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted aromatic carbocyclic (Q-1) or a group which is a group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aro
  • R 10a and R 10b are each independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted aromatic carbocyclic group, (Q-1) or (q) which is a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group -2) or
  • R 10a and R 10b are each independently halogen; cyano; unsubstituted alkyl; alkyl substituted with hydroxy; unsubstituted alkyloxy; unsubstituted alkylsulfonyl; unsubstituted non-aromatic
  • R 10a and R 10b are each independently halogen; unsubstituted alkyl; unsubstituted alkyloxy; unsubstituted alkylsulfonyl; unsubstituted non-aromatic heterocyclic group; or alkyl
  • Q-12 The compound represented by (q-1) or (q-2) above, wherein R 10a and R 10b are each independently halogen; alkyl; haloalkyl; alkyloxy; Pharmaceutically acceptable salt.
  • (R) The compound according to any one of the following (r-1) to (r-11) or a pharmaceutically acceptable salt thereof.
  • (R-1) R 3 is (In the formula, ring F1 is a substituted or unsubstituted 5-membered non-aromatic carbocyclic ring, a substituted or unsubstituted 5-membered aromatic heterocyclic ring, or a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring; Ring G1 is a substituted or unsubstituted 6-membered aromatic carbocyclic ring, a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring, a substituted or unsubstituted 6-membered aromatic heterocyclic ring, or a substituted or unsubstituted 6-membered non-membered ring.
  • R 9a and R 9b are as defined above (q-1); R 10a1, said a group represented by R 10a and are as defined) of (q-1), formula (I), and the (a) ⁇ any compound or a pharmaceutically shown in the (p) Top acceptable salt.
  • R 10a1 means a substituent on ring B.
  • R-2) R 3 is A compound represented by formula (I) and any one of the above (a) to (p) or a pharmaceutically acceptable salt thereof.
  • Ring F1 is substituted or unsubstituted cyclopentene, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole
  • R-4 The compound represented by the above (r-1) or (r-2) or a pharmaceutically acceptable salt thereof, wherein Ring F1 is substituted or unsubstituted cyclopentene, or substituted or unsubstituted thiazole.
  • R-5 The compound represented by the above (r-1) or (r-2) or a compound thereof, wherein Ring F1 is an unsubstituted cyclopentene; or thiazole substituted with one or more groups selected from alkyl Pharmaceutically acceptable salt.
  • Ring G1 is substituted or unsubstituted benzene, substituted or unsubstituted cyclohexane, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyran Substituted or unsubstituted dihydropyran, substituted or unsubstituted dihydropyridine, substituted or unsubstituted tetrahydropyridine, substituted or unsubstituted dihydropyrazine, substituted or unsubstituted tetrahydropyrazine, substituted or unsubstituted oxazine, substituted or unsubstituted A compound represented by any one of the above (r-1) to (r-5) or a pharmaceutically acceptable salt thereof, which is a substituted dihydrooxazine, a substituted or unsubstitute
  • R 10a1 is halogen, hydroxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted alkenyl A compound represented by any one of the above (r-1) to (r-8), or a pharmaceutically acceptable salt thereof, which is amino, or substituted or unsubstituted alkynylamino.
  • R 9a and R 9b are halogen, hydroxy, amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted
  • R 9a and R 9b are halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfanyl, or substituted or unsubstituted alkylamino, I) and the compound according to any one of the above (a) to (r), or a pharmaceutically acceptable salt thereof.
  • (T) The compound according to any one of the following (t-1) to (t-10) or a pharmaceutically acceptable salt thereof.
  • (T-1) R 3 is (In the formula, ring F3 is a substituted or unsubstituted 5-membered non-aromatic carbocyclic ring, a substituted or unsubstituted 5-membered aromatic heterocyclic ring, or a substituted or unsubstituted 5-membered non-aromatic heterocyclic ring; Ring G3 is a substituted or unsubstituted 6-membered aromatic carbocyclic ring, a substituted or unsubstituted 6-membered non-aromatic carbocyclic ring, a substituted or unsubstituted 6-membered aromatic heterocyclic ring, or a substituted or unsubstituted 6-membered non-membered aromatic ring.
  • R 10a1 means a substituent on ring B.
  • T-3 The compound represented by the above (t-1) or a pharmaceutically acceptable salt thereof, wherein Ring F3 is a substituted or unsubstituted pyrrole.
  • T-4 The compound represented by the above (t-1) or a pharmaceutically acceptable salt thereof, wherein Ring F3 is unsubstituted pyrrole.
  • Ring G3 is substituted or unsubstituted benzene, substituted or unsubstituted cyclohexene, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyran Substituted or unsubstituted dihydropyran, substituted or unsubstituted dihydropyridine, substituted or unsubstituted tetrahydropyridine, substituted or unsubstituted dihydropyrazine, substituted or unsubstituted tetrahydropyrazine, substituted or unsubstituted oxazine, substituted or unsubstituted A compound represented by any one of the above (t-1) to (t-4) or a pharmaceutically acceptable salt thereof, which is a substituted dihydrooxazine, a substituted or unsubstitute
  • R 10a2 is halogen, hydroxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino, substituted or unsubstituted alkenyl A compound represented by any one of the above (t-1) to (t-7), or a pharmaceutically acceptable salt thereof, which is amino, or substituted or unsubstituted alkynylamino.
