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WO2016088813A1 - Nouveau dérivé diazabicyclo[2.2.2]octane - Google Patents

Nouveau dérivé diazabicyclo[2.2.2]octane Download PDF

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Publication number
WO2016088813A1
WO2016088813A1 PCT/JP2015/083926 JP2015083926W WO2016088813A1 WO 2016088813 A1 WO2016088813 A1 WO 2016088813A1 JP 2015083926 W JP2015083926 W JP 2015083926W WO 2016088813 A1 WO2016088813 A1 WO 2016088813A1
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group
compound
formula
acid
alkyl group
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Japanese (ja)
Inventor
大道 堀田
勲 櫻田
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Mochida Pharmaceutical Co Ltd
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Mochida Pharmaceutical Co Ltd
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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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to a compound having an orexin receptor antagonistic action, particularly a compound having a 2,5-diazabicyclo [2.2.2] octane structure represented by the following formula (I), or a compound thereof:
  • the present invention relates to a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutical composition characterized by containing them as an active ingredient.
  • Orexin is a neuropeptide specifically expressed in neurons existing in the lateral hypothalamic area, OX-A consisting of 33 amino acids and 28 OX-B consisting of the following amino acids has been identified.
  • OX receptors which are specific receptors for these peptides, are OX1 receptor (hereinafter sometimes abbreviated as “OX1R”), and OX2 receptor (hereinafter, abbreviated as “OXR”).
  • OX1R OX1 receptor
  • OX2 receptor hereinafter, abbreviated as “OXR”.
  • Two subtypes have been reported (sometimes abbreviated as “OX2R”). All receptors are 7-transmembrane G protein-coupled receptors (GPCRs) expressed in the central nervous system, but the tissue distribution varies depending on the subtype and has various effects on various nerves. This suggests that orexin has complex physiological activities.
  • Insomnia insomnia symptoms
  • BZ benzodiazepines
  • BZ drugs including ultra-short-time BZ drugs zolpidem, zopiclone, etc.
  • institutions such as NIH
  • BZ drugs including ultra-short-time BZ drugs zolpidem, zopiclone, etc.
  • Non-Patent Document 3 OX knockout mice and OX2R knockout mice, inhibition of arousal is observed. From such knowledge, it is considered that the OXR antagonist is an excellent therapeutic agent for insomnia as a sleep induction agent that induces sleep by suppressing the arousal state.
  • OXR antagonists suvorexant (trade name: Bersomura (registered trademark)) and almorexant (ACT-0778573, clinical trial number NCT00608985) are known. These OXR antagonists are substances (dual orexin receptor antagonists (DORA)) that antagonize OX1R and OX2R to the same extent, and improvement of insomnia has been reported (Non-patent Documents 4 and 5). ).
  • DORA dual orexin receptor antagonists
  • an OX2R selective antagonist may be a therapeutic agent for insomnia that induces physiological sleep and reduces the risk of side effects.
  • OX2R selective antagonists MIN-202 (Minerva Neurosciences. Inc. (http://www.minerneunosciences.com)) and MK-1064 (Merck Sharp & Dohm Corp.) (non-patent documents) are currently available. It has been clinically developed as a treatment for insomnia.
  • Patent Document 1 discloses a compound having a cross-linked structure in the molecule as an OXR antagonist.
  • WO 2011/050198 pamphlet (Patent Document 2) and WO 2012/145581 pamphlet (Patent Document 3) include octahydropyrrolo [3,4-c] pyrrole in the molecule as an OXR regulator.
  • a compound having a structure is disclosed.
  • Patent Document 4 In WO 2011/050200 (Patent Document 4) and WO 2011/050202 (Patent Document 5), as an OXR regulator, 3,8-diaza-bicyclo [4. Compounds having 2.0] octane and 3,6-diazabicyclo [3.2.0] heptane structures are disclosed. However, the compounds disclosed therein are different in basic skeleton from the compounds having a diazabicyclo [2.2.2] octane structure, and the compounds having a diazabicyclo [2.2.2] octane structure are also disclosed. Nor.
  • Patent Document 6 a 5-substituted-2,5-diazabicyclo [2.2.2] octane-2-carbonyl structure is partially used as a potentiator of metabotropic glutamate receptors.
  • Patent Document 6 a 5-substituted-2,5-diazabicyclo [2.2.2] octane-2-carbonyl structure is partially used as a potentiator of metabotropic glutamate receptors.
  • Patent Document 7 discloses a partial 5-substituted-2,5-diazabicyclo [2.2.2] octane-2-carbonyl structure as an mTOR (mammalian target of rapamycin) inhibitor. Although a compound having a structure is disclosed, there is no disclosure of a specific compound of the present invention as shown below.
  • insomnia drugs including BZ drugs are available for pharmacotherapy of insomnia (insomnia symptoms), which is one of sleep disorders.
  • insomnia insomnia symptoms
  • the patient's treatment satisfaction is low due to side effects caused by the drug, and the development of a new insomnia drug having a better drug profile than that of existing drugs is required.
  • the present inventors have conducted extensive research to obtain an OXR antagonist that is highly safe and / or excellent in effectiveness, and as a result, is represented by the formula (I). That a compound having a 2,5-diazabicyclo [2.2.2] octane structure, or a pharmaceutically acceptable salt thereof, or a solvate thereof has an OXR antagonistic action. I found it.
  • the compound of the present invention has an OXR antagonistic action, and has an action of improving psychiatric and neurological disorders including sleep disorders such as insomnia.
  • the present invention relates to a compound having a 2,5-diazabicyclo [2.2.2] octane structure represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a A solvate and a pharmaceutical composition characterized by containing them as active ingredients.
  • the compound of the present invention has an OXR antagonistic action, and has an action of improving psychological and neurological disorders including sleep disorders such as insomnia.
  • the pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally, and OXR antagonists, diseases involving OXR, psychiatric and neurological disorders, particularly sleep disorders such as insomnia It is expected as a preventive and / or therapeutic agent.
  • the compound group of the present invention has at least one or more of such properties as good solubility, high metabolic stability, excellent oral absorption, and little hERG channel inhibitory action. Since it has characteristics, it is highly useful.
  • the present invention relates to a compound having a 2,5-diazabicyclo [2.2.2] octane structure represented by the following formula (I) shown in the following embodiments, or a pharmaceutically acceptable product thereof: Or a solvate thereof, and a pharmaceutical composition characterized by containing them as an active ingredient, and their pharmaceutical use, an OXR antagonist.
  • the present invention includes the following embodiments [1] to [14].
  • the first aspect of the present invention is The following formula (I): [In formula (I), m is an integer from 0 to 4; n is an integer of 0-4; ring A represents a C 6 ⁇ 14 aryl group or a 5-7 membered heteroaryl group, ; ring B represents a C 6 ⁇ 14 aryl group or a 5-7 membered heteroaryl group,; Q (the Q is diazabicyclo [2.2.2] amide bond at the adjacent position to couple the octane ring and ring B (o-position) to always replace: the substitution position of Q is also the same defined during each aspect described below), the C 3 ⁇ 8 cycloalkyl group, or -OR c or partial structural formula, (SF- Group represented by 1): Wherein (SF-1), ring C is C 6 ⁇ 14 aryl group, 5- to 7-membered heteroaryl group or 3
  • C 1-6 means that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, carbon atoms of a linear, branched or cyclic group Represents a number.
  • the chain group means “straight or branched chain having 1 to 6 carbon atoms”.
  • the cyclic group means “a cyclic group having 1 to 6 carbon atoms in the ring”.
  • the group containing a chain group and a cyclic group means “a group having 1 to 6 total carbon atoms”.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • halogenated means having 1 to 5 of the above “halogen atoms” as a substituent. “Halogenation” is also referred to as “halogeno”.
  • examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Hexyl, isohexyl and the like can be mentioned.
  • halogenated C 1-6 alkyl group means a group in which the “C 1-6 alkyl group” is optionally substituted with 1 to 5 halogen atoms. Meaning, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.
  • hydroxyhalogenated C 1-6 alkyl group means that the above “halogenated C 1-6 alkyl group” is optionally substituted with 1 to 5 hydroxyl groups.
  • C 3 ⁇ 8 cycloalkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the “aryl group” means “monocyclic aryl group”, “condensed aryl group (including bicyclic or tricyclic)” or “partially It may be a hydrogenated fused-ring aryl group.
  • the “partially hydrogenated condensed aryl group” means any hydrogen from a partially hydrogenated condensed ring in the above “condensed aryl group”. It means a monovalent group formed by removing an atom, and either a hydrogen atom in an aromatic ring part of a condensed ring or a hydrogen atom in a hydrogenated part may be removed.
  • C 6 ⁇ 14 aryl group for example, phenyl, 1-naphthyl, 2-naphthyl, 2-, 3-, 4-biphenyl anthryl, phenanthryl, acenaphthyl, Indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl and the like can be mentioned.
  • the “heterocyclic group” means a 3 to 14-membered monocyclic or condensed ring containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. A monovalent group formed by removing any hydrogen atom from a cyclic ring.
  • examples of the “heterocyclic group” include “heteroaryl group” and “non-aromatic heterocyclic group”.
  • heteroaryl group means a 5- to 14-membered heteroaryl ring group containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. means.
  • examples of the “heteroaryl group” include “monocyclic heteroaryl group”, “condensed heteroaryl group”, and “partially hydrogenated condensed ring”.
  • Formula heteroaryl group ".
  • the above “monocyclic heteroaryl group” is preferably one having 5 to 7 ring members (5 to 7 membered heteroaryl group), such as pyrrolyl, furyl, thienyl, Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 Oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2, 4-triazinyl, 1,3,5-triazinyl, 2H-1
  • condensed heteroaryl group means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “monocyclic heteroaryl group”.
  • the above-mentioned “condensed heteroaryl group” is preferably one having 8 to 12 ring members, for example, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, iso Benzothienyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzimidazolyl, 1H-indazolyl, 1H-benzotriazolyl, chromenyl, isochromenyl, quinolyl , Isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzoxazepinyl, benzoazepinyl, benzodiazepinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl
  • the “partially hydrogenated condensed heteroaryl group” means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “heterocyclic group”.
  • a condensed ring formed by condensing an “aryl group” it means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring.
  • the arbitrary hydrogen atom is a hydrogen atom in any of the "heterocyclic group", “aryl group” and “heteroaryl group” in the condensed ring, or a hydrogen atom in the hydrogenated ring part.
  • quinoline is partially hydrogenated tetrahydroquinolyl
  • 5,6,7,8-tetrahydroquinolyl, 1,2,3,4-tetrahydroquinolyl and the like can be mentioned.
  • these groups can be, for example, 5,6,7,8-tetrahydroquinolyl-2-yl, -3-yl, -4-yl, -5-yl.
  • -6-yl, -7-yl, -8-yl and the like 1,2,3,4-tetrahydroquinolyl, for example, -1-yl, -2-yl, -3- Il, -4-yl, -5-yl, -6-yl, -7-yl, -8-yl and the like are exemplified.
