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WO2020085234A1 - Dérivé de morphinane - Google Patents

Dérivé de morphinane Download PDF

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Publication number
WO2020085234A1
WO2020085234A1 PCT/JP2019/041076 JP2019041076W WO2020085234A1 WO 2020085234 A1 WO2020085234 A1 WO 2020085234A1 JP 2019041076 W JP2019041076 W JP 2019041076W WO 2020085234 A1 WO2020085234 A1 WO 2020085234A1
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Prior art keywords
group
substituent
compound
nmr
cyclopropylmethyl
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English (en)
Japanese (ja)
Inventor
渡邉義一
茂木雄三
齊藤大祐
林田康平
山元広平
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Nippon Chemiphar Co Ltd
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Nippon Chemiphar 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a morphinan derivative having a kappa opioid receptor agonistic action.
  • ⁇ opioid receptor agonists Three types of opioid receptors are known, ⁇ , ⁇ , and ⁇ . Morphine, which has a strong affinity for the ⁇ receptor, has long been used as an analgesic.
  • ⁇ opioid receptor agonists are known to cause adverse events such as dependence formation and respiratory depression via the ⁇ opioid receptor.
  • kappa opioid receptor agonists also show an analgesic effect, but it is known that they do not participate in the adverse events seen in morphine.
  • kappa opioid receptor agonists are generally known to exhibit sedative action and drug aversion.
  • Patent Document 1 The only kappa opioid receptor agonist that separates drug aversion is nalfurafine (Patent Document 1), but since nalfurafine exhibits a sedative effect at an analgesic dose, approval as an antipruritic drug was obtained, but an analgesic drug. Has not been approved. That is, there are still no kappa opioid receptor-selective agonists approved as analgesics. Therefore, a ⁇ receptor-selective agonist that does not exhibit sedative action or drug aversion is expected as an excellent therapeutic or ameliorating or preventive drug for diseases and symptoms related to ⁇ opioid receptors such as analgesics.
  • Patent Document 2 the following formula (A),
  • An object of the present invention is to provide a medicine effective for treating, ameliorating, and preventing various diseases and symptoms related to the ⁇ opioid receptor, in which sedation and drug aversion are suppressed.
  • the present invention provides the following general formula (I):
  • R 1 is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 3-6 cycloalkyl group which may have a substituent, or a substituent C 3-6 cycloalkyl C 1-6 alkyl group, aryl group optionally having substituent (s), heteroaryl group optionally having substituent (s), aralkyl optionally having substituent (s) Group, heteroarylalkyl group optionally having substituent (s), C 2-6 alkenyl group optionally having substituent (s), C 2-6 alkynyl group optionally having substituent (s), substituent (s) Represents an acyl group or an amino protecting group which may have, R 2 and R 3 are the same or different and each is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, a halogen atom, a hydroxy group.
  • R 2 and R 3 together represent a carbonyl group or a thiocarbonyl group, or R 2 and R 3 are bonded to each other to represent a cyclic ketal which may have a substituent
  • R 4 and R 5 are the same or different and each have a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, and a substituent.
  • R 6 is a hydrogen atom, a C 1-6 alkoxy group which may have a substituent, an amino group which may have a substituent, a halogen atom, a hydroxy group, a cyano group, a carboxy group, a carboxylic acid ester group Or a carbamoyl group which may have a substituent
  • R 7 represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or a hydroxy group
  • R 8 and R 9 are the same or different and each is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, a halogen atom or a hydroxy group.
  • R 8 and R 9 together represent a carbonyl group or a thiocarbonyl group, or R 8 and R 9 are bonded to each other to form a C 3-6 saturated hydrocarbon ring which may have a substituent or a substituent.
  • Indicates a cyclic ketal that may have, R 10 and R 11 are the same or different and each is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, a halogen atom, a hydroxy group.
  • R 10 and R 11 together represent a carbonyl group or a thiocarbonyl group, or R 10 and R 11 are bonded to each other to form a C 3-6 saturated hydrocarbon ring which may have a substituent or a substituent.
  • R 12 and R 13 on the same carbon are bonded to each other to represent a C 3-6 saturated hydrocarbon ring which may have a substituent, a saturated heterocyclic ring which may have a substituent, or n
  • a pair of adjacent R 12 is bonded to form a C 3-6 saturated hydrocarbon ring which may have a substituent or a saturated heterocycle which may have a substituent.
  • R 14 is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 3-6 cycloalkyl group which may have a substituent, or a C 2 which may have a substituent.
  • a double line consisting of a solid line and a broken line represents a single bond or a double bond, and m represents an integer of 0 to 1, n represents an integer of 0 to 3.
  • a tautomer, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof is also provided.
  • the present invention also provides the morphinan derivative according to the above [1], wherein R 6 is a hydroxy group or a C 1-6 alkoxy group which may have a substituent, a tautomer of the compound, and stereoisomerism.
  • the present invention relates to the body, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the present invention also provides the morphinan derivative according to the above [1] or [2], wherein R 6 is a hydroxy group, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or Regarding their solvates.
  • the present invention also provides the morphinan derivative according to any one of the above [1] to [3], wherein R 7 is a hydrogen atom, a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof. Or, it relates to a solvate thereof.
  • the present invention also provides the morphinan derivative according to any one of the above [1] to [5], wherein Z is NR 15 , an oxygen atom, a bond or an ethenylene group which may have a substituent.
  • the present invention relates to a pharmaceutical composition containing a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
  • the present invention also provides the morphinan derivative according to any one of the above [1] to [5], wherein Z is either NR 15 or a bond, a tautomer, a stereoisomer of the compound, or a pharmaceutical thereof.
  • R 14 is an amino group which may have a substituent, a C 6-10 aryl group which may have a substituent, and a heteroaryl which may have a substituent. Or a saturated heterocyclic group which may have a substituent, the morphinan derivative according to any one of the above [1] to [6], a tautomer or stereoisomer of the compound, or a pharmaceutical thereof. Relates to a pharmaceutical composition containing a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.
  • the present invention also provides the morphinan derivative according to the above [7], wherein the C 6-10 aryl group which may have a substituent according to the above [7] is a phenyl group, a tautomer of the compound,
  • the present invention relates to a pharmaceutical composition containing a stereoisomer, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
  • the present invention also provides that the heteroaryl group optionally having a substituent described in [7] above is a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group.
  • 1,3,4-thiadiazolyl group isothiazolyl group, triazolyl group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidyl group, 2-oxopyridyl group, 4-oxopyridyl group, 2-oxopyrazinyl group, quinolyl group, isoquinolyl group , Indolyl group, indazolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzothiazolyl group, imidazopyridinyl group, imidazo [1,2-a] pyrimidyl group, pyrazolopyridinyl group, purine, adenine Or guanine, the morphinan derivative according to the above [7], Tautomers of the object, stereoisomer, or a pharmaceutical composition containing as an active ingredient a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also provides the morphinan derivative according to the above [7], wherein the saturated heterocyclic group optionally having a substituent according to the above [7] is a cyclic amino group, a tautomer of the compound,
  • the present invention relates to a pharmaceutical composition containing a stereoisomer, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
  • the present invention also provides that the cyclic amino group which may have a substituent as described in [10] above is an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, an azepanyl group, a morpholinyl group, a thiomorpholinyl group, 7- Azabicyclo [2.2.1] heptyl group, 3-oxa-8-azabicyclo [2.2.2] octyl group, 3-oxa-8-azabicyclo [3.2.1] octyl group, 8-azabicyclo [3 1.2.1]
  • a morphinan derivative according to the above [10] which is any of octyl groups, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the present invention relates to a pharmaceutical composition containing as an ingredient.
  • the present invention also provides the morphinan derivative according to any one of the above [1] to [11], wherein X is a nitrogen atom, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof. Or, it relates to a pharmaceutical composition containing a solvate thereof as an active ingredient.
  • the present invention also provides the morphinan derivative according to any one of the above [1] to [12], wherein Y is C ⁇ O, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable form thereof.
  • the present invention relates to a pharmaceutical composition containing a salt or a solvate thereof as an active ingredient.
  • the present invention also provides the morphinan derivative according to any one of the above [1] to [13], a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Relates to a pharmaceutical composition containing as an active ingredient.