  • T-9 The compound represented by any one of (t-1) to (t-7) above, wherein R 10a2 is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or a compound thereof Pharmaceutically acceptable salt.
  • T-10 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (t-1) to (t-7), wherein R 10a2 is halogen.
  • (U) The compound according to any one of the following (u-1) to (u-5) or a pharmaceutically acceptable salt thereof.
  • (U-1) The compound represented by the formula (I) and any one of the above (a) to (t), wherein the ring B is benzene, cyclohexene, or a 6-membered aromatic heterocyclic ring, or a pharmaceutically acceptable salt thereof Salt.
  • (U-2) The compound represented by formula (I) and any one of the above (a) to (t), or a pharmaceutically acceptable salt thereof, wherein ring B is benzene or a 6-membered aromatic heterocyclic ring .
  • (V) The compound according to any one of the following (v-1) to (v-4) or a pharmaceutically acceptable salt thereof.
  • (V-1) The compound represented by the formula (I) and any one of the above (a) to (u), or a pharmaceutically acceptable product thereof, wherein the ring C is cyclopentane or a 5-membered aromatic heterocycle salt.
  • (V-2) The compound represented by the formula (I) and any one of the above (a) to (u) or a pharmaceutically acceptable salt thereof, wherein Ring C is a 5-membered aromatic heterocyclic ring.
  • p1 hydrogen atoms bonded to the ring-constituting atom of ring B can be replaced by R 10a or R 10c .
  • p2 hydrogen atoms bonded to the ring constituent atoms of Ring C can be replaced by R 10b or R 10d.
  • p3 hydrogen atoms bonded to the ring constituent atoms of Ring D may be replaced by R 10e.
  • q1 hydrogen atoms bonded to the ring constituent atoms of Ring E can be replaced by R 12. Further, q2 hydrogen atoms bonded to the ring constituent atoms of Ring E can be replaced by R 13.
  • p1b number of hydrogen atoms bonded to the ring constituent atoms of Ring B may be replaced by R 10a1.
  • p1d hydrogen atoms bonded to the ring-constituting atoms of ring B can be replaced by R 10a2 .
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Other suitable methods for preparing tritium labeled compounds can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”.
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • an alkali metal for example, lithium, sodium, potassium, etc.
  • an alkaline earth metal for example, Calcium, barium, etc.
  • magnesium transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid Tartaric acid, oxalic acid, maleic acid, fum
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included.
  • a method for selecting and producing an appropriate prodrug derivative is described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may themselves have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent.
  • the compound according to the present invention has a P2X 7 receptor antagonistic action, it is useful as a therapeutic and / or prophylactic agent for diseases involving the P2X 7 receptor.
  • Diseases P2X 7 receptor is involved, pain, central diseases, such as immune and inflammatory diseases and the like, preferably pain (Non-Patent Documents 7-8 and Patent Document 1, etc.).
  • the effect of opioid drugs on analgesic resistance can be expected.
  • the pain preferably herpes zoster pain, postherpetic neuralgia, trigeminal neuralgia, thalamic pain, cancer pain, postoperative pain, sciatica, afferent blockage pain, etc .; Strangulated neuropathy, carpal tunnel syndrome, diabetes, Guillain-Barre syndrome, myofascial pain syndrome, fibromyalgia syndrome, complex local pain syndrome, causalgia, spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, intervertebral disc herniation , Arthritis, rheumatoid arthritis, osteoarthritis, cervical spondylosis, spinal stenosis, brachial plexus withdrawal syndrome, shoulder syndrome, cystitis (including acute and interstitial), ulcerative colitis, Crohn's disease Pain associated with diseases such as irritable bowel syndrome, gout, depression; Pain associated with drug therapy and pain associated with radiation
  • Central diseases include Alzheimer's dementia (Alzheimer's disease, Alzheimer's senile dementia, etc.), cerebral amyloid angiopathy, Parkinson's disease, Creutzfeldt-Jakob disease, Huntington's chorea, depression, schizophrenia, attention deficit Examples include dyskinetic disorder, sleep disorder, autism, epilepsy, stroke, multiple sclerosis, spinal cord injury, amyotrophic lateral sclerosis, opioid drugs and mental dependence due to cocaine, nicotine, and the like.
  • Alzheimer's dementia Alzheimer's senile dementia, etc.
  • cerebral amyloid angiopathy Alzheimer's dementia
  • Parkinson's disease Creutzfeldt-Jakob disease
  • Huntington's chorea depression
  • schizophrenia attention deficit
  • Examples include dyskinetic disorder, sleep disorder, autism, epilepsy, stroke, multiple sclerosis, spinal cord injury, amyotrophic lateral sclerosis, opioid drugs and mental dependence due to cocaine, nicotine, and the like.
  • Alzheimer type dementia Alzheimer type senile dementia etc.
  • cerebral amyloid angiopathy Parkinson's disease
  • Parkinson's disease depression
  • schizophrenia attention deficit hyperactivity disorder
  • sleep disorder Examples include autism, epilepsy, stroke, multiple sclerosis, spinal cord injury, amyotrophic lateral sclerosis, opioid drugs and mental dependence due to cocaine, nicotine, and the like.