  • the “partially hydrogenated condensed heteroaryl group” preferably has 8 to 12 ring members, such as indolinyl, 4, 5, 6, 7 -Tetrahydro-1H-indonyl, 2,3-dihydrobenzofuranyl, 4,5,6,7-tetrahydro-benzofuranyl, 2,3-dihydrobenzo [d] oxazolyl, 2,3-dihydrobenzo [d] thiazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, chromanyl, 2H-chromenyl, 4H-chromenyl, isochromanyl, 1H-isochromenyl, 1,3-benzodioxolyl, 2,3-dihydrofuro [3,2-c ] Pyridyl etc. are mentioned.
  • the “monocyclic non-aromatic heterocyclic group (3- to 8-membered non-aromatic heterocyclic group)” is a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. Represents a monovalent group formed by removing any hydrogen atom from a saturated or unsaturated heterocyclic ring, which is a 3- to 8-membered monocycle containing 1 to 4.
  • examples of the “monocyclic non-aromatic heterocyclic group (3- to 8-membered non-aromatic heterocyclic group)” include aziridinyl, azetidinyl, oxiranyl, thiranyl, oxetanyl, thietanyl, and the like.
  • the “—NR A R B group” means a group in which two hydrogen atoms on the nitrogen atom of the “amino group” are substituted with R A and R B. That is, “—NR A R B group” means that two hydrogen atoms on the nitrogen atom of “amino group” are each independently “hydrogen atom”, “C 1-6 alkyl group”, “halogenated C”.
  • n 0 to 2.
  • the ring A is preferably a group selected from a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrazinyl group, a thiazolyl group, or an oxazolyl group.
  • the ring A is more preferably ring A is a phenyl group, a pyridin-2-yl group, a pyrimidin-2-yl group, a pyrazin-2-yl group, a thiazole-2 -A group selected from an yl group and an oxazol-2-yl group.
  • the ring A is particularly preferably a pyridin-2-yl group or a pyrimidin-2-yl group.
  • the ring B is preferably a group selected from a phenyl group, a pyridinyl group, a pyridazinyl group, a furanyl group, a 1H-pyrazolyl group, and a thiazolyl group.
  • the ring B is more preferably the formula (B-1), the formula (B-2), the formula (B-3), the formula (B-4) or the formula (B -5) [in the formula (B-1), X 4 , X 5 , X 6 and X 7 each independently represents N or C—H] (provided that the formula (B— 1) to (B-5), the —C (O) — group and the Q group are not included in the ring B).
  • X 4 represents N or C-R 2a, where the R 2a represents a hydrogen atom, a halogen atom or -O-C 1 ⁇ 6 alkyl group,;
  • X 5 Represents C—R 2b , where R 2b is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a 5- to 7-membered heteroaryl group (the 5- to 7-membered heteroaryl group is a halogen atom
  • X 1 represents N or C—R 2c , where R 2C represents a hydrogen atom, a halogen atom, a C atom, or a C 1-6 alkyl group (which may be substituted with 1 to 4 alkyl groups).
  • 1-6 alkyl group or -O-C 1 ⁇ represents an alkyl group
  • X 7 represents N or C-R 2d, wherein said R 2d represents a hydrogen atom or a halogen atom.
  • ring B is particularly preferably a group selected from formula (B-1-1), formula (B-1-2), or formula (B-3). (However, in formula (B-1-1), formula (B-1-2) and formula (B-3), the —C (O) — group and Q group are not included in ring B).
  • Q is —O-halogenated C 1-6 alkyl group (more specifically, 1,1,2,2-tetrafluoroethoxy group, and 2,2,2-trifluoroethoxy), and a group represented by the partial structural formula (SF-1):
  • ring C represents a pyridin-2-yl group, a 1H-pyrazol-1-yl group, a 2H-1,2,3-triazol-2-yl group, or 1,2,4.
  • p is an integer of 0 or 1
  • R 3 is a C 1-6 alkyl group (more specifically, R 3 is a methyl group) Represents).
  • R 1 is preferably a halogen atom, a cyano group, —R a1 , —OR a1 , —C (O) R a1 , —C (O) OR a1 , —SR a1 , —NR A R B group, 3- to 8-membered non-aromatic heterocyclic group, or oxo group (R A and R B in the —NR A R B group are each independently a hydrogen atom, or C 1- It represents an alkyl group; the R a1 is a C 1 ⁇ 6 alkyl group, a halogenated C 1 ⁇ 6 alkyl group, hydroxy halogenated C 1 ⁇ 6 alkyl group or an C 3 ⁇ 8 cycloalkyl group) .
  • R 1 a cyano group, C 1 ⁇ 6 alkyl group, C 3 ⁇ 8 cycloalkyl group, or -O-C 1 ⁇ 6 alkyl group, More specifically, R 1 is a cyano group, a methyl group, a cyclopropyl group, and a methoxy group.
  • R 2 is preferably a halogen atom, a cyano group, —R b1 , —OR b1 (where R b1 is a C 1-6 alkyl group, or a halogenated C 1 Represents a 6- alkyl group), a pyrazolyl group, or a pyridyl group (the pyrazolyl group and the pyridyl group may be substituted with 1 to 4 halogen atoms or a C 1-6 alkyl group).
  • R 2 is more preferably a halogen atom or a C 1-6 alkyl group, and more specifically, R 2 is fluorine and a methyl group.
  • the combination of the ring A and (R 1 ) m is preferably the following partial structural formula (A-1) or (A-2):
  • X 1 represents N or C—H
  • X 2 represents N or C—R 1a (wherein R 1a represents a hydrogen atom, a halogen atom, C 1-6 alkyl group, C 3 ⁇ 8 cycloalkyl group, -O-C 1 ⁇ 6 alkyl group, -S-C 1 ⁇ 6 alkyl group, -NR A R B group (said -NR A R in R B groups A and R B Each independently represents a hydrogen atom and a C 1-6 alkyl group), or a 3- to 8-membered non-aromatic heterocyclic group);
  • X 3 represents N or C—R 1b (the R 1b is a hydrogen atom, a cyano group, C 1 ⁇ 6 alkyl group, a hal
  • the combination of the ring A and (R 1 ) m is more preferably a formula (A-1) or a formula (A) which is a partial structural formula in the above embodiment [1-8].
  • X 1 represents N or C—H
  • X 2 represents N or C—R 1a (wherein R 1a represents a hydrogen atom, a fluorine atom, chlorine) An atom, a methyl group, a methoxy group, an ethoxy group, a (methoxy-d 3 ) group, a cyclopropyl group, a pyrrolidin-1-yl group, a methylthio group, or a dimethylamino group)
  • X 3 is N or C—R 1b (wherein R 1b represents a hydrogen atom, a cyano group, a methyl group, an ethyl group, a cyclopropyl group, an acetyl group, a methoxy group, a difluoromethoxy group, a trifluoromethyl group, 1-hydroxy-2,2,2- Trifluoroethyl group or methoxycarbonyl group
  • R 1c each independently represents a hydrogen atom, a flu
  • the combination of the ring A and (R 1 ) m is more preferably a 3,5-dimethylphenyl group, a 3-chloro-4-cyano-pyridin-2-yl group, 3-methyl-4- (trifluoromethyl) pyridin-2-yl group, 3-methoxy-4- (trifluoromethyl) pyridin-2-yl group, 4-acetylpyridin-2-yl group, 4-cyano- Pyridin-2-yl group, 4-cyano-3-cyclopropyl-pyridin-2-yl group, 4-cyano-3-methoxy-pyridin-2-yl group, 4-cyano-3-ethoxy-pyridine-2- Yl group, 4-cyano-3- (methoxy-d3) -pyridin-2-yl group, 4-cyano-6-methyl-pyridin-2-yl group, 4-cyano-3-fluoro-pyridin-2-yl Group 4-cyano
  • the combination of the ring A and (R 1 ) m is particularly preferably a 4-cyano-3-methoxy-pyridin-2-yl group, 4-cyano-3-cyclopropyl -Pyridin-2-yl group or 4,6-dimethylpyrimidin-2-yl group.
  • the combination of the rings B, Q and (R 2 ) n is preferably a partial structural formula of the formula (BQ-1), formula (BQ-2), formula (BQ -3), formula (BQ-4), or formula (BQ-5) (wherein, in formulas (BQ-1) to (BQ-5), the —C (O) — group represents ring B, Q and (R 2 ) Not included in the combination of n ):
  • X 4 represents N or C-R 2a (the R 2a represents a hydrogen atom, a halogen atom or -O-C 1 ⁇ 6 alkyl group,);
  • X 5 is C—R 2b (wherein R 2b is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a 5- to 7-membered heteroaryl group (the 5- to 7-membered heteroaryl group is a halogen atom,
  • the combination of the rings B, Q and (R 2 ) n is more preferably a formula (BQ-1) which is a partial structural formula in the embodiment [1-9], Formula (BQ-2), Formula (BQ-3), Formula (BQ-4), or Formula (BQ-5)
  • X 4 represents N or C—R 2a
  • R 2a represents a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group, or an ethoxy group
  • X 5 represents C—R 2b (wherein R 2b represents a hydrogen atom, a fluorine atom, a methyl group
  • 1H— X 6 is N or C—R 2c (wherein R 2C is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl atom), or a pyrazol-1-yl group or a 5-chloro-pyridin-3-yl
  • the combination of rings B, Q and (R 2 ) n is more preferably a 5-fluoro-3- (pyrimidin-2-yl) pyridin-2-yl group, 2,2′-bipyridin) -3-yl group, 2- (1H-1,2,3-triazol-1-yl) pyridin-3-yl group, 2- (1H-pyrazol-1-yl) pyridine- 3-yl group, 2- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl group, 2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl group 2- (3-cyano-1H-pyrazol-1-yl) pyridin-3-yl group, 2- (3-methyl-1H-pyrazol-1-yl) pyridin-3-yl group, 2- (thiazol- 2-yl) pyridin-3-yl group, 2,5- (1H-
  • the combination of rings B, Q and (R 2 ) n is particularly preferably a 2- (2H-1,2,3-triazol-2-yl) phenyl group, 2 -Fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl group, 5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl group, 2- ( 3-methyl-1,2,4-oxadiazol-5-yl) phenyl group, 2- (1H-pyrazol-1-yl) pyridin-3-yl group, 2- (2,2,2-trifluoro) An ethoxy) phenyl group or a 2- (1,1,2,2-tetrafluoroethoxy) phenyl group.
  • the combination of the ring B, Q and (R 2 ) n is preferably the following partial structural formula (BQ-6) or (BQ-7) (provided that In the formulas (BQ-6) and (BQ-7), the —C (O) — group is not included in the combination of ring B, Q and (R 2 ) n ):
  • [In formula (BQ-6) and formula (BQ-7), p and R 3 are the same as defined in the above embodiment [1-5];
  • X represents N or C—H;
  • R 2e represents a hydrogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group].
  • the combination of the rings B, Q and (R 2 ) n is more preferably a formula (BQ-6) which is a partial structural formula in the embodiment [1-10] or Formula (BQ-7) [In Formula (BQ-6) and Formula (BQ-7), p is an integer of 0 or 1; R 3 represents a cyano group; X is N or C—H. Y 2 represents S; R 2e represents a hydrogen atom, a cyano group, a methyl group, or a trifluoromethyl group.