  • the present invention also relates to the medicament according to the above [14], which is a therapeutic, ameliorating, or prophylactic agent for diseases associated with ⁇ opioid receptors.
  • the present invention also relates to the medicament according to [14] or [15] above, which is an analgesic drug.
  • the present invention also relates to the medicine according to the above [14] or [15], which is an antipruritic drug.
  • the C 1-6 alkyl group in the C 1-6 alkyl group which may have a substituent represented by R 1 to R 5 and R 7 to R 16 includes a methyl group, an ethyl group, a propyl group and an isopropyl group.
  • a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, and other linear or branched alkyl groups are preferred, and a methyl group, an ethyl group, a propyl group are preferred, and a methyl group is more preferred.
  • a methyl group, an ethyl group, a propyl group are preferred, and a methyl group is more preferred.
  • Examples of the C 3-6 cycloalkyl group in the C 3-6 cycloalkyl group which may have a substituent represented by R 1 and R 14 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. And preferably a cyclopropyl group.
  • the substituent in the C 1-6 alkyl group which may have a substituent and the C 3-6 cycloalkyl group which may have a substituent, which is represented by R 1 is a methyl group, an ethyl group or a propyl group.
  • C 1-6 alkyl group such as group, fluoromethyl group, difluoromethyl group, halogenated methyl group such as trifluoromethyl group, halogen atom such as fluorine atom and chlorine atom, hydroxy group, C 1-6 alkylamino group, Di C 1-6 alkylamino group, acylamino group, amino group which may have a substituent such as protected amino group, formyl group, acetyl group, cyclopropylcarbonyl group, acyl group such as benzoyl group, azetidinyl Group, a pyrrolidinyl group, a piperazinyl group, a cyclic amino group such as morpholinyl group, a lactam group such as ⁇ -lactam, ⁇ -lactam, and ⁇ -lactam. That.
  • Examples of the C 1-6 alkoxy group in the C 1-6 alkoxy group which may have a substituent represented by R 2 to R 11 and R 14 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group and a butoxy group. Group, a linear or branched alkoxy group such as an isobutoxy group, and preferably a methoxy group.
  • substituents examples include a C 1-6 alkoxy group such as a methoxy group and an ethoxy group, a phenoxy group, a halogen atom such as a fluorine atom and a chlorine atom, preferably a fluorine atom, specifically a fluoromethoxy group, Examples thereof include difluoromethoxy group, trifluoromethoxy group, and 2,2,2-trifluoroethoxy group.
  • Examples of the aryl group represented by R 1 and R 14 which may have a substituent include a phenyl group and a naphthyl group.
  • heteroaryl group represented by R 1 and R 14 which may have a substituent include a furanyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group and a thiazolyl group.
  • 5-membered heteroaryl group such as isothiazolyl group, triazolyl group and tetrazolyl group
  • 6 such as pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidyl group, 2-oxopyridyl group, 4-oxopyridyl group and 2-oxopyrazinyl group Membered ring heteroaryl group
  • quinolyl group isoquinolyl group, quinazolyl group, quinoxalyl group, indolyl group, indazolyl group, isoindazolyl group, benzimidazolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzothiazolyl group, imidazopyridydi group Group, pyrazolopyridinyl group, 2-oxoquinolinyl group, purine base such as purine, adenine, guanine
  • Examples thereof include monocyclic or bicyclic heteroaryl groups containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom as ring-constituting atoms.
  • Preferred heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,3,4-thiadiazolyl, isothiazolyl, triazolyl, pyridyl, pyridazinyl.
  • pyrazinyl group pyrimidyl group, 2-oxopyridyl group, 4-oxopyridyl group, 2-oxopyrazinyl group, quinolyl group, isoquinolyl group, indolyl group, indazolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, Examples thereof include a benzothiazolyl group, an imidazopyridinyl group, an imidazo [1,2-a] pyrimidyl group, a pyrazolopyridinyl group, purine, adenine, and guanine.
  • furanyl group More preferred are a furanyl group, a thienyl group, a pyrrolyl group, and an imidazolyl group.
  • Examples include a pyridinyl group. Further, tautomers may exist depending on the substituents on these heteroaryl groups.
  • the 6-hydroxypyridin-2-yl group and its tautomer 6-oxo-1,6-dihydropyridin-2-yl group and 4-hydroxypyridin-2-yl group and 4-oxo-1,4-dihydropyridin-2-yl group as its tautomer
  • the optionally substituted aryl group and the optionally substituted heteroaryl group represented by R 1 and R 14 may have 1 to 3 substituents on the ring.
  • a linear or branched C 1-6 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group; halogenated methyl group such as fluoromethyl group, difluoromethyl group, trifluoromethyl group, etc.
  • Hydroxyalkyl group such as hydroxymethyl group, hydroxyethyl group, 1-hydroxypropyl group; linear or branched C 1-6 alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group; cyclo fluorine atom, a halogen atom such as a chlorine atom; propyl group, a cyclopentyl group, C 3-6 cycloalkyl groups such as cyclohexyl group hydroxy group, Toromoto, cyano group; C 1-6 alkylamino group, di C 1-6 alkylamino group, an acylamino group, a protected substituent or protecting an amino group which may have a group such as an amino group; a formyl group , Acyl groups such as acetyl group, cyclopropylcarbonyl group and benzoyl group; cyclic amino groups such as azetidinyl group, pyrrolidinyl group,
  • the C 3-6 cycloalkyl C 1-6 alkyl group in the C 3-6 cycloalkyl C 1-6 alkyl group which may have a substituent represented by R 1 includes a cyclopropylmethyl group and a cyclopropylethyl group.
  • cyclopropylpropyl group cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclopentylpropyl group, cyclohexylmethyl group, cyclohexylethyl group, cyclohexylpropyl group and the like, preferably cyclopropylmethyl group Group, cyclopropylethyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, more preferably cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, most preferably Mashiku can be mentioned cyclopropylmethyl group.
  • C 1-6 alkyl group in the C 3-6 cycloalkyl C 1-6 alkyl group represented by R 1 include those similar to the aforementioned.
  • substituent the same substituents as those for the above-mentioned optionally substituted C 3-6 cycloalkyl group can be mentioned.
  • the aralkyl group which may have a substituent represented by R 1 has an aryl moiety having a carbon number of C 6 to 10 and an alkylene moiety having a carbon number of C 1 to 5, and is substituted with, for example, phenyl or naphthyl. And a methyl group (benzyl group) substituted with phenyl are preferred.
  • the heteroaryl moiety in the optionally substituted heteroarylalkyl group represented by R 1 includes 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom as ring-constituting atoms.
  • the heteroaryl include C 1-6 alkyl groups such as a methyl group, an ethyl group and a propyl group, and examples of the alkyl moiety include (pyridin-2-yl) methyl group and (pyridin-3-yl).
  • the aralkyl group which may have a substituent and the heteroarylalkyl group which may have a substituent represented by R 1 may have a substituent on the aryl and the heteroaryl, and as the substituent, Are the same as the above-mentioned substituents in the aryl group which may have a substituent and the heteroaryl group which may have a substituent.
  • Examples of the C 2-6 alkenyl group in the C 2-6 alkenyl group which may have a substituent represented by R 1 and R 14 include a C 2-6 linear or branched alkenyl group, Allyl group, vinyl group, 1-propenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group And alkenyl groups such as 5-hexenyl group.
  • the C 2-6 alkynyl group in the C 2-6 alkynyl group which may have a substituent represented by R 1 and R 14 is a C 2-6 linear or branched alkynyl group. Examples include ethynyl group, propynyl group, butynyl group and the like.
  • Examples of the group capable of substituting the alkenyl group and alkynyl group include alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group; benzyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenyl Aralkyl group such as butyl group; alkoxy group such as methoxy group, ethoxy group, propoxy group, butoxy group; aralkyloxy group such as benzyloxy group and 2-phenylethyloxy group; C 1-6 straight or branched chain Examples thereof include an amino group which may be substituted with an alkyl group; a halogen atom such as a fluorine atom and a chlorine atom; a carboxy group and a hydroxy group.
  • alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group
  • Examples of the optionally substituted acyl group represented by R 1 include a formyl group; a C 2-6 alkanoyl group such as an acetyl group, a propionyl group, a butanoyl group, a pentanoyl group and a hexanoyl group; a cyclopropylcarbonyl group; C 4-7 cycloalkanoyl group such as cyclobutylcarbonyl group and cyclopentylcarbonyl group; aroyl group or furoyl group such as benzoyl group and naphthoyl group; heteroaroyl group having 5 to 6 membered ring such as thiophencarbonyl group, nicotinyl group and isonicotinoyl group Etc.
  • a formyl group such as an acetyl group, a propionyl group, a butanoyl group, a pentanoyl group and a hexan
  • examples of the substituent in the C 2-6 alkanoyl group and C 4-7 cycloalkanoyl group include the same as the above-mentioned substituents in the C 1-6 alkyl group which may have a substituent.
  • examples of the substituent in the group and the heteroaroyl group include the same substituents as those in the aryl group which may have a substituent and the heteroaryl group which may have a substituent.
  • examples of the substituent in the amino group which may have a substituent represented by R 4 to R 6 and R 14 include the same amino protecting group as the amino protecting group represented by R 1 in addition to the above.
  • amino protecting group represented by R 1 examples include methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, tert-amyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, p- Chlorobenzyloxycarbonyl group, p-methoxybenzylcarbonyl group, p-nitrobenzyloxycarbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group, 9-fluorenyl Carbamate-based protecting groups such as rumethyloxy
  • Examples of the halogen atom represented by R 2 to R 6 , R 8 to R 11 and R 14 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom, and more preferably a fluorine atom. Is mentioned.
  • Examples of the group forming an ester in the carboxylic acid ester group represented by R 6 include methyl group, ethyl group, propyl group, 2-propyl group, butyl group, isobutyl group, tert-butyl group, pentyl group and hexyl group.
  • C 2-6 alkenyl group such as vinyl group, allyl group, 1-propenyl group, butenyl group, pentenyl group, hexenyl group
  • aralkyl group such as benzyl group
  • phenyl group Examples thereof include an aryl group such as a naphthyl group, a C 1-6 alkanoyloxy C 1-4 alkyl group such as an acetoxymethyl group and a pivaloyloxymethyl group.
  • Examples of the saturated heterocyclic group represented by R 14 which may have a substituent include a cyclic amino group, a lactam group and a cyclic ether group.
  • Examples of the cyclic amino group are an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, an azepanyl group, a morpholinyl group and a thiomorpholinyl group, a 7-azabicyclo [2.2.1] heptyl group, 3-oxa-8-azabicyclo [2.
  • lactam group examples include ⁇ -lactam, ⁇ -lactam, ⁇ -lactam and the like.
  • cyclic ether group examples include an oxetanyl group, a tetrahydrofuranyl group and a tetrahydropyranyl group.
  • Preferred saturated heterocyclic groups include cyclic amino groups, and preferred cyclic amino groups include azetidinyl groups, pyrrolidinyl groups, piperidinyl groups, piperazinyl groups, azepanyl groups, morpholinyl groups and thiomorpholinyl groups, 7-azabicyclo [2.2.1]. ] Heptyl group, 3-oxa-8-azabicyclo [2.2.2] octyl group, 3-oxa-8-azabicyclo [3.2.1], and more preferably pyrrolidinyl group, piperidinyl group, azepanyl group , And a morpholinyl group.
  • a linear or branched C 1-6 alkyl group such as a methyl group, an ethyl group, a propyl group or an isopropyl group; a linear chain such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a butoxy group Or a branched C 1-6 alkoxy group; a C 3-6 cycloalkyl group such as a cyclopropyl group, a cyclopentyl group, a cyclohexyl group; a halogen atom such as a fluorine atom and a chlorine atom; a formyl group, an acetyl group, a cyclopropylcarbonyl group, Acyl group such as benzoyl group; C 3-6 cycloalkyl C 1-6 alkyl group such as cyclopropylmethyl group, cyclopropylethyl group, and cyclopropyl
  • R 8 and R 9 may have a substituent formed by bonding, and a C 3-6 saturated hydrocarbon ring, and R 10 and R 11 may have a substituent formed by bonding.
  • Examples of the saturated heterocyclic group in the saturated heterocyclic group which may have a substituent represented by R 14 include a 3- to 6-membered saturated heterocyclic group, and examples thereof include aziridine, azetidine, pyrrolidine, piperidine, piperazine, Examples thereof include cyclic amines such as morpholine and thiomorpholine, cyclic ethers such as epoxide, oxetane, tetrahydrofuran, tetrahydropyran and dioxane, and cyclic thioethers such as thietane, thiolane and thiane.
  • a substituent such as a C 1-6 alkyl group, an acyl group or an amino-protecting group may be present on the nitrogen. These substituents are the same as the above-mentioned substituents in the cyclic amino group.
  • Examples of the nitrogen-containing saturated heterocyclic ring which may be formed by the combination of R 14 and R 15 include a 3- to 6-membered nitrogen-containing saturated heterocyclic ring, and examples thereof include aziridine, azetidine and pyrrolidine. And cyclic amino groups such as piperidine, piperazine, azepane, morpholine and thiomorpholine.
  • nitrogen-containing saturated heterocycles may be further condensed with saturated hydrocarbons, saturated heterocycles, unsaturated hydrocarbons or unsaturated heterocycles such as decahydroquinoline, decahydroisoquinoline, indoline, isoindoline, 1 2,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzomorpholine, benzothiomorpholine and the like.
  • these nitrogen-containing heterocycles have a nitrogen atom as a ring-constituting atom in addition to the nitrogen atom to which R 15 is bonded, they have a substituent such as a C 1-6 alkyl group, an acyl group and an amino-protecting group. You may have. These substituents are the same as the above-mentioned substituents in the cyclic amino group.
  • a C 3-6 saturated hydrocarbon ring which may have a substituent formed by combining R 12 and R 13 on the same carbon, and is formed by combining R 12 and R 13 on the same carbon.
  • Saturated heterocyclic ring optionally having substituent (s) C 3-6 saturated optionally having substituent (s) formed by bonding a pair of adjacent R 12 's when n is 2 to 3.
  • a hydrocarbon ring or a saturated heterocycle which may have a substituent and a nitrogen-containing saturated heterocycle which may have a substituent formed by the combination of R 14 and R 15 are the above-mentioned cyclic groups. Examples thereof are the same as the substituents on the amino group.
  • Examples of the cyclic ketal which may have a substituent formed by combining R 2 and R 3 , R 8 and R 9 and R 10 and R 11 include dioxolane and dioxane.
  • Examples of the substituent include a C 1-6 alkyl group such as a methyl group, an ethyl group and a propyl group.
  • X represents a nitrogen atom or an N-oxide, and a nitrogen atom is preferable.
  • Z represents NR 15 , an oxygen atom, a bond, an ethenylene group which may have a substituent or an ethynylene group, and is preferably NR 15 , an oxygen atom, a bond or ethylene.
  • substituent in the ethenylene group which may have a substituent include those described in paragraph [0027].
  • n represents an integer of 0 to 1, and is preferably 1.
  • n an integer of 0 to 3, and is preferably 1.
  • R 1 is a C 1-6 alkyl group which may have a substituent or a C 3-6 cycloalkyl which may have a substituent.
  • 6 alkoxy group, halogen atom, hydroxy group or R 2 and R 3 are taken together to form a carbonyl group, and R 4 and R 5 are the same or different and are each a hydrogen atom or C 1 -which may have a substituent.
  • R 7 is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, or a hydroxy group
  • R 8 and R 9 Are the same or different and each is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 1-6 alkoxy group which may have a substituent, a halogen atom, a hydroxy group or R 8 and R 9 together are a carbonyl group
  • R 10 and R 11 are the same or different and each is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, or a C which may have a substituent.
  • R 12 and R 13 are the same or different and are a hydrogen atom or a C 1-6 alkyl group which may have a substituent, and R 14 is a substituent.
  • R 14 is a substituent. which may have a C 6-10 aryl , A heteroaryl group which may have a substituent or a cyclic amino group which may have a substituent,
  • X is a nitrogen atom or an N-oxide, and Y is C ⁇ O or C ⁇ S.
  • Z is NR 15 , an oxygen atom, a bond, an ethenylene group which may have a substituent or an ethynylene group, and R 15 is a hydrogen atom, a C 1-6 alkyl group which may have a substituent.