  • Immune / inflammatory diseases include rheumatoid arthritis, osteoarthritis, osteoarthritis, asthma, bronchitis, chronic obstructive pulmonary disease, emphysema, septic shock, hepatitis (including non-alcoholic steatohepatitis), liver fibrosis, Cirrhosis, cholecystitis, glomerulonephritis, nephrotic syndrome, pancreatitis (including acute and chronic), cystitis (including acute and interstitial), urethritis (including acute and chronic), prostatitis, ulcerative colitis , Crohn's disease, irritable bowel syndrome, psoriasis, atopic dermatitis, contact dermatitis, eczema skin disease, delayed hypersensitivity reaction, conjunctivitis, uveitis, malignant cells (prostate cancer, breast cancer, lung cancer, uterine cancer, Pancreatic cancer, colon cancer, etc.) proliferation and met
  • cardiovascular diseases such as atherosclerosis, ischemic heart disease and diabetes
  • bone diseases such as osteoporosis, bone Paget's disease, osteonecrosis, and temporomandibular disorders.
  • Active bladder stress urinary incontinence, prostatic hypertrophy and the like.
  • an immune / inflammatory disease preferably rheumatoid arthritis, osteoarthritis, osteoarthritis, asthma, bronchitis, chronic obstructive pulmonary disease, cystitis (including acute and interstitial), ulcerative colitis, clone Diseases and the like.
  • the compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed in a normal organic chemistry experiment. The synthesis of the compound of the present invention can be carried out in consideration of a technique known in the art.
  • R A1 is a hydrogen atom or substituted or unsubstituted alkyl
  • G 1 is halogen, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkylsulfinyl, or substituted or unsubstituted alkylsulfonyl, etc.
  • a leaving group; other symbols have the same meanings as in (1) above.
  • Process 1 Compound (A-3) can be obtained by reacting compound (A-1) and compound (A-2) in the presence of a base in an appropriate solvent.
  • Examples of the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc. It is done.
  • 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents can be used relative to compound (A-2).
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , Halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine and the like, which can be used alone or in combination.
  • the reaction temperature is 0 ° C. to 80 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 16 hours.
  • the obtained desired compound (A-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (A-4) can be obtained by reacting compound (A-3) and trimethylsilyl isothiocyanate in a suitable solvent or without solvent. In this reaction, trimethylsilyl isothiocyanate can be used at 1.0 molar equivalent or more, preferably 1.0-10.0 molar equivalent relative to compound (A-3).
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, NMP, acetonitrile, DMA and the like can be used alone or in combination.
  • the reaction temperature is 40 ° C to 200 ° C, preferably 80 ° C to 150 ° C.
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , DMF, NMP, acetonitrile, DMA and the like, and can be used alone or in combination.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 8 hours.
  • the obtained desired compound (A-5) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (I ⁇ ) can be obtained by reacting compound (A-5) and compound (A-6) in the presence of a base or acid in the absence of a solvent or in a suitable solvent. In this reaction, compound (A-6) can be used at 1.0 molar equivalent or more, preferably 1.0-5.0 molar equivalents, relative to compound (A-5).
  • Examples of the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc. It is done.
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (A-5).
  • Examples of the acid include acetic acid and propionic acid. 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (A-5).
  • Reaction solvents include alcohols (eg, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples include tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, water, etc., used alone or in combination.
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , Acetonitrile and the like, and can be used alone or in combination.
  • the reaction temperature is ⁇ 10 to 110 ° C., preferably 0 to 80 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (I ⁇ ′) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • C ⁇ S can be appropriately converted to C ⁇ N (R 6 ) at a desired stage based on the following synthesis method of Ab method.
  • This reaction is not limited to the synthesis of the compound represented by the formula (I ⁇ ), but can also be used for the synthesis of other compounds of the present invention.
  • [Ab method] In the formula, Y 1a is N (R 6 ); other symbols have the same meanings as in the above (1).
  • Compound (I ⁇ ′′) can be obtained by reacting compound (I ⁇ ′) obtained by Method Aa with compound (Ab-1) in the presence of an acid or base in an appropriate solvent.
  • compound (Ab-1) can be used at 1.0 molar equivalent or more, preferably 1.0-5.0 molar equivalents, relative to compound (I ⁇ ′).
  • the acid include acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like.
  • 0.05 mol equivalent or more, preferably 0.1 to 2.0 mol equivalent, can be used with respect to compound (I ⁇ ′).
  • the base include pyridine, triethylamine, DIEA and the like.
  • 1.0 molar equivalent or more, preferably 1.0 to 20.0 molar equivalent can be used with respect to compound (I ⁇ ′).
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, NMP, acetonitrile, DMA and the like can be used alone or in combination.
  • the reaction temperature is 0 to 150 ° C., preferably 0 to 80 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (I ⁇ ′′) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Reaction solvents include alcohols (eg, methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples include tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP, acetonitrile and the like, which can be used alone or in combination.
  • the reaction temperature is 0 ° C. to 80 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 16 hours.
  • the obtained desired compound (B-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 The compound (B-4) can be obtained by reacting the compound (B-3) with trimethylsilyl isothiocyanate according to the synthesis method described in Method A Step 2, and the desired compound (B-4) obtained is If necessary, it can be purified by a conventional method (eg, column chromatography, recrystallization, etc.).