  • the combination of rings B, Q and (R 2 ) n is more preferably a 3-methyl-1- (3-cyanophenyl) -1H-pyrazol-5-yl group 1- (pyridin-2-yl) -1H-pyrazol-5-yl group, 3-cyano-1- (pyridin-2-yl) -1H-pyrazol-5-yl group, 3-methyl-1- ( Pyridin-2-yl) -1H-pyrazol-5-yl group, 3- (trifluoromethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl group, 1- (pyridazine-3- Yl) -1H-pyrazol-5-yl group or 1- (thiazol-2-yl) -1H-pyrazol-5-yl group.
  • the combination of rings B, Q and (R 2 ) n is particularly preferably a 1- (pyridin-2-yl) -1H-pyrazol-5-yl group.
  • the combination of the ring A and (R 1 ) m is preferably the same as defined in the embodiment [1-8]; the rings B, Q and (R 2 )
  • the combination of n is the same as defined in the above embodiment [1-9] or the above embodiment [1-10].
  • m is preferably an integer of 0 to 3.
  • m 2 is more preferable.
  • n is preferably an integer of 0 to 2.
  • n 0 or 1 is more preferable.
  • R 1 is preferably a halogen atom, a cyano group, —R a1 , —OR 1 , —C (O) R a1 , —C (O) OR a1 , —SR a1 , —NR A R B group, or 3- to 8-membered non-aromatic heterocyclic group (the above R a1 , R A , and R B are the same as defined in the above embodiment [1-6]) It is.
  • R 1 is more preferably the same as defined in the above embodiment [1-6-1].
  • R 2 is preferably a halogen atom, —R b1 , —OR b1 (wherein R b1 has the same definition as in the above embodiment [1-7]). ), A pyrazolyl group, or a pyridyl group (the pyrazolyl group and the pyridyl group may be substituted with 1 to 4 halogen atoms and a C 1-6 alkyl group).
  • R 2 represents more preferably a halogen atom or a C 1-6 alkyl group, and more specifically a fluorine and a methyl group.
  • the combination of the ring A ′ and (R 1 ) m is more preferably a combination of the ring A and the (R 1 ) m in the embodiment [1-8-1]. Same as definition.
  • the combination of the ring A ′ and (R 1 ) m is more preferably a combination of the ring A and the (R 1 ) m in the embodiment [1-8-2]. Same as definition.
  • the combination of the ring A ′ and (R 1 ) m is particularly preferably a combination of the ring A and the (R 1 ) m in the embodiment [1-8-3]. Same as definition.
  • the combination of the rings B ′, Q and (R 2 ) n is preferably a ring B, Q and (R 2 ) n in the embodiment [1-9].
  • the definition is the same as
  • n is more preferably a ring B, Q and (R) in the embodiment [1-9-1]. 2 ) Same definition as n .
  • n is more preferably a combination of the rings B, Q and (R) in the embodiment [1-9-2]. 2 ) Same definition as n .
  • the combination of the rings B ′, Q and (R 2 ) n is particularly preferably a ring B, Q and (R) in the above embodiment [1-9-3]. 2 ) Same definition as n .
  • m is preferably an integer of 0 to 3.
  • m 2 is more preferable.
  • Q is a group represented by the partial structural formula (SF-1): Wherein (SF-1), ring C is a phenyl group, pyridin-2-yl group, pyridazin-3-yl group or represents a group selected from thiazol-2-yl group,; p and R 3 are, It is the same as defined in the above embodiment [1-5-1].
  • Q is more preferably a pyridin-2-yl group.
  • R 1 is preferably a halogen atom, a cyano group, —R a2 , or —OR a2 (wherein R a2 is a C 1-6 alkyl group, and a halogenated group). Represents a group arbitrarily selected from a C 1-6 alkyl group.
  • R 1 is more preferably a cyano group, a C 1-6 alkyl group, or an —O—C 1-6 alkyl group, and more specifically, A cyano group, a methyl group, and a methoxy group;
  • R 2 is preferably a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group.
  • the combination of the ring A ′ and (R 1 ) m is preferably the same as the definition of the ring A and (R 1 ) m in the embodiment [1-8]. It is.
  • the combination of the ring A ′ and (R 1 ) m is more preferably a combination of the ring A and the (R 1 ) m in the embodiment [1-8-1]. Same as definition.
  • the combination of the ring A ′ and (R 1 ) m is more preferably 4-cyano-pyridin-2-yl group, 4-trifluoromethyl-pyridine-2.
  • the combination of the ring A ′ and (R 1 ) m is particularly preferably a 4,6-dimethylpyrimidin-2-yl group.
  • the preferred embodiments can be arbitrarily formed.
  • the fourth aspect of the present invention is the compound of the above formula (I) of the above aspect [1], wherein the preferred compounds are the compounds listed below, or pharmaceutically acceptable salts thereof, or those: Solvates thereof, or optical isomers thereof.
  • the names of the compounds shown below are based on English names obtained according to the compound name naming program of ChemBioDraw (registered trademark) Ultra 14.0.0.117 (PerkinElmer Informations).
  • variable substituent R x in the following formula A can be substituted on any of the carbon atoms i, ii, iii or iv in the formula A
  • variable substituent R y in the following formula B can be substituted with the formula B It can be substituted with either carbon atom v or vi.
  • a fifth aspect of the present invention contains at least one of the compound represented by the above formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. It is a pharmaceutical composition characterized by these.
  • a sixth aspect of the present invention contains at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for diseases involving OXR.
  • OXR is widely involved in biological functions. This suggests a potential role for OXR in the course of various diseases in humans or other species.
  • OXR OXR-associated disorders
  • sleep disorders such as insomnia, circadian rhythm sleep disorder, and sleep-related disorders
  • depression anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum
  • Mental disorders such as disorders, drug dependence
  • neurodegenerative diseases such as Alzheimer's disease
  • memory disorders such as dementia
  • eating disorders such as bulimia.
  • An eighth aspect of the present invention contains at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • At least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof is contained as an active ingredient, thereby preventing sleep disorder And / or a therapeutic agent, more preferably a prophylactic and / or therapeutic agent for insomnia.
  • insomnia include insomnia, circadian rhythm sleep disorder, and sleep-related complications. More specific examples of insomnia include primary insomnia, insomnia due to mental illness, insomnia due to physical disease, insomnia due to drugs, and the like. However, it is not limited to these.
  • a “mental disorder” specifically, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug Addiction etc. are mentioned. However, it is not limited to these.
  • neurodegenerative diseases include Alzheimer's disease. However, it is not limited to these.
  • the “memory disorder” specifically includes dementia and the like. However, it is not limited to these.
  • treating disorders specifically includes bulimia and the like. However, it is not limited to these.
  • a ninth aspect of the present invention is an OXR antagonist comprising one or more of the compounds represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. .
  • a tenth aspect of the present invention is an OX2R selective antagonist comprising one or more of the compounds represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. It is.
  • Another aspect of the present invention is an OXR dual antagonist comprising one or more of the compounds represented by formula (I) above, or a pharmaceutically acceptable salt or solvate thereof.
  • the “OXR dual antagonist” means an orexin receptor antagonist having an orexin 1 receptor antagonistic action and an orexin 2 receptor antagonistic action.
  • An eleventh aspect of the present invention is the use of at least one pharmaceutical composition of a compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
  • a twelfth aspect of the present invention is the use of a compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as at least one orexin receptor antagonist. is there.
  • a thirteenth aspect of the present invention is a method for treating a disease selected from sleep disorder, mental disorder, neurodegenerative disorder, memory disorder and eating disorder, and is represented by the above formula (I) Administering at least one of a compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need of treatment of the disease or condition.
  • a method for treating a sleep disorder wherein at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof is administered in the disease or condition.
  • a method comprising administering to a subject in need of treatment, more preferably a method of treating insomnia.
  • treatment refers to the progression of a “disease or condition” or one or more “diseases or conditions”. Means to mitigate, or suppress. Further, in the present specification, “treatment” refers to “disease” including preventing the onset of “disease or condition” or any symptoms related to “disease or condition” depending on the condition of the patient. Or prevention of “a condition” as well as reducing the severity of a “disease or condition” or any symptom thereof before onset. As used herein, “treating” is intended to include preventing and ameliorating the recurrence of a “disease or condition”.
  • the disease is insomnia, circadian rhythm sleep disorder, parasomnia, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism Or a prophylactic and / or therapeutic agent according to aspect [8] or [8-1] selected from the group consisting of: autism spectrum disorder, drug dependence, Alzheimer's disease, dementia, bulimia, or aspect [13] Or it is the method as described in [13-1].
  • the compound of the present invention is a compound having an IC 50 value for OXR of 1 ⁇ M or less when measured by a method in which orexin receptor antagonism is appropriately selected, for example, Pharmacological Experiment Example 1 (orexin receptor antagonism evaluation) described later. preferable. More preferred is a compound having an IC 50 value for the orexin receptor of 100 nM or less. Further, as a compound having a OX2R antagonism is preferably a compound an IC 50 value is less than 1 ⁇ M for OX2R, and more preferably not more than 100nM compound.
  • the compound having such an activity is a compound having an OXR antagonistic action, particularly an OX2R antagonistic action, and can be used as an OXR antagonist, particularly an OX2R antagonist, or a pharmaceutical composition.
  • diseases involving OXR sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, autism , Autism spectrum disorders, drug addiction, etc.), neurodegenerative diseases (Alzheimer's disease etc.), memory disorders (dementia etc.) or eating disorders (eg bulimia), especially OX2R-related diseases, insomnia, etc. It can be used as a preventive and / or therapeutic agent for sleep disorders.
  • the compounds of the present invention include compounds having orexin 2 receptor antagonistic activity but not having orexining orexin 1 receptor antagonistic activity.
  • Such compounds include orexin 2 receptor. It can be used as a compound having a selective antagonism or an orexin 2 receptor selective antagonist.
  • a compound having an IC 50 value for orexin 1 receptor of 10 times or more, 20 times or more, 50 times or more, or 100 times or more of the IC 50 value for orexin 2 receptor can be mentioned.
  • a compound having an orexin 2 receptor selective antagonism is useful as a pharmaceutical composition having no side effects due to orexin 1 receptor antagonism.
  • diseases involving orexin 2 receptor sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, Autism, autism spectrum disorder, drug addiction, etc.), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) or eating disorders (eg, bulimia), especially sleep disorders such as insomnia It can be used as a preventive and / or therapeutic agent.
  • the compounds of the present invention include compounds having orexin 2 receptor antagonism as well as orexin 1 receptor antagonism, and such compounds are compounds having orexin receptor dual antagonism, It can be used as an orexin receptor dual antagonist or a pharmaceutical composition. Moreover, it can utilize as a preventive and / or therapeutic agent of the disease in which the above orexin receptor is involved.
  • the compound of the present invention may form an acid addition salt or a salt with a base depending on the type of substituent.
  • a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basics, Or the salt with an acidic amino acid etc. are mentioned.
  • the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, besides a mono salt, a disodium salt and a dipotassium salt are also included).
  • the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine.
  • the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc.