  • the double line consisting of the solid line and the broken line is a single bond or a double bond, m is an integer of 0 or 1, and n is an integer of 0 to 3.
  • R 1 is a C 1-6 alkyl group which may have a substituent or a C 3-6 cycloalkyl which may have a substituent.
  • a C 1-6 alkyl group, R 2 and R 3 are the same or different and are a C 1-6 alkyl group optionally having a hydrogen atom or a substituent, and R 4 and R 5 are the same or different.
  • R 6 is a C 1-6 alkoxy group which may have a substituent or a hydroxy group
  • R 7 is a hydrogen atom
  • R 8 and R 9 are the same or different and each is a hydrogen atom.
  • R 10 and R 11 are each independently hydrogen or optionally substituted C 1-6 alkyl radical
  • R 12 and R 13 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group which may have a substituent
  • R 14 is a C 6-10 aryl group which may have a substituent, and a substituent.
  • a heteroaryl group which may have a group or a cyclic amino group which may have a substituent
  • X is a nitrogen atom or an N-oxide
  • Y is C ⁇ O or C ⁇ S
  • Z is NR 15 , an oxygen atom, a bond or an ethenylene group which may have a substituent
  • R 15 is a hydrogen atom, a C 1-6 alkyl group which may have a substituent
  • a double line composed of a broken line is a single bond or a double bond
  • m is 0 or 1.
  • a number, n represents include when an integer of 0-3.
  • R 1 is a C 1-6 alkyl group which may have a substituent or a C 3-6 cycloalkyl which may have a substituent.
  • a C 1-6 alkyl group, R 2 and R 3 are the same or different and are a hydrogen atom or a C 1-6 alkyl group which may have a substituent, more preferably a hydrogen atom, and R 4 and R 3 5 is a hydrogen atom, R 6 is a hydroxy group, R 7 is a hydrogen atom or a hydroxy group, and R 8 and R 9 are the same or different and may be a hydrogen atom or a C 1 group which may have a substituent.
  • R 10 and R 11 are the same or different, a hydrogen atom or a C 1-6 alkyl group optionally having a substituent, more preferably a hydrogen atom, R 12 and R 13 are the same or Differently, a hydrogen atom or a C 1-6 alkyl group which may have a substituent, more preferably a hydrogen atom, R 14 is a heteroaryl group which may have a substituent, and X is nitrogen.
  • An atom, Y is C O
  • Z is NR 15 or a bond, more preferably a bond
  • R 15 is a hydrogen atom or a C 1-6 alkyl group optionally having a substituent.
  • a double line consisting of a solid line and a broken line is a single bond
  • m is an integer of 0 or 1
  • n is an integer of 0 or 1.
  • the pharmaceutically acceptable salt is preferably acid addition.
  • the acid addition salt include (a) salts with mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, (ro) formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid.
  • Examples thereof include salts with organic carboxylic acids such as acids and tartaric acid, and (c) salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • stereoisomers include cis and trans. Examples include isomers, racemates and optically active forms.
  • the compounds of this invention include all crystalline forms and hydrates or solvates thereof.
  • Method A Production method in which R 7 to R 11 are hydrogen atoms, X is a nitrogen atom, and the double line consisting of a solid line and a broken line is a single bond (Method A-1) A 7-membered ring in the general formula (I) When the nitrogen atom which is a constituent atom of is bonded to a benzyloxycarbonyl group (Cbz) or a hydrogen atom, the invention compounds (a-10) to (a-13) can be obtained by the method described below.
  • R 1 to R 6 have the same meanings as described above.
  • aprotic polar solvent in the presence or absence of a base such as sodium hydrogen carbonate, lithium carbonate, sodium carbonate or potassium carbonate at 80 to 190 ° C. for 3 to 24 hours, or in a sealed tube,
  • a base such as sodium hydrogen carbonate, lithium carbonate, sodium carbonate or potassium carbonate
  • the hydrolysis reaction can be carried out using an acid or a base by a generally known method, but a base is preferable, for example, ethers such as tetrahydrofuran and dioxane; 1 to 10 mol in an alcohol solvent such as methanol and ethanol.
  • the starting material (a-1) can be synthesized by a generally known method. For example, J. Chem. Soc. C, 1966, 617 or J. Chem. Soc. C, 1969, 2569, J. Chem. Soc. Perkin Trans. It can be synthesized by the method described in I, 1994, 911.
  • -Organic bases such as dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxide, sodium ethoxide; lithium carbonate, sodium carbonate, potassium carbonate Reacting with hydroxylamine (eg, hydroxylamine aqueous solution, hydroxylamine hydrochloride, hydroxylamine sulfate, etc.) in the presence of an inorganic base such as sodium hydroxide or potassium hydroxide at room temperature to under reflux for 1 to 24 hours.
  • hydroxylamine eg, hydroxylamine aqueous solution, hydroxylamine hydrochloride, hydroxylamine sulfate, etc.
  • an inorganic base such as sodium hydroxide or potassium hydroxide at room temperature to under reflux for 1 to 24 hours.
  • Compound (a-3) Compound (a-3), aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc. Aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin; potassium bis (trimethylsilyl) amide (KHMDS) in an aprotic polar solvent such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide or in the absence of solvent.
  • aromatic hydrocarbons such as benzene, toluene, xylene
  • ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme
  • Bases such as lithium diisopropylamide (LDA); trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, die Triethanolamine, organic bases cyclohexylamine, procaine, such as sodium methoxide, sodium ethoxide; lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide in the presence of an inorganic base such as potassium hydroxide, L-Cl or L 2 O After reacting with a reagent represented by (wherein L represents a methanesulfonyl group, a p-toluenesulfonyl group, a trifluoromethanesulfonyl group, a 2-nitrobenzenesulfonyl group, etc.) at -78 ° C to under heating under reflux for 1 to 24 hours.
  • L lithium di
  • the compound (a-4) can be synthesized by hydrolysis.
  • the hydrolysis reaction can be carried out using an acid by a generally known method.
  • ethers such as tetrahydrofuran and dioxane
  • alcohols such as methanol, ethanol and 2-propanol
  • acetonitrile N, N-dimethylformamide and dimethyl.
  • An aprotic polar solvent such as sulfoxide; 1 to 6 equivalents or a solvent amount of 1 to 10 mol / L of an inorganic acidic aqueous solution such as hydrochloric acid or sulfuric acid is added to a solvent such as acetic acid or no solvent, and the mixture is heated at room temperature to under reflux.
  • Compound (a-4) is converted to diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme or the like ether under a hydrogen atmosphere or in the presence of potassium formate (1 to 5 equivalents) or the like; alcohols such as methanol, ethanol or 2-propanol; In a solvent such as water or acetic acid or a mixed solvent thereof, a metal catalyst such as a nickel catalyst such as Raney nickel, a palladium-activated carbon (Pd / C) and a Pearlman's catalyst (Pearlman's Catalyst: Pd (OH) 2 ) Compound (a-5) can be synthesized by reacting at room temperature to reflux for 1 to 24 hours in the presence of a platinum catalyst such as a palladium catalyst or an Adams 'catalyst (Adams' Catalyst: PtO 2 ).
  • a metal catalyst such as a nickel catalyst such as Raney nickel, a palladium
  • a hydride reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium tri (sec-butyl) borohydride, potassium tri (sec-butyl) borohydride in a solvent, 30 °C ⁇ heating under reflux
  • Compound (a-6) can be synthesized by reacting under the conditions of 1 to 24 hours. (Sixth step) The compound (a-6) is heated at 0 ° C.
  • Compound (a-7) can be synthesized by reacting under the conditions of 1 to 24 hours.
  • Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride Aprotic polar solvent such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide; in a solvent such as water or a mixed solvent thereof, trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, Organic bases such as N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, sodium methoxide, sodium ethoxide; sodium hydrogen carbonate, lithium carbonate, sodium carbonate Compound (a-8) can be synthe
  • Compound (a-8) as aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.
  • Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, potassium bis (trimethylsilyl) amide (KHMDS), lithium diisopropylamide ( LDA) and the like; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, Organic bases such as chlorhexylamine, procaine, sodium methoxide, sodium ethoxide, potassium tert-butoxide; lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydroxide Reacting with a reagent represented by L-Cl or L 2 O (
  • Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, potassium bis (trimethylsilyl) amide (KHMDS), lithium diisopropylamide ( LDA) and the like; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, N-methylpiperidine, N
  • the invention compound (a-10) is treated with an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; an alcohol such as methanol, ethanol, 2-propanol; a solvent such as water or acetic acid, or a mixture thereof.