  • Process 3 The compound (B-5) can be obtained by reacting compound (B-4) with methyl iodide according to the synthesis method described in Method A, Step 3.
  • the obtained desired compound (B-5) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (I ⁇ -a) can be obtained by reacting compound (B-5) and compound (B-6) according to the synthesis method described in Method A, Step 4.
  • the obtained desired compound (I ⁇ -a) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Examples of the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc. It is done.
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used relative to compound (C-2).
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, etc., used alone or in combination. be able to.
  • alcohols eg, methanol, ethanol, tert-butanol, isopropanol, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons
  • the reaction temperature is ⁇ 10 to 80 ° C., preferably 0 to 40 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • the obtained desired compound (C-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (C-4) can be obtained by reacting compound (C-3) and sodium dithionite in an appropriate solvent in the presence of a base. In this reaction, sodium dithionite can be used in an amount of 1.0 molar equivalent or more, preferably 2.0 to 5.0 molar equivalents, relative to compound (C-3).
  • the reaction temperature is 0 to 80 ° C., preferably 20 to 50 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • the obtained desired compound (C-4) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (C-6) can be obtained by reacting compound (C-4) and compound (C-5) in a suitable solvent or without solvent. In this reaction, compound (C-5) is The compound (C-4) can be used at 1.0 molar equivalent or more, preferably 3.0 to 20.0 molar equivalent.
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, NMP, acetonitrile, DMA and the like can be used alone or in combination.
  • the reaction temperature is 40 ° C. to 200 ° C., optionally under microwave irradiation, preferably 80 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 12 hours.
  • the obtained desired compound (C-6) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (C-7) can be obtained by reacting compound (C-6) and methyl iodide according to the synthesis method described in Method A, Step 3.
  • the obtained desired compound (C-7) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 5 Compound (I ⁇ -b) can be obtained by reacting compound (C-7) and compound (C-8) according to the synthesis method described in Method A, Step 4.
  • the obtained desired compound (I ⁇ -b) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • G 2 is a leaving group such as halogen, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkylsulfinyl, or substituted or unsubstituted alkylsulfonyl;
  • R 5A and R 5B are each independently And hydrogen or any group shown as R 5 in the above (1); other symbols are the same as those in the above (1).
  • Process 1 Compound (D-2) can be obtained by reacting compound (C-6) and compound (D-1) obtained by Method C in a suitable solvent in the presence of a base.
  • compound (D-1) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents relative to compound (C-6).
  • the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc.
  • metal hydroxides eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.
  • metal hydrides eg, sodium hydride, lithium hydride, etc.
  • metal carbonates eg, Sodium carbonate, potassium carbon
  • Reaction solvents include alcohols (eg, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples include tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, water, etc., used alone or in combination.
  • alcohols eg, tert-butanol, isopropanol, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane, hexane
  • the reaction temperature is 0 to 200 ° C., optionally under microwave irradiation, preferably 20 to 100 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (D-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (I ⁇ -c) can be obtained by reacting compound (D-2) and compound (D-3) according to the synthesis method described in Method A, Step 4.
  • the obtained desired compound (I ⁇ -c) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Compound (I ⁇ -c) can also be synthesized by using the following E method instead of D method.
  • E method Wherein R C1 and R C2 are each independently hydrogen, or substituted or unsubstituted alkyl, or taken together to form a substituted or unsubstituted non-aromatic heterocycle; R 5A and R 5B has the same meaning as method D; the other symbols have the same meaning as in the above (1).
  • Process 1 Compound (E-2) is reacted with boronic acid or boronic ester (E-1) obtained by Method C in a suitable solvent in the presence of a metal catalyst and a base. Obtainable.
  • boronic acid or boronic acid ester (E-1) is used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (C-6). It can.
  • the metal catalyst include copper (II) acetate.
  • the base can be used at 001 to 0.2 molar equivalent relative to compound (C-6).
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , DMF, DMA, NMP, DMSO, and mixed solvents thereof.
  • the reaction temperature is 0 to 150 ° C., optionally under microwave irradiation, preferably 20 to 100 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (E-2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 2 Compound (I ⁇ -c) can be obtained by reacting compound (E-2) and compound (E-3) according to the synthesis method described in Method A, Step 4.
  • the obtained desired compound (I ⁇ -c) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • the halogenating reagent can be used at 1.0 molar equivalent or more, preferably 1.0 to 3.0 molar equivalent, relative to compound (I ⁇ -c1).
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , Halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile and the like, and can be used alone or in combination.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclohexane, hexane, etc.
  • ethers
  • the reaction temperature is 0 to 120 ° C, preferably 0 to 80 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (I ⁇ -c2) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Examples of the base include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, tripotassium phosphate, etc.), metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal carbonates (eg, Sodium carbonate, potassium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyl (eg, butyllithium, etc.), pyridine, triethylamine, DIEA, etc. It is done.
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used relative to compound (G-2).
  • the obtained desired compound (G-4) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 The compound (G-5) can be obtained by reacting the compound (G-4) and methyl iodide according to the synthesis method described in Method A, Step 3.
  • the obtained desired compound (G-5) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (I ⁇ -d) can be obtained by reacting compound (G-5) and compound (G-6) according to the synthesis method described in Method A, Step 4.