  • Salt with organic carboxylic acid salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
  • Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine
  • preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the salt is formed by mixing the compound of the present invention with a solution containing an appropriate amount of acid or base to form the desired salt, and then separated by filtration, or the mixed solvent is distilled off. Can be obtained.
  • the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol or glycerol.
  • solvate means a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.).
  • solvent molecules eg, water, ethanol, etc.
  • hydrate When the solvent molecule is water, it is particularly called “hydrate”.
  • the description relating to the compound of the present invention includes the description relating to the salt, solvate, and solvate of the salt.
  • Prodrugs of the compounds of the present invention are also encompassed by the compounds of the present invention.
  • a “prodrug” is, for example, when a certain derivative of a compound of the invention, which may exhibit little or no desired pharmacological activity, is administered in or on the body, eg, hydrolysis. When converted to the compound of the present invention having the desired pharmacological activity by the like, the compound before administration is called “prodrug”.
  • the “prodrug” of the compound of the present invention can be prepared by, for example, converting an appropriate functional group present in the compound of the present invention into a method known in the literature, for example, Design of Products, H.P. It can be produced according to the method described in Bundgaard (Elsevier, 1985).
  • the compound of the present invention is substituted with a carboxy group (—COOH): the ester, ie, the hydrogen atom of the carboxy group (—COOH) is substituted with a “C 1-6 alkyl group” Compound.
  • the hydroxyl group (-OH) to a compound of the present invention is substituted: Part alkanoyloxy or ethers, i.e., a hydrogen atom is "C 2 ⁇ 7 alkanoyl group” in the hydroxyl group (-OH) or "C 2 compounds substituted with 1-7 alkanoyloxymethyl group ".
  • the compound of the present invention is a geometric isomer (geometric isomer), configurational isomer (configurational isomer), tautomer (tortomeric isomer), optical isomer (optical isomer), stereoisomer (diastereomer).
  • Positional isomers Regio isomers
  • rotational isomers Rotational isomers
  • both isomers and mixtures are also included in the compound of the present invention.
  • the optical isomer resolved from the racemate is also encompassed in the compound of the present invention.
  • the compound of the present invention has one or more asymmetric carbon atoms, two or more stereoisomers can exist. Further, the compounds of the present invention, if it contains "C 2 ⁇ 6 alkenyl group", geometric isomers (cis / trans or Z / E,) can be present. Also, tautomerism can occur when structural isomers can be interconverted by a low energy barrier. Examples of tautomerism include proton tautomerism in compounds having an imino, keto, or oxime group.
  • the formula (OC) includes both (1S, 4S) form (formula (OC-1)) and (1R, 4R) form (formula (OC-2)) isomers. It means that the body is included.
  • the compounds having * mark at the 1-position and 4-position of the formula (OC) have either steric configuration of the formula (OC-1) or the formula (OC-2). Meaning a compound.
  • the racemate when the compound of the present invention is an optically active substance, the racemate can be separated into a (+) isomer or a ( ⁇ ) isomer [D isomer or L isomer] by an ordinary optical resolution means.
  • each isomer is converted to a single isomer by a known synthesis method or separation method. It can be obtained as a compound.
  • optical resolution method include methods known per se, such as (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like.
  • Fractionation recrystallization method After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. This is a method for obtaining a free optically pure compound.
  • the optical resolution agent include (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, Examples include cinchonine, ( ⁇ )-cinchonidine, brucine and the like.
  • Diastereomer method An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography). , HPLC (High Performance Liquid Chromatography, etc.) etc., and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. This is a method for obtaining an optical isomer.
  • separation means eg, fractional recrystallization, silica gel column chromatography).
  • HPLC High Performance Liquid Chromatography, etc.
  • the compound of the present invention when the compound of the present invention has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], (-)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively.
  • an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Each of the separated diastereomers is converted to an optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • Chiral column method a method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting to a chromatography on a chiral column (optical isomer separation column).
  • a chiral column such as Daicel's CHIRAL series, water, various buffers (eg, phosphate buffer)
  • Optical isomers can be separated by developing using an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution.
  • the separation can be performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
  • the compound of the present invention when it is an optically active substance, it can be synthesized by asymmetric synthesis in which one of optical isomers is selectively synthesized.
  • Optically active compounds are: (1) asymmetric synthesis reaction in which a racemic compound is enantioselectively reacted to lead to an optically active form, (2) diastereoselective from a naturally occurring optically active compound (sugar, amino acid, etc.). It can be synthesized by the synthesis method.
  • the compound of the present invention may be a crystal, and the compound of the present invention includes a single crystal form or a crystal form mixture.
  • the compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compounds of the present invention include isotopes (eg, hydrogen isotopes, 2 H and 3 H, carbon isotopes, 11 C, 13 C, and 14 C, chlorine isotopes, 36 Cl, etc., fluorine Isotopes, 18 F, iodine isotopes, 123 I and 125 I, nitrogen isotopes, 13 N and 15 N, oxygen isotopes, 15 O, 17 O, and 18 O, phosphorus Also included are compounds labeled or substituted with isotopes, 32 P and the like, as well as sulfur isotopes, 35 S and the like.
  • isotopes eg, hydrogen isotopes, 2 H and 3 H, carbon isotopes, 11 C, 13 C, and 14 C, chlorine isotopes, 36 Cl, etc.
  • fluorine Isotopes, 18 F iodine isotopes, 123 I and 125 I
  • Compounds of the invention labeled or substituted with certain isotopes can be synthesized, for example, by Positron Emission Tomography; PET ) Can be used as a tracer (PET tracer) for use in medical diagnosis and the like.
  • Compounds of the invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies.
  • 3 H and 14 C are useful for this research purpose because they are easy to label or displace and easy to detect.
  • the isotope-labeled compound of the present invention can be obtained by a common technique known to those skilled in the art or by a method similar to the synthesis method described in the Examples below.
  • the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
  • a compound labeled or substituted with 2 H (or sometimes referred to as D or deuterium) (D compound, deuterated compound) is expected to have high stability and is useful as an active compound itself. is there.
  • a compound in which a hydrogen atom at a position to undergo metabolism is substituted with 2 H can be mentioned, and the metabolic reaction rate can be reduced with little influence on the properties of the compound.
  • a compound in which the position of irreversibly binding to a metabolic enzyme is substituted with 2 H can suppress the inhibition of the action of the metabolic enzyme, and can reduce the drug interaction at the time of combined use.
  • the isotope-labeled compound of the present invention can be obtained by a common technique known to those skilled in the art or by a method similar to the synthesis method described in the Examples below.
  • the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
  • the definitions of Q, ring A, ring B, R 1 , R 2 , R 3 , m, n, p, and the like in each formula of the following production methods are the formulas ( It is the same as each definition of I).
  • the definition of M in the production method is a metal such as lithium, sodium and potassium unless otherwise specified.
  • the definition of X in the production method is a halogen atom or trifluoromethanesulfonyloxy (OTf) unless otherwise specified.
  • Definition of AR in the production process unless otherwise specified, a C 6 ⁇ 14 aryl group or 5- to 7-membered heteroaryl group.
  • B in the production method is boronic acid ester, boronic acid, trifluoroborate salt, boronic acid, or N-methyliminodiacetic acid ester unless otherwise specified.
  • P 1 and P 2 in the production method are a protecting group for a hydrogen atom or an imino group.
  • R alpha in the production process unless otherwise specified, is a C 1 ⁇ 6 alkyl group, C 6 ⁇ 14 aryl group or a benzyl group.
  • R beta in the production process unless otherwise specified, is a C 1 ⁇ 6 alkyl group or a C 3 ⁇ 8 cycloalkyl group.
  • R gamma in the manufacturing method, unless otherwise specified, C 3-8 cycloalkyl group, -O-C 1 ⁇ 6 alkyl group, -S-C 1 ⁇ 6 alkyl group, 3- to 8-membered non-aromatic A heterocyclic group, or a —NR A R B group;
  • each raw material compound used for the production of formula (I) may form a salt, and as such a salt, the same salts as those of the aforementioned formula (I) can be mentioned. Can be mentioned.
  • Each raw material compound used in the production of formula (I) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from a reaction mixture according to a conventional method. It can be easily purified by known means, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
  • Examples of the solvent used for the recrystallization include water; alcohols such as methanol, ethanol, 2-propanol and butanol; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; n-hexane, cyclohexane and heptane.
  • Hydrocarbons such as benzene, toluene, xylene, etc .; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; chloroform , Halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; nitriles such as acetonitrile; ketones such as acetone and diphenyl ketone; esters such as methyl acetate and ethyl acetate; sulfoxides such as dimethyl sulfoxide; , Trifluoroacetic acid, methanesulfur Phosphate, organic acids such as p- toluenesulfonic acid; and the like.
  • solvents can be used alone, or two or more kinds of solvents can be mixed at an appropriate ratio, for example, a ratio of 1: 1 to 1:10.
  • a ratio of 1: 1 to 1:10 can be used when the compound in a formula is marketed, a commercial item can also be used as it is, and what was manufactured by the method known per se or a method according to it can also be used.
  • substituent having the formula (I) is transformable functional group (e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto group, -C (O) -O-C 1 ⁇ 6 alkyl group, -C ( O) -O-C 6 ⁇ 14 aryl group, -C (O) -O- benzyl group, a sulfo group, when containing a halogen atom, etc.), is converted by a method analogous to these functional groups per se known methods or in As a result, various compounds can be produced.
  • transformable functional group e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto group, -C (O) -O-C 1 ⁇ 6 alkyl group, -C ( O) -O-C 6 ⁇ 14 aryl group, -C (O) -O- benzy
  • a “carboxy group” it can be converted by a reaction such as esterification, reduction, amidation, or a conversion reaction to an optionally protected amino group.
  • amino group it can be converted by a reaction such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.
  • hydroxyl group it can be converted by a reaction such as esterification, carbamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation, and the like.
  • carbonyl group it can be converted by a reaction such as reduction, oxidation, iminization (including oximation and hydrazone formation), (thio) ketalization, alkylidene formation, thiocarbonylation and the like.
  • mercapto group it can be converted by a reaction such as alkylation or oxidation.
  • halogen atom In the case of a “halogen atom”, it can be converted by, for example, various nucleophilic substitution reactions, various coupling reactions, and the like.
  • a hydroxyl group an alcoholic hydroxyl group, a phenolic hydroxyl group, a heterocyclic hydroxyl group, etc.
  • an amino group as a substituent
  • Examples of the protective group for the hydroxyl group include, for example, C 1-6 alkyl groups (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group). group, and tert- butyl group); - C 1 ⁇ 6 alkyl -O-C 1 ⁇ 6 alkyl group (methoxymethyl group, methoxyethoxymethyl group, etc.); a tetrahydropyranyl group; C 7 ⁇ 20 aralkyl group (e.g.