  • an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme
  • an alcohol such as methanol, ethanol, 2-propanol
  • a solvent such as water or acetic acid, or a mixture thereof.
  • a metal catalyst for example, a nickel catalyst such as Raney nickel, a palladium catalyst such as palladium-activated carbon (Pd / C) and Pearlman's catalyst (Pearlman's Catalyst: Pd (OH) 2 ), or an Adams catalyst (Adams' Catalyst: Inventive compound (a-11) can be synthesized by reacting in the presence of a platinum catalyst such as PtO 2 ) at room temperature to under reflux for 1 to 24 hours.
  • a nickel catalyst such as Raney nickel
  • a palladium catalyst such as palladium-activated carbon (Pd / C) and Pearlman's catalyst
  • Pd (OH) 2 ) Pearlman's catalyst
  • an Adams catalyst Adams' Catalyst: Inventive compound (a-11) can be synthesized by reacting in the presence of a platinum catalyst such as PtO 2 ) at room temperature to under reflux for 1 to 24 hours.
  • R 6 is a C 1-6 alkoxy group
  • the invention compound (a-11) is treated with halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; organic solvents such as acetic acid and ethyl acetate; aprotons such as acetonitrile.
  • halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride
  • organic solvents such as acetic acid and ethyl acetate
  • aprotons such as acetonitrile.
  • boron tribromide, trimethylsilyl iodide, hydrogen bromide, pyridinium hydrochloride or the like at -30 to 180 ° C for 30 minutes to 5 hours, or N, N-dimethylformamide, 100-180 ° C.
  • the compound of the invention (a-12) is obtained by reacting at 30 ° C. for 30 minutes to 24 hours. It is possible to obtain.
  • the invention compound (a-13) can be obtained by subjecting the invention compound (a-10) to the same reaction as in the eleventh step.
  • the invention compound (a-12) can be obtained by carrying out the same reaction as the tenth step on the invention compound (a-13).
  • the compound (a-5) can also be synthesized by the method described below.
  • R 1 to R 6 and L have the same meanings as described above.
  • Compound (a-2) is converted to diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme or the like ether under a hydrogen atmosphere or in the presence of potassium formate (1 to 5 equivalents) or the like; alcohols such as methanol, ethanol or 2-propanol; In a solvent such as water or acetic acid or a mixed solvent thereof, a metal catalyst, for example, a nickel catalyst such as Raney nickel, palladium-activated carbon (Pd / C) and palladium such as Pearlman's Catalyst (Pd (OH) 2 ).
  • a metal catalyst for example, a nickel catalyst such as Raney nickel, palladium-activated carbon (Pd / C) and palladium such as Pearlman's Catalyst (Pd (OH) 2 ).
  • the compound (a-14) can be synthesized by reacting in the presence of a catalyst or a platinum catalyst such as Adams' catalyst (PtO 2 ) at room temperature to heating under reflux for 1 to 24 hours.
  • a catalyst or a platinum catalyst such as Adams' catalyst (PtO 2 )
  • PtO 2 Adams' catalyst
  • Compound (a-15) can be synthesized in the same manner as the second step in the synthesis of compound (a-3) from compound (a-2).
  • (Third step) and (Fourth step) Compound (a-15) and compound (a-5) are synthesized in the same manner as the third step in the synthesis of compound (a-4) from compound (a-3). You can
  • M is a halogen atom
  • Z is a bond, an ethenylene group which may have a substituent or an ethynylene group
  • R 1 to R 6 , R 12 to R 14 , Y and n are the same as those described above. Show the one.
  • Inventive compound (a-11) obtained by (Method A-1) is supplemented with aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme: dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride: Alcohols such as methanol and ethanol; Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; Aprotic substances such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc.
  • aromatic hydrocarbons such as benzene, toluene, xylene
  • ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme: dichloromethane, chloroform
  • the acid halide represented by (a-18) was treated with N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N- Methylpiperidine
  • Organic bases such as N-methylmorpholine, diethylamine, cyclohexylamine, and procaine: In the presence or absence of an inorganic base such as potassium carbonate and lithium carbonate, the reaction is performed at 0 ° C.
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
  • Inventive compound (a-19) is aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated carbonization such as dichloromethane, chloroform and carbon tetrachloride.
  • Hydrogen In an aliphatic hydrocarbon such as pentane, hexane, heptane, ligroin, etc., using a generally known sulfidizing agent such as diphosphorus pentasulfide, Lawesson's reagent, Davy's reagent, Japanese reagent, Bereau's reagent, etc., heating at 0 ° C to reflux.
  • a-20 of the invention can be converted by reacting under the condition of 1 to 12 hours.
  • Z represents NR 15 or an oxygen atom
  • a in the methylating agent (Me-A) represents halogen, trifluoromethanesulfonate, etc.
  • a ⁇ represents its counter anion
  • R 1 to R 6 , R 12 to R 15 , Z and n are the same as above.
  • Inventive compound (a-23) includes aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme: halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride.
  • Alcohols such as methanol and ethanol; Aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; N, N-dimethyl in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide
  • Aminopyridine trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine
  • Organic base such as procaine: In the presence or absence of an inorganic base such as potassium carbonate or lithium carbonate, a methylating agent such as methyl iodide, dimethyl sulfate, trifluoromethanesulfonate, meerwein reagent is heated at 0 ° C.
  • the compound (a-24) of the invention can be synthesized by reacting for 12 to 48 hours.
  • Inventive compound (a-24) aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.
  • Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; N, N-dimethylaminopyridine, trimethylamine, triethylamine, N, in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide
  • Organic bases such as N-diisopropylethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine and procaine: potassium carbonate, charcoal
  • the compound of the invention is obtained by reacting the amine represented by (a-25) or the alcohol represented by (a-26) in the presence of an inorganic base such as lithium at 0 ° C.
  • B is a C 6-10 aryl group or heteroaryl group which may have a substituent, hal is a halogen atom, and R 1 to R 6 are the same as those described above.
  • R 1 to R 6 have the same meanings as described above.
  • the conversion of the compound (a-5) to the invention compound (b-1) can be carried out by a hydrolysis reaction of a cyano group.
  • the hydrolysis reaction can be carried out using an acid or a base by a generally known method.
  • an acid for example, ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide; acetic acid and the like.
  • R 1 to R 6 , R 12 to R 14 , Y, Z, m, and n are the same as above.
  • Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme to the invented compound (b-1) obtained by (Method B): dichloromethane, chloroform, tetra Halogenated hydrocarbons such as carbon chloride: In aliphatic hydrocarbons such as pentane, hexane, heptane, and ligroin, a borane-dimethyl sulfide complex, borane-tetrahydrofuran complex tetrahydrofuran solution or a reducing agent such as lithium aluminum hydride at room temperature is used.
  • the invention compound (c-1) can be synthesized by reacting under heating to reflux for 2 to 24 hours.
  • the compound (c-2) of the invention can be synthesized by carrying out the same reaction as the method described in (Method A-2) to (Method A-5) on the compound (c-1) of the invention. it can.
  • the invention compound (c-3) can be obtained from the invention compound (c-2) in the same manner as in (Method A-1).
  • R 7 to R 11 are hydrogen atoms
  • X is a nitrogen atom
  • Y is a sulfonyl group (SO 2 )
  • SO 2 sulfonyl group
  • Z represents a bond, an ethenylene group or an ethynylene group, and R 1 to R 6 , R 12 to R 14 , n and hal are the same as above.
  • Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; and dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, (a-1 ) Is a sulfonyl chloride represented by N, N-dimethylaminopyridine, trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethy
  • Shi Organic bases such as lohexylamine and procaine:
  • Inventive compound (d-1) by reacting in the presence or absence of an inorganic base such as potassium carbonate and lithium carbonate at 0 ° C. to reflux under heating for 1 to 12 hours. Can be synthesized.
  • R 6 is a C 1-6 alkoxy group
  • the invented compound (d-2) can be obtained from the invented compound (d-1) in the same manner as in the eleventh step of (Method A-1).
