WO2010016554A1 - Composé amine cyclique - Google Patents

Composé amine cyclique Download PDF

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Publication number
WO2010016554A1
WO2010016554A1 PCT/JP2009/063964 JP2009063964W WO2010016554A1 WO 2010016554 A1 WO2010016554 A1 WO 2010016554A1 JP 2009063964 W JP2009063964 W JP 2009063964W WO 2010016554 A1 WO2010016554 A1 WO 2010016554A1
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alkyl
hydrogen atom
compound
atom
optionally substituted
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PCT/JP2009/063964
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Japanese (ja)
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雄二 石地
英司 木村
淳 寺内
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武田薬品工業株式会社
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Publication of WO2010016554A1 publication Critical patent/WO2010016554A1/fr

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    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
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    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
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    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to a cyclic amine compound having excellent monoamine reuptake inhibitory activity and useful as a therapeutic / preventive agent for depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence, and the like.
  • the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are widely present in the brain and have various functions such as neurotransmission via their receptors. .
  • serotonin transporter: SERT, norepinephrine transporter: NET and dopamine transporter: DAT neurotransmission Ends.
  • Compounds showing inhibitory activity on monoamine reuptake are known to be effective in various diseases including neuropsychiatric diseases such as depression, and are widely used as therapeutic agents.
  • Triple Reuptake Inhibitor A compound that inhibits three types of reuptake, serotonin, norepinephrine, and dopamine, is called Triple Reuptake Inhibitor, and is expected to be used as a therapeutic agent for neuropsychiatric disorders and the like.
  • Depressive drugs include tricyclic antidepressants (TCA) typified by imipramine, selective serotonin reuptake inhibitors (SSRI) typified by fluoxetine, and selective serotonin norepinephrine typified by venlafaxine.
  • TCA tricyclic antidepressants
  • SSRI selective serotonin reuptake inhibitors
  • SNRI norepinephrine / dopamine reuptake inhibitors such as bupropion, monoamine oxidase inhibitors, etc. are used. From a point etc., it cannot necessarily be said that satisfaction is high (refer nonpatent literatures 1 and 2).
  • TCA, SSRI and SNRI are not only for depression, but also for neuropsychiatric disorders such as anxiety, attention deficit / hyperactivity disorder, neurodegenerative diseases such as Alzheimer's disease, diabetic pain, myofibrosis, etc. There are also reports that it is useful as a treatment for pain in the stomach or as a treatment for gastrointestinal diseases such as irritable bowel syndrome.
  • Patent Document 5 discloses a piperidine compound useful as a therapeutic agent for central nervous system diseases such as major depression and premature ejaculation due to monoamine reuptake inhibitory action.
  • R represents a hydrogen atom, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, trifluoromethyl, cyano, halogen atom, or hydroxy.
  • R represents a hydrogen atom, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, trifluoromethyl, cyano, halogen atom, or hydroxy. The compound represented by this is described.
  • Patent Document 6 Patent Document 7, Patent Document 8, Patent Document 9, Patent Document 10, and Patent Document 11 describe a preventive / therapeutic agent for central nervous diseases such as vasomotor syndrome and major depression caused by monoamine reuptake inhibitory action.
  • central nervous diseases such as vasomotor syndrome and major depression caused by monoamine reuptake inhibitory action.
  • Patent Document 12 discloses a therapeutic agent for diseases involving inhibition of tachykinin and / or selective serotonin reuptake, for example, the formula
  • Patent Document 13 discloses, for example, a formula as an antipsychotic drug with dopamine receptor antagonistic action.
  • Patent Document 14 discloses a therapeutic agent for extrapyramidal symptoms when using a tranquilizer with 5-HT2 receptor antagonism.
  • Patent Document 16 as an antipsychotic drug, for example, a formula
  • Monoamine serotonin, norepinephrine, dopamine, etc.
  • reuptake inhibitory activity useful as a preventive or therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence, etc.
  • Development of a compound having excellent properties in terms of action time, specificity, low toxicity and the like is desired.
  • the present invention is a compound having a chemical structure different from known compounds including the above-mentioned compounds, having a monoamine reuptake inhibitory activity and the like, and novel such as depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence
  • the purpose is to provide preventive and therapeutic drugs.
  • X a is, -CRaRb -, - CO -, - NRa -, - NRaCO -, - CONRa -, - NRaCONRb -, - NRaY -, - CONRaY -, - OY -, - SY -, - YS -, - YSO 2 —, —SO 2 Y—, —N ⁇ CH—, —SO 2 NRa—, —NRaSO 2 — or
  • Y is an optionally substituted C 1-6 alkylene
  • Ra and Rb are the same or different and each represents a hydrogen atom or C 1-6 alkyl
  • Z a is CR 12a or N
  • R 1a may be substituted with a hydrogen atom, optionally substituted C 1-6 alkyl, cyano, hydroxy, optionally substituted C 1-6 alkoxy, C 3-6 cycloalkyl, or oxo.
  • R 2a is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl
  • R 3a to R 11a are the same or different and each represents a hydrogen atom or C 1-6 alkyl
  • R 12a is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkoxy, an optionally substituted C 1-6 alkyl or cyano
  • R 13a to R 15a are the same or different and each represents a hydrogen atom or a halogen atom (in this case, at least one group of R 13a to R 15a represents a chlorine atom), or R 13a represents a hydrogen atom or a chlorine atom.
  • R 14a and R 15a together with the adjacent benzene ring forms an optionally substituted naphthalene ring or an optionally substituted benzofuran ring;
  • R 16a and R 17a are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
  • n represents 1 or 2 (when n is 2, two R 7a and two R 8a may be the same or different from each other).
  • Z a is N
  • X a represents —CH 2 —, —C (CH 3 ) 2 —, —CO—, —OY—, —NRaCO— or
  • R 1a represents a hydrogen atom, C 1-6 alkyl, hydroxy, C 1-6 alkoxy or C 3-6 cycloalkyl (provided that when X a is —CH 2 —, R 1a represents hydroxy or C 1-6 alkoxy).
  • X represents —CH 2 —, —CO—, —NRa—, —NRaCO—, —CONRa—, —NRaCONRb—, —NRaY—, —CONRaY—, —OY—, —SY—, —YS—, —YSO.
  • Y is an optionally substituted C 1-6 alkylene
  • Ra and Rb are the same or different and each represents a hydrogen atom or C 1-6 alkyl
  • R 1 is a hydrogen atom, C 1-6 alkyl, cyano, hydroxy, C 1-6 alkoxy, C 3-6 cycloalkyl, or a 4-7 membered heterocyclic group optionally substituted with oxo
  • R 2 represents a hydrogen atom or an optionally substituted C 1-6 alkyl
  • R 3 to R 11 are the same or different and each represents a hydrogen atom or C 1-6 alkyl
  • R 12 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkoxy, an optionally substituted C 1-6 alkyl or cyano
  • R 13 to R 15 are the same or different and each represents a hydrogen atom or a halogen atom (in this case, at least one group of R 13 to R 15 represents a chlorine atom), or
  • X is —CO— and R 1 is hydroxy, 1- (4-chlorophenyl) -1-piperidin-4-ylmethanamine, 4- (4-chlorophenyl) -4-piperidin-4-ylbutane -1-ol, 1- (6-chloronaphthalen-2-yl) -1- (1-methylpiperidin-4-yl) methanamine, 1- (4-chlorophenyl) -N, N-dimethyl-1-piperidine- 4-ylmethanamine, N-[(4-chlorophenyl) (piperidin-4-yl) methyl] -N-ethylethanamine and 1- (3,4-dichlorophenyl) -N, N-dimethyl-1-piperidine- Or a salt thereof, excluding 4-ylmethanamine
  • X c is —CH 2 —, —C (CH 3 ) 2 —, —CO—, —OY c —, —NRaCO— or
  • n 1 or 2
  • Y c is C 1-6 alkylene
  • Ra is a hydrogen atom or C 1-6 alkyl
  • R 1c is a hydrogen atom, C 1-6 alkyl, hydroxy, C 1-6 alkoxy or C 3-6 cycloalkyl
  • R 13c to R 15c are the same or different and each represents a hydrogen atom or a halogen atom (in this case, at least one group of R 13c to R 15c represents a chlorine atom), or R 13c represents a hydrogen atom or a chlorine atom
  • R 14c and R 15c together with the adjacent benzene ring form a naphthalene ring optionally substituted with C 1-6 alkoxy.
  • X c is —CH 2 —
  • R 1c is hydroxy or C 1-6 alkoxy.
  • X d represents —OY d —, —CO— or —CONH—
  • Y d is C 1-6 alkylene
  • Z d is CH or N
  • R 1d is a hydrogen atom
  • R 13d to R 15d are the same or different and each represents a hydrogen atom or a halogen atom (provided that at least one group of R 13d to R 15d represents a chlorine atom).
  • a compound according to [1], [11] X d is —OCH 2 —, —OC (CH 3 ) 2 —, —CO— or —CONH—, Z d is CH or N, R 1d is a hydrogen atom, methyl, isopropyl or methoxy, R 13d is a hydrogen atom, R 14d is a chlorine atom or a fluorine atom,
  • R 15d is a chlorine atom
  • the compound of the present invention or a prodrug thereof has excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, for example, depression, anxiety, attention deficit / hyperactivity disorder, stress urinary incontinence, etc. It is useful as a preventive and therapeutic drug for
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • C 1-6 alkyl examples include linear or branched C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,2,2 -Trimethylpropyl and the like.
  • C 1-6 alkoxy includes linear or branched C 1-6 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy. , Tert-butoxy, 1-methylpropoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy, hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1, Examples include 2-dimethylbutoxy and 1,2,2-trimethylpropoxy.
  • C 3-6 cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 1-6 alkylene includes linear or branched C 1-6 alkylene, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, — CH (CH 3 ) —, —C (CH 3 ) 2 —, —CH (CH 3 ) —CH 2 —, —CH 2 —CH (CH 3 ) —, —C (CH 3 ) 2 —CH 2 —, —CH 2 —C (CH 3 ) 2 — and the like can be mentioned.
  • the “4- to 7-membered heterocyclic group optionally substituted with oxo” includes 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (preferably 4 to 7-membered heterocyclic group which may be substituted with oxo (preferably 1 or 2 oxo) containing 1 to 3, more preferably 1 or 2).
  • Oxo preferably 1 or 2) containing 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom 4-7 membered saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (eg azetidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, tetrahydropyrani) optionally substituted with 2 oxo) , Morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl (eg, 1,4-diazepanyl), oxazepanyl (eg, 1,4-oxazepanyl), oxazolidinyl, isoxazolidinyl, thiazo
  • C 1-6 alkyl of the “ optionally substituted C 1-6 alkyl” may have, (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (2) cyano, (3) hydroxy, (4) Nitro, (5) Formyl, (6) amino, (7) mono- or di-C 1-6 alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino, etc.), (8) C 1-6 alkyl-carbonylamino (eg, acetylamino, ethylcarbonylamino, etc.) (9) C 1-6 alkoxy-carbonylamino (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino,
  • Halogen atom
  • Examples of the substituent that “C 1-6 alkoxy” of “optionally substituted C 1-6 alkoxy” may have include “the optionally substituted C 1-6 alkyl” of “ Examples thereof include the same substituents that may be possessed by “C 1-6 alkyl”.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • C 1-6 alkylene of the “ optionally substituted C 1-6 alkylene” may have, (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (2) cyano, (3) hydroxy, (4) The substituent chosen from nitro etc. is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • the substituent that the “naphthalene ring” of the “optionally substituted naphthalene ring” or the “benzofuran ring” of the “optionally substituted benzofuran ring” may have, (A) the substituent which the “C 1-6 alkyl” of the “ optionally substituted C 1-6 alkyl” may have, and (b) (1) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxy and C 1-6 alkoxy (e.g., methoxy, ethoxy, 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from propoxy) ( Examples, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl
  • X a represents —CRaRb—, —CO—, —NRa—, —NRaCO—, —CONRa—, —NRaCONRb—, —NRaY—, —CONRaY—, —OY—, —SY—, —YS—, —YSO 2 —, —SO 2 Y—, —N ⁇ CH—, —SO 2 NRa—, —NRaSO 2 — or
  • X a is —CRaRb—, —CO—, —CONRa—, —NRaCONRb—, —OY—, —SY—, —YS—, —YSO 2 —, —SO 2 Y—, —SO 2 NRa— or -NRaSO 2 -is preferred.
  • C 1-6 alkylene optionally substituted to 1 selected from halogen atoms and hydroxy to 4 substituents .
  • Y is preferably C 1-6 alkylene, more preferably —CH 2 — or —C (CH 3 ) 2 —, and particularly preferably —CH 2 —.
  • C 1-6 alkyl As the “optionally substituted C 1-6 alkyl” represented by R 1a, it includes C 1-6 alkyl optionally substituted with C 1-6 alkoxy.
  • Examples of the “optionally substituted C 1-6 alkoxy” represented by R 1a include C 1-6 alkoxy optionally substituted with C 1-6 alkoxy.
  • the “4- to 7-membered heterocyclic group optionally substituted with oxo” represented by R 1a has 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom (preferably Is preferably a 4 to 7-membered saturated non-aromatic heterocyclic group which may be substituted with oxo (preferably 1 or 2 oxo), containing 1 to 3, more preferably 1 or 2.
  • oxadiazolidinyl eg, 1,2,4-oxadiazolidinyl, 1,3,4
  • pyrrolidinyl or oxazolidinyl eg, 2-oxopyrrolidinyl, 2-oxooxazolidinyl
  • oxazolidinyl eg, 2-oxopyrrolidinyl, 2-oxooxazolidinyl
  • 1 or 2 oxo groups is particularly preferable.
  • R 1a is preferably a hydrogen atom, C 1-6 alkyl, hydroxy or C 1-6 alkoxy.
  • C 1-6 alkyl represented by R 2a, include one to three C 1-6 alkyl optionally substituted with a substituent selected from halogen atoms and hydroxy It is done.
  • R 2a is preferably a hydrogen atom or C 1-6 alkyl, more preferably a hydrogen atom.
  • R 3a to R 10a are preferably hydrogen atoms.
  • R 11a is preferably a hydrogen atom.
  • optionally substituted C 1-6 alkoxy represented by R 12a, include one to three optionally substituted with a substituent C 1-6 alkoxy are selected from halogen atoms and hydroxy It is done.
  • C 1-6 alkyl represented by R 12a, include one to three C 1-6 alkyl optionally substituted with a substituent selected from halogen atoms and hydroxy It is done.
  • R 12a is preferably a hydrogen atom or C 1-6 alkoxy, more preferably a hydrogen atom.
  • Examples of the optionally substituted naphthalene ring or the optionally substituted benzofuran ring that R 14a and R 15a each form together with the adjacent benzene ring include: (1) a halogen atom, (2) hydroxy, (3) 1 to 1 selected from three optionally substituted by a halogen atom C 1-6 alkyl, and (4) 1 to 3 halogen atoms optionally substituted by a C 1-6 alkoxy And a naphthalene ring or a benzofuran ring, each of which may be substituted with 4 substituents.
  • a naphthalene ring which may be substituted with C 1-6 alkoxy is preferable, and an unsubstituted naphthalene ring is more preferable.
  • R 13a to R 15a are preferably the same or different and are a hydrogen atom or a halogen atom, and at least one group of R 13a to R 15a is a chlorine atom.
  • R 13a is a hydrogen atom
  • R 14a and R 15a are both halogen atoms (provided that at least one group of R 14a and R 15a is a chlorine atom).
  • R 13a is a hydrogen atom
  • R 14a is a chlorine atom or a fluorine atom
  • R 15a is a chlorine atom.
  • R 13a is a hydrogen atom
  • R 14a and R 15a together with an adjacent benzene ring form a naphthalene ring which may be substituted with C 1-6 alkoxy.