  • Silyl group for example, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, and t-butyldiphenylsilyl group); —C (O) —C 1- 6 alkyl group (e.g., acetyl group, ethylcarbonyl group, and pivaloyl group); - C (O) -C 7 ⁇ 20 aralkyl group (e.g., Ben Le carbonyl group); - C (O) -C 6 ⁇ 14 aryl group (e.g., benzoyl group); - C (O) -O -C 1 ⁇ 6 alkyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group , and t- butoxycarbonyl group or the like); - C (O) -O -C 7 ⁇ 20 aralkyl group (e.g., a benzyl group
  • the protecting group of the carboxyl group for example, C 1 ⁇ 6 alkyl group (e.g., methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group, and tert- butyl group); C 2 ⁇ 7 alkenyl group (vinyl group, and allyl group, etc.); C 6 ⁇ 14 aryl group (e.g., phenyl, etc.); C 7 ⁇ 20 aralkyl group (e.g., benzyl, and triphenylmethyl group); a silyl group (e.g. , Trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc.).
  • C 1 ⁇ 6 alkyl group e.g., methyl group, ethyl group, n- propyl group, an isopropyl
  • Examples of the protecting group for the thiol group include C 1-6 alkyl groups (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, etc.) ); C 7 ⁇ 20 aralkyl group (e.g., benzyl, and triphenylmethyl group and the like); - C (O) -C 1 ⁇ 6 alkyl group (e.g., acetyl group, ethylcarbonyl group, and pivaloyl group); -C (O) -C 6 ⁇ 14 aryl group (e.g., benzoyl group) and the like.
  • C 1-6 alkyl groups eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, etc.
  • Such protecting group introduction / removal method is appropriately carried out depending on the group to be protected or the type of protecting group.
  • Green, et al. Protective Groups in Organic Synthesis (Protective Groups in Organic). (Synthesis), 4th edition, 2007, John Wiley & Sons, can be performed by the method described in the book.
  • the deprotection methods of protecting groups e.g., -C (O) -C 1 ⁇ 6 alkyl group (e.g., acetyl group, ethylcarbonyl group, and pivaloyl group); - C (O) -O -C 1 ⁇ 6 alkyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, and t- butoxycarbonyl group or the like); - acyl type protecting groups such as C (O) -C 6 ⁇ 14 aryl group (e.g., benzoyl group, etc.),
  • a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • -C 1 ⁇ 6 alkyl -O-C 1 ⁇ 6 alkyl group (methoxymethyl group, methoxyethoxymethyl group, etc.); a tetrahydropyranyl group; -C (O) -O-C 1 ⁇ 6 alkyl group (e.g., methoxy group, an ethoxycarbonyl group, and t- butoxycarbonyl group or the like); - C (O) -O -C 7 ⁇ 20 aralkyl group (e.g., benzyloxycarbonyl group, and para-methoxybenzyloxycarbonyl group, etc.); silyl groups Protecting groups such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group and the like are, for example, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, triflu
  • the silyl group can also be deprotected by using a suitable fluorine ion (F ⁇ ) generating reagent, for example, a reagent such as tetrabutylammonium fluoride or hydrogen fluoride.
  • a suitable fluorine ion (F ⁇ ) generating reagent for example, a reagent such as tetrabutylammonium fluoride or hydrogen fluoride.
  • C 7 ⁇ 20 aralkyl group e.g., benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, and para-nitrobenzyloxycarbonyl group and the like
  • C 7 ⁇ 20 aralkyl group e.g., benzyl group And the like can be deprotected by hydrogenolysis using, for example, a palladium-carbon (Pd—C) catalyst.
  • the above C 7 ⁇ 20 aralkyl group (e.g., benzyl group) protecting groups are, for example, in liquid ammonia, can be deprotected by Birch reduction using metal sodium.
  • the triphenylmethyl group can be deprotected by using an appropriate acid, for example, an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination thereof. . It can also be deprotected by liquid Birch reduction using metallic sodium or metallic lithium or hydrogenolysis using a palladium carbon catalyst.
  • an appropriate acid for example, an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination thereof.
  • an appropriate acid for example, an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination thereof.
  • It can also be deprotected by liquid Birch reduction using metallic sodium or metallic
  • deprotection can be achieved by using one-electron reduction using Na / anthracene or Na / naphthalene at low temperature or Birch reduction using metallic sodium or metallic lithium in liquid ammonia.
  • 2-nitrobenzenesulfonyl group and a 2,4-nitrobenzenesulfonyl group for example, the presence of a basic reagent such as potassium carbonate or triethylamine, reacting the thiol, Can be deprotected under mild conditions.
  • a basic reagent such as potassium carbonate or triethylamine
  • the protecting group deprotection method shown here is only one example.
  • Green et al. “Protective Groups in Organic Synthesis, 4th Edition, 2007. Deprotection is possible by applying the method described in the book of John Wiley & Sons or various published papers.
  • the reaction conditions in the production method described below are as follows unless otherwise specified.
  • the reaction temperature is in the range from ⁇ 78 ° C. to the temperature at which the solvent is refluxed. When the temperature is not described, it is room temperature (0 to 35 ° C.), and the reaction time is the time for which the reaction proceeds sufficiently. .
  • each step in the production method can be performed without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate reaction before the reaction.
  • solvents that do not participate in the reaction include water; saturated hydrocarbon solvents such as cyclohexane and hexane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, and xylene; methanol, ethanol, 1-propanol, 2 Alcohol solvents such as propanol, tert-butyl alcohol, 2-methoxyethanol; N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone Polar amide solvents such as: sulfoxide solvents such as dimethyl sulfoxide; nitrile solvents such as acetonitrile and propionitrile; diethyl ether, diisopropyl ether, diphenyl
  • the base (or deoxidizer) used in the method for producing the compound of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, Inorganic bases such as cesium carbonate, calcium carbonate, sodium bicarbonate; triethylamine, N, N-diisopropylethylamine (DIPEA), tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N, N- Dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1 , 8-diazabicyclo [5.4.0] -7-undece
  • Organic bases such as imidazole; sodium methoxide, sodium e
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid; acetic acid, trifluoroacetic acid, oxalic acid , Organic acids such as phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid; boron trifluoride ether complex, zinc iodide, anhydrous Lewis acids such as aluminum chloride, anhydrous zinc chloride, and anhydrous iron chloride.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid
  • acetic acid trifluoroacetic acid, oxalic acid
  • Organic acids such as phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulf
  • the salt of the formula (I) is prepared according to a method known per se.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • organic acids such as formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
  • formula (I) is an acidic compound, ammonia, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N -Diisopropylethylamine, N, N'-dibenzylethylenediamine, N, N-dialkyl
  • an organic base such as ruaniline or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide
  • a Pd catalyst such as tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), and 4,5′-bis (diphenylphosphino)
  • phosphine reagents such as -9,9'-dimethylxanthene (XANTPHOS) and organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate, toluene, xylene, N , N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, acetonitrile (
  • the compound represented by the formula (AM-3) can be produced by reacting at a temperature at which the solvent is refluxed.
  • ⁇ Step 2> [Production Method A] Using a compound represented by the formula (AM-3) obtained in ⁇ Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis” 4ThEdition) 4th edition, 2007, John Wiley & Sons (John Wiley & Sons), in accordance with the method described in textbooks of green (Greene) et al ", in accordance with the type of the protecting group the protecting group P 2 By reacting by the method, a compound represented by the formula (AM-4) in which the P 2 group is deprotected can be produced.
  • ⁇ Step 3> [Production Method A] Using the amine of formula (AM-4) obtained in ⁇ Step 2> and the carboxylic acid of formula (CA), a method known in the literature, for example, “Experimental Chemistry Course 4th Edition 22 Organic Synthesis” In accordance with the method described in IV Acid / Amino Acid / Peptide, 191-309, 1992, Maruzen, etc., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl) ) Carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), benzotriazole-1-iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic Chloride (BOP-Cl), 2-chloro-1,3-dimethylimidazolinium
  • carboxylic acid of the formula (CA) is converted into a method known in the literature, for example, “Journal of the American Chemical Society, 109 (24), p7488-7494, 1987”.
  • a base such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine, thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, trichloride.
  • halogenating agent such as phosphorus, phosphorus pentachloride or phosphorus tribromide and a solvent inert to the reaction such as dioxane, tetrahydrofuran, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, or a mixed solvent thereof.
  • a solvent inert such as dioxane, tetrahydrofuran, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, or a mixed solvent thereof.
  • ⁇ Step 2> [Production Method B] Using a compound of formula (AM-5) obtained in ⁇ Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition” 4th edition, 2007, according to the method described in the book of John Wiley & Sons, Greene et al., The protecting group P 1 is reacted by a method according to the type of the protecting group. Thus, a compound represented by the formula (AM-6) in which the P 1 group is deprotected can be produced.
  • ⁇ Step 2> [Method C] Compounds of ⁇ Step 1> In the resulting formula (IM-1), and halogenated C 6 ⁇ 14 aryl compound of formula (RG-1) (the compound document from commercially available compounds, or commercially available compound The compound is a compound that can be produced by a known production method), and a method known in the literature, for example, “Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI —Organic synthesis using metals—327-352, 2004, Maruzen And palladium (II) acetate (Pd (OAc) 2 ) according to the methods described in Journal of Medicinal Chemistry, 48 (20), p 6326-6339, 2005.
  • trialkylborate such as trimethylborate and triisopropylborate was added, and the reaction was carried out at ⁇ 78 ° C. at room temperature, and then acid such as hydrochloric acid and sulfuric acid was added. The reaction is carried out at a temperature at which the solvent refluxes from -1) boronic acids can be produced.
  • a compound of formula (AR-2-1) and a compound of formula (AM-1) (formula (AR-2-1) and compound of formula (AM-1) are commercially available compounds, or known production from literature
  • the compound of formula (D-1) can be produced by carrying out a reaction according to [Production Method B] ⁇ Step 3> using a compound of (a compound that can be produced by the method).
  • the compound of formula (AR-2-2), and the compound of formula (AM-1) (formula (AR-2-2) and compound of formula (AM-1) are commercially available compounds, or prepared from commercially available compounds in the literature
  • the compound of formula (D-3) can be produced by carrying out a reaction according to [Production Method B] ⁇ Step 3>.
  • ⁇ Step 7> [Production Method D] Using the compound of the formula (D-3) obtained in ⁇ Step 6> and trifluoroacetic anhydride (TFAA), a method known in the literature, for example, “Patent of International Publication No. WO 2007/043777. In the presence of a base such as triethylamine, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. in the presence of a base such as triethylamine. Compounds can be produced.
  • TFAA trifluoroacetic anhydride
  • a compound of formula (E-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature), and a compound of formula (RG-2) or formula (RG-3)
  • the compound of formula (E-2) can be produced by carrying out a reaction according to [Production method C] ⁇ Step 4>.
  • the compound of the formula (CA-3) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction such as 4-dioxane and tetrahydrofuran, or a mixed solvent thereof.
  • reaction can be carried out at a temperature at which the solvent is refluxed from 0 ° C. to produce a compound of formula (CA-3).
  • a compound of the formula (G-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a method known in the literature), and a hydrazine compound of the formula (G-2) (the compound is a commercially available compound) Or a compound that can be produced from a commercially available compound by a production method known in the literature), in the presence of acetic acid according to a method known in the literature, for example, the method described in “International Publication No. 2007/043777 pamphlet” or the like.