  • the substituent of the sulfonylamide of the invention compound (d-1) is represented by Ar
  • the invention compound (d-4) in which Ar is a 2-nitrophenyl group or a 2,4-dinitrophenyl group is Can also be synthesized.
  • the invented compound (d-4) can be converted to the invented compound (a-11) in one step.
  • Ar represents a 2-nitrophenyl or 2,4-dinitrophenyl group, and R 1 to R 6 and hal are the same as above.
  • Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; Halogenated hydrocarbons such as carbon tetrachloride; Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin; 2-Nitrobenzenesulfonyl in aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc.
  • the compound (d-4) of the invention is treated with an organic base such as potassium tert-butoxide or sodium tert-butoxide in an aprotic polar solvent such as N, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide; By reacting 1-propanethiol, 1-dodecanethiol, thiophenol, 4-mercaptobenzoic acid, etc. at room temperature to 180 ° C. for 30 minutes to 24 hours in the presence of an inorganic base such as potassium, lithium carbonate or sodium carbonate. Inventive compound (a-11) can be obtained.
  • an organic base such as potassium tert-butoxide or sodium tert-butoxide
  • an aprotic polar solvent such as N, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide
  • the compound obtained by each of the above steps can be purified, for example, by silica gel column chromatography, if necessary. Further, if necessary, an acid addition salt can be formed by a conventional method.
  • the compound (I) of the invention can be prepared by dissolving the compound (I) in an organic solvent such as ethyl acetate: an alcohol such as methanol or ethanol: or a polar solvent such as water.
  • the compound (I) of the present invention is a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, an organic carboxylic acid such as formic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid or maleic acid, methanesulfonic acid or benzenesulfone. It is carried out by heating at room temperature or appropriately in the presence of an acid, an organic sulfonic acid such as p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • an organic sulfonic acid such as p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • the morphinan derivative represented by the general formula (I), a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof is parenterally administered to humans,
  • the composition can be formulated with a pharmaceutically acceptable carrier, such as for oral administration in solid or liquid form. It is also possible to use it in combination with other analgesics.
  • solid preparations for oral administration include capsules, tablets, pills, powders and granules.
  • Excipients, disintegrants, binders, lubricants, dyes and the like can be used in the preparation of this solid preparation.
  • the excipient lactose, D-mannitol, crystalline cellulose, glucose and the like
  • the disintegrant starch, carboxymethyl cellulose calcium (CMC-Ca) and the like
  • the lubricant magnesium stearate, Talc or the like
  • examples of the binder include hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP) and the like.
  • a buffer may be further used. The tablets and pills may be enteric coated.
  • compositions of the present invention for injection include pharmaceutically acceptable sterile water or non-aqueous solution, suspension or emulsion.
  • suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
  • Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, soothing agents, buffers, preservatives and dispersing agents.
  • compositions are reduced, for example, by filtration through a bacteria-retaining filter, or by incorporating the sterilant in the form of a sterile solid composition which may be dissolved in the sterilant or some other sterile injectable medium immediately before use.
  • the formulation for eye drop administration may preferably contain a solubilizing agent, a preservative, an isotonicity agent, a thickening agent and the like in addition to the compound of the present invention.
  • Liquid formulations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used by those skilled in the art, such as water.
  • the composition can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, and sweetening, flavoring and flavoring agents.
  • Formulations for rectal administration may preferably contain, in addition to a compound of this invention, an excipient such as cocoa butter or a suppository wax.
  • the dose is usually, in adults, the morphinan derivative represented by the above general formula (I) which is an active ingredient, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
  • the solvate is 0.01 ⁇ g to 1 g / day, preferably 0.0001 to 200 mg / day for an injection, and 0.1 ⁇ g to 10 g / day for an oral administration, preferably 0.001 to 2000 mg / day. It is administered, but it can be increased or decreased depending on the age, symptoms and the like. If desired, this daily dose can be divided into 2 to 4 divided doses for administration.
  • Examples of diseases and symptoms related to ⁇ opioid receptors include cardiovascular disorders, digestive system disorders, blood system disorders, respiratory system disorders, liver disorders, nervous system disorders, urinary system disorders, pain, cough, pruritus, Examples include ischemic brain disease and drug dependence. Since the compound of the present invention has a high ⁇ opioid receptor selectivity and a strong agonist activity to the ⁇ opioid receptor, it is effective in treating, ameliorating and preventing these diseases and symptoms.
  • the obtained concentrated residue was dissolved in ethanol (144 mL), 1M aqueous sodium hydroxide solution (36 mL) was added, and the mixture was heated under reflux for 3 hr. After allowing to cool, water (200 mL) was added, and the mixture was extracted twice with diethyl ether. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (25-50% ethyl acetate / hexane) to give the title compound (2.5 g, 44%) as a colorless amorphous.
  • the obtained concentrated residue was dissolved in tetrahydrofuran (10 mL), 2M hydrochloric acid (8 mL) was added, and the mixture was stirred at room temperature for 16 hr.
  • the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution to make it basic, and extracted three times with chloroform.
  • the combined extracts were dried over sodium sulfate and then concentrated under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (30-60% ethyl acetate / heptane) to give the title compound (620.1 mg, 96%) as a colorless solid.
  • Triethylamine (598.7 ⁇ L, 4.29 mmol) and methanesulfonyl chloride (331.3 ⁇ L, 4.29 mmol) were added to a dichloromethane (21 mL) solution of compound 6 (1.11 g, 2.14 mmol), and the mixture was stirred at room temperature for 4 hours. did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure.
  • Methyl iodide (790.3 ⁇ L, 12.7 mmol) was added to a solution of compound 10 (194.8 mg, 0.42 mmol) in acetonitrile (5 mL), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. The obtained concentrated residue was not purified, and a crude product of the title compound (255.4 mg, quantitative) was obtained as a colorless amorphous substance.
  • Trifluoroacetic acid (0.5 mL) was added to a dichloromethane (1 mL) solution of compound 13 (16.1 mg, 0.025 mmol) under ice cooling, and the mixture was stirred at room temperature for 4.5 hours.
  • the reaction mixture was concentrated under reduced pressure, chloroform was added, and the mixture was washed 3 times with saturated aqueous sodium hydrogen carbonate solution and once with saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure.
  • Acetyl chloride (17 ⁇ L, 0.24 mmol) was added to a solution of the obtained crude product and triethylamine (34 ⁇ L, 0.25 mmol) in dichloromethane (1.5 mL) under ice cooling, and the mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (0-5% methanol / chloroform) to give the title compound (9.8 mg, 69%) as a pale-yellow oily substance.
  • Example 31 the title compound was obtained from compound 11 and oxazol-5-ylmethanol (synthesized by the method described in WO2015138895).
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.06-0.13 (m, 2H), 0.43-0.53 (m, 2H), 0.73-0.82 (m , 1H), 1.01-1.11 (m, 1H), 1.24-1.75 (m, 5H), 2.13-2.42 (m, 5H), 2.59-2.65.
  • Example 42 According to the method described in Example 42, the title compound was obtained from compound 9 and 6-oxo-1,6-dihydropyridine-2-carboxylic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.07-0.12 (m, 2H), 0.43-0.52 (m, 2H), 0.72-0.82 (m , 1H), 1.08-1.18 (m, 1H), 1.22-1.59 (m, 4H), 1.72-1.87 (m, 1H), 2.20-2.45.
  • Example 42 According to the method described in Example 42, the title compound was obtained from compound 9 and 2-hydroxynicotinic acid.
  • Example 42 According to the method described in Example 42, the title compound was obtained from compound 9 and 1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (synthesized by the method described in WO2016148232).
  • Example 42 According to the method described in Example 42, the title compound was obtained from compound 60 and thiazole-4-carboxylic acid.
  • Example 68 According to the method described in Example 68, the title compound was obtained from compound 60 and isothiazole-4-carboxylic acid.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and isothiazole-5-carboxylic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.04-0.15 (m, 2H), 0.41-0.56 (m, 2H), 0.70-0.90 (m , 1H), 1.07-1.89 (m, 6H), 2.12-2.48 (m, 5H), 2.60-2.70 (m, 1H), 2.79-3.19 (m, 3H) ), 3.45-3.68 (m, 1H), 3.76-4.85 (m, 6H), 6.57-6.66 (m, 1H), 6.69-6.78 (m , 1H), 7.32-7.51 (m, 1H), 8.44-8.52 (m, 1H).