  • R 16a and R 17a are preferably a hydrogen atom.
  • N is 1 or 2, preferably n is 1.
  • X a is, -CRaRb -, - CO -, - NRa -, - NRaCO -, - CONRa -, - NRaCONRb -, - NRaY -, - CONRaY -, - OY -, - SY -, - YS -, - YSO 2 —, —SO 2 Y—, —N ⁇ CH—, —SO 2 NRa—, —NRaSO 2 — or
  • Y is C 1-6 alkylene which may be substituted with 1 to 4 substituents selected from a halogen atom and hydroxy;
  • Ra and Rb are the same or different and each represents a hydrogen atom or C 1-6 alkyl;
  • Z a is CR 12a or N;
  • R 1a is a hydrogen atom, C 1-6 alkoxy optionally substituted by C 1-6 alkyl, cyano, hydroxy, C 1-6 alkoxy optionally substituted by C 1-6 alkoxy, C 3- 6- cycloalkyl, or a 4 to 7-membered heterocyclic group optionally substituted with oxo
  • R 2a is a hydrogen atom, a halogen atom, or C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy
  • R 3a to R 11a are the same or different and each represents a hydrogen atom or C 1-6 alkyl;
  • R 12a is optionally substituted with 1
  • X a is —CRaRb—, —CO—, —NRa—, —NRaCO—, —CONRa—, —NRaCONRb—, —CONRaY—, —OY—, —SY—, —SO 2 Y—, —N ⁇ CH -, -SO 2 NRa- or
  • Y is C 1-6 alkylene, Ra and Rb are the same or different and each represents a hydrogen atom or C 1-6 alkyl;
  • Z a is CR 12a or N;
  • R 1a is a hydrogen atom, C 1-6 alkoxy optionally substituted by C 1-6 alkyl, hydroxy, C 1-6 optionally substituted alkoxy C 1-6 alkoxy or C 3-6 cycloalkyl Alkyl,
  • R 2a is a hydrogen atom or C 1-6 alkyl;
  • R 3a to R 10a are a hydrogen atom, R 11a is a hydrogen atom or C 1-6 alkyl;
  • R 12a is a hydrogen atom,
  • R 13a to R 15a are the same or different and are a hydrogen atom or a halogen atom (in this case, at least one group of R 13a to R 15a is a chlorine atom), or
  • R 13a is a hydrogen atom , R 14a and R 15a together with the adjacent
  • X a is —CRaRb—, —CO—, —CONRa—, —NRaCONRb—, —OY—, —SY—, —YS—, —YSO 2 —, —SO 2 Y—, —SO 2 NRa— or — Compound (Ia) which is NRaSO 2 —.
  • X a is —CRaRb—, —CO—, —CONRa—, —NRaCONRb—, —OY—, —SY—, —YS—, —YSO 2 —, —SO 2 Y—, —SO 2 NRa— or — NRaSO 2- , Compound (Ia) wherein R 1a is a hydrogen atom, C 1-6 alkyl, hydroxy or C 1-6 alkoxy.
  • X a is —CRaRb—, —CO—, —CONRa—, —NRaCONRb—, —OY—, —SY—, —YS—, —YSO 2 —, —SO 2 Y—, —SO 2 NRa— or — NRaSO 2-
  • R 1a is a hydrogen atom, C 1-6 alkyl, hydroxy or C 1-6 alkoxy
  • R 13a to R 15a are the same or different and each represents a hydrogen atom or a halogen atom
  • Compound (Ia) wherein at least one group of R 13a to R 15a is a chlorine atom.
  • n is 1, Z a is CH, X a is —CH 2 —; R 1a is C 1-6 alkoxy; R 2a is a hydrogen atom or C 1-6 alkyl; R 3a to R 11a are hydrogen atoms, R 13a to R 15a are the same or different and each represents a hydrogen atom or a halogen atom; At least one group of R 13a to R 15a is a chlorine atom, Compound (Ia), wherein R 16a and R 17a are hydrogen atoms.
  • n is 1, Z a is N, X a is —CO—, R 1a is C 1-6 alkyl; R 2a is a hydrogen atom, R 3a to R 11a are hydrogen atoms, R 13a to R 15a are the same or different and each represents a hydrogen atom or a halogen atom; At least one group of R 13a to R 15a is a chlorine atom, Compound (Ia), wherein R 16a and R 17a are hydrogen atoms.
  • X a and R 1a include the following embodiments.
  • R 1a is hydroxy (Ia).
  • X represents —CH 2 —, —CO—, —NRa—, —NRaCO—, —CONRa—, —NRaCONRb—, —NRaY—, —CONRaY—, —OY—, —SY—, —YS—, —YSO 2 — or —SO 2 Y— is represented.
  • the left bond is bonded to R 1 and the right bond is bonded to the carbon atom adjacent to R 2 .
  • Preferred examples of X include —CH 2 —, —CO—, —CONRa—, —NRaCONRb—, —OY—, —SY—, —YS—, —YSO 2 — or —SO 2 Y—.
  • X is —CH 2 —, —CO—, —NRa—, —NRaCO—, —CONRa—, —NRaCONRb—, —CONRaY—, —OY—, —SY— or —SO 2 Y -.
  • C 1-6 alkylene optionally substituted to 1 selected from halogen atoms and hydroxy to 4 substituents .
  • Y is preferably C 1-6 alkylene, more preferably —CH 2 — or —C (CH 3 ) 2 —, and more preferably —CH 2 —.
  • the “4- to 7-membered heterocyclic group optionally substituted with oxo” represented by R 1 has 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom (preferably Is preferably a 4 to 7-membered saturated non-aromatic heterocyclic group which may be substituted with oxo (preferably 1 or 2 oxo), containing 1 to 3, more preferably 1 or 2.
  • oxadiazolidinyl eg, 1,2,4-oxadiazolidinyl, 1,3,4
  • pyrrolidinyl or oxazolidinyl eg, 2-oxopyrrolidinyl, 2-oxooxazolidinyl
  • oxazolidinyl eg, 2-oxopyrrolidinyl, 2-oxooxazolidinyl
  • 1 or 2 oxo groups is particularly preferable.
  • R 1 include a hydrogen atom, C 1-6 alkyl, hydroxy or C 1-6 alkoxy.
  • R 1 examples include a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl.
  • C 1-6 alkyl represented by R 2
  • R 2 include one to three C 1-6 alkyl optionally substituted with a substituent selected from halogen atoms and hydroxy It is done.
  • R 2 is preferably a hydrogen atom or C 1-6 alkyl, more preferably a hydrogen atom.
  • R 3 to R 10 are preferably hydrogen atoms.
  • R 11 is preferably a hydrogen atom.
  • optionally substituted C 1-6 alkoxy represented by R 12, include one to three optionally substituted with a substituent C 1-6 alkoxy are selected from halogen atoms and hydroxy It is done.
  • C 1-6 alkyl which may be substituted include one to three C 1-6 alkyl optionally substituted with a substituent selected from halogen atoms and hydroxy It is done.
  • R 12 is preferably a hydrogen atom or C 1-6 alkoxy, more preferably a hydrogen atom.
  • naphthalene ring or the optionally substituted benzofuran ring in which R 14 and R 15 are each formed integrally with an adjacent benzene ring, (1) a halogen atom, (2) hydroxy, (3) 1 to 1 selected from three optionally substituted by a halogen atom C 1-6 alkyl, and (4) 1 to 3 halogen atoms optionally substituted by a C 1-6 alkoxy And a naphthalene ring or a benzofuran ring, each of which may be substituted with 4 substituents.
  • a naphthalene ring which may be substituted with C 1-6 alkoxy is preferable, and an unsubstituted naphthalene ring is more preferable.
  • R 13 to R 15 are preferably the same or different and are a hydrogen atom or a halogen atom, and at least one group of R 13 to R 15 is a chlorine atom.
  • R 13 is a hydrogen atom and R 14 and R 15 are both halogen atoms (provided that at least one group of R 14 and R 15 is a chlorine atom). Particularly preferably, R 13 is a hydrogen atom, R 14 is a chlorine atom or a fluorine atom, and R 15 is a chlorine atom.
  • R 13 is a hydrogen atom
  • R 14 and R 15 together with the adjacent benzene ring form a naphthalene ring.
  • Preferable examples of the compound represented by formula (I) or a salt thereof include the following compounds.
  • Compound (I) -1 X is —CH 2 —, —CO—, —NRa—, —NRaCO—, —CONRa—, —NRaCONRb—, —NRaY—, —CONRaY—, —OY—, —SY—, —YS—, —YSO 2 -or -SO 2 Y- Y is C 1-6 alkylene which may be substituted with 1 to 4 substituents selected from a halogen atom and hydroxy; Ra and Rb are the same or different and each represents a hydrogen atom or C 1-6 alkyl; R 1 is a hydrogen atom, C 1-6 alkyl, cyano, hydroxy, C 1-6 alkoxy, C 3-6 cycloalkyl, or a 4-7 membered heterocyclic group optionally substituted with o
  • X is —CH 2 —, —CO—, —NRa—, —NRaCO—, —CONRa—, —NRaCONRb—, —CONRaY—, —OY—, —SY— or —SO 2 Y—
  • Y is C 1-6 alkylene
  • Ra and Rb are the same or different and each represents a hydrogen atom or C 1-6 alkyl
  • R 1 is a hydrogen atom, C 1-6 alkyl, hydroxy or C 1-6 alkoxy
  • R 2 is a hydrogen atom or C 1-6 alkyl
  • R 3 to R 10 are hydrogen atoms
  • R 11 is a hydrogen atom or C 1-6 alkyl
  • R 12 is a hydrogen atom
  • R 13 to R 15 are the same or different and are a hydrogen atom or a halogen atom (in this case, at least one group of R 13 to R 15 is a chlorine atom), or R 13 is a hydrogen atom , R 14 and
  • X is —CH 2 —, —CO—, —NRa—, —NRaCO—, —CONRa—, —NRaCONR—, —NRaY—, —OY—, —SY— or —SO 2 Y—
  • Y is C 1-6 alkylene
  • Ra and Rb are the same or different and each represents a hydrogen atom or C 1-6 alkyl
  • R 1 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl
  • R 2 is a hydrogen atom or C 1-6 alkyl
  • R 3 to R 11 are the same or different and each represents a hydrogen atom or C 1-6 alkyl
  • R 12 is a hydrogen atom
  • R 13 to R 15 are the same or different and are a hydrogen atom or a halogen atom (in this case, at least one group of R 13 to R 15 is a chlorine atom), or R 13 is a hydrogen atom atom
  • X is —CH 2 —, —CO—, —CONRa—, —NRaCONRb—, —OY—, —SY—, —YS—, —YSO 2 — or —SO 2 Y—, Compound (I) wherein R 1 is a hydrogen atom, C 1-6 alkyl, hydroxy or C 1-6 alkoxy.
  • X is —CH 2 —, —CO—, —CONRa—, —NRaCONRb—, —OY—, —SY—, —YS—, —YSO 2 — or —SO 2 Y—
  • R 1 is a hydrogen atom, C 1-6 alkyl, hydroxy or C 1-6 alkoxy
  • R 2 is a hydrogen atom or C 1-6 alkyl
  • R 3 to R 12 are hydrogen atoms
  • Compound (I) wherein R 13 to R 15 are the same or different and are a hydrogen atom or a halogen atom, and at least one group of R 13 to R 15 is a chlorine atom.
  • X is —CH 2 —; R 1 is C 1-6 alkoxy; R 2 is a hydrogen atom or C 1-6 alkyl, R 3 to R 12 are hydrogen atoms, R 13 to R 15 are the same or different and each represents a hydrogen atom or a halogen atom; Compound (I) wherein at least one group of R 13 to R 15 is a chlorine atom.
  • X and R 1 include the following embodiments.
  • a compound in which X is —NRa—, —NRaCO—, —NRaCONRb— or —NRaY—, and R 1 is a hydrogen atom, C 1-6 alkyl or C 3-6 cycloalkyl.
  • X b is, -CRaRb -, - CO -, - NRa -, - NRaCO -, - CONRa -, - NRaCONRb -, - CONRaY b -, - OY b -, - SY b -, - SO 2 Y b —, —N ⁇ CH— or —SO 2 NRa— is represented.
  • the left bond is bonded to R 1b and the right bond is bonded to the carbon atom adjacent to R 2b .
  • Y b is more preferably —CH 2 — or —C (CH 3 ) 2 —, and particularly preferably —CH 2 —.
  • R 2b is preferably a hydrogen atom.
  • R 3b to R 10b are preferably hydrogen atoms.
  • R 11b is preferably a hydrogen atom.
  • R 13b to R 15b are preferably the same or different and are a hydrogen atom or a halogen atom, and at least one group of R 13b to R 15b is a chlorine atom.
  • R 13b is a hydrogen atom and R 14b and R 15b are both halogen atoms (provided that at least one group of R 14b and R 15b is a chlorine atom).
  • R 13b is a hydrogen atom
  • R 14b is a chlorine atom or a fluorine atom
  • R 15b is a chlorine atom.
  • compound (Ib) Preferable examples of the compound represented by formula (Ib) or a salt thereof (hereinafter referred to as compound (Ib)) include the following compounds.
  • X b is —CH 2 —; R 1b is C 1-6 alkoxy; R 2b is a hydrogen atom or C 1-6 alkyl; R 3b to R 11b are hydrogen atoms, R 13b to R 15b are the same or different and each represents a hydrogen atom or a halogen atom; Compound (Ib), wherein at least one group of R 13b to R 15b is a chlorine atom.
  • X b and R 1b include the following embodiments.
  • X b is -OY b - or -SY b - a and, R 1b is a hydrogen atom or a C substituted with 1-6 alkoxy is also C 1-6 alkyl compound, (Ib).
  • X c represents —CH 2 —, —C (CH 3 ) 2 —, —CO—, —OY c —, —NRaCO— or
  • N is 1 or 2, preferably n is 1.
  • Y c is preferably —CH 2 — or —C (CH 3 ) 2 —.
  • R 13c to R 15c are preferably the same or different and are a hydrogen atom or a halogen atom, and at least one group of R 13c to R 15c is a chlorine atom.
  • R 13c is a hydrogen atom
  • R 14c and R 15c are both halogen atoms (provided that at least one group of R 14c and R 15c is a chlorine atom).
  • R 13c is a hydrogen atom
  • R 14c is a chlorine atom or a fluorine atom
  • R 15c is a chlorine atom.
  • compound (Ic) Preferred examples of the compound represented by the formula (Ic) or a salt thereof (hereinafter referred to as compound (Ic)) include the following compounds.
  • n 1, X c is —CO—, R 1c is C 1-6 alkyl; R 13c to R 15c are the same or different and each represents a hydrogen atom or a halogen atom, Compound (Ic), wherein at least one group of R 13c to R 15c is a chlorine atom.
  • n 2
  • X c is —CO—
  • R 1c is C 1-6 alkyl
  • R 13c to R 15c are the same or different and each represents a hydrogen atom or a halogen atom
  • Compound (Ic) wherein at least one group of R 13c to R 15c is a chlorine atom.
  • X c and R 1c include the following embodiments.
  • X c is -CH 2 - or -C (CH 3) 2 - a and compound R 1c is hydroxy or C 1-6 alkoxy (Ic).
  • Compound (Ic) wherein X c is —NRaCO—, and R 1c is a hydrogen atom or C 1-6 alkyl.
  • Xc is
  • X d represents —OY d —, —CO— or —CONH—.
  • the left bond is bonded to R 1d and the right bond is bonded to the carbon atom adjacent to the phenyl group.
  • Y d is preferably —CH 2 — or —C (CH 3 ) 2 —.