  • the obtained desired compound (I ⁇ -d) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • R 5E and R 5F are each independently hydrogen or any group represented as R 5 in (1) above; the symbols in the formula are as defined above in (1).
  • Process 1 Compound (H-2) can be obtained by reacting compound (A-4) obtained by Method A with compound (H-1) in a suitable solvent. In this reaction, compound (H-1) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (A-4).
  • the reaction temperature is 0 to 150 ° C., preferably 20 to 80 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 1 to 12 hours.
  • the desired compound (H-2) obtained can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • the compound (H-3) can be obtained by reacting the compound (H-2) and methyl iodide according to the synthesis method described in Method A, Step 3.
  • the obtained desired compound (H-3) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (I ⁇ -e) can be obtained by reacting compound (H-3) and compound (H-4) according to the synthesis method described in Method A, Step 4.
  • the obtained desired compound (I ⁇ -e) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Examples of the base include metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal alkoxides (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyls (eg, butyl lithium, etc.) ) And the like.
  • metal hydrides eg, sodium hydride, lithium hydride, etc.
  • metal alkoxides eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • metal alkyls eg, butyl lithium, etc.
  • Reaction solvents include aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.) , DMF, DMSO, NMP, acetonitrile and the like, and can be used alone or in combination.
  • the reaction temperature is -78 to 150 ° C, preferably 0 to 120 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 1 to 12 hours.
  • the desired compound (I-5) obtained can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Compound (I ⁇ ) can be obtained by reacting compound (I-5) and compound (I-6) in an appropriate solvent in the presence of a palladium catalyst and a base, if necessary. In this reaction, compound (I-6) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents relative to compound (I-5).
  • Reaction solvents include alcohols (eg, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples include tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP, acetonitrile and the like, which can be used alone or in combination.
  • the reaction temperature is 0 to 200 ° C., optionally under microwave irradiation, preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (I ⁇ ) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • the base can be used at 1 to 10 molar equivalents relative to compound (J-1).
  • the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane and its complex, lithium borohydride, potassium borohydride, diisobutylaluminum hydride and the like.
  • the base can be used at 1 to 10 molar equivalents relative to compound (J-1).
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, water, etc. Can be used.
  • alcohols eg, methanol, ethanol, tert-butanol, isopropanol, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons eg, cyclo
  • the reaction temperature is -78 ° C to 150 ° C, preferably 0 to 40 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 1 to 6 hours.
  • the desired compound (J-3) obtained can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Compound (J-4) can be obtained by reacting compound (J-3) with alkoxycarbonylisothiocyanate in the presence or absence of a base in a suitable solvent. In this reaction, alkoxycarbonyl isothiocyanate can be used at 1.0 molar equivalent or more, preferably 1.0-10.0 molar equivalent relative to compound (J-3).
  • Examples of the base include metal hydrides (eg, sodium hydride, lithium hydride, etc.), metal alkoxides (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), metal alkyls (eg, butyl lithium, etc.) ), Pyridine, triethylamine, DIEA and the like.
  • metal hydrides eg, sodium hydride, lithium hydride, etc.
  • metal alkoxides eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • metal alkyls eg, butyl lithium, etc.
  • Pyridine triethylamine
  • DIEA diethylamine
  • Reaction solvents include alcohols (eg, methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP, acetonitrile, DMA and the like can be mentioned, and these can be used alone or in combination.
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 150 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 18 hours.
  • the obtained desired compound (J-4) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 The compound (J-5) can be obtained by reacting the compound (J-4) and methyl iodide according to the synthesis method described in Method A, Step 3.
  • the obtained desired compound (J-5) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (I ⁇ ) can be obtained by reacting compound (J-5) and compound (J-6) according to the synthesis method described in Method A, Step 4.
  • the obtained desired compound (I ⁇ ) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • R E1 , R E2 and R E3 are each independently hydrogen or substituted or unsubstituted alkyl; G 1 has the same meaning as Method A; G 2 has the same meaning as Method I Yes; other symbols have the same meanings as in (1) above.)
  • Process 1 Compound (K-2) can be obtained by reacting compound (J-1) with compound (K-1) in a suitable solvent. In this reaction, compound (K-1) can be used at 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalents, relative to compound (J-1).
  • Reaction solvents include alcohols (eg, methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.) , Ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, etc., used alone or in combination. be able to.
  • alcohols eg, methanol, ethanol, tert-butanol, isopropanol, etc.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • saturated hydrocarbons
  • the reaction temperature is 0 to 200 ° C., optionally under microwave irradiation, preferably 0 to 150 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 1 to 6 hours.
  • the desired compound (K-2) obtained can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • the compound (K-4) can be obtained by reacting the compound (K-2) with the compound (K-3) according to the synthesis method described in Method A, Step 1.
  • the desired compound (K-4) obtained ) Can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 3 Compound (K-5) can be obtained by reacting compound (K-4) with a basic aqueous solution.
  • Examples of the base include metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), metal carbonate (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.) and the like.
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (K-4).
  • Examples of the reaction solvent include ethers (eg, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP, water, and mixed solvents thereof.
  • the reaction temperature is 0 ° C to 100 ° C, preferably 0 ° C to 20 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 16 hours.
  • the obtained desired compound (K-5) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (K-6) can be obtained by reacting compound (K-5) with DPPA in the presence or absence of a base in a suitable solvent.