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 1H-indole-2-carboxylic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.04-0.18 (m, 2H), 0.44-0.57 (m, 2H), 0.75-0.92 (m , 1H), 1.07-1.89 (m, 6H), 2.12-2.49 (m, 5H), 2.58-2.70 (m, 1H), 2.82-3.16.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 5-chloropyrimidine-2-carboxylic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.03-0.16 (m, 2H), 0.41-0.56 (m, 2H), 0.70-0.93 (m , 1H), 1.04-1.90 (m, 5H), 2.11-2.45 (m, 6H), 2.59-2.69 (m, 1H), 2.76-3.12.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 5-fluoropyrimidine-2-carboxylic acid.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (1H-imidazol-2-yl) acetic acid hydrochloride.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.00-0.15 (m, 2H), 0.45-0.65 (m, 2H), 0.70-0.85 (m , 1H), 1.00-1.15 (m, 1H), 1.20-2.00 (m, 6H), 2.00-2.10 (m, 0.6H), 2.10-2 .45 (m, 4.4H), 2.55-2.67 (m, 1H), 2.67-2.88 (m, 1H), 2.90-3.08 (m, 2H), 3 .30-3.40 (m, 0.4H), 3.50-3.60 (m, 0.6H), 3.70-4.00 (m, 5.6H), 4.10-4.
  • the free form of the title compound was obtained from compound 102 (11.0 mg, 0.023 mmol).
  • the obtained free form was dissolved in methanol (1 mL), 2M hydrochloric acid-methanol solution (100 ⁇ L) was added dropwise under ice cooling, and the mixture was stirred for 30 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the concentrated residue was dried on a lyophilizer to give the title compound (2.5 mg, 20%) as pale yellow crystals.
  • Example 42 According to the method described in Example 42, the title compound was obtained from compound 9 and 2- (isoxazol-3-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.05-0.16 (m, 2H), 0.43-0.54 (m, 2H), 0.72-0.85 (m , 1H), 1.03-1.16 (m, 1H), 1.18-1.82 (m, 5H), 1.98-2.13 (m, 1H), 2.17-2.46.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (oxazol-4-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.05-0.17 (m, 2H), 0.43-0.55 (m, 2H), 0.73-0.90 (m , 1H), 1.05-1.81 (m, 6H), 1.96-2.51 (m, 5H), 2.55-2.69 (m, 1H), 2.75-2.89.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (benzo [d] oxazol-2-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.03-0.19 (m, 2H), 0.40-0.55 (m, 2H), 0.67-0.93 (m , 1H), 1.04-1.82 (m, 6H), 2.07-2.48 (m, 5H), 2.53-3.12 (m, 4H), 3.31-3.92.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (thiazol-2-yl) acetic acid (synthesized by the method described in Bioorganic & Medicinal Chemistry Letters 2010, 20, 7414).
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (thiazol-5-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.03-0.17 (m, 2H), 0.42-0.56 (m, 2H), 0.71-0.92 (m , 1H), 1.03-1.79 (m, 5H), 1.94-2.47 (m, 6H), 2.55-3.09 (m, 4H), 3.28-4.12.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (5-chloropyrimidin-2-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.05-0.17 (m, 2H), 0.43-0.55 (m, 2H), 0.71-0.92 (m , 1H), 1.03-1.80 (m, 6H), 2.11-2.48 (m, 5H), 2.57-3.10 (m, 4H), 3.33-3.62.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and (E) -3- (oxazol-2-yl) acrylic acid (synthesized by the method described in US20070167426).
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.07-0.15 (m, 2H), 0.45-0.54 (m, 2H), 0.75-0.85 (m , 1H), 1.09-1.77 (m, 6H), 2.12-2.45 (m, 5H), 2.60-2.66 (m, 1H), 2.86-2.94.
  • Example 112 1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -3-phenylprop-2-yn-1-one (132)
  • Example 117 According to the method described in Example 117, the title compound was obtained from compound 9 and 2-chloropyrimidine.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.00-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.20 (m, 1H), 1.20-1.90 (m, 5H), 2.10-2.50 (m, 5H), 2.50-2.65.
  • Example 121 1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano-4 , 13-Methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrimidin-2-yl) ethan-1-one (142)
  • Triethylamine 150 ⁇ L, 1.08 mmol
  • 2-nitrobenzenesulfonyl chloride 144 mg, 0.65 mmol
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and water, dried over sodium sulfate, and concentrated under reduced pressure.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (1H-indazol-5-yl) acetic acid.
  • Example 132 1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (2H-1,2,3-triazol-2-yl) ethane-1 Synthesis of one-on (156)
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (2H-1,2,3-triazol-2-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 5H), 2.10-2.50 (m, 5H), 2.60-2.70.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 171 and 2- (pyrimidin-2-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.03-0.18 (m, 2H), 0.41-0.58 (m, 2H), 0.75-1.76 (m , 8H), 2.13-2.43 (m, 5H), 2.51-2.87 (m, 2.4H), 2.92-3.18 (m, 3H), 3.60-3.
  • Example 42 According to the method described in Example 42, the title compound was obtained from compound 9 and 2- (5-bromopyrimidin-2-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.05-0.15 (m, 2H), 0.43-0.54 (m, 2H), 0.72-0.85 (m , 1H), 1.04-1.58 (m, 5H), 1.62-1.79 (m, 1H), 2.11-2.46 (m, 5H), 2.59-2.68.
  • Example 14-7 ((4R, 4aS, 8R, 8aR, 13bS) -3- (Cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8-ethano Synthesis of -4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) (pyrrolidin-1-yl) methanone (177)
  • Example 150 Azepan-1-yl ((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H- Synthesis of 4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) methanone (180)
  • Example 151 Azepan-1-yl ((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) methanone (181)
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and isobutyric acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.80 (m, 11H), 2.05-2.45 (m, 5H), 2.55-2.70 (m, 1H), 2.70-3.10.
  • Example 68 According to the method described in Example 68, the title compound was obtained from compound 60 and 1- (pyrimidin-2-yl) cyclopropane-1-carboxylic acid.
  • Example 161 1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (5-ethynylpyrimidin-2-yl) ethan-1-one (195) Synthesis of
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 3-methylpyrazine-2-carboxylic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-2.00 (m, 5H), 2.10-2.50 (m, 5H), 2.50-2.70 (m, 4H), 2.80-3.20.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 3,6-dimethylpyrazine-2-carboxylic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.90 (m, 7H), 2.15-2.50 (m, 5H), 2.50-2.60.
  • Example 171 1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (dimethylamino) ethan-1-one (205)
  • Example 42 According to the method described in Example 42, the title compound was obtained from compound 9 and 2- (5-cyclopropylpyrimidin-2-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.05-0.16 (m, 2H), 0.42-0.54 (m, 2H), 0.70-0.84 (m , 3H), 1.02-1.12 (m, 3H), 1.13-1.58 (m, 4H), 1.61-1.78 (m, 1H), 1.80-1.91.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 6-oxo-1,6-dihydropyrazine-2-carboxylic acid.
  • Example 175 (6-aminopyrazin-2-yl) ((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a -Octahydro-7H-4a, 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) methanone (209)
  • Example 17-7 1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-morpholinoethane-1-one (211) synthesis
  • Example 180 (3-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, Synthesis of 8-ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) azetidin-1-yl) (phenyl) methanone (214)
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 213 and benzoic acid.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 60 and 2- (6-methoxypyridin-2-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 5H), 1.85-1.95 (m, 1H), 2.15-2.40.
  • Example 115 According to the method described in Example 115, the title compound was obtained from compound 60 and tetrahydro-4H-pyran-4-one.
  • Example 18-7 1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyridin-2-yl) ethan-1-one (221) synthesis
  • Example 179 the title compound was obtained from compound 60 and tert-butyl 4-oxopiperidine-1-carboxylate.
  • Example 201 1- (2-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H- Synthesis of 4a, 8-Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2-oxoethyl) pyridin-2 (1H) -one (235)
  • Example 115 the title compound was obtained from compound 9 and tert-butyl 3-oxopyrrolidine-1-carboxylate, respectively.