  • a solvent that does not participate in the reaction such as tetrahydrofuran, 2-methoxyethanol, or a mixed solvent thereof, at a temperature at which the solvent is refluxed from 0 ° C. to produce a compound of formula (G-3). it can.
  • LDA lithium diisopropylamide
  • J-1 the compound was a commercially available compound or It is a compound that can be produced from a commercially available compound by a known production method in the literature
  • the reaction solution is added with excess dry ice (solid piece) or excess carbon dioxide gas to carry out the reaction.
  • an acid such as (CA-5-3) It can be prepared of compounds.
  • Combination agent containing the compound of the present invention can be used in combination with other drugs or drugs by a general method used in the medical field.
  • Examples of the drug that can be combined or used in combination with the compound of the present invention include (A) a sleep disorder-related drug, (B) a therapeutic drug for a disease that easily causes sleep disorder, and the like.
  • Examples of the drug (A) include: (1) sleep inducers ((i) benzodiazepine-based sleep inducers [specifically, nitrazepam, estazolam, flurazepam hydrochloride, nimetazepam, flurazepam, haloxazolam, flunitrazepam, rilmazapine hydrochloride, Lormetazepam, triazolam, etc.], (ii) thienodiazepine sleep inducer [specifically, brotizolam, etc.], (iii) non-benzodiazepine sleep inducer [specifically, zolpidem, etc.], (iv) melatonin receptor operation Drugs (specifically, ramelteon, etc.), (v) cyclopyrrolone sleep inducers [specifically, zopiclone, etc.], (vi) orexin receptor antagonists [specifically, suvorexant, etc.], ( 2) Drugs prescribed for sleep apnea
  • Examples of the drug of (B) include (4) atypical antipsychotic drugs [specifically, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, paliperidone, perospirone, blonanserin, lurasidone, aripiprazole, sertindole, amisulpride, Iloperidone, bifeprunox, asenapine, melperone, brexpiprazole, zotepine, etc.], (5) typical antipsychotics [specifically, chlorpromazine, pchlorperazine, perphenazine, levomepromazine, fluphenazine, thioridazine, propericazine, spiperone] , Moperon, haloperidol, timiperone, bromperidol, pimozide, fluropipamide, sulpiride, thioprid, s
  • Muscarinic M1 acetylcholine receptor activity modulator (21) Muscarinic M2 acetylcholine receptor activity modulator, (22) Adenosine receptor modulator, (23) Muscarinic M4 acetylcholine receptor activity regulator, (24 ) Muscarinic M5 acetylcholine receptor activity modulator, (25) adenosine receptor modulator, (26) glycine transporter 1 (GlyT1) inhibitor [specifically, ALX5407, SSR504734, etc.], (27) glutamate enhancer [Specifically, ampakine], (28) NMDA receptor inhibitor [specifically, memantine hydrochloride and the like], (29) metabolic glutamate receptor modulator (mGlu) [specifically, CDPPB, MPEP Etc.], (30) Anti-anxiety drugs ((i) benzodiazepine anxiolytic drugs [specifically Chlordiazepoxide, diazepam, oxazolam, medazep
  • Antidiabetic agent ((i) PPAR ⁇ agonist (agonist, inhibitor) [specifically, pioglitazone, rosiglitazone, troglitazone, siglitazone, darglitazone, englitazone, netoglitazone, etc.], (ii) insulin Secretion enhancer [(a) sulfonylurea (specifically, tolbutamide, acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, glipentide, glyquidone, glisolamide, tolazamide, etc.), (b) non-sulfonylurea Agents, etc.], (iii) fast-acting insulin secretagogues (specifically, nateglinide, mitiglinide, repaglinide, etc.), (iv) ⁇ -glucosidase inhibitors [specifically, acarbose, a
  • GPR40 agonists GPR40 agonists, (g) GPR119 agonists, (h) GPR120 agonists], (vi) hepatic gluconeogenesis inhibitors [specifically, glucagon antagonists, etc.], vii) biguanides [specifically, metformin, buformin, phenformin, etc.], (viii) insulin or insulin derivatives [specifically, insulin Phosphorus zinc suspension, insulin lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemir, mixed insulin, etc.], (ix) ⁇ 2 antagonist [specifically, midaglyzol, isagridol, deliglidol, idazoxan , Efaloxane, etc.]),
  • anti-obesity drugs ((i) adrenergic ⁇ 3 receptor agonists [specifically, KRP-204, TRK-380 / TAC-301, etc.], (ii) CB-1 receptor antagonists [specifically Rimonabant, SR-147778, BAY-65-2520 etc.], (iii) Neuropeptide Y (NPY) receptor antagonist [specifically, S-2367 etc.], (iv) Antifeedant [monoamine] Reuptake inhibitors [specifically sibutramine, mazindol, etc.]], (v) lipase inhibitors [specifically, orlistat, cetiristat, etc.], (vi) peptide YY (PYY) receptor antagonists, etc.), (40) Antihyperlipidemic drugs such as cholesterol-lowering drugs ((i) ⁇ 3 fatty acids [specifically, ethyl icosapentate (EPA-E preparation, for example, product name: Epadale (registered trademark) ), Docos,
  • Antihypertensive agent (i) diuretic [specifically, trichlormethiazide, hydrochlorothiazide, mefluside, indapamide, methiclan, chlorthalidone, tripamide, furosemide, torasemide, bumetanide, ethacrynic acid, spironolactone, triamterene, eplerenone, etc.]
  • (Ii) Calcium receptor antagonists [specifically, amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nitrendipine, nilvadipine, alanidipine, azelnidipine, manidipine, varnidipine, efonidipine, cilnidipine, benidipine, diltiazem etc.], (synten) Converting enzyme inhibitors [specifically, captopril, lisinopril,
  • Non-steroidal anti-inflammatory drugs [specifically, meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.], (43) disease-modifying anti-rheumatic drugs, (44) anti-cytokine drugs [44] Specifically, TNF inhibitors, MAP kinase inhibitors], (45) steroid drugs [specifically, dexamethasone, hexestrol, cortisone acetate, etc.], (46) sex hormones or derivatives thereof [specifically, , Progesterone, estradiol, estradiol benzoate, etc.], (47) parathyroid hormone, (48) opioid agonist [specifically, morphine, pentazocine, tramadol], (49) pilin antipyretic analgesic [specifically, Sulpyrine], (50) non-pyrine antipyretic analgesics [specific Acetamin
  • the combination method using the drug is not limited to the above diseases, and the drug used in combination is not limited to the compounds exemplified above.
  • the compound of the present invention when used in combination with a drug used in combination, it may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.
  • the compounds of the present invention can be administered either alone or in combination with a pharmaceutically acceptable carrier, either single or multiple doses.
  • suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution, and various organic solvents.
  • the pharmaceutical composition thereby formed can then be easily administered in various dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injection solutions and the like.
  • These pharmaceutical compositions can optionally contain additional ingredients such as flavoring agents, binders, excipients and the like.
  • the compounds of the present invention may be used for oral, buccal, nasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), transdermal (eg, patch), or rectal administration, or by inhalation or insufflation.
  • parenteral eg, intravenous, intramuscular, or subcutaneous
  • transdermal eg, patch
  • rectal administration or by inhalation or insufflation.
  • the administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Such dosage forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference, (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the
  • the concomitant drug and the compound of the present invention may be administered at the same time, but after administering the concomitant drug, the compound of the present invention may be administered.
  • a concomitant drug may be administered after administration of the compound of the invention.
  • the time difference varies depending on the active ingredient to be administered, dosage form, and administration method.
  • administering the concomitant drug first preferably within 1 minute to 3 days after administering the concomitant drug.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. The method of doing is mentioned.
  • the daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptom, etc., for example, when orally administered to a patient with schizophrenia (adult, body weight about 60 kg), Usually, the dose is about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer once to several times (eg, 2, 3, 4 or 8 times). When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, and the like which can be oral or parenteral (Eg, topical, rectal, intravenous, etc.).
  • the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the administration subject is a human
  • 0.01 to 100 parts by mass of the concomitant drug may be used per 1 part by mass of the compound of the present invention.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0, based on the whole preparation. The range is from 1 to 50% by mass, and more preferably from about 0.5 to 20% by mass.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0.1 to about It is in the range of 50% by weight, more preferably in the range of about 0.5 to about 20% by weight.
  • the content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by mass, preferably about 10 to about 90% with respect to the whole preparation. It is the range of mass%.
  • the same content may be used when the compound of the present invention and the concomitant drug are formulated separately. As described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.
  • the medicament of the present invention is administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention only needs to contain at least one of the compounds represented by the formula (I) of the present invention, and is optionally combined with a pharmaceutically acceptable additive.
  • excipients eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch
  • binders eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricants (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrants (eg; starches (corn starch, potato starch), carboxymethyl starch sodium, potassium Lumellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, cellulose
  • triethyl citrate, macrogol masking agents (e.g. titanium oxide), colorants, flavoring agents, preservatives (e.g. benzalkonium chloride, paraoxybenzoate), isotonic agents (e.g .; Glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH adjuster (eg; buffer solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stabilizer (eg; Sugar, sugar alcohol, xanthan gum), dispersant, antioxidant (eg Asco Binic acid, butylhydroxyanisole (BHA), propyl gallate, dl- ⁇ -tocopherol), buffer, preservative (eg, paraben, benzyl alcohol, benzalkonium chloride), fragrance (eg, vanillin, l-menthol) , Rose oil), solubilizers (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene
  • Various dosage forms include, for example, tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, troches, liquids, spirits, suspensions Agents, extracts, elixirs and the like.
  • the medicament of the present invention is, for example, oral, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration. It can be administered to patients by intraventricular administration, rectal administration, inhalation and the like.
  • the compounds of the present invention can be formulated for parenteral administration by injection, including using conventional catheter techniques or infusion.
  • injectable formulations may be presented as unit dosage forms, for example, in ampoules or multi-dose containers, with the addition of preservatives.
  • These formulations can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and contain formulation agents such as suspending, stabilizing, and / or dispersing agents. be able to.
  • the active ingredient can be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.
  • the product solution is isolated and included in water (or other aqueous medium) in an amount sufficient to produce a solution of the strength required for oral or parenteral administration to the patient. It can be produced by dissolving the complex.
  • These compounds can be formulated into rapidly dispersed dosage forms (fddf) that are designed to release the active ingredient in the oral cavity. These formulations are often formulated using a matrix based on fast dissolving gelatin. These dosage forms are well known and can be used to deliver a wide range of drugs. Most rapid dispersion dosage forms utilize gelatin as a carrier or structure-forming agent. Gelatin is typically used to give a dosage form sufficient strength to prevent breakage when removed from the package, but once in the mouth, gelatin allows the dosage form to break down immediately. . Alternatively, various starches are used to achieve the same effect.
  • the compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the invention may be administered in the form of a solution or suspension from a pump spray container which is squeezed or pumped by the patient, or a suitable propellant such as dichloromethane.
  • a suitable propellant such as dichloromethane.
  • the dosage unit can be determined by providing a valve that delivers a metered amount.
  • a pressurized container or nebulizer can contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator should be formulated containing a mixed powder of a compound of the invention and a suitable powder base such as lactose or starch. Can do.