  • R 13d is a hydrogen atom and R 14d and R 15d are both halogen atoms (provided that at least one group of R 14d and R 15d is a chlorine atom). Particularly preferably, R 13d is a hydrogen atom, R 14d is a chlorine atom or a fluorine atom, and R 15d is a chlorine atom.
  • Preferred examples of the compound represented by the formula (Id) or a salt thereof include the following compounds.
  • X d is —OCH 2 —, —OC (CH 3 ) 2 —, —CO— or —CONH—, Z d is CH or N;
  • R 1d is a hydrogen atom, methyl, isopropyl or methoxy;
  • R 13d is a hydrogen atom,
  • R 14d is a chlorine atom or a fluorine atom;
  • Compound (Id) wherein R 15d is a chlorine atom.
  • X d and R 1d include the following embodiments.
  • Examples of the compound (Ia) include the compounds described in Examples 1, 2, 4 to 25, 27, 29 to 36, 44, 46, 50 to 52, 55, 57 to 85, 102 to 106, and 108 to 111. preferable.
  • compounds described in Examples 1, 2, 4 to 25, 27, 29 to 36, 44, 46, 50 to 52, 55, 57 to 68, and 102 to 106 are preferable.
  • the compounds described in Examples 69 to 85 and 108 to 111 are preferable.
  • salts include salts with inorganic bases, ammonium And a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • salt with an organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • salts pharmaceutically acceptable salts are preferable.
  • Compound (Ia) includes within its scope solvates such as hydrates.
  • Compound (Ia) may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.).
  • Compound (Ia) may be a deuterium converter.
  • isomers such as enantiomers or diastereomers may exist. All such isomers and mixtures thereof are included within the scope of the present invention. In addition, isomers due to conformation may be produced, and such isomers or mixtures thereof are also included in the compound (Ia) of the present invention.
  • the manufacturing method of the compound of this invention is demonstrated.
  • “lower” means a group having 1 to 6 carbon atoms unless otherwise specified.
  • the starting compound and the production intermediate may be used as a salt. Examples of such a salt include the same salts as the salt of compound (Ia).
  • the compound (Ia-1) and the compound (Ia-2) contained in the compound (Ia) of the present invention can be produced, for example, using the following steps 1 and 2.
  • PRG represents an amino protecting group, and other symbols are as defined above.
  • amino protecting group represented by PRG
  • protecting groups described in Greene's protective groups in organic synthesis 4 th edition can be used.
  • Amino protecting groups include, for example, formyl, optionally substituted C 1-6 alkyl-carbonyl (eg acetyl, ethylcarbonyl, trifluoroacetyl, chloroacetyl, etc.), benzoyl, C 1-6 alkyl -Oxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl etc.), phenyloxycarbonyl (eg phenoxycarbonyl etc.), C 7-15 aralkyloxy-carbonyl (eg benzyloxycarbonyl, 9-fluorenyl) Acyl groups such as methyloxycarbonyl) or hydrocarbon groups such as methyl, benzyl, and trityl.
  • C 1-6 alkyl-carbonyl eg acetyl
  • tert-butoxycarbonyl (Boc) group tert-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz) group, 9-fluorenylmethyl, etc.
  • Oxycarbonyl (Fmoc) Carbamate protecting group such as acetyl (Ac) group, an amide-based protecting group such as trifluoroacetyl group or a benzyl group, or an alkyl type protecting group such as a methyl group.
  • Step 1 is generally performed in a “solvent used for organic synthesis”, and a solvent that does not inhibit the reaction is appropriately selected.
  • solvents used in organic synthesis include alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl).
  • the reaction time varies depending on the type of compound (IIa), the type of solvent and base, the reaction temperature, etc., but is usually about 1 minute to about 100 hours, preferably about 5 minutes to about 48 hours.
  • the amino protecting group is a Boc group
  • deprotection by acid treatment with hydrochloric acid, trifluoroacetic acid or the like is preferable.
  • the acid can be used in a molar equivalent or a large excess relative to compound (IIa).
  • the solvent is appropriately selected from the above-mentioned “solvents used in organic synthesis”, and among them, alcohols such as ethanol, or water is preferable. If necessary, the acid itself may be used as a solvent.
  • deprotection can be performed by, for example, catalytic hydrogenation using a metal catalyst.
  • the catalyst used in the catalytic hydrogenation include metals such as palladium, platinum, nickel and rhodium or oxides, salts and complexes thereof, and these catalysts can be used by being supported on various supports such as carbon.
  • the catalytic hydrogenation can be carried out at normal pressure or under pressure.
  • the solvent is appropriately selected from the above-mentioned “solvents used in organic synthesis”. Among them, alcohols such as ethanol, ethers such as tetrahydrofuran or water are preferable.
  • compound (Ia-1) By subjecting compound (Ia-1) to Step 2, compound (Ia-1) can be N-alkylated to produce compound (Ia-2) which is a tertiary amine.
  • N-alkylation for example, a method based on a reductive alkylation reaction described in Organic Reactions, vol. 59, 1-714 can be used.
  • the reductive alkylation reaction is a method for producing an amine by reacting compound (Ia-1) with an aldehyde or a ketone and reducing the produced imine or iminium ion.
  • the aldehyde or ketone is selected depending on R 11a to be introduced, and is selected from lower aldehydes such as formaldehyde, acetaldehyde, propionaldehyde and butyraldehyde, and lower ketones such as acetone, methyl ethyl ketone and 3-pentanone.
  • lower aldehydes such as formaldehyde, acetaldehyde, propionaldehyde and butyraldehyde
  • ketones such as acetone, methyl ethyl ketone and 3-pentanone.
  • a corresponding cyclic oligomer such as 1,3,5-trioxane or a corresponding polymer such as paraformaldehyde may be used.
  • 1 mole equivalent or large excess (preferably 1 to 10 mole equivalent) of aldehyde or ketone can be used with respect to compound (Ia-1).
  • an acid for example, a mineral acid such as hydrochloric acid, phosphoric acid or sulfuric acid, or an organic acid such as toluenesulfonic acid, methanesulfonic acid or acetic acid
  • An equivalent amount may be added.
  • a metal hydride complex compound such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, a reduction method using a reducing agent such as diborane, catalytic reduction in the presence of a catalyst such as palladium or Raney nickel, Examples thereof include electrolytic reduction using lead and platinum as a cathode, and the reducing agent is used in an amount of 0.3 molar equivalent to large excess (preferably 1 to 10 molar equivalents) relative to compound (Ia-1).
  • “solvent used for organic synthesis” shown in Step 1 is used. Among them, alcohols such as methanol and ethanol, and carboxylic acids such as acetic acid are preferable.
  • the reaction time is usually about 0.5 to about 72 hours, preferably about 1 to about 24 hours.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C., preferably about 0 ° C. to about 60 ° C.
  • step 2 in addition to the above reductive alkylation reaction, for example, an alkyl halide or sulfonic acid alkyl ester described in Journal of the American Chemical Society (J. Am. Chem. Soc.), 68, 1053, (1946) is used. It can be carried out by an alkylation reaction.
  • the reaction is carried out in the presence of a base and an alkyl halide or sulfonic acid alkyl ester in a solvent that does not affect the reaction.
  • the base include potassium carbonate, sodium carbonate, sodium hydride, potassium hydride and the like.
  • Alkyl halide is selected depending on R 11a to be introduced, but C 1-6 alkyl chloride such as methyl chloride, ethyl chloride, propyl chloride, butyl chloride, corresponding C 1-6 alkyl bromide, corresponding C 1-6 alkyl Examples include iodide.
  • the sulfonic acid alkyl ester is selected depending on R 11a to be introduced, but C 1-6 alkyl methanesulfonate (eg, methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, butyl methanesulfonate, etc.), p -Toluenesulfonic acid C 1-6 alkyl (for example, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, propyl p-toluenesulfonate, butyl p-toluenesulfonate) and the like.
  • C 1-6 alkyl methanesulfonate eg, methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, butyl methane
  • the amount of the base and alkyl halide or sulfonic acid alkyl ester to be used is preferably about 1 to about 5 molar equivalents relative to compound (Ia-1), respectively.
  • the “solvent used for organic synthesis” shown in Step 1 is used, and alcohols such as ethanol, ethers such as tetrahydrofuran, and amides such as N, N-dimethylformamide are particularly preferable.
  • Z represents an acid amide group (—CONH 2 ) or a carboxylic acid group (—CO 2 H), and other symbols are as defined above.
  • Step 3 can be performed in accordance with, for example, the methods described in Bioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.), 16, 3874, (2006) and United States Patent Application Publication (US2004 / 0063744). .
  • Intermediate (VIa) can be produced by reduction of intermediate (Va) in step 4.
  • the reduction in step 4 is, for example, sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, dibutylaluminum hydride, aluminum hydride , A method using a reducing agent such as lithium aluminum hydride, borane complex (borane-THF complex, etc.), catecholborane, a method using a catalytic reduction reaction using a transition metal catalyst such as palladium, platinum, rhodium, or a metal such as magnesium. This can be done depending on the method used.
  • the “solvent used in organic synthesis” shown in Step 1 is used.
  • alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, amides such as N, N-dimethylformamide, acetic acid, etc.
  • the carboxylic acids are preferred.
  • the amount of the reducing agent used is preferably about 0.3 to about 5 molar equivalents relative to intermediate (Va).
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.1 to about 5 hours.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C., preferably about 0 ° C. to about 60 ° C.
  • a method using 0.5 to 2 molar equivalents of sodium borohydride (sodium tetrahydroborate) as a reducing agent in an alcohol solvent (eg, methanol) is preferable.
  • Intermediate (VIIa-a) can be produced by partial hydrolysis of the nitrile of intermediate (VIa) in Step 5.
  • Intermediate (VIIa-b) can be produced by complete hydrolysis of the nitrile of intermediate (VIa).
  • the hydrolysis can be performed by selecting from alkaline conditions and acidic conditions. Alkaline conditions are performed in the presence of a base with a solvent that does not affect the reaction. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the base used is preferably about 1 to about 5 molar equivalents relative to intermediate (VIa).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1.
  • solvents such as ethanol, ethers such as tetrahydrofuran, or water is preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Acidic conditions are performed in the presence of an acid with a solvent that does not affect the reaction.
  • mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and perchloric acid are preferable.
  • the solvent to be used is selected from, for example, “solvents used for organic synthesis” shown in Step 1.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • the method using sodium peroxide described in Journal of Organic Chemistry (J. Org. Chem.), 40, 1187, (1975) for example, Journal of the American A method using sodium nitrite in an acidic solvent such as sulfuric acid described in Chemical Society (J. Am. Chem. Soc.), 78, 5416, (1956) may be used.
  • the hydrolysis tends to be complete, but partial or complete hydrolysis can be selectively performed by adjusting the conditions. For example, selective hydrolysis is possible by appropriately adjusting the type and concentration of the alkali and acid used, the reaction temperature, the solvent, the reaction time, and the like.
  • selective hydrolysis is possible by appropriately adjusting the type and concentration of the alkali and acid used, the reaction temperature, the solvent, the reaction time, and the like.
  • L 1 represents a leaving group
  • R 16 represents C 1-6 alkyl
  • R 17 represents C 1-6 alkyl
  • R 18 represents C 1-6 alkyl
  • C 1-6 alkoxy C 3-
  • the 4- to 7-membered heterocyclic group which may be substituted with 6 cycloalkyl, amino, C 1-6 alkylamino, or oxo, the other symbols are as defined above.
  • Examples of the leaving group represented by L 1 include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methanesulfonyloxy) optionally substituted with a halogen atom. , Ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 6-10 arylsulfonyloxy optionally substituted with C 1-6 alkyl (eg, benzenesulfonyloxy, p-toluenesulfonyloxy).
  • a halogen atom for example, iodine atom
  • methanesulfonyloxy are particularly preferable.
  • Step 6 can be performed using, for example, an alkylating agent R 16 -L 1 in the presence of a base.
  • the “base” is, for example, 1) Alkali metal or alkaline earth metal hydrides (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (eg, lithium amide, sodium amide) , Lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc., lower alkoxides of alkali metals or alkaline earth metals (eg, sodium methoxide, sodium Strong bases such as ethoxide, potassium tert-butoxide); 2) Alkali metal or alkaline earth metals (eg, sodium methoxide, sodium Strong bases such as ethoxide,
  • Amines such as DBU (1,8-diazabicyclo [5.4.0] undes-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene); pyridine Basic heterocyclic compounds such as dimethylaminopyridine, imidazole and 2,6-lutidine An example is a machine base.
  • the “base” examples include alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkaline earth metal amide such as sodium amide, and alkali metal or alkali such as potassium tert-butoxide. Earth metal lower alkoxides are preferred.
  • the amount of the base used is preferably about 1 to about 10 molar equivalents relative to intermediate (VIIa-a).
  • the amount of the alkylating agent used is preferably about 1 to about 10 molar equivalents relative to intermediate (VIIa-a).
  • the solvent used is selected from, for example, “solvents used in organic synthesis” shown in Step 1.
  • ethers such as tetrahydrofuran and amides such as N, N-dimethylformamide are preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Step 7 can be produced in Step 7 by, for example, Hoffman rearrangement of intermediate (VIIa-a) in the presence of alcohol (R 17 OH).
  • Step 7 can be performed according to the methods described in, for example, Organic Reactions (Org. React.), 3, 267, (1946) and Organic Synthesis (Org. Syn.), 10, 549, (2004).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran and hydrocarbons such as toluene are preferable.
  • Alcohol (R 17 OH) is used in a molar equivalent to a large excess with respect to intermediate (VIIa-a), but is often used also as a solvent.
  • step 7 is carried out in the presence of an alcohol, an intermediate (IIa-b) is obtained, but if it is carried out in the absence of an alcohol, the corresponding isocyanate is produced.
  • alcohol may be allowed to act after the isocyanate is once isolated.
  • the bromine source for example, simple bromine (Br 2 ), hypobromite such as sodium hypobromite, N-bromosuccinimide (NBS) or the like is used, and bromine is particularly preferable. Other corresponding halogen equivalent compounds such as chlorine and sodium hypochlorite may also be used.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about ⁇ 70 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Step 8 can also be produced in Step 8 by the Curtius rearrangement of intermediate (VIIa-b) in the presence of, for example, alcohol (R 17 OH).
  • Step 8 is performed according to the method described in, for example, Organic Reactions (Org. React.), 3, 337, (1947) and Journal of Organic Chemistry (J. Org. Chem.), 52, 4875, (1987). It can be done by the following three methods.
  • Method A First, intermediate (VIIa-b) is converted to an acyl halide by treating with 1 molar equivalent to a large excess of a halogenating agent (eg thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.).
  • a halogenating agent eg thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.
  • a basic compound such as pyridine, 4-N, N-dimethylaminopyridine or triethylamine may be used in an amount of 1 to 10 molar equivalents relative to the intermediate (VIIa-b).
  • a catalytic amount of N, N-dimethylformamide may be added as a reaction accelerator.
  • the solvent used in this case is selected from, for example, “solvents used in organic synthesis” shown in Step 1.
  • ethers for example, tetrahydrofuran, dioxane, diethyl ether, etc.
  • halogenated hydrocarbons for example, chloride
  • ketones eg, acetone, methyl ethyl ketone, etc.
  • esters eg, ethyl acetate, etc.
  • aprotic polar solvents eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.
  • acyl halide thus obtained is reacted with 1 molar equivalent to a large excess of an alkali metal azide (such as sodium azide) relative to the intermediate (VIIa-b) to produce an acyl azide.
  • an alkali metal azide such as sodium azide
  • a basic compound such as pyridine, 4-N, N-dimethylaminopyridine or triethylamine may be used in an amount of 1 to 10 molar equivalents relative to the intermediate (VIIa-b).