  • Diastereomer B (237): 1 H-NMR (400 MHz, CDCl 3 ) ⁇ (ppm): 0.05-0.19 (m, 2H), 0.42-0.56 (m, 2H), 0.73-1.03 (m , 2H), 1.11-3.71 (m, 32H), 3.86 (s, 3H), 4.42-4.58 (m, 2H), 6.52-6.64 (m, 1H) ), 6.71 (d, J 8 Hz, 1H).
  • Example 203 According to the method described in Example 203, the title compound was obtained from compound 237.
  • Example 115 According to the method described in Example 115, the title compound was obtained from compound 241 and benzaldehyde.
  • Example 211 1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-methoxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (3,3-difluoropiperidin-1-yl) ethan-1-one ( 246) synthesis
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and (tert-butoxycarbonyl) -L-proline.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.00-0.15 (m, 2H), 0.40-0.60 (m, 2H), 0.70-0.90 (m , 1H), 1.00-1.15 (m, 1H), 1.20-1.80 (m, 14H), 1.80-2.00 (m, 3H), 2.00-2.50.
  • Example 211 the title compound was obtained from compound 60 and 2-chloro-1- (piperidin-1-yl) ethan-1-one (synthesized by the method described in WO2018148576).
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and 2- (pyrrolidin-1-yl) acetic acid hydrochloride.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.04-0.18 (m, 2H), 0.40-0.56 (m, 2H), 0.70-0.92 (m , 1H), 1.01-2.00 (m, 10H), 2.06-2.46 (m, 5H), 2.51-3.10 (m, 8H), 3.17-3.36.
  • Example 22-7 1-((4R, 4aS, 8R, 8aR, 13bS) -3- (cyclopropylmethyl) -10-hydroxy-1,2,3,4,5,6,8,8a-octahydro-7H-4a, 8 -Ethano-4,13-methanobenzofuro [2,3-c] pyrido [4,3-d] azepin-7-yl) -2- (pyrrolidin-1-yl) ethan-1-one (262)
  • a crude product of the title compound was obtained from compound 9 (8.0 mg, 0.023 mmol) and 2- (azepan-1-yl) acetic acid (5.5 mg, 0.035 mmol).
  • methanol a solution of the obtained crude product in methanol (1 mL) was added 10% palladium-activated carbon (55% wet) (2 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours.
  • the reaction mixture was filtered with a membrane filter, and the filtrate was concentrated under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (0-5% methanol / chloroform) to give the title compound (6.1 mg, 53%) as a pale-yellow solid substance.
  • Example 60 According to the method described in Example 60, the title compound was obtained from compound 9 and (R) -2- (4- (tert-butoxycarbonyl) morpholin-3-yl) acetic acid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ (ppm): 0.03-0.18 (m, 2H), 0.41-0.57 (m, 2H), 0.71-0.93 (m , 1H), 1.02-1.83 (m, 15H), 2.08-3.32 (m, 12H), 3.38-4.23 (m, 10H), 4.30-4.74. (M, 3H), 6.52-6.66 (m, 1H), 6.67-6.81 (m, 1H).

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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne un dérivé de morphinane qui a un effet agoniste du récepteur kappa opioïde et qui est représenté par la formule générale (I). (Dans la formule, R1 représente un atome d'hydrogène, un groupe alkyle en C1-6 qui peut avoir un substituant, ou similaire ; R2 et R3 sont identiques ou différents et représentent chacun un atome d'hydrogène, un groupe alkyle en C1-6 qui peut avoir un substituant, ou similaire ; R4 et R5 sont identiques ou différents et représentent chacun un atome d'hydrogène, un groupe alkyle en C1-6 qui peut avoir un substituant, ou similaire ; R6 représente un atome d'hydrogène, un groupe alcoxy en C1-6 qui peut avoir un substituant, ou similaire ; R7 représente un atome d'hydrogène, un groupe alkyle en C1-6 qui peut avoir un substituant, ou similaire ; R8 et R9 sont identiques ou différents et représentent chacun un atome d'hydrogène, un groupe alkyle en C1-6 qui peut avoir un substituant, ou similaire ; R10 et R11 sont identiques ou différents et représentent chacun un atome d'hydrogène, un groupe alkyle en C1-6 qui peut avoir un substituant, ou similaire ; R12 et R13 sont identiques ou différents et représentent chacun un atome d'hydrogène ou similaire ; R14 représente un groupe hétéroaryle qui peut avoir un substituant ou similaire ; X représente un atome d'azote ou similaire ; Y représente C=O ou similaire ; Z représente un atome d'oxygène ou similaire ; une ligne double constituée d'une ligne solide et d'une ligne brisée indique une liaison simple ou similaire ; m représente un nombre entier de 0 à 1 ; et n représente un nombre entier de 0 à 3.) La présente invention concerne également un tautomère, un stéréoisomère ou un sel pharmaceutiquement acceptable dudit composé, ou un solvate desdites substances.
PCT/JP2019/041076 2018-10-22 2019-10-18 Dérivé de morphinane Ceased WO2020085234A1 (fr)

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JP2018198525A JP2022017604A (ja) 2018-10-22 2018-10-22 モルヒナン誘導体

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2021065898A1 (fr) * 2019-09-30 2021-04-08
WO2022127320A1 (fr) * 2020-12-18 2022-06-23 四川大学 Intermédiaire, son procédé de préparation et son utilisation
WO2022210479A1 (fr) * 2021-03-29 2022-10-06 日本ケミファ株式会社 UTILISATION D'UN DÉRIVÉ D'AZÉPANE POUR LE TRAITEMENT, L'AMÉLIORATION OU LA PRÉVENTION DE MALADIES ASSOCIÉES AUX RÉCEPTEURS OPIOÏDES κ

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009196933A (ja) * 2008-02-21 2009-09-03 Toray Ind Inc オキサビシクロ［２．２．２］オクタンを有するモルヒナン誘導体およびその医薬用途
JP2015515986A (ja) * 2012-05-02 2015-06-04 サザン リサーチ インスティテュート 複素環式縮合モルフィナン類、その使用及びその製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009196933A (ja) * 2008-02-21 2009-09-03 Toray Ind Inc オキサビシクロ［２．２．２］オクタンを有するモルヒナン誘導体およびその医薬用途
JP2015515986A (ja) * 2012-05-02 2015-06-04 サザン リサーチ インスティテュート 複素環式縮合モルフィナン類、その使用及びその製造方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FLEISCHHACKER, W. ET AL.: "Über 14‐(Oxyalkyl)morphin‐Derivate", CHEMISCHE BERICHTE, vol. 112, September 1979 (1979-09-01), pages 3054 - 3062 *
LESSOR, R. A. ET AL.: "Probes for Narcotic Receptor Mediated Phenomena. 13.1 Potential Irreversible Narcotic Antagonist-Based Ligands Derived from 6,14-emfo-Ethenotetrahydrooripavine with 7-(Methoxyfumaroyl)amino, (Bromoacetyl)amino, or Isothiocyanate Electrophiles: Chemistry, Biochemistry, and Pharmacology", JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 11, 1 November 1986 (1986-11-01), pages 2136 - 2141, XP002286998 *
SUZUKI, S. ET AL.: "Discovery of highly selective κ-opioid receptor agonists: 10α-Hydroxy TRK-820 derivatives", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 27, no. 16, 12 June 2017 (2017-06-12), pages 3920 - 3924, XP055710940 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2021065898A1 (fr) * 2019-09-30 2021-04-08
WO2021065898A1 (fr) * 2019-09-30 2021-04-08 日本ケミファ株式会社 Dérivé d'azépane
JP7678756B2 (ja) 2019-09-30 2025-05-16 日本ケミファ株式会社 アゼパン誘導体
WO2022127320A1 (fr) * 2020-12-18 2022-06-23 四川大学 Intermédiaire, son procédé de préparation et son utilisation
WO2022210479A1 (fr) * 2021-03-29 2022-10-06 日本ケミファ株式会社 UTILISATION D'UN DÉRIVÉ D'AZÉPANE POUR LE TRAITEMENT, L'AMÉLIORATION OU LA PRÉVENTION DE MALADIES ASSOCIÉES AUX RÉCEPTEURS OPIOÏDES κ

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