  • Aerosol formulations for treating the above-described conditions (eg, migraine) in the average adult preferably each metered dose or “puff” of the aerosol contains from about 20 mg to about 1000 mg of the compound of the invention. Is set as follows.
  • the total daily dose with an aerosol will be within the range of about 100 mg to about 10 mg.
  • Administration can be several times daily, for example 2, 3, 4 or 8 times, for example 1, 2 or 3 doses each time.
  • Proposed daily doses of the compounds of the invention administered orally, parenterally, rectally, or buccally to the average adult to treat the above conditions are, for example, units that can be administered 1 to 4 times daily From about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg, of the active ingredient of formula (I) per dose.
  • OXR antagonistic activity of the test compounds OX2R and IC 50 values of OXlR (an IC 50 value is ++ with 100 nmol / L the following compounds, an IC 50 value is the compound of greater than 1000 nmol / L or less of the present invention 100 nmol / L + The compounds with IC 50 values greater than 1000 nmol / L are expressed as ⁇ ).
  • ADL-OXB is a peptide in which two amino acids of human orexin B are substituted, and has a 400 times higher affinity for OX2R than OX1R.
  • rats are cannulated and kept for at least 1 week as a recovery period.
  • 100 ng / 5 ⁇ L of angiotensin 2 (Peptide Institute) is administered intraventricularly as a preliminary test, and the amount of water consumed for 30 minutes after the administration is measured. Only rats that have reached 5 g of drinking water are used in this study. Rats are acclimated for at least 120 minutes in the measurement cage until this test.
  • either vehicle or test compound is administered and immediately returned to the measurement cage.
  • 30 to 120 minutes after administration of the test compound the rat is again taken out from the housing cage, and the solvent (saline) or ADL-OXB (3 nmol / 5 ⁇ L / rat) is administered into the ventricle and immediately returned to the measurement cage.
  • Spontaneous momentum is measured in a spontaneous momentum measurement chamber (Muromachi Kikai) equipped with an infrared sensor. Spontaneous exercise is counted every 10 minutes, and cumulative counts for 30, 60, 120 minutes after ADL-OXB administration are calculated for each treatment group. All data are expressed as mean and standard error of the mean.
  • comparison between the control group and ADL-OXB single administration group was performed using Student's t-test (significant difference at p ⁇ 0.05), and comparison between ADL-OXB single administration group and test compound administration group Uses Dunnett's test (significantly different at p ⁇ 0.05).
  • Pharmacological experiment example 3 Sleep EEG measurement test After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals are used for experiments with an acclimatization period of at least one week. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water. In order to confirm the effect on sleep, a sleep electroencephalogram test in rats is performed. Rats are subjected to EEG and EMG electrode implantation surgery for electroencephalogram (EEG) and electromyogram (EMG) measurement, and are kept for at least 1 week as a recovery period. After administration of vehicle or test compound, EEG and EMG signals are recorded for 6-12 hours.
  • EEG electroencephalogram
  • EMG electromyogram
  • the analysis is performed by using an automatic analysis software SleepSign (registered trademark) (Kissei Comtech) to analyze an electroencephalogram frequency and an electromyogram activity signal to classify one of three stages of arousal, REM sleep, and NREM sleep.
  • the cumulative time of each stage is calculated, and the sleep action of the test compound is confirmed from the decrease in the awakening time and the increase in the total sleep time (REM sleep + NREM sleep).
  • the percentage of REM sleep with respect to the total sleep time is calculated, and it is examined whether a physiological sleep pattern is shown by comparing with the result of the control group.
  • DMSO Precipitation Solubility (Kinetic Solubility) A 10 mM DMSO solution of the compound of the present invention is added to 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 ⁇ M. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, then filtered through a filter plate (MultiScreen HTS- PCF filter plate (Merck Millipore)), and using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). Then, the absorbance of the filtrate is measured at the maximum absorption wavelength.
  • a filter plate MultiScreen HTS- PCF filter plate (Merck Millipore)
  • Powerscan HT Powerscan HT (Dainippon Pharmaceutical)
  • the absorbance of each standard solution is measured using a DMSO solution to which a known concentration (1, 3, 10, 30, 100 ⁇ M) of the test compound is added as a calibration curve standard solution, and a calibration curve is created.
  • the solubility ( ⁇ M) of the compound is calculated from the absorbance values of the filtrate and standard solution.
  • Crystal solubility Thermodynamic Solubility
  • the compound of the present invention is added to a solvent (eg, water, buffer) so as to be 1 mg / mL. The solution is incubated with stirring at 1000 rpm for 24 hours at 25 ° C. or 37 ° C. and then filtered through a filter plate.
  • the filtrate is analyzed by HPLC, the peak is detected at the maximum absorption wavelength, and the peak area is measured.
  • a solution eg, DMSO solution, 1,4-dioxane solution
  • a known concentration of the test compound eg, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 ⁇ g / mL
  • Methanol solution is used as a standard curve standard solution to measure each peak area, and the solubility ( ⁇ g / mL) of the compound is calculated from the peak area of the standard curve.
  • Metabolic stability test (1) Liver microsomal solution (human, rat, mouse, dog or monkey; XenoTech), NADPH generating solution ( ⁇ -NADP, Glucose-6-phosphate, G- 6-PDH (Y), water containing MgCl 2 ). The solution is incubated at 37 ° C. for 5, 10, 20 or 30 minutes and then quenched with acetonitrile. The reaction solution is centrifuged through a filter plate (MultiScreen HTS- HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry.
  • a filter plate MultiScreen HTS- HV plate (Merck Millipore
  • the reaction solution is centrifuged through a filter plate (MultiScreenHTS-HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry.
  • a sample with a reaction time of 0 minutes is measured as a control, and the residual rate (%) at each time point is calculated from the ratio of the hepatocyte reaction sample and the control.
  • the reaction time is plotted on the horizontal axis and the residual ratio is plotted on the vertical axis, and the clearance ( ⁇ L / min / mg protein) is calculated from the slope.
  • hERG Inhibition Test by Patch Clamp Method The effect on hERG (human ether-a-go related gene) channels is measured using a fully automatic patch clamp system (QPatch HT (Sophion Bioscience)).
  • QPatch HT fully automatic patch clamp system
  • the membrane potential is held at ⁇ 80 mV, followed by a depolarization pulse of ⁇ 50 mV, 0.02 seconds and 20 mV, 4.8 seconds. -50 mV, 5 seconds of repolarization pulse given once every 15 seconds.
  • the effect of the test compound on the hERG channel is confirmed by the tail current change induced by the repolarization pulse.
  • the measurement is performed at room temperature.
  • the hERG channel inhibition rate is calculated as the reduction rate (suppression rate) of the tail current 4 minutes after the addition relative to the tail current peak value before the addition of the test compound. By calculating this suppression rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.
  • PK test The compound of the present invention was applied to animals (male Crl: CD (SD) rats of about 7 to 8 weeks of age, male beagle dogs of about 4 years of age, or male cynomolgus monkeys of about 6 years of age).
  • test compounds 0.001, 0.002, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 10 ⁇ g / (mL) is measured, the plasma concentration ( ⁇ g / mL) is calculated from the prepared calibration curve, and the maximum plasma concentration is defined as Cmax ( ⁇ g / mL).
  • Pharmacological experiment example 9 Calculation of various parameters in pharmacokinetics test Model-independent analysis of the time course of plasma concentration obtained by PK test (the above pharmacological experiment example 7) in rat, dog and monkey animal species Systemic clearance CLtot (L / kg / hr), distribution volume Vdss in steady state (L / kg), plasma concentration-time curve area AUC ( ⁇ g ⁇ hr / mL), half-life T1 / 2 (hr) Is calculated.
  • the bioavailability is calculated by comparing the AUC at the time of intravenous administration with the AUC at the time of oral administration.
  • Pharmacological experiment example 10 Prediction of pharmacokinetic parameters in humans Various parameters in animal pharmacokinetic tests, metabolic stability in in vitro tests, proteins obtained by the method described in pharmacological experiment examples 5, 7 or 8 above Using parameters such as binding rate, pharmacokinetic parameters in humans are predicted by methods known to those skilled in the art such as allometric scaling or IVIVE (in vitro / in vivo extrapolation).
  • Pharmacological experiment example 11 Safety test The compound of the present invention is orally administered to a mouse or rat once, and no deaths are observed, and no remarkable behavioral abnormality is observed. It is.
  • the compound of the present invention has an excellent orexin receptor antagonistic action. Furthermore, orexin antagonism is shown by an antagonism test against [Ala 11 , D-Leu 15 ] -orexin B-induced locomotor activity enhancement using rats, and sleep action is shown by a sleep electroencephalogram measurement test. In addition, no abnormality is observed in the safety test, indicating the low toxicity of the present invention. Furthermore, it is confirmed that the compound of the present invention is good in one point such as solubility, metabolic stability, pharmacokinetics, and avoidance of hERG channel inhibitory effect by conducting the above test.
  • the compounds of the present invention are orexin receptor antagonists, such as sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficits Prevention of diseases such as mobility disorders, autism, autism spectrum disorders, drug addiction, etc.), neurodegenerative diseases (such as Alzheimer's disease), memory disorders (such as dementia), and eating disorders (such as bulimia) And / or expected to be used in therapeutic agents.
  • the compounds of the present invention are expected to show promising preventive or therapeutic effects for various diseases shown below.
  • insomnia circadian rhythm sleep disorder
  • sleep-related comorbidities depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug addiction
  • Promising therapeutic effects can be expected for Alzheimer's disease, dementia, bulimia and the like.
  • JEOL JNM-ECX400 FT-NMR (JEOL) or JEOL JNM-ECX300 FT-NMR (JEOL) was used.
  • Liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by one of the following methods.
  • Root temperature in the examples and production examples represents the temperature in the laboratory, usually 20 ⁇ 15 ° C.
  • Step 2 Synthesis of 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane hydrochloride (intermediate 1) tert-butyl 5- (4,6 -Dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 1-1) (0.50 g) in 4N hydrochloric acid-dioxane solution (3.0 mL) ) And stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure to obtain the title compound (0.40 g) as a white solid.
  • Step 4> of tert-butyl 5- (4-cyano-3-methoxypyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 2-4) Synthesis 2-chloro-3-methoxyisonicotinonitrile (intermediate 2-3) (0.26 g), tert-butyl 2,5-diazabicyclo [2.2.2] octane-2-carboxylate (0.30 g) ), RuPhos (66 mg), and a mixed solution of cesium carbonate (0.69 g) in tetrahydrofuran (3.0 mL) were added with RuPhos Pd G2 (0.11 g) and stirred at 90 ° C.
  • Step 5 Synthesis of 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3-methoxyisonicotinonitrile (intermediate 2) tert-butyl 5- (4-cyano- 3-methoxypyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 2-4) (0.13 g) was added trifluoroacetic acid (1.0 mL). The mixture was further stirred at room temperature for 1 hour.
  • the solvent was evaporated under reduced pressure, 1N aqueous hydrochloric acid solution was added to the resulting residue, and the mixture was washed with an ethyl acetate-heptane mixed solvent (1: 1).