  • DPPA can be used at 1.0 molar equivalent or more, preferably 1.0-10.0 molar equivalent relative to compound (K-5).
  • the base include pyridine, triethylamine, DIEA and the like.
  • 1.0 molar equivalent or more, preferably 1.0 to 5.0 molar equivalent can be used with respect to compound (K-5).
  • Reaction solvents include alcohols (eg, methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), ethers ( Examples, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), DMF, DMSO, NMP, acetonitrile, DMA and the like can be mentioned, and these can be used alone or in combination.
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 120 ° C.
  • the reaction time is 0.1 to 72 hours, preferably 0.5 to 8 hours.
  • the obtained desired compound (K-6) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • Process 4 Compound (I ⁇ ) can be obtained by reacting compound (K-6) and compound (K-7) according to the synthesis method described in Method I Step 4.
  • the obtained desired compound (I ⁇ ) can be purified by conventional methods (eg, column chromatography, recrystallization, etc.) if necessary.
  • optically active form of the compound represented by the formula (I) is an optically active starting material, an asymmetric synthesis is carried out at an appropriate stage to obtain an optically active intermediate, or an intermediate or final product that is a racemate. It can be manufactured by optical resolution at an appropriate stage.
  • Optical resolution methods include separation of optical isomers using an optically active column, kinetic optical resolution using enzymatic reactions, etc., diastereomers by salt formation using chiral acids and chiral bases. There are crystallization division, preferential crystallization method and the like.
  • Preferred compounds of the present invention not only P2X 7 receptor antagonism, has a utility as a pharmaceutical, it has the following one, or all of the outstanding features.
  • a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
  • d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
  • h) high P2X 7 receptor selectivity for example, a selectivity, etc.
  • to other receptors P2X family has the following one, or all of the outstanding features.
  • parenteral administration When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally.
  • parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
  • Oral administration is in accordance with conventional methods, such as solid preparations for internal use (eg, tablets, powders, granules, capsules, pills, films, etc.), liquids for internal use (eg, suspensions, emulsions, elixirs, syrups, It may be prepared and administered in any commonly used dosage form such as a limonade agent, an alcoholic agent, an aromatic water agent, an extract, a decoction, a tincture and the like.
  • solid preparations for internal use eg, tablets, powders, granules, capsules, pills, films, etc.
  • liquids for internal use eg, suspensions, emulsions, elixirs, syrups
  • It may be prepared and administered in any commonly used dosage form such as a limonade agent, an alcoholic agent, an aromatic water agent, an extract, a decoction, a tincture and the like.
  • the tablet may be a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a sustained-release tablet, a troche tablet, a sublingual tablet, a buccal tablet, a chewable tablet or an orally disintegrating tablet, and the powder and granules are dry syrup.
  • the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
  • Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also The pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years.
  • the pediatric pharmaceutical composition can also be administered to patients less than 28 days after birth, between 28 and 23 months after birth, between 2 and 11 years, or between 12 and 17 or 18 years.
  • the elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
  • the dose of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc., but when administered orally, usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day.
  • parenteral administration although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • Process 3 Compound 4 (5.8 g, 23.4 mmol) and formamide (24 mL, 602 mmol) were mixed and stirred at 170 ° C. for 30 minutes. The mixture was cooled to room temperature, and the resulting solid was collected by filtration to give compound 5 (4.9 g, yield: 81%) as a pale yellow solid.
  • Process 4 To a mixture of compound 5 (4.9 g, 19.0 mmol) and water (98 mL), a 1 mol / L aqueous sodium hydroxide solution (32.3 mL, 32.3 mmol) and methyl iodide (1.78 mL, 28.5 mmol) were added. And stirred at room temperature for 1 hour.
  • the value of the maximum fluorescence intensity when the DMSO solution as the solvent of the compound of the present invention is added is 0% inhibition (negative control), and the value of the maximum fluorescence intensity when the known inhibitor is added is 100% inhibition (positive control).
  • the inhibitory activity of the compound of the present invention was evaluated by calculating the concentration (IC 50 ) at which inhibition was 50% by the logistic approximation method.
  • DMSO solutions of the compounds of the present invention diluted to different concentrations using a buffer for dilution are dispensed at 15 ⁇ L per well with a built-in automatic dispenser and measurement of fluorescence intensity is continued for 20 minutes.
  • the value of the maximum fluorescence intensity when the DMSO solution as the solvent of the compound of the present invention is added is 0% inhibition (negative control), and the value of the maximum fluorescence intensity when the known inhibitor is added is 100% inhibition (positive control).
  • the inhibition rate is calculated from the following equation based on the amount of change represented by the difference between the maximum value and the minimum value of the fluorescence intensity immediately before the addition of the compound of the present invention and after 20 minutes.
  • Test 3-1 Evaluation of drug efficacy by Seltzer model ⁇ Preparation of rat Partial Scientific Nerve Ligation model (sciatic nerve partial ligation model)> Rats are anesthetized with isoflurane and the left leg is shaved. An incision is made in the upper thigh skin and the muscle is broken to expose the sciatic nerve. About half of the sciatic nerve is tightly ligated with nylon thread and the muscles and skin are sutured. This is the operation side. For the right foot, perform the same procedure except for sciatic nerve ligation, and make it the sham operation side. ⁇ Evaluation (1)> Two weeks after surgery, the effect on mechanical allodynia is assessed by von Frey filaments.