  • Examples of the solvent used in this case include ethers (for example, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (for example, methylene chloride, chloroform, etc.), ketones (for example, acetone, methyl ethyl ketone, etc.), esters ( And aprotic polar solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide, etc.).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Method B Intermediate (VIIa-b) was converted to acyl halide by the method shown in Method A, and then this was treated with 1 molar equivalent to a large excess of hydrazine relative to intermediate (VIIa-b). Make hydrazide.
  • a basic compound such as pyridine, 4-N, N-dimethylaminopyridine or triethylamine may be used in an amount of 1 to 10 molar equivalents relative to the intermediate (VIIa-b).
  • Examples of the solvent used in this case include ethers (for example, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (for example, methylene chloride, chloroform, etc.), ketones (for example, acetone, methyl ethyl ketone, etc.), esters ( Examples thereof include ethyl acetate and the like, and aprotic polar solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide and the like).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • hydrazide is treated with 1 molar equivalent to a large excess of nitrous acid (which can also be generated from a metal nitrite such as sodium nitrite in the presence of acid) relative to intermediate (VIIa-b).
  • nitrous acid which can also be generated from a metal nitrite such as sodium nitrite in the presence of acid
  • VIa-b metal nitrite
  • the solvent used in this case is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and for example, water, alcohols (eg, methanol, ethanol, etc.), ethers (eg, tetrahydrofuran, dioxane, Diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N , N-dimethylformamide, dimethyl sulfoxide, etc.).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 50 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • intermediate (VIIa-b) is reacted with 1 molar equivalent or a large excess of diphenylphosphoryl azide (DPPA).
  • DPPA diphenylphosphoryl azide
  • a process for producing intermediate (IIa-b) via acyl azide for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-N, N-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0].
  • a basic compound such as 7-undecene and 1,4-diazabicyclo [2.2.2] octane (DABCO) may be used in an amount of 1 to 10 molar equivalents relative to the intermediate (VIIa-b).
  • the solvent used in this case is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and for example, water, alcohols (eg, methanol, ethanol, etc.), ethers (eg, tetrahydrofuran, dioxane, Diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N , N-dimethylformamide, dimethyl sulfoxide, etc.).
  • the reaction time is usually about 10 minutes to about 24 hours, preferably about 0.5 to about 6 hours.
  • the reaction temperature is usually about ⁇ 20 ° C. to about 200 ° C.
  • the resulting acyl azide is derived into an isocyanate by subjecting it to a Curtius rearrangement reaction.
  • the reaction is carried out by heating the resulting acyl azide to 30 ° C. to 200 ° C.
  • DMAP N-dimethylaminopyridine
  • 1,8-diazabicyclo [5.4.0] -7-undecene 1,4-diazabicyclo [2.2 .2]
  • a basic compound such as octane (DABCO) may be used at 1 to 10 molar equivalents relative to intermediate (VIIa-b).
  • the solvent used in this case is selected from, for example, “solvents used in organic synthesis” shown in Step 1.
  • solvents used in organic synthesis For example, water, alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, Diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N , N-dimethylformamide, dimethyl sulfoxide, etc.).
  • the reaction time is usually about 10 minutes to about 24 hours, preferably about 0.5 to about 6 hours. Under this reaction condition, it is also possible to carry out the subsequent reaction after the intramolecular cyclization reaction subsequent to the Curtius reaction proceeds in the same system.
  • a series of reactions from the intermediate (VIIa-b) to the intermediate (IIa-b) can be performed in the same system without isolating each intermediate.
  • method C using diphenylphosphoryl azide is more preferred.
  • Step 9 can be produced by removing the carbamate group of intermediate (IIa-b) in step 9.
  • Step 9 for example, can be carried out in Greene's protective groups in organic synthesis 4 th edition methods described, conditions are selected depending on the type of "amino protecting group” represented by PRG.
  • the “amino protecting group” represented by PRG is a tert-butoxycarbonyl (Boc) group
  • alkaline conditions that is, the intermediate (IIa-b) is removed from the solvent (eg, water) so that the Boc group is not affected.
  • a method of heating and stirring in an aqueous solution of sodium oxide or a mixed solvent of hydrazine and alcohol (such as ethanol) is used.
  • the reaction time is usually about 10 minutes to about 48 hours, preferably about 0.5 to about 10 hours.
  • the reaction temperature is usually about ⁇ 20 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • intermediate (IIa-c) can be directly produced without isolation of intermediate (IIa-b) by carrying out the same step in the presence of water.
  • Step 10 can be performed by allowing various acylating agents to act on the amino group.
  • the "acylating agent" can be appropriately selected depending on the kind of the substituents (R 18) to introduce the substituent (R 18) is C 1-6 alkyl, optionally substituted with C 3-6 cycloalkyl or oxo, In the case of 4 to 7-membered heterocyclic groups which may be substituted, the corresponding acid anhydride, acid halide (eg acid chloride, acid bromide), acid imidazolide, active ester (eg phenyl ester, nitro or halogen substituted phenyl ester (eg 4-nitrophenyl ester, pentafluorophenyl ester, etc.), 1-hydroxy-7-azabenzotriazole ester, 1-hydroxybenzotriazole ester, N-hydroxysuccinimide ester, N-hydroxy
  • R 18 When the substituent (R 18 ) is C 1-6 alkoxy, a corresponding alkyl formate halide or the like (for example, methyl chloroformate or the like) is used.
  • a corresponding alkyl formate halide or the like for example, methyl chloroformate or the like
  • an acid anhydride, an acid halide, an acid imidazolide, or an active ester is used in the acylating agent, the reaction is performed in a solvent that does not adversely influence the reaction in the presence or absence of a base.
  • the base is selected from, for example, the “bases” mentioned in Step 6.
  • amines such as triethylamine, N-methylmorpholine and N, N-dimethylaniline
  • alkali metal carbonates such as potassium carbonate and sodium carbonate
  • alkali metal hydrogen carbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate
  • alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide.
  • the amount of the base used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to the “acylating agent”.
  • the solvent to be used is selected from, for example, “solvents used for organic synthesis” shown in Step 1, for example, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran, And ethers such as dioxane and diethyl ether; ethyl acetate, water, N, N-dimethylformamide and the like.
  • the amount of the “acylating agent” to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIa-c).
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • Step 10 can also be carried out by allowing various carboxylic acids to act on the amino group in the presence of a condensing agent.
  • the condensing agent include carbodiimide-based condensing reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and hydrochloride thereof; phosphorus cyanophosphate such as diethyl cyanophosphate and diphenylphosphoryl azide.
  • Acid-based condensing reagents generally known condensing agents such as carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate are listed.
  • a carbodiimide-based condensing reagent such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and its hydrochloride
  • an appropriate condensation accelerator eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.
  • condensation accelerator eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.
  • a phosphoric acid-based condensing reagent such as diethyl cyanophosphate or diphenylphosphoryl azide
  • an organic amine base such as triethylamine
  • the carboxylic acid include organic acids such as acetic acid and butyric acid.
  • the amount of the condensing agent to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIa-c).
  • the amount of the above condensation accelerator and organic amine base used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIa-c).
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 to about 60 hours.
  • R 18 is amino or C 1-6 alkylamino
  • a method using an alkyl isocyanate eg, ethyl isocyanate
  • an aryl formate halide eg, phenyl chloroformate, etc.
  • a method of substituting with an amine is used.
  • These reactions can be performed in the presence of a base.
  • the “base”, for example, the base in Step 6 is used, and among them, amines such as triethylamine, diisopropylethylamine, N-methylmorpholine are preferable.
  • the amount of alkyl isocyanate or aryl formic acid halide to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIa-c).
  • the amount of the base used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIa-c).
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 to about 60 hours.
  • R 19 is C 1-6 alkyl
  • R 20 is C 1-6 alkyl
  • R 21 is C 1-6 alkyl
  • the same as the leaving group L 1 can be used, and a halogen atom (for example, chlorine atom, bromine atom, iodine atom, etc.), methanesulfonyloxy and the like are particularly preferable.
  • the leaving group represented by L 3 is the same as the leaving group L 1 described above, for example, N, O-dimethylhydroxylamino group, imidazolyl group, phenoxy group, substituted phenoxy group (eg, 4-nitrophenoxy group).
  • alkoxy groups alkoxy groups, azide groups, 7-azabenzotriazol-1-yloxy groups, benzotriazol-1-yloxy groups, succinimidyloxy groups, and phthalimidyloxy groups.
  • alkoxy groups azide groups, 7-azabenzotriazol-1-yloxy groups, benzotriazol-1-yloxy groups, succinimidyloxy groups, and phthalimidyloxy groups.
  • a chlorine atom, N, O-dimethylhydroxylamino group, imidazolyl group, phenoxy group, alkoxy group, azide group, succinimidyloxy group and the like are preferable.
  • Step 11 can be prepared in step 11, for example by O-alkylation of intermediate (VIIa-b).
  • Step 11 is performed by using an alkylating agent R 19 -L 2 in the presence of a base as described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 44, 2425, (1979). Can do.
  • a base for example, the same “base” as in Step 6 is used, and for example, an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or Inorganic bases such as alkaline earth metal bicarbonates are desirable.
  • Alkylating agent R 19 -L 2 is selected depending on R 19 to be introduced, and examples thereof include alkyl halides and sulfonic acid alkyl esters.
  • alkyl halide include C 1-6 alkyl chlorides such as methyl chloride, ethyl chloride, propyl chloride, and butyl chloride, corresponding C 1-6 alkyl bromides, and corresponding C 1-6 alkyl iodides.
  • sulfonic acid alkyl esters examples include C 1-6 alkyl methanesulfonate (eg, methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, butyl methanesulfonate, etc.), C 1-6 alkyl p-toluenesulfonate. (For example, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, propyl p-toluenesulfonate, butyl p-toluenesulfonate, and the like).
  • C 1-6 alkyl methanesulfonate eg, methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, butyl methanesulfonate, etc.
  • the amount of base and alkyl halide or sulfonic acid alkyl ester to be used is preferably about 1 to about 5 molar equivalents relative to intermediate (VIIa-b), respectively.
  • the “solvent used in organic synthesis” shown in Step 1 is used. Among them, alcohols such as ethanol, ethers such as tetrahydrofuran, and amides such as N, N-dimethylformamide are preferable.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • the intermediate (IIa-e) is obtained by using an acid catalyst in the corresponding alcohol according to the method described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 50, 2128, (1985).
  • the acid catalyst include hydrochloric acid, sulfuric acid, carboxylic acids (eg, formic acid, acetic acid, propionic acid, etc.), sulfonic acids (eg, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid) Etc.) is used.
  • the amount of the acid catalyst to be used is 0.0001 to 1 molar equivalent, preferably 0.001 to 0.1 molar equivalent, relative to intermediate (VIIa-b).
  • the reaction temperature is usually about ⁇ 30 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 to about 60 hours.
  • R 19 is a methyl group
  • diazomethane may be used as described in Organic Synthesis (Org. Syn.), 2, 165, (1943). Trimethylsilyldiazomethane may be used as an alternative to diazomethane.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 200 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 to about 10 hours.
  • Intermediate (IIa-f) can be produced by reduction of intermediate (VIIa-b) in step 12.
  • the reducing agent is used in an amount of 0.1 molar equivalent to large excess (preferably 0.3 to 10 molar equivalents) relative to intermediate (VIIa-b).
  • the reducing agent for example, the reducing agent mentioned in Step 4 is used, and among them, lithium aluminum hydride, borane complex (borane-THF complex and the like) and the like are preferable.
  • the solvent for example, the “solvent used in organic synthesis” shown in Step 1 is used, and ethers such as tetrahydrofuran are particularly preferable.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • Step 13 can be performed, for example, by using an alkylating agent in the presence of a base, as described in Journal of Organic Chemistry (J. Org. Chem.), 52, 4665, (1987).
  • Base includes, for example, alkali metal or alkaline earth metal hydrides such as sodium hydride, alkali metal or alkaline earth metal amides such as sodium amide, and alkali metal or alkaline earth such as potassium tert-butoxide.
  • Base includes, for example, alkali metal or alkaline earth metal hydrides such as sodium hydride, alkali metal or alkaline earth metal amides such as sodium amide, and alkali metal or alkaline earth such as potassium tert-butoxide. A lower alkoxide of a similar metal is preferred.
  • alkylating agent is selected depending on R 20 to be introduced, but C 1-6 alkyl chloride such as methyl chloride, ethyl chloride, propyl chloride, butyl chloride, the corresponding C 1-6 alkyl bromide, the corresponding C 1 -6 alkyl iodide, the corresponding methanesulfonic acid C 1-6 alkyl, such as corresponding p- toluenesulfonate C 1-6 alkyl.
  • sulfonic acid esters such as alkyl halides (methyl iodide, ethyl bromide, etc.), alkyl tosylate, and alkyl mesylate are preferable.
  • the amount of the base used is 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to intermediate (IIa-f).
  • the amount of the alkylating agent to be used is 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to intermediate (IIa-f).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran and amides such as N, N-dimethylformamide are preferred.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • the intermediate (IIa-h) is prepared by the method described in Step 14 when, for example, L 3 is an N, O-dimethylhydroxylamino group, for example, Tetrahedoron Lett., 22, 3815, (1981). Similarly, it can be synthesized from intermediate (VIIa-b) and N, O-dimethylhydroxylamine.
  • L 3 is an imidazolyl group
  • intermediate (VIIa-b) and N, N′- are prepared according to the method described in Journal of Medicinal Chemistry (J. Med. Chem.), 25, 618, (1982). It can be synthesized from carbonyldiimidazole.
  • L 3 examples include halogen atoms (such as chlorine atoms), phenoxy, substituted phenoxy (eg, 4-nitrophenoxy group, pentafluorophenoxy group, etc.), 7-azabenzotriazol-1-yloxy group, benzotriazole- Examples include 1-yloxy group, succinimidyloxy group, phthalimidyloxy group, and the like.
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran and amides such as N, N-dimethylformamide are preferred.
  • the reaction time is 0.1 to 72 hours, preferably 0.3 to 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • Intermediate (IIa-i) can be produced by reacting intermediate (IIa-h) with a carbon nucleophile in Step 15.
  • L 3 is an N, O-dimethylhydroxylamino group, for example, according to the method described in Tetrahedoron Lett., 22, 3815, (1981)
  • intermediate (IIa-h) and alkyl or It can be synthesized from an arylmagnesium reagent.
  • L 3 is an imidazolyl group, it can be synthesized from an intermediate (IIa-h) and an alkyl or arylmagnesium reagent according to the method described in Synlett, 9, 1013, (1998).
  • Examples of the carbon nucleophile in Step 15 include organolithium reagents such as alkyl or aryllithium, organomagnesium reagents such as alkyl or arylmagnesium bromide (for example, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide), nitromethane, and the like.
  • organolithium reagents such as alkyl or aryllithium
  • organomagnesium reagents such as alkyl or arylmagnesium bromide (for example, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide), nitromethane, and the like.
  • Examples thereof include enol ether compounds such as alkyl nitro compounds, alkyl enol ethers and alkyl silyl enol ethers, and active methylene compounds such as alkyl or aryl
  • Step 15 is performed in the presence of a base as necessary.
  • a base for example, the bases mentioned in Step 6 are used.
  • alkali metal or alkaline earth metal hydride such as sodium hydride
  • alkali metal or alkaline earth metal amide such as sodium amide
  • Alkali metal or alkaline earth metal lower alkoxides such as potassium tert-butoxide are preferred.
  • the amount of the base used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIa-h).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran are particularly preferable.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • Step 16 can be performed, for example, according to the method described in International Publication (WO2005 / 100324 A1).
  • the amount of glyoxylic acid monohydrate (IX) and amine (X) used is preferably about 1 to about 5 molar equivalents relative to phenylboronic acid (VIII), respectively.