  • the aqueous layer was basified with 1N aqueous sodium hydroxide solution, sodium chloride was added, and the mixture was extracted 5 times with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (21 mg) as a pale yellow gum.
  • Step 2> Synthesis of 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (intermediate 4) Methyl 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylate (intermediate) Lithium hydroxide monohydrate (0.11 g) was added to a THF (2.0 mL) -water (0.50 mL) mixed solution of Compound 3-1) (0.35 g), and the mixture was heated at 60 ° C. under a nitrogen atmosphere. Stir for 2 hours. 1N Hydrochloric acid aqueous solution was added to stop the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine.
  • Step 3> Synthesis of 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane optical isomer (intermediate 5-B) Step of Production Example 5 2 or a method analogous thereto, tert-butyl 5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2] obtained in Step 1 of Production Example 5 was used. .2] The title compound (85 mg) was obtained as a pale yellow solid from the optical isomer of Octane-2-carboxylate (Intermediate 5-1-B) (0.13 g). UPLC: 219 [M + H] + (retention time 0.51 minutes)
  • Step 2 Synthesis of 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3-methoxyisonicotinonitrile optical isomer (intermediate 6-A)
  • tert-butyl 5- (4-cyano-3-methoxypyridin-2-yl) -2,5-diazabicyclo [O] obtained in Step 1 of Production Example 6 2.2.2
  • the title compound (40 mg) was obtained as an orange gum from the optical isomer of the octane-2-carboxylate (6-1-A) (60 mg).
  • Step 3 Synthesis of optical isomer of 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotinonitrile (intermediate 6-B)
  • tert-butyl 5- (4-cyano-3-methoxypyridin-2-yl) -2,5-diazabicyclo [O] obtained in Step 1 of Production Example 6 2.2.2
  • the title compound (41 mg) was obtained as an orange gum from the optical isomer of the octane-2-carboxylate (6-1-B) (58 mg).
  • tert-butyl 5- (4-cyano-3-cyclopropylpyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 7-2)
  • tert-butyl 5- (3-chloro-4-cyanopyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 7-1) (0.
  • tetrakis (triphenylphosphine) palladium (0.35 g) was added to a THF (2.5 mL) mixed solution of cyclopropyl zinc bromide (0.5 N THF solution) (9 mL), and the mixture was heated to 100 ° C. under a nitrogen atmosphere. And stirred for 15 hours. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate.
  • Step 5 Synthesis of optical isomer of 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicotinonitrile (intermediate 7-B)
  • Production Example 5 Tert-Butyl 5- (4-cyano-3-cyclopropylpyridin-2-yl) -2,5- obtained in Step 3 of Production Example 7 in the same manner as in Step 2 above or a method analogous thereto.
  • the title compound (42 mg) was obtained as a yellow oil from the optical isomer of diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 7-3-B) (52 mg).
  • Example 1 (5- (4,6-Dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-yl) (5-methyl-2- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone tert-butyl 5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2- Trifluoroacetic acid (0.88 mL) was added to a dichloromethane solution of carboxylate (intermediate 1-1) (0.11 g), and the reaction solution was stirred at room temperature for 2 hours.
  • Example 7 2- (5- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2,5-diazabicyclo [2.2.2] octane-2-yl)- Synthesis of 3-methoxyisonicotinonitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotinonitrile (intermediate 2) (11 mg), 2- ( To a mixed solution of 2H-1,2,3-triazol-2-yl) benzoic acid (9.5 mg) and HATU (21 mg) in DMF (1.0 mL) was added triethylamine (9.5 ⁇ L), and the mixture was stirred at room temperature for 64 hours.
  • Example 8 2- (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino Synthesis of nitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotinonitrile (intermediate 2) (25 mg), 2- (1H-pyrazole-1- Il) 2,6-lutidine (36 ⁇ L) was added to a mixed solution of nicotinic acid (23 mg) and HATU (58 mg) in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere.
  • Example 11 (5- (4,6-Dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-yl) (1- (pyridin-2-yl)- Synthesis of 1H-pyrazol-5-yl) methanone optical isomer 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane optical isomer (intermediate 5 -B) (35 mg), 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 4) (31 mg), in a mixed solution of DMF (1.0 mL), HATU (63 mg), diisopropyl Ethylamine (72 ⁇ L) was added and stirred at room temperature for 30 minutes.
  • Example 12 (5- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2,5-diazabicyclo [2.2.2] octane-2-yl)- Synthesis of 3-methoxyisonicotinonitrile optical isomer 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3 in the same manner as in Example 7 or a method analogous thereto The title compound (13 mg) was obtained as a colorless amorphous form from the optical isomer of 2-methoxyisonicotinonitrile (Intermediate 6-A) (14 mg). UPLC: 416 [M + H] + (retention time 1.02 minutes) 1 H-NMR was consistent with (Example 7).
  • Example 13 2- (5- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2,5-diazabicyclo [2.2.2] octane-2-yl)- Synthesis of 3-methoxyisonicotinonitrile optical isomer 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3 in the same manner as in Example 7 or a method analogous thereto The title compound (7.7 mg) was obtained as a colorless amorphous form from the optical isomer of 2-methoxyisonicotinonitrile (intermediate 6-B) (18 mg). UPLC: 416 [M + H] + (retention time 1.02 minutes) 1 H-NMR was consistent with (Example 7).
  • Example 14 (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino
  • optical isomer of nitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino by the same method as in Example 7 or a method analogous thereto
  • the title compound (6.2 mg) was obtained as a colorless amorphous form from the optical isomer of nitrile (Intermediate 6-A) (12 mg).
  • Example 15 2- (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino Synthesis of optical isomer of nitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino by the same method as in Example 7 or a method analogous thereto The title compound (9.6 mg) was obtained as a colorless amorphous form from the optical isomer of nitrile (Intermediate 6-B) (12 mg). UPLC: 416 [M + H] + (retention time 0.99, 1.01 min, rotamer) 1 H-NMR was consistent with (Example 8).
  • Example 16 2- (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicoti Synthesis of optical isomers of nononitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicotinonitrile optical isomer (intermediate 7-A) ( 22 mg), 2- (1H-pyrazol-1-yl) nicotinic acid (16 mg), and HATU (40 mg) in dichloromethane (2 mL) were added with 2,6-lutidine (20 ⁇ L), and a nitrogen atmosphere at room temperature was added.
  • Example 17 2- (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicoti Synthesis of optical isomers of nononitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropyliso-isolated by a method similar to or equivalent to that in Example 16. The title compound (26 mg) was obtained as a colorless amorphous form from the optical isomer of nicotinonitrile (Intermediate 7-B) (21 mg). UPLC: 426 [M + H] + (retention time 1.02, 1.06 min, rotamer)
  • Example 18 2- (5- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2,5-diazabicyclo [2.2.2] octane-2-yl)- Synthesis of optical isomers of 3-cyclopropylisonicotinonitrile 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) in the same manner as in Example 16 or a method analogous thereto The title compound (26 mg) was obtained as a colorless amorphous form from the optical isomer of -3-cyclopropylisonicotinonitrile (Intermediate 7-A) (22 mg).

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Abstract

La présente invention concerne un composé ayant une activité antagoniste d'un récepteur de l'orexine, un sel pharmaceutiquement acceptable du composé, ou un solvate du composé ou le sel pharmaceutiquement acceptable ; une composition pharmaceutique caractérisée en ce qu'elle contient le composé, le sel ou le solvate pharmaceutiquement acceptable comme ingrédient actif ; et une utilisation du composé ou de la composition pharmaceutique à des fins médicales, particulièrement une utilisation du composé ou de la composition pharmaceutique comme agent prophylactique et/ou thérapeutique pour les maladies associées à un récepteur de l'orexine, telles que les troubles du sommeil, les maladies mentales, les maladies neurodégénératives, les troubles de la mémoire et les troubles alimentaires, particulièrement l'insomnie (un symptôme d'insomnie) qui représente l'un des troubles du sommeil. La présente invention concerne plus particulièrement un composé représenté par la formule (I), un sel pharmaceutiquement acceptable du composé, ou un solvate du composé ou le sel pharmaceutiquement acceptable.
PCT/JP2015/083926 2014-12-03 2015-12-02 Nouveau dérivé diazabicyclo[2.2.2]octane Ceased WO2016088813A1 (fr)

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WO2018228909A1 (fr) 2017-06-14 2018-12-20 Bayer Pharma Aktiengesellschaft Dérivés de diazépane pontés substitués et leur utilisation en tant qu'inhibiteurs de task-1 et de task-3
WO2018228907A1 (fr) 2017-06-14 2018-12-20 Bayer Aktiengesellschaft Imidazopyrimidines à substitution diazabicyclique et leur utilisation pour traiter des maladies des voies respiratoires
US10414765B2 (en) 2015-12-10 2019-09-17 Bayer Pharma Aktiengesellschaft Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10759794B2 (en) 2015-12-10 2020-09-01 Bayer Pharma Aktiengesellschaft 2-phenyl-3-(piperazinomethyl)imidazo[1,2-A]pyridine derivatives as blockers of task-1 and task-2 channels, for the treatment of sleep-related breathing disorders
CN111892599A (zh) * 2020-08-14 2020-11-06 黄芳 一种2,5-二氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯的合成方法
CN118598880A (zh) * 2024-08-07 2024-09-06 艾斯拓康生物医药(天津)有限公司 一类含氮桥环化合物及其制备方法和应用

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KR20210024563A (ko) 2018-06-27 2021-03-05 메이지 세이카 파루마 가부시키가이샤 염증성 질환, 자가면역 질환, 섬유화 질환 및 암 질환의 치료제

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US10414765B2 (en) 2015-12-10 2019-09-17 Bayer Pharma Aktiengesellschaft Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
US10759794B2 (en) 2015-12-10 2020-09-01 Bayer Pharma Aktiengesellschaft 2-phenyl-3-(piperazinomethyl)imidazo[1,2-A]pyridine derivatives as blockers of task-1 and task-2 channels, for the treatment of sleep-related breathing disorders
WO2018015196A1 (fr) 2016-07-20 2018-01-25 Bayer Aktiengesellschaft Composés diazahétérobicycliques substitués et leur utilisation
WO2018228909A1 (fr) 2017-06-14 2018-12-20 Bayer Pharma Aktiengesellschaft Dérivés de diazépane pontés substitués et leur utilisation en tant qu'inhibiteurs de task-1 et de task-3
WO2018228907A1 (fr) 2017-06-14 2018-12-20 Bayer Aktiengesellschaft Imidazopyrimidines à substitution diazabicyclique et leur utilisation pour traiter des maladies des voies respiratoires
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CN111892599A (zh) * 2020-08-14 2020-11-06 黄芳 一种2,5-二氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯的合成方法
CN111892599B (zh) * 2020-08-14 2023-01-13 黄芳 一种2,5-二氮杂双环[2.2.2]辛烷-2-羧酸叔丁酯的合成方法
CN118598880A (zh) * 2024-08-07 2024-09-06 艾斯拓康生物医药(天津)有限公司 一类含氮桥环化合物及其制备方法和应用

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