  • the compound of the present invention is pulverized using a mortar and pestle, and the suspension or solution is adjusted with a 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg. Animals are administered orally using an oral sonde. 1 to 5 hours after administration, the pain threshold value of the left and right hind legs is evaluated, and the pain threshold value after the treatment is used. The% reversal value is calculated by the following method and compared as the analgesic effect of the compound.
  • % Reversal value (logarithm of pain threshold value after surgical side treatment ⁇ logarithm of pain threshold value before surgical side treatment) / (logarithm of pain threshold value before surgical side treatment ⁇ logarithm of pain threshold value before surgical side treatment) ⁇ 100 ⁇ Evaluation (2)> Analgesiometer (Randall Selitto) evaluates the effect on mechanical hyperalgesia. Two weeks after the operation, the rat hind limb is compressed by an analgesiometer so that the stimulation pressure increases by 16 g per second, and the pressure when the rat exhibits escape behavior is set as a pain threshold. Pain thresholds are evaluated for the left and right hind limbs and set as pre-treatment pain thresholds.
  • Animals with a surgical threshold of 60-90 g and a sham surgical threshold of 100-175 g are employed. In order to train the animal, the same operation is performed before measuring the pre-treatment pain threshold.
  • the compound of the present invention is administered to the adopted animal.
  • the compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared using 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg, and an oral sonde is used.
  • Orally administered to animals. 1 to 5 hours after administration the pain threshold value of the left and right hind limbs is evaluated and set as a post-treatment pain threshold value.
  • Test 3-2 Evaluation of drug efficacy using the cauda equina nerve compression model ⁇ Production of model animals>
  • the lower back of the rat is incised under anesthesia to expose the fourth, fifth, and sixth lumbar vertebrae. Incisions are made on the 4th-5th and 5th-6th lumbar vertebral joints. Silicon rubber is inserted into the 4th and 6th lumbar spinal canals from the vertebral joint incision and placed, and the incision is sutured.
  • the above-described operation is subjected to an operation excluding silicon rubber insertion and indwelling operations.
  • Animals with a pain threshold of 8-15 g in the sham-operated group are adopted for drug efficacy evaluation. For animal training, the same operation is performed before measuring the pain threshold before treatment.
  • the compound of the present invention is administered to the adopted animal.
  • the compound of the present invention is pulverized using a mortar and pestle, and the suspension or solution is adjusted with a 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg. Animals are administered orally using an oral sonde. 1 to 5 hours after administration, the pain threshold value of the left and right hind legs is evaluated, and the pain threshold value after the treatment is used.
  • The% reversal value is calculated by the following method and compared as the analgesic effect of the compound.
  • Test 3-3 Efficacy Evaluation by EAE Model ⁇ Production of Rat Experimental Autoimmune Encephalomyelitis Model (Experimental Autoimmune Encephalomyelitis Model)> Rats (Lewis rat females) are anesthetized with isoflurane and the back of the ridge is shaved. Immunization is carried out by preparing a 1 g / L emulsion prepared by mixing 1: 1 CFA (complete Freund's Adjuvant) and MBP (Myelin Basic Protein) saline solution, and administering 100 uL subcutaneously on the back of the rat tail. This is a treatment group.
  • 1 CFA complete Freund's Adjuvant
  • MBP Myelin Basic Protein
  • % Reversal value (logarithm of pain threshold value after treatment group drug administration ⁇ logarithm of pain threshold value before treatment group drug administration) / (logarithm of pain threshold value before sham treatment drug administration ⁇ pain threshold value before treatment group drug administration) Logarithm) x 100
  • the inhibitory activity against the P2X7 receptor can also be evaluated by using the evaluation method described in British Journal of Pharmacology (2013) 170 624-640.
  • Test Example 4 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.
  • each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction.
  • NADPH a coenzyme
  • resorufin CYP1A2 metabolite
  • a fluorescent multilabel counter or LC / MS / MS
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxylated The body (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system.
  • Test Example 5-2 CYP3A4 (MDZ) MBI Test This test evaluates the mechanism based inhibition (MBI) ability from the enhancement by metabolic reaction regarding CYP3A4 inhibition of the compounds of the present invention. Pooled human liver microsomes are used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
  • MBI mechanism based inhibition
  • reaction conditions are as follows: substrate, 10 ⁇ mol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsome, pre-reaction 0.5 mg / mL, reaction time 0.05 mg / mL (when diluted 10-fold); concentration at the time of pre-reaction of the compound of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when the compound of the present invention was added at each concentration was calculated.
  • Preincubation 0 min IC / Preincubation 30 min IC is the Shifted IC value, and if the Shifted IC is 1.5 or more, it is “Positive”, and if the Shifted IC is 1.0 or less, it is “Negative”.
  • Intravenous administration is performed from the tail vein using a syringe with an injection needle.
  • the bioavailability (BA) of the inventive compound is calculated.
  • Test Example 7 Fluctuation Ames Test The mutagenicity of the compound of the present invention is evaluated. Twenty microliters of Salmonella typhimurium TA98, TA100) cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution. 7.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate:
  • the cells are suspended in 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L), and 120 mL of Exposure medium (biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL) To the MicroF buffer).