  • the “solvent used for organic synthesis” shown in Step 1 is used, and ethers such as tetrahydrofuran and nitriles such as acetonitrile are particularly preferable.
  • the reaction temperature is usually about ⁇ 50 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is, for example, about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • L 4 and L 5 represent leaving groups, and R 22 , R 23 , R 24 , R 25 , R 26 and R 27 represent C 1-6 alkyl, C 3-6 cycloalkyl, or oxo, respectively.
  • R 22 , R 23 , R 24 , R 25 , R 26 and R 27 represent C 1-6 alkyl, C 3-6 cycloalkyl, or oxo, respectively.
  • the other symbols are as defined above.
  • the same as the leaving group L 1 can be used, and a halogen atom (for example, an iodine atom) and methanesulfonyloxy are particularly preferable.
  • a halogen atom for example, an iodine atom
  • methanesulfonyloxy are particularly preferable.
  • leaving group represented by L 5 those similar to the above-described leaving group L 3 are used, and among them, a chlorine atom, N, O-dimethylhydroxylamino group, imidazolyl group, phenoxy group, alkoxy group, azide Group, succinimidyloxy group and the like are preferable.
  • Step 17 can be prepared in step 17, for example by O-alkylation of intermediate (XI).
  • Step 17 is performed by using an alkylating agent R 22 -L 4 in the presence of a base, as described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 44, 2425, (1979). Can do.
  • a base for example, the same “base” as in step 6 is used, and among them, alkali metal or alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate, alkali metal or Inorganic bases such as alkaline earth metal hydrogen carbonate are desirable.
  • Alkylating agent R 22 -L 4 is selected depending on R 22 to be introduced, and examples thereof include alkyl halides and sulfonic acid alkyl esters.
  • the amount of the base and alkyl halide or sulfonic acid alkyl ester to be used is preferably about 1 to about 5 molar equivalents relative to intermediate (XI), respectively.
  • the “solvent used in organic synthesis” shown in Step 1 is used. Among them, alcohols such as ethanol, ethers such as tetrahydrofuran, and amides such as N, N-dimethylformamide are preferable.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • the intermediate (IIa-j) is obtained by using an acid catalyst in the corresponding alcohol according to the method described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 50, 2128, (1985).
  • the acid catalyst include hydrochloric acid, sulfuric acid, carboxylic acids (eg, formic acid, acetic acid, propionic acid, etc.), sulfonic acids (eg, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid) Etc.) is used.
  • the amount of the acid catalyst to be used is 0.0001 to 1 molar equivalent, preferably 0.001 to 0.1 molar equivalent, relative to intermediate (XI).
  • the reaction temperature is usually about ⁇ 30 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 to about 60 hours.
  • R 22 is a methyl group
  • diazomethane may be used as described in Organic Synthesis (Org. Syn.), 2, 165, (1943). Trimethylsilyldiazomethane may be used as an alternative to diazomethane.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 200 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 to about 10 hours.
  • Compound (IIa-k) can be produced in Step 18, for example, by reacting intermediate (IIa-j) with a carbon nucleophile.
  • a carbon nucleophile for example, the “carbon nucleophile” shown in Step 15 is used, and among them, organic magnesium reagents such as alkyl or arylmagnesium bromide (for example, methylmagnesium bromide, ethylmagnesium bromide, propyl Magnesium bromide etc.) are preferred.
  • the amount of the “carbon nucleophile” to be used is 0.1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (IIa-j).
  • Step 18 is performed in the presence of a base as necessary.
  • the “base” for example, those similar to the “base” in Step 6 are used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkaline earth such as sodium amide, etc. Metal amides and alkali metal or alkaline earth metal lower alkoxides such as potassium tert-butoxide are preferred.
  • the amount of the “base” to be used is 0.1-10 molar equivalents, preferably 0.3-3 molar equivalents, relative to compound (IIa-j).
  • the solvent those similar to the “solvent used for organic synthesis” shown in Step 1 can be used, and ethers such as tetrahydrofuran are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to About 24 hours.
  • Intermediate (IIa-l) can be produced by reduction of intermediate (XI) in step 19.
  • a reducing agent is used in an amount of 0.1 molar equivalent to large excess (preferably 0.3 to 10 molar equivalents) relative to intermediate (XI).
  • the reduction in step 19 is, for example, sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, dibutylaluminum hydride, aluminum hydride ,
  • a method using a reducing agent such as lithium aluminum hydride, borane complex (borane-THF complex, etc.), catecholborane, a method using a catalytic reduction reaction using a transition metal catalyst such as palladium, platinum, rhodium, or a metal such as magnesium. This can be done depending on the method used.
  • lithium aluminum hydride, borane complex (borane-THF complex, etc.) and the like are preferable.
  • the “solvent used in organic synthesis” shown in Step 1 is used, and ethers such as tetrahydrofuran are particularly preferable.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • Step 20 can be performed by using an alkylating agent in the presence of a base as described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 52, 4665, (1987).
  • an alkali metal or alkaline earth metal hydride such as sodium hydride, an alkali metal or alkaline earth metal such as sodium amide is used.
  • Amides and lower alkoxides of alkali metals or alkaline earth metals such as potassium tert-butoxide are preferred.
  • alkylating agent is selected depending on the R 24 to be introduced, but C 1-6 alkyl chloride such as methyl chloride, ethyl chloride, propyl chloride, butyl chloride, the corresponding C 1-6 alkyl bromide, the corresponding C 1 -6 alkyl iodide, the corresponding methanesulfonic acid C 1-6 alkyl, such as corresponding p- toluenesulfonate C 1-6 alkyl.
  • sulfonic acid esters such as alkyl halides (methyl iodide, ethyl bromide, etc.), alkyl tosylate, and alkyl mesylate are preferable.
  • the amount of the base to be used is 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to intermediate (IIa-l).
  • the amount of the alkylating agent to be used is 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to intermediate (IIa-l).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran and amides such as N, N-dimethylformamide are preferred.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • the intermediate (XII) is prepared in accordance with the method described in, for example, Tetrahedoron Lett., 22, 3815, (1981) when L 5 is an N, O-dimethylhydroxylamino group in Step 21. Can be synthesized from intermediate (XI) and N, O-dimethylhydroxylamine.
  • L 5 is an imidazolyl group
  • intermediate (XI) and N, N′-carbonyl dioxygen can be synthesized according to the method described in Journal of Medicinal Chemistry (J. Med. Chem.), 25, 618, (1982). It can be synthesized from imidazole.
  • L 5 examples include halogen atoms (such as chlorine atoms), phenoxy, substituted phenoxy (eg, 4-nitrophenoxy group, pentafluorophenoxy group, etc.), 7-azabenzotriazol-1-yloxy group, benzotriazole- Examples include 1-yloxy group, succinimidyloxy group, phthalimidyloxy group, and the like.
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran and amides such as N, N-dimethylformamide are preferred.
  • the reaction time is 0.1 to 72 hours, preferably 0.3 to 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • Intermediate (IIa-n) can be produced by reacting intermediate (XII) with a carbon nucleophile in step 22.
  • L 5 is an N, O-dimethylhydroxylamino group, for example, according to the method described in Tetrahedoron Lett., 22, 3815, (1981), intermediate (XII) and alkyl or aryl magnesium It can be synthesized from reagents.
  • L 5 is an imidazolyl group, it can be synthesized from an intermediate (XII) and an alkyl or arylmagnesium reagent according to the method described in Synlett, 9, 1013, (1998).
  • Examples of the carbon nucleophile in Step 22 include organolithium reagents such as alkyl or aryllithium, organomagnesium reagents such as alkyl or arylmagnesium bromide (eg, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide), nitromethane, and the like.
  • organolithium reagents such as alkyl or aryllithium
  • organomagnesium reagents such as alkyl or arylmagnesium bromide (eg, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide), nitromethane, and the like.
  • Examples thereof include enol ether compounds such as alkyl nitro compounds, alkyl enol ethers, and alkylsilyl enol ethers, and active methylene compounds such as alkyl or ary
  • Step 22 is performed in the presence of a base as necessary.
  • a base for example, the “base” mentioned in Step 6 is used.
  • alkali metal or alkaline earth metal hydride such as sodium hydride
  • alkali metal or alkaline earth metal amide such as sodium amide, etc.
  • lower alkoxides of alkali metals or alkaline earth metals such as potassium tert-butoxide are preferred.
  • the amount of the base to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (XII).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran are particularly preferable.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to
  • Step 23 can be performed by the method described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 55, 270 (1990), and the corresponding amine and its hydrochloride and condensing agent (for example, carbodiimide condensation).
  • Reagents (dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, etc.), phosphoric acid condensation reagents (diethyl cyanophosphate, diphenylphosphoryl azide, etc.), 4- (4,6- Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMTMM: Kunishima et al., Tetrahedron, 55, 13159, (1999), etc.) can be used.
  • DTMM 4- (4,6- Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride
  • carbodiimide condensing reagents such as carbodiimide and its hydrochloride
  • a suitable condensation accelerator eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.
  • the amount of the “hydrochloride” is usually 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, and preferably 1 to 2 molar equivalents per 1 mol of the compound (XI).
  • the amount of the “condensation accelerator” used is usually 0.1 to 10 molar equivalents relative to compound (XI), and is usually 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents.
  • the solvent is preferably 0.3 to 3 molar equivalents, and as the solvent, for example, those similar to the “solvent used for organic synthesis” shown in Step 1 can be used, and among them, N, N-dimethylformamide and the like can be used. Amides are preferred Arbitrariness. Also, this reaction may be carried out by addition of a suitable base.
  • the “base” those equivalent to the “base” in Step 6 are used, and as the base to be added to the amidation, for example, triethylamine or the like is preferable.
  • the amount of the “base” to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (XI).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Intermediates (XIV) and (XVI) can be produced by bromination of intermediates (XIII) and (XV) in step 24, respectively.
  • Examples of the brominating agent in step 24 include bromine, N-bromosuccinimide (NBS), and tert-butyl bromide.
  • bromine examples include the methods described in Journal of Medicinal Chemistry (J. Med. Chem.) 46, 1546 (2003).
  • solvent those similar to the “solvent used for organic synthesis” shown in the above (Step 1) can be used. Among them, halogenated hydrocarbons such as carbon tetrachloride, ethers such as diethyl ether, etc. Acetic acid is preferred.
  • the reaction temperature is usually about ⁇ 50 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • N-bromosuccinimide examples include the methods described in Journal of Medicinal Chemistry (J. Med. Chem) 24, 481 (1981).
  • the solvent those similar to the “solvent used for organic synthesis” shown in the above (Step 1) can be used. Among them, halogenated hydrocarbons such as carbon tetrachloride, hydrocarbons such as cyclohexane and benzene.
  • the reaction temperature is usually about ⁇ 50 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • the “acid” is preferably, for example, a 48% hydrogen bromide aqueous solution.
  • the “radical initiator” is preferably benzoyl peroxide or azobisisobutyronitrile, for example.
  • tert-butyl bromide examples include the methods described in Tetrahedron 40, 2035, and 1984.
  • the solvent those similar to the “solvent used for organic synthesis” shown in the above (Step 1) can be used, and among them, dimethyl sulfoxide is preferable.
  • the reaction temperature is usually about ⁇ 50 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • Intermediates (IIa-j) and (IIa-n) can be prepared in step 25 by N-alkylation of amine (X) with intermediates (XIV) and (XVI), respectively.
  • a method described in Bioorganic and Medicinal Chemistry Letters (Bioorg.orgMed. Chem. Lett.) 12, 3195 (2002) can be mentioned.
  • the reaction is carried out in the presence of a base in a solvent that does not affect the reaction.
  • a base those similar to the “base” shown in the above (Step 6) can be used, among which potassium carbonate, sodium carbonate, sodium hydride, potassium hydride and the like are preferable.
  • the amount of the “base”, intermediate (XIV) and intermediate (XVI) to be used is preferably about 1 to about 5 molar equivalents relative to amine (X), respectively.
  • the “solvent used for organic synthesis” shown in the above (Step 1) is used, and alcohols such as ethanol, ethers such as tetrahydrofuran, and amides such as N, N-dimethylformamide are particularly preferable.
  • the reaction temperature is usually about ⁇ 50 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • the compound (I-1) and the compound (I-2) contained in the compound (I) of the present invention can be produced, for example, using the following steps 1 and 2.
  • PRG represents an amino protecting group, and other symbols are as defined above.
  • amino protecting group represented by PRG
  • protecting groups described in Greene's protective groups in organic synthesis 4 th edition can be used.
  • Amino protecting groups include, for example, formyl, optionally substituted C 1-6 alkyl-carbonyl (eg acetyl, ethylcarbonyl, trifluoroacetyl, chloroacetyl, etc.), benzoyl, C 1-6 alkyl -Oxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl etc.), phenyloxycarbonyl (eg phenoxycarbonyl etc.), C 7-15 aralkyloxy-carbonyl (eg benzyloxycarbonyl, 9-fluorenyl) Acyl groups such as methyloxycarbonyl) or hydrocarbon groups such as methyl, benzyl, and trityl.
  • C 1-6 alkyl-carbonyl eg acetyl
  • tert-butoxycarbonyl (Boc) group tert-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz) group, 9-fluorenylmethyl, etc.
  • Oxycarbonyl (Fmoc) Carbamate protecting group such as acetyl (Ac) group, an amide-based protecting group such as trifluoroacetyl group or a benzyl group, or an alkyl type protecting group such as a methyl group.
  • Step 1 is generally performed in a “solvent used for organic synthesis”, and a solvent that does not inhibit the reaction is appropriately selected.
  • solvents used in organic synthesis include alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl).
  • the reaction time varies depending on the type of compound (II), the type of solvent and base, the reaction temperature, etc., but is usually about 1 minute to about 100 hours, preferably about 5 minutes to about 48 hours.
  • the amino protecting group is a Boc group
  • deprotection by acid treatment with hydrochloric acid, trifluoroacetic acid or the like is preferable.
  • the acid can be used in a molar equivalent or large excess relative to compound (II).
  • the solvent is appropriately selected from the above-mentioned “solvents used in organic synthesis”, and among them, alcohols such as ethanol, or water is preferable. If necessary, the acid itself may be used as a solvent.
  • deprotection can be performed by, for example, catalytic hydrogenation using a metal catalyst.
  • the catalyst used in the catalytic hydrogenation include metals such as palladium, platinum, nickel and rhodium or oxides, salts and complexes thereof, and these catalysts can be used by being supported on various supports such as carbon.
  • the catalytic hydrogenation can be carried out at normal pressure or under pressure.
  • the solvent is appropriately selected from the above-mentioned “solvents used in organic synthesis”. Among them, alcohols such as ethanol, ethers such as tetrahydrofuran or water are preferable.
  • compound (I-1) By subjecting compound (I-1) to step 2, compound (I-1) can be N-alkylated to produce compound (I-2) which is a tertiary amine.
  • N-alkylation for example, a method based on a reductive alkylation reaction described in Organic Reactions, vol. 59, 1-714 can be used.
  • the reductive alkylation reaction is a method for producing an amine by reacting compound (I-1) with an aldehyde or a ketone and reducing the produced imine or iminium ion.
  • the aldehyde or ketone is selected depending on R 11 to be introduced, and is selected from lower aldehydes such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, and lower ketones such as acetone, methyl ethyl ketone, and 3-pentanone.
  • lower aldehydes such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, and lower ketones such as acetone, methyl ethyl ketone, and 3-pentanone.
  • a corresponding cyclic oligomer such as 1,3,5-trioxane or a corresponding polymer such as paraformaldehyde may be used.
  • 1 mole equivalent or large excess (preferably 1 to 10 mole equivalent) of aldehyde or ketone can be used with respect to compound (I-1).
  • an acid for example, a mineral acid such as hydrochloric acid, phosphoric acid or sulfuric acid or an organic acid such as toluenesulfonic acid, methanesulfonic acid or acetic acid
  • An equivalent amount may be added.
  • a metal hydride complex compound such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, a reduction method using a reducing agent such as diborane, catalytic reduction in the presence of a catalyst such as palladium or Raney nickel, Examples thereof include electrolytic reduction using lead and platinum as a cathode, and the reducing agent is used in an amount of 0.3 molar equivalent to large excess (preferably 1 to 10 molar equivalents) relative to compound (I-1).
  • “solvent used for organic synthesis” shown in Step 1 is used. Among them, alcohols such as methanol and ethanol, and carboxylic acids such as acetic acid are preferable.
  • the reaction time is usually about 0.5 to about 72 hours, preferably about 1 to about 24 hours.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C., preferably about 0 ° C. to about 60 ° C.
  • step 2 in addition to the above reductive alkylation reaction, for example, an alkyl halide or sulfonic acid alkyl ester described in Journal of the American Chemical Society (J. Am. Chem. Soc.), 68, 1053, (1946) is used. It can be carried out by an alkylation reaction.
  • the reaction is carried out in the presence of a base and an alkyl halide or sulfonic acid alkyl ester in a solvent that does not affect the reaction.
  • the base include potassium carbonate, sodium carbonate, sodium hydride, potassium hydride and the like.
  • Alkyl halide is selected depending on R 11 to be introduced, but C 1-6 alkyl chloride such as methyl chloride, ethyl chloride, propyl chloride, butyl chloride, corresponding C 1-6 alkyl bromide, corresponding C 1-6 alkyl Examples include iodine.
  • the sulfonic acid alkyl ester is selected depending on R 11 to be introduced, but C 1-6 alkyl methanesulfonate (eg, methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, butyl methanesulfonate, etc.), p -Toluenesulfonic acid C 1-6 alkyl (for example, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, propyl p-toluenesulfonate, butyl p-toluenesulfonate) and the like.
  • C 1-6 alkyl methanesulfonate eg, methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, butyl methanes
  • the amount of the base and alkyl halide or sulfonic acid alkyl ester to be used is preferably about 1 to about 5 molar equivalents relative to compound (I-1), respectively.
  • the “solvent used for organic synthesis” shown in Step 1 is used, and alcohols such as ethanol, ethers such as tetrahydrofuran, and amides such as N, N-dimethylformamide are particularly preferable.
  • Z represents an acid amide group (—CONH 2 ) or a carboxylic acid group (—CO 2 H), and other symbols are as defined above.
  • Step 3 can be performed in accordance with, for example, the methods described in Bioorganic and Medicinal Chemistry Letters (Bioorg. Med. Chem. Lett.), 16, 3874, (2006) and United States Patent Application Publication (US2004 / 0063744). .
  • Intermediate (VI) can be produced by reduction of intermediate (V) in step 4.
  • the reduction in step 4 is, for example, sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, dibutylaluminum hydride, aluminum hydride , A method using a reducing agent such as lithium aluminum hydride, borane complex (borane-THF complex, etc.), catecholborane, a method using a catalytic reduction reaction using a transition metal catalyst such as palladium, platinum, rhodium, or a metal such as magnesium. This can be done depending on the method used.
  • the “solvent used in organic synthesis” shown in Step 1 is used.
  • alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, amides such as N, N-dimethylformamide, acetic acid, etc.
  • the carboxylic acids are preferred.
  • the amount of the reducing agent used is preferably about 0.3 to about 5 molar equivalents relative to intermediate (V).
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.1 to about 5 hours.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C., preferably about 0 ° C. to about 60 ° C.
  • a method using 0.5 to 2 molar equivalents of sodium borohydride (sodium tetrahydroborate) as a reducing agent in an alcohol solvent (eg, methanol) is preferable.
  • Intermediate (VIIa) can be produced in Step 5 by partial hydrolysis of the nitrile of intermediate (VI).
  • Intermediate (VIIb) can be produced by complete hydrolysis of the nitrile of intermediate (VI).
  • the hydrolysis can be performed by selecting from alkaline conditions and acidic conditions. Alkaline conditions are performed in the presence of a base with a solvent that does not affect the reaction. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the base used is preferably about 1 to about 5 molar equivalents relative to intermediate (VI).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Acidic conditions are performed in the presence of an acid with a solvent that does not affect the reaction.
  • mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and perchloric acid are preferable.
  • the solvent to be used is selected from, for example, “solvents used for organic synthesis” shown in Step 1.
  • alcohols such as ethanol or water is preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • the hydrolysis reaction does not proceed under these conditions, for example, the method using sodium peroxide described in Journal of Organic Chemistry (J. Org. Chem.), 40, 1187, (1975), for example, Journal of the American A method using sodium nitrite in an acidic solvent such as sulfuric acid described in Chemical Society (J. Am. Chem. Soc.), 78, 5416, (1956) may be used.
  • the hydrolysis tends to be complete, but partial or complete hydrolysis can be selectively performed by adjusting the conditions.
  • selective hydrolysis is possible by appropriately adjusting the type and concentration of the alkali and acid used, the reaction temperature, the solvent, the reaction time, and the like.
  • the amino protecting group (PRG) is cleaved during hydrolysis, the amino protecting group (PRG) can be introduced again.
  • L 1 represents a leaving group
  • R 16 represents C 1-6 alkyl
  • R 17 represents C 1-6 alkyl
  • R 18 represents C 1-6 alkyl
  • C 1-6 alkoxy C 3-
  • the 4- to 7-membered heterocyclic group which may be substituted with 6 cycloalkyl, amino, C 1-6 alkylamino, or oxo, the other symbols are as defined above.
  • Examples of the leaving group represented by L 1 include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methanesulfonyloxy) optionally substituted with a halogen atom. , Ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 6-10 arylsulfonyloxy optionally substituted with C 1-6 alkyl (eg, benzenesulfonyloxy, p-toluenesulfonyloxy).
  • a halogen atom for example, iodine atom
  • methanesulfonyloxy are particularly preferable.
  • Step 6 can be prepared in Step 6 by N-alkylation of intermediate (VIIa).
  • Step 6 can be performed using, for example, an alkylating agent R 16 -L 1 in the presence of a base.
  • the “base” is, for example, 1) Alkali metal or alkaline earth metal hydrides (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (eg, lithium amide, sodium amide) , Lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc., lower alkoxides of alkali metals or alkaline earth metals (eg, sodium methoxide, sodium Strong bases such as ethoxide, potassium tert-butoxide); 2) Alkali metal or alkaline earth
  • Amines such as DBU (1,8-diazabicyclo [5.4.0] undes-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene); pyridine Basic heterocyclic compounds such as dimethylaminopyridine, imidazole and 2,6-lutidine An example is a machine base.
  • Examples of the “base” include alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkaline earth metal amide such as sodium amide, and alkali metal or alkali such as potassium tert-butoxide. Earth metal lower alkoxides are preferred.
  • the amount of base used is preferably about 1 to about 10 molar equivalents relative to intermediate (VIIa).
  • the amount of the alkylating agent used is preferably about 1 to about 10 molar equivalents relative to intermediate (VIIa).
  • the solvent used is selected from, for example, “solvents used in organic synthesis” shown in Step 1. For example, ethers such as tetrahydrofuran and amides such as N, N-dimethylformamide are preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Step 7 can be produced in Step 7 by, for example, Hoffman rearrangement of intermediate (VIIa) in the presence of alcohol (R 17 OH).
  • Step 7 can be performed according to the methods described in, for example, Organic Reactions (Org. React.), 3, 267, (1946) and Organic Synthesis (Org. Syn.), 10, 549, (2004).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran and hydrocarbons such as toluene are preferable.
  • Alcohol (R 17 OH) is used in a molar equivalent to a large excess with respect to intermediate (VIIa), but is often used also as a solvent.
  • step 7 is carried out in the presence of alcohol, intermediate (IIb) is obtained, but if it is carried out in the absence of alcohol, the corresponding isocyanate is produced.
  • alcohol may be allowed to act after the isocyanate is once isolated.
  • the bromine source for example, simple bromine (Br 2 ), hypobromite such as sodium hypobromite, N-bromosuccinimide (NBS) or the like is used, and bromine is particularly preferable. Other corresponding halogen equivalent compounds such as chlorine and sodium hypochlorite may also be used.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about ⁇ 70 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Step 8 can also be produced in Step 8 by, for example, the Curtius rearrangement of intermediate (VIIb) in the presence of alcohol (R 17 OH).
  • Step 8 is performed according to the method described in, for example, Organic Reactions (Org. React.), 3, 337, (1947) and Journal of Organic Chemistry (J. Org. Chem.), 52, 4875, (1987). It can be done by the following three methods.
  • Step 1 Intermediate (VIIb) is first converted to an acyl halide by treating with 1 molar equivalent to a large excess of a halogenating agent (eg thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.).
  • a halogenating agent eg thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.
  • a basic compound such as pyridine, 4-N, N-dimethylaminopyridine and triethylamine may be used in an amount of 1 to 10 molar equivalents relative to the intermediate (VIIb).
  • a catalytic amount of N, N-dimethylformamide may be added as a reaction accelerator.
  • the solvent used in this case is selected from, for example, “solvents used in organic synthesis” shown in Step 1.
  • ethers for example, tetrahydrofuran, dioxane, diethyl ether, etc.
  • halogenated hydrocarbons for example, chloride
  • ketones eg, acetone, methyl ethyl ketone, etc.
  • esters eg, ethyl acetate, etc.
  • aprotic polar solvents eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.
  • acyl halide thus obtained is reacted with 1 molar equivalent to a large excess of an alkali metal azide (such as sodium azide) relative to the intermediate (VIIb) to produce an acyl azide.
  • an alkali metal azide such as sodium azide
  • a basic compound such as pyridine, 4-N, N-dimethylaminopyridine and triethylamine may be used in an amount of 1 to 10 molar equivalents relative to the intermediate (VIIb).
  • Examples of the solvent used in this case include ethers (for example, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (for example, methylene chloride, chloroform, etc.), ketones (for example, acetone, methyl ethyl ketone, etc.), esters ( And aprotic polar solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide, etc.).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Method B Intermediate (VIIb) is converted to acyl halide by the method shown in Method A, and then this is treated with 1 molar equivalent to a large excess of hydrazine to hydrazide with respect to intermediate (VIIb).
  • a basic compound such as pyridine, 4-N, N-dimethylaminopyridine and triethylamine may be used in an amount of 1 to 10 molar equivalents relative to the intermediate (VIIb).
  • Examples of the solvent used in this case include ethers (for example, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (for example, methylene chloride, chloroform, etc.), ketones (for example, acetone, methyl ethyl ketone, etc.), esters ( Examples thereof include ethyl acetate and the like, and aprotic polar solvents (for example, N, N-dimethylformamide, dimethyl sulfoxide and the like).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • acyl azide is treated with 1 molar equivalent to a large excess of nitrous acid (which can also be generated from a nitrite metal salt such as sodium nitrite in the presence of acid) relative to intermediate (VIIb) to give acyl azide. Generate.
  • the solvent used in this case is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and for example, water, alcohols (eg, methanol, ethanol, etc.), ethers (eg, tetrahydrofuran, dioxane, Diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N , N-dimethylformamide, dimethyl sulfoxide, etc.).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 50 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • intermediate (VIIb) is reacted with 1 molar equivalent or a large excess of diphenylphosphoryl azide (DPPA) to produce acyl azide.
  • DPPA diphenylphosphoryl azide
  • DMAP N-dimethylaminopyridine
  • a basic compound such as 7-undecene and 1,4-diazabicyclo [2.2.2] octane (DABCO) may be used in an amount of 1 to 10 molar equivalents relative to intermediate (VIIb).
  • the solvent used in this case is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and for example, water, alcohols (eg, methanol, ethanol, etc.), ethers (eg, tetrahydrofuran, dioxane, Diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N , N-dimethylformamide, dimethyl sulfoxide, etc.).
  • the reaction time is usually about 10 minutes
  • the resulting acyl azide is derived into an isocyanate by subjecting it to a Curtius rearrangement reaction.
  • the reaction is carried out by heating the resulting acyl azide to 30 ° C. to 200 ° C.
  • DMAP N-dimethylaminopyridine
  • 1,8-diazabicyclo [5.4.0] -7-undecene 1,4-diazabicyclo [2.2 .2]
  • a basic compound such as octane (DABCO) may be used in an amount of 1 to 10 molar equivalents relative to intermediate (VIIb).
  • the solvent used in this case is selected from, for example, “solvents used in organic synthesis” shown in Step 1.
  • solvents used in organic synthesis For example, water, alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, Diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, ethyl acetate, etc.), and aprotic polar solvents (eg, N , N-dimethylformamide, dimethyl sulfoxide, etc.).
  • the reaction time is usually about 10 minutes to about 24 hours, preferably about 0.5 to about 6 hours. Under this reaction condition, it is also possible to carry out the subsequent reaction after the intramolecular cyclization reaction subsequent to the Curtius reaction proceeds in the same system.
  • a series of reactions from intermediate (VIIb) to intermediate (IIb) can be carried out in the same system without isolating each intermediate.
  • method C using diphenylphosphoryl azide is more preferred.
  • Step 9 can be produced by removing the carbamate group of intermediate (IIb) in step 9.
  • Step 9 for example, can be carried out in Greene's protective groups in organic synthesis 4 th edition methods described, conditions are selected depending on the type of "amino protecting group” represented by PRG.
  • the “amino protecting group” represented by PRG is a tert-butoxycarbonyl (Boc) group
  • alkaline conditions that is, intermediate (IIb) is removed from the solvent (for example, sodium hydroxide) so that the Boc group is not affected.
  • a method of heating and stirring in an aqueous solution, a mixed solvent of hydrazine and alcohol (ethanol or the like) is used.
  • the reaction time is usually about 10 minutes to about 48 hours, preferably about 0.5 to about 10 hours.
  • the reaction temperature is usually about ⁇ 20 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • intermediate (IIc) can be directly produced without isolating intermediate (IIb) by carrying out the same step in the presence of water.
  • Step 10 can be performed by allowing various acylating agents to act on the amino group.
  • the "acylating agent" can be appropriately selected depending on the kind of the substituents (R 18) to introduce the substituent (R 18) is C 1-6 alkyl, optionally substituted with C 3-6 cycloalkyl or oxo, In the case of 4 to 7-membered heterocyclic groups which may be substituted, the corresponding acid anhydride, acid halide (eg acid chloride, acid bromide), acid imidazolide, active ester (eg phenyl ester, nitro or halogen substituted phenyl ester (eg 4-nitrophenyl ester, pentafluorophenyl ester, etc.), 1-hydroxy-7-azabenzotriazole ester, 1-hydroxybenzotriazole ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide este
  • R 18 When the substituent (R 18 ) is C 1-6 alkoxy, a corresponding alkyl formate halide or the like (for example, methyl chloroformate or the like) is used.
  • a corresponding alkyl formate halide or the like for example, methyl chloroformate or the like
  • an acid anhydride, an acid halide, an acid imidazolide, or an active ester is used in the acylating agent, the reaction is performed in a solvent that does not adversely influence the reaction in the presence or absence of a base.
  • the base is selected from, for example, the “bases” mentioned in Step 6.
  • amines such as triethylamine, N-methylmorpholine and N, N-dimethylaniline
  • alkali metal carbonates such as potassium carbonate and sodium carbonate
  • alkali metal hydrogen carbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate
  • alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide.
  • the amount of the base used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to the “acylating agent”.
  • the solvent to be used is selected from, for example, “solvents used for organic synthesis” shown in Step 1, for example, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran, And ethers such as dioxane and diethyl ether; ethyl acetate, water, N, N-dimethylformamide and the like.
  • the amount of the “acylating agent” to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIc).