  • TA100 strain is added to 130 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • Test Example 8 hERG Test
  • hERG hERG Test
  • the cell was held at a membrane potential of ⁇ 80 mV by a whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV.
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • SPE solid phase extraction
  • the composition of JP-1 solution is as follows. Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL.
  • the composition of JP-2 solution is one of the following.
  • Composition 1. Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL.
  • Composition 2. 1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to 1000 mL.
  • Test Example 10 Metabolic Stability Test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.
  • Test Example 11 Powder Solubility Test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water), 20 mmol / L sodium taurocholate (TCA) / JP-2 200 ⁇ L of the solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) is added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added.
  • JP-1 solution 2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL
  • JP-2 solution (1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of an
  • the mixture is filtered, and 100 ⁇ L of methanol is added to 100 ⁇ L of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Test Example 12 Brain transfer test The compound according to the present invention is intravenously administered to rats at a dose of 0.5 mg / mL / kg, and 30 minutes later, the blood is exsanguinated by whole blood collection from the lower aorta under isoflurane anesthesia. Thereafter, the brain is removed and 20-25% homogenate is prepared with distilled water. On the other hand, the obtained blood is made into plasma after centrifugation. Thereafter, control plasma is added to the brain sample and control brain is added to the plasma sample at a ratio of 1: 1, and each sample is measured using LC / MS / MS. The obtained area ratio (brain / plasma) at the time of measurement is defined as the brain Kp value.
  • Test Example 13 P-gp Substrate Test A compound according to the present invention is added to one side of a transwell (registered trademark, CORNING), in which human MDR1-expressing cells or parent cells are cultured in a monolayer, and allowed to react for a certain period of time.
  • a transwell registered trademark, CORNING
  • the membrane permeability coefficient was calculated from the axial side to the basolateral side (A ⁇ B) and from the basolateral side to the apical side (B ⁇ A), and the EFFlux ratio (ER; Calculate the ratio of B ⁇ A and A ⁇ B membrane permeability coefficient).
  • the Efflux Ratio (ER value) of the MDR1-expressing cell and the parent cell is compared to determine whether the compound of the present invention is a P-gp substrate.
  • Test Example 14 mdr1a ( ⁇ / ⁇ ) B6 mouse P-gp substrate test animals used mdr1a ( ⁇ / ⁇ ) B6 mouse (knockout mouse) or C57BL / 6J mouse (wild mouse) Method 1. Mice have free access to chow and sterile tap water. 2. The compound of the present invention is administered to three animals at each time point, and blood and brain samples are given at predetermined time points after administration (eg, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours or 24 hours). Time). Blood (0.3-0.7 mL) is collected with a syringe containing anticoagulants (EDTA and heparin). Blood and brain samples are immediately chilled on ice. 3.
  • EDTA anticoagulants
  • Plasma and brain concentration values (ng / mL and ng / g) are analyzed with an appropriate method for determining pharmacokinetic parameters, such as the WinNonlin® pharmacokinetic analysis software program.
  • Kp Brain / blood concentration ratio
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule The compound of the present invention, lactose and calcium stearate are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules The compound of the present invention, lactose and calcium stearate are uniformly mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
  • Formulation Example 4 Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed and tableted after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 5 Dry syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
  • Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to form an injection.
  • Formulation Example 7 Instillation A compound of the present invention and a phosphate buffer are mixed to form an instillation.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to make an inhalant.
  • Formulation Example 9 Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.
  • Compounds according to the present invention has an inhibitory effect on P2X 7 receptors, believed to be useful as therapeutic and / or prophylactic agent for a disease or condition P2X 7 receptors are involved.

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Abstract

La présente invention concerne un nouveau composé présentant une activité inhibitrice du récepteur P2X7 ; et une composition pharmaceutique présentant une activité inhibitrice du récepteur P2X7. L'invention concerne un composé représenté par la formule (I) ou son sel de qualité pharmaceutique. (Dans la formule, Z1 représente C(R4) ou N ; R4 représente un atome d'hydrogène ou similaire ; chacun de Z2 et de Z3 représente indépendamment un atome de carbone ou un atome d'azote ; la ligne discontinue représente la présence ou l'absence d'une liaison ; le noyau Q représente un noyau de carbone aromatique à six chaînons ou similaire ; chaque R5 représente indépendamment un atome d'halogène ou similaire ; Y1 représente O ou analogue ; R1 représente un groupe carbocyclique aromatique substitué ou non substitué ou similaire ; chacun de R2a et de R2b représente indépendamment un atome d'hydrogène ou similaire; X représente N(R7a) ou similaire ; R7a représente un atome d'hydrogène ou similaire ; R3 représente un groupe représenté par la formule (A) ou similaire ; le noyau B représente un noyau de carbone aromatique à six chaînons ou similaire ; chacun de R9a et de R10a représente indépendamment un atome d'halogène ou similaire ; n représente un nombre entier de 1 à 5 ; m représente un nombre entier de 0 à 4 ; p1 représente un nombre entier de 0 à 3 ; et s représente un nombre entier de 0 à 4.)
PCT/JP2017/020532 2016-06-03 2017-06-02 Dérivé hétérocyclique bicyclique et composition pharmaceutique comprenant le dérivé hétérocyclique bicyclique WO2017209265A1 (fr)

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