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • Step 10 can also be carried out by allowing various carboxylic acids to act on the amino group in the presence of a condensing agent.
  • the condensing agent include carbodiimide-based condensing reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and hydrochloride thereof; phosphorus cyanophosphate such as diethyl cyanophosphate and diphenylphosphoryl azide.
  • Acid-based condensing reagents generally known condensing agents such as carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate are listed.
  • a carbodiimide-based condensing reagent such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and its hydrochloride
  • an appropriate condensation accelerator eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.
  • condensation accelerator eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.
  • a phosphoric acid-based condensing reagent such as diethyl cyanophosphate or diphenylphosphoryl azide
  • an organic amine base such as triethylamine
  • the carboxylic acid include organic acids such as acetic acid and butyric acid.
  • the amount of the condensing agent to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIc).
  • the amount of the above condensation accelerator and organic amine base used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIc).
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 to about 60 hours.
  • R 18 is amino or C 1-6 alkylamino
  • a method using an alkyl isocyanate eg, ethyl isocyanate
  • an aryl formate halide eg, phenyl chloroformate, etc.
  • a method of substituting with an amine is used.
  • These reactions can be performed in the presence of a base.
  • the “base”, for example, the base in Step 6 is used, and among them, amines such as triethylamine, diisopropylethylamine, N-methylmorpholine are preferable.
  • the amount of alkyl isocyanate or aryl formic acid halide to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIc).
  • the amount of the base used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIc).
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 to about 60 hours.
  • R 19 is C 1-6 alkyl
  • R 20 is C 1-6 alkyl
  • R 21 is C 1-6 alkyl
  • the same as the leaving group L 1 can be used, and a halogen atom (for example, chlorine atom, bromine atom, iodine atom, etc.), methanesulfonyloxy and the like are particularly preferable.
  • the leaving group represented by L 3 is the same as the leaving group L 1 described above, for example, N, O-dimethylhydroxylamino group, imidazolyl group, phenoxy group, substituted phenoxy group (eg, 4-nitrophenoxy group).
  • alkoxy groups alkoxy groups, azide groups, 7-azabenzotriazol-1-yloxy groups, benzotriazol-1-yloxy groups, succinimidyloxy groups, and phthalimidyloxy groups.
  • alkoxy groups azide groups, 7-azabenzotriazol-1-yloxy groups, benzotriazol-1-yloxy groups, succinimidyloxy groups, and phthalimidyloxy groups.
  • a chlorine atom, N, O-dimethylhydroxylamino group, imidazolyl group, phenoxy group, alkoxy group, azide group, succinimidyloxy group and the like are preferable.
  • Step 11 can be prepared in step 11, for example by O-alkylation of intermediate (VIIb).
  • Step 11 is performed by using an alkylating agent R 19 -L 2 in the presence of a base as described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 44, 2425, (1979). Can do.
  • a base for example, the same “base” as in Step 6 is used, and for example, an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or Inorganic bases such as alkaline earth metal bicarbonates are desirable.
  • Alkylating agent R 19 -L 2 is selected depending on R 19 to be introduced, and examples thereof include alkyl halides and sulfonic acid alkyl esters.
  • alkyl halide include C 1-6 alkyl chlorides such as methyl chloride, ethyl chloride, propyl chloride, and butyl chloride, corresponding C 1-6 alkyl bromides, and corresponding C 1-6 alkyl iodides.
  • sulfonic acid alkyl esters examples include C 1-6 alkyl methanesulfonate (eg, methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, butyl methanesulfonate, etc.), C 1-6 alkyl p-toluenesulfonate. (For example, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, propyl p-toluenesulfonate, butyl p-toluenesulfonate, and the like).
  • C 1-6 alkyl methanesulfonate eg, methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, butyl methanesulfonate, etc.
  • the amount of the base and the alkyl halide or sulfonic acid alkyl ester to be used is preferably about 1 to about 5 molar equivalents relative to the intermediate (VIIb).
  • the “solvent used in organic synthesis” shown in Step 1 is used. Among them, alcohols such as ethanol, ethers such as tetrahydrofuran, and amides such as N, N-dimethylformamide are preferable.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 100 ° C.
  • the reaction time is usually about 0.1 to about 48 hours.
  • Intermediate (IIe) is produced by using an acid catalyst in the corresponding alcohol according to the method described in, for example, Journal of Organic Chemistry (J. Org. Chem.), 50, 2128, (1985).
  • the acid catalyst include hydrochloric acid, sulfuric acid, carboxylic acids (eg, formic acid, acetic acid, propionic acid, etc.), sulfonic acids (eg, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid) Etc.) is used.
  • the amount of the acid catalyst to be used is 0.0001 to 1 molar equivalent, preferably 0.001 to 0.1 molar equivalent, relative to intermediate (VIIb).
  • the reaction temperature is usually about ⁇ 30 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 to about 60 hours.
  • R 19 is a methyl group
  • diazomethane may be used as described in Organic Synthesis (Org. Syn.), 2, 165, (1943). Trimethylsilyldiazomethane may be used as an alternative to diazomethane.
  • the reaction temperature is usually about ⁇ 30 ° C. to about 200 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 to about 10 hours.
  • Intermediate (IIf) can be produced by reduction of intermediate (VIIb) in step 12.
  • the reducing agent is used in an amount of 0.1 molar equivalent to large excess (preferably 0.3 to 10 molar equivalents) relative to intermediate (VIIb).
  • the reducing agent for example, the reducing agent mentioned in Step 4 is used, and among them, lithium aluminum hydride, borane complex (borane-THF complex and the like) and the like are preferable.
  • the solvent for example, the “solvent used in organic synthesis” shown in Step 1 is used, and ethers such as tetrahydrofuran are particularly preferable.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • Step 13 can be performed, for example, by using an alkylating agent in the presence of a base, as described in Journal of Organic Chemistry (J. Org. Chem.), 52, 4665, (1987).
  • base and “alkylating agent”, those similar to those in Step 6 can be used.
  • Base includes, for example, alkali metal or alkaline earth metal hydrides such as sodium hydride, alkali metal or alkaline earth metal amides such as sodium amide, and alkali metal or alkaline earth such as potassium tert-butoxide. A lower alkoxide of a similar metal is preferred.
  • alkylating agent is selected depending on R 20 to be introduced, but C 1-6 alkyl chloride such as methyl chloride, ethyl chloride, propyl chloride, butyl chloride, the corresponding C 1-6 alkyl bromide, the corresponding C 1 -6 alkyl iodide, the corresponding methanesulfonic acid C 1-6 alkyl, such as corresponding p- toluenesulfonate C 1-6 alkyl.
  • sulfonic acid esters such as alkyl halides (methyl iodide, ethyl bromide, etc.), alkyl tosylate, and alkyl mesylate are preferable.
  • the amount of the base used is 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to intermediate (IIf).
  • the amount of the alkylating agent to be used is 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to intermediate (IIf).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran and amides such as N, N-dimethylformamide are preferred.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • the intermediate (IIh) is prepared in accordance with the method described in, for example, Tetrahedoron Lett., 22, 3815, (1981) when L 3 is an N, O-dimethylhydroxylamino group in Step 14. Can be synthesized from intermediate (VIIb) and N, O-dimethylhydroxylamine.
  • L 3 is an imidazolyl group
  • intermediate (VIIb) and N, N′-carbonyl dioxygen can be synthesized according to the method described in Journal of Medicinal Chemistry (J. Med. Chem.), 25, 618, (1982). It can be synthesized from imidazole.
  • L 3 examples include halogen atoms (such as chlorine atoms), phenoxy, substituted phenoxy (eg, 4-nitrophenoxy group, pentafluorophenoxy group, etc.), 7-azabenzotriazol-1-yloxy group, benzotriazole- Examples include 1-yloxy group, succinimidyloxy group, phthalimidyloxy group, and the like.
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran and amides such as N, N-dimethylformamide are preferred.
  • the reaction time is 0.1 to 72 hours, preferably 0.3 to 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • Intermediate (IIi) can be produced by reacting intermediate (IIh) with a carbon nucleophile in step 15.
  • L 3 is an N, O-dimethylhydroxylamino group, for example, according to the method described in Tetrahedoron Lett., 22, 3815, (1981), intermediate (IIh) and alkyl or aryl magnesium It can be synthesized from reagents.
  • L 3 is an imidazolyl group, it can be synthesized from intermediate (IIh) and an alkyl or arylmagnesium reagent according to the method described in Synlett, 9, 1013, (1998).
  • Examples of the carbon nucleophile in Step 15 include organolithium reagents such as alkyl or aryllithium, organomagnesium reagents such as alkyl or arylmagnesium bromide (for example, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide), nitromethane, and the like.
  • organolithium reagents such as alkyl or aryllithium
  • organomagnesium reagents such as alkyl or arylmagnesium bromide (for example, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide), nitromethane, and the like.
  • Examples thereof include enol ether compounds such as alkyl nitro compounds, alkyl enol ethers and alkyl silyl enol ethers, and active methylene compounds such as alkyl or aryl
  • Step 15 is performed in the presence of a base as necessary.
  • a base for example, the bases mentioned in Step 6 are used.
  • alkali metal or alkaline earth metal hydride such as sodium hydride
  • alkali metal or alkaline earth metal amide such as sodium amide
  • Alkali metal or alkaline earth metal lower alkoxides such as potassium tert-butoxide are preferred.
  • the amount of the base used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to intermediate (IIh).
  • the solvent is selected from, for example, “solvents used in organic synthesis” shown in Step 1, and ethers such as tetrahydrofuran are particularly preferable.
  • the reaction time is usually about 0.1 to about 72 hours, preferably about 0.3 to about 24 hours.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • Compound (Ia) produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
  • the compound (Ia) contains an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, these are also contained as the compound (Ia), as well as synthetic methods and separation methods known per se (for example, , Concentration, solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product.
  • synthetic methods and separation methods known per se for example, Concentration, solvent extraction, column chromatography, recrystallization, etc.
  • the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
  • a method known per se for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Chiral column method A method in which a racemate or a salt thereof is separated by applying to a column for optical isomer separation (chiral column).
  • a column for optical isomer separation chiral column
  • a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Chemical Industries), and water, various buffers (eg, phosphoric acid)
  • the optical isomers are separated by developing the solution as a single or mixed solution of a buffer solution or the like and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.).
  • an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.
  • the separation is performed using a
  • Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method, etc.). Then, the optical isomer is obtained by separating the optically active reagent site by chemical treatment such as hydrolysis reaction.
  • the compound (Ia) when the compound (Ia) has hydroxy or 1,2-amino in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( -)-Mentoxyacetic acid and the like) are subjected to a condensation reaction to give ester or amide diastereomers, respectively.
  • an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • Compound (Ia) may be a crystal.
  • the crystal of compound (Ia) can be produced by crystallization by applying a crystallization method known per se to compound (Ia).
  • examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.
  • the “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent.
  • a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method.
  • solvent used examples include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane).
  • aromatic hydrocarbons eg, benzene, toluene, xylene, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • saturated hydrocarbons eg, hexane, heptane, cyclohexane.
  • Etc. ethers
  • ethers eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.
  • nitriles eg, acetonitrile, etc.
  • ketones eg, acetone, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • acid amides Eg, N, N-dimethylformamide, etc.
  • esters eg, ethyl acetate, etc.
  • alcohols eg, methanol, ethanol, isopropyl alcohol, etc.
  • Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
  • crystallization from melt examples include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method, Liquid phase epitaxy method) and the like.
  • compound (Ia) is dissolved in an appropriate solvent (eg, alcohol such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved.
  • an appropriate solvent eg, alcohol such as methanol, ethanol, etc.
  • a method of cooling to a temperature below for example, 0 to 50 ° C., preferably 0 to 20 ° C.
  • the crystals of the present invention thus obtained can be isolated by, for example, filtration.
  • a method for analyzing the obtained crystal a crystal analysis method by powder X-ray diffraction is generally used. Further, examples of the method for determining the crystal orientation include a mechanical method and an optical method.
  • crystal of the present invention has high purity, high quality, low hygroscopicity, and is stored for a long time under normal conditions. Is very stable. In addition, it has excellent biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of drug efficacy, etc.) and is extremely useful as a medicine.
  • the specific rotation ([ ⁇ ] D ) is measured by using, for example, a polarimeter (JASCO, P-1030 polarimeter (No. AP-2)) and the like. Means degrees.
  • the melting point means a melting point measured using, for example, a trace melting point measuring device (Yanako, MP-500D type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000).
  • the prodrug of compound (Ia) is a compound that is converted into compound (Ia) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (Ia) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (Ia) upon hydrolysis by gastric acid or the like.
  • the prodrug of compound (Ia) is a compound in which the amino group of compound (Ia) is acylated, alkylated or phosphorylated [eg, the amino group of compound (Ia) is eicosanoylated, alanylated, pentylaminocarbonylated.
  • the prodrug of compound (Ia) is a compound that changes to compound (Ia) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, pages 163 to 198. It may be.
  • the compound (Ia) or a salt thereof or a prodrug thereof (hereinafter abbreviated as compound (I ′)) of the present invention has an excellent monoamine (such as serotonin, norepinephrine, dopamine) reuptake inhibitory activity. Moreover, the compound (I ′) of the present invention has low toxicity and is safe. In particular, it is useful in that it does not exhibit phototoxicity.
  • the compound (I ′) of the present invention can be used for a monoamine in the brain (serotonin, norepinephrine) against mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.). Inhibiting the reuptake of monoamines in the brain as a substance having reuptake inhibitory activity, and improving symptoms of neuropsychiatric disorders such as depression and anxiety.
  • mammals eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.
  • Psychiatric and neurological diseases eg, depression (eg, major depression, cerebrovascular disorder depression, seasonal depression, drug-induced depression, HIV depression, etc.), anxiety (eg, general) sexual anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder), attention deficit / hyperactivity disorder (ADHD), bipolar disorder, mania, recurrent depression, persistent mood emotion disorder ( Eg, mood circulatory disorder, dysthymia, etc.), depressive neurosis, sleep disorder, diurnal rhythm disorder, eating disorder, drug dependence, premenstrual tension, autism, mood disorders due to menopause, senile dementia Mild cognitive dysfunction, hypersomnia, psychosomatic disorder, manic depression, posttraumatic stress disorder (PTSD), schizophrenia, anxiety, obsessive-
  • Pelvic organ prolapse anterior vaginal prolapse, retrovaginal prolapse, uterine prolapse, vaginal prolapse, rectal prolapse (rectal aneurysm), small intestinal aneurysm, cystocele, urethral aneurysm, etc.
  • Other diseases eg, diabetes, obesity, irritable bowel syndrome (IBS), Musm's leg syndrome (RLS), chronic fatigue syndrome, premenstrual syndrome (PMS), functional gastroenteropathy (FD), digestive system (Disease, smoking cessation, various addictions)
  • the compound (I ′) of the present invention is useful as a monoamine reuptake inhibitor, and particularly useful as a prophylactic / therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence.
  • the compound (I ′) of the present invention has a reuptake inhibitory activity for serotonin, norepinephrine and dopamine, and thus is useful as a Triple® Reuptake® Inhibitor.
  • the “monoamine reuptake inhibitor” means a reuptake inhibitor of at least one monoamine selected from serotonin, norepinephrine and dopamine which are neurotransmitters.
  • Monoamine reuptake inhibitors include serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, serotonin-dopamine reuptake inhibitors Drugs, serotonin-norepinephrine-dopamine reuptake inhibitors.
  • the preparation containing the compound (I ′) of the present invention may be any of solid preparations such as powders, granules, tablets, capsules, orally disintegrating films, and liquids such as syrups, emulsions and injections.
  • the prophylactic / therapeutic agent of the present invention can be produced by a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization treatment, emulsification, etc., depending on the form of the preparation. Regarding the production of the preparation, for example, each item of the Japanese Pharmacopoeia General Rules for Preparations can be referred to.
  • the agent of the present invention may be formed into a sustained release agent containing an active ingredient and a biodegradable polymer compound.
  • the sustained-release agent can be prepared according to the method described in JP-A-9-263545.
  • the content of compound (I ′) varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 100% by weight as compound (Ia) relative to the whole preparation. It is about 50% by weight, more preferably about 0.5 to 20% by weight.
  • the compound (I ′) of the present invention is used as the above-mentioned pharmaceutical, it is used as it is or an appropriate pharmacologically acceptable carrier, for example, an excipient (for example, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.) , Binders (eg starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone etc.), lubricants (eg stearic acid, magnesium stearate, calcium stearate, talc etc.), Disintegrating agents (for example, carboxymethylcellulose calcium, talc, etc.), diluents (for example, water for injection, physiological saline, etc.), and additives (for example, stabilizers, preservatives, coloring agents, fragrances, dissolution aids) as necessary , Emulsifiers, buffers, isotonic agents, etc.) Mixed by law,
  • Compound (I ') can also be directly administered to the affected area of a joint disease when it is formed into a topical preparation and administered.
  • an injection is preferable.
  • a parenteral agent for local administration eg, injection into intramuscular, subcutaneous, organ, joint sites, solid preparations such as implants, granules, powders, liquids such as suspensions, ointments, etc.
  • It can also be administered.
  • compound (I ′) is used as a dispersant (eg, surfactants such as Tween 80, HCO-60, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, polysorbate, etc.), storage Agents (eg, methylparaben, propylparaben, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), buffers (eg, calcium carbonate, etc.), pH adjusters (eg, sodium phosphate, phosphorus, etc.)
  • a dispersant eg, surfactants such as Tween 80, HCO-60, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, polysorbate, etc.
  • storage Agents eg, methylparaben, propylparaben, etc.
  • isotonic agents eg, sodium chloride, mannitol, sorbito
  • Injectables that can be used as oily suspensions by dispersing with vegetable oils such as sesame oil and corn oil or phospholipids such as lecithin mixed with them, or medium chain fatty acid triglycerides (eg, miglycol 812). To do.
  • vegetable oils such as sesame oil and corn oil or phospholipids such as lecithin mixed with them, or medium chain fatty acid triglycerides (eg, miglycol 812).
  • the prophylactic / therapeutic agent of the present invention can be used together with other drugs.
  • examples of the drug that can be blended or used in combination with compound (I ′) include the following.
  • Other central nervous disease prophylactic / therapeutic drugs Depressive drugs, anxiety drugs (eg, chlordiazepoxide, diazepam, potassium chlorazepate, lorazepam, clonazepam, alprazolam and other benzodiazepines), mood stabilizers (eg, carbonic acid carbonate) Lithium), 5-HT2 antagonists (eg, nefazodone, etc.), 5-HT1A agonists (eg, tandospirone, buspirone, Gepiron, etc.), CRF antagonists (eg, Pecacerfont, etc.), ⁇ 3 agonists (eg, Amibegron, etc.) ), Melatonin agonists (eg, ramelteon, ago
  • ⁇ -amyloid vaccine eg., ⁇ -amyloid degrading enzyme, etc.
  • brain function activator eg, aniracetam, nicergoline
  • Parkinson's disease drug eg, dopamine receptor agonist (eg, L-dopa, bromocryptene, pergolide] , Talipexol, Prasipexole, Cabergoline, Adamantazine, etc.), COMT inhibitors (eg, Entacapone, etc.)], Attention deficit / hyperactivity disorder (eg, modafinil, etc.), Amyotrophic lateral sclerosis (eg, , Riluzole, neurotrophic factor, etc.), insomnia drug (eg, etizolam, zopiclone, triazolam, zolpidem, indiplon), hypersomnia drug (eg, modafinil, etc.), anti-cytokine drug (TNF inhibitor,
  • dopamine receptor agonist eg,
  • Adrenaline ⁇ 1 receptor agonist eg, ephedrine hydrochloride, mitodrine hydrochloride, etc.
  • Adrenaline ⁇ 2 receptor agonist eg, Clenbuterol, etc.
  • Norepinephrine uptake inhibitor eg, Norepinephrine and serotonin uptake inhibitors (eg, duloxetine, etc.)
  • tricyclic antidepressants eg, imipramine hydrochloride, etc.
  • anticholinergic drugs or smooth muscle stimulants eg, oxybutynin hydrochloride, propiverine hydrochloride, selimevelin hydrochloride, etc.
  • female Hormonal drugs eg, conjugated estrogens (premarin), estriol, etc.
  • Diabetes therapeutic agent Insulin preparations [eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin fragments Or derivatives (eg, INS-1 etc.)], insulin sensitivity enhancers (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP) -297, FK-614, CS-011, etc.), ⁇ -glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), sulfonylurea agents (eg, Tolbutamide Glibenclamide, gliclazide, chlorpropamide
  • Aldose reductase inhibitors eg, tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minarerestat (ARI-509), CT-112 etc.
  • nerve Nutritional factors eg, NGF, NT-3, etc.
  • AGE inhibitors eg, ALT-945, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT-766), EXO-226, etc.
  • active oxygen elimination Drugs eg, thioctic acid, etc.
  • cerebral vasodilators eg, thioprid, etc.
  • Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt), etc.), squalene synthase Fibrate compounds having an inhibitor or triglyceride lowering effect (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.) and the like.
  • cholesterol synthesis inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt), etc.
  • squalene synthase Fibrate compounds having an inhibitor or triglyceride lowering effect eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.
  • Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonist (eg, losartan, candesartan cilexetil, etc.), calcium antagonist (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine) Etc.), clonidine and the like.
  • Angiotensin converting enzyme inhibitor eg, captopril, enalapril, delapril, etc.
  • angiotensin II antagonist eg, losartan, candesartan cilexetil, etc.
  • calcium antagonist eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine
  • Anti-obesity agents Central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), pancreatic lipase inhibitor (Eg, orlistat, etc.), ⁇ 3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9679, AZ40140, etc.), peptidic appetite suppressant (eg, leptin, CNTF (hair-like) Somatic neurotrophic factor)), cholecystokinin agonists (eg, Lynchtripto, FPL-15849, etc.) and the like.
  • ⁇ 3 agonist eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9679, AZ40140, etc.
  • Diuretics Xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclo Thiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, etacrine Acid, piretanide, bumetanide, furosemide, etc.
  • Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plants Derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide, etc., among others, 5-fluorouracil derivatives such as furtulon or neoflutulon.
  • alkylating agents eg, cyclophosphamide, ifosfamide, etc.
  • antimetabolites eg, methotrexate, 5-fluorouracil, etc.
  • anticancer antibiotics eg, mitomycin, adriamycin, etc.
  • plants Derived anticancer agents eg, vincristine, vindesine
  • Immunotherapeutic agents Microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL), etc.), colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.), among them IL-1, IL-2, IL-12, etc.
  • cytokines obtained by genetic engineering techniques
  • IL Interferon, interleukin (IL), etc.
  • colony stimulating factors eg, granulocyte colony stimulating factor, erythropoietin, etc.
  • Anti-inflammatory agents Steroids (eg, dexamethasone, etc.), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.) and the like.
  • cyclooxygenase inhibitors eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.
  • Glycation inhibitors eg, ALT-711, etc.
  • nerve regeneration promoters eg, Y-128, VX853, prostide, etc.
  • central nervous system agonists eg, desipramine, amitriptyline, imipramine, floxetine, paroxetine
  • Antidepressants such as doxepin
  • antiepileptic drugs eg, lamotrigine, carbamazepine
  • antiarrhythmic drugs eg, mexiletine
  • acetylcholine receptor ligands eg, ABT-594
  • endothelin receptor antagonists eg, ABT) -627
  • monoamine uptake inhibitors eg, tramadol
  • indoleamine uptake inhibitors eg, floxetine, paroxetine
  • narcotic analgesics eg, morphine
  • GABA receptor agonists eg, gabapentin
  • anticholinergic agent examples include atropine, scopolamine, homatropine, tropicamide, cyclopentrate, butylscopolamine bromide, propantheline bromide, methylbenactidium bromide, mepenzolate bromide, flavoxate, pirenzepine, ipratopium bromide, trihepium Xyphenidyl, oxybutynin, propiverine, darifenacin, tolterodine, temiverine, trospium chloride or its salts (eg, atropine sulfate, scopolamine hydrobromide, homatropine hydrobromide, cyclopentrate hydrochloride, flavoxate hydrochloride, pirenzepine hydrochloride, trihepine Xyphenidyl, oxybutynin hydrochloride, tolterodine tartrate, etc.) are used.
  • oxybutynin, propiverine, darifenacin, tolterodine, temiverine, Supiumu or a salt thereof are preferred.
  • oxybutynin hydrochloride, etc. tolterodine tartrate are preferred.
  • acetylcholinesterase inhibitors eg, distigmine and the like
  • distigmine and the like can also be used.
  • NK-2 receptor antagonists include GR159897, GR1499861, SR48968 (saredutant), SR144190, YM35375, YM38336, ZD7944, L-743986, MDL105212A, ZD6021, MDL105172A, SCH205528, pelysin RIS62373, R132 Perhydroisoindole derivatives such as RPR-106145, quinoline derivatives such as SB-414240, pyrrolopyrimidine derivatives such as ZM-253270, MEN11420 (nepadutant), SCH217048, L-659877, PD-147714 (CAM-2291), MEN10376, Pseudopeptide derivatives such as S16474 Other, GR100679, DNK333, GR94800, UK-224671, MEN10376, MEN10627, or the like salts thereof.
  • the administration time of the compound (I ′) and the concomitant drug is not limited, and the compound (I ′) or a pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are administered simultaneously to the administration subject.
  • administration may be performed with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the combination is not particularly limited as long as compound (I ′) and the concomitant drug are combined at the time of administration.
  • dosage forms include: (1) Administration of a single preparation obtained by simultaneously compounding compound (I ′) or a pharmaceutical composition thereof and a concomitant drug, (2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating Compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof, (3) Administration of two types of preparations obtained by separately formulating compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof at the same administration route with a time difference; (4) Simultaneous administration by different administration routes of two types of preparations obtained by separately formulating Compound (I ′) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof, (5) Administration of two types of preparations obtained by separately formulating Compound (I ′) or a pharmaceutical composition
  • the compounding ratio of the compound (I ′) and the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of compound (I ′) in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight based on the whole preparation. %, More preferably about 0.5 to 20% by weight.
  • 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 about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
  • the same content may be used when compound (I ′) and the concomitant drug are formulated separately.
  • the dose varies depending on the type of compound (I ′), administration route, symptoms, patient age, etc., but for example, for adult patients with depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence
  • about 0.005 to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg is divided into about 1 to 3 times as the compound (Ia) per kg body weight per day. Can be administered.
  • the dosage is the type and content of compound (I ′), dosage form, duration of drug release, animal to be administered (eg, human, rat, mouse, Mammals such as cats, dogs, rabbits, cows, pigs, etc.), which vary depending on the purpose of administration. For example, when applied by parenteral administration, about 0.1 to about 100 mg of compound (I ′) is administered per week. It may be released from the dosage form.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the mammal by oral administration. Is usually administered in 1 to 4 divided doses per day.
  • the concomitant drug of the present invention When administering the concomitant drug of the present invention, it may be administered at the same time, but after administering the concomitant drug first, compound (I ′) may be administered, or compound (I ′) may be administered first.
  • the concomitant drug may be administered thereafter.
  • the time difference varies depending on the active ingredient, dosage form, and administration method to be administered.
  • the method includes administering Compound (I ′) within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • 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 administration of compound (I ′).
  • the method of administration is mentioned.
  • the pharmaceutical composition of the present invention has low toxicity and can be used safely.
  • the Example compounds shown below are excellent in absorbability when administered orally and can be advantageously used for oral preparations. It is also excellent in that it does not show phototoxicity.
  • NMR spectra were measured with a Bruker AVANCE-300 or Varian VNMRS-300 spectrometer using tetramethylsilane as an internal or external reference, chemical shifts were expressed as ⁇ values, and coupling constants were expressed in Hz.
  • Specific rotation was measured using JASCO P-1030 type at a measurement temperature of 25 ° C., a cell length of 100 mm, and a methanol solvent.
  • the numerical value shown in parentheses is the volume mixing ratio of each solvent. Further,% in the solution represents the number of grams in 100 mL of the solution. Room temperature usually means a temperature of about 10 ° C to 30 ° C.
  • the symbols in the examples have the following meanings.
  • the fraction containing the optically active substance having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 4- [1- (3,4-dichlorophenyl) -2-hydroxyethyl] piperidine-1- Tert-butyl carboxylate (short retention time) (6.05 g, 48%,> 99% ee) was obtained.
  • the fraction containing the optically active substance having the longer retention time was concentrated to tert-butyl 4- [1- (3,4-dichlorophenyl) -2-hydroxyethyl] piperidine-1-carboxylate (retention). Large time) (5.72 g, 45%,> 99% ee).
  • Ethyl isocyanate (0.097 mL, 1.23) was added to a solution of tert-butyl 4- [amino (3,4-dichlorophenyl) methyl] piperidine-1-carboxylate (400 mL, 1.11 mmol) obtained in Reference Example 43 in tetrahydrofuran (10 mL). mmol) was added and stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • the title compound was obtained as a colorless oil (3.95 g, 95%) by purification by silica gel column chromatography (developing solvent; hexane: ethyl acetate (19: 1-1: 1)).
  • Reference Example 70 4- [1- (3-Chloro-4-fluorophenyl) -2-hydroxyethyl] piperidine-1-carboxylate tert-butyl (optically active substance having a longer retention time under the following analysis conditions (optically active substance B) ))
  • reaction mixture was extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate (9: 1-2: 1)) to give the title compound as a colorless oil (313 mg, 90%) Got as.
  • the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate (9: 1-0: 1)) to give the title compound as a colorless oil (309 mg, 39%).
  • the reaction solution was diluted with ethyl acetate, washed successively with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • the obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate (9: 1-0: 1)) to give the title compound as a colorless oil (566 mg, 54%). .
  • the reaction solution was diluted with ethyl acetate, washed successively with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • the obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate (9: 1-0: 1)) to give the title compound as a colorless oil (336 mg, 53%). .
  • Example 2 The same operation as in Example 1 was carried out using tert-butyl 4- [1- (3,4-dichlorophenyl) -2-methoxyethyl] piperidine-1-carboxylate (480 mg, 1.24 mmol) obtained in Reference Example 24. To give the title compound as colorless crystals (351 mg, 87%) having a melting point of 187-188 ° C. That is, to a solution of tert-butyl 4- [1- (3,4-dichlorophenyl) -2-methoxyethyl] piperidine-1-carboxylate (480 mL, 1.24 mmol) obtained in Reference Example 24 in ethanol (10 mL).
  • Example 2 The same operation as in Example 1 is carried out using tert-butyl 4- [1- (3-chlorophenyl) -2-methoxyethyl] piperidine-1-carboxylate (1.38 g, 3.90 mmol) obtained in Reference Example 27. This gave the title compound as colorless crystals (0.823 g, 73%) with a melting point of 147-148 ° C.
  • Example 2 The same operation as in Example 1 was performed using tert-butyl 4- [1- (4-chlorophenyl) -2-methoxyethyl] piperidine-1-carboxylate (0.88 g, 2.48 mmol) obtained in Reference Example 28. This gave the title compound as colorless crystals (0.50 g, 70%) with a melting point of 158-159 ° C.
  • Example 4 The same operation as in Example 1 was performed using tert-butyl 4- [1- (3,4-dichlorophenyl) -2-oxobutyl] piperidine-1-carboxylate obtained in Reference Example 40 (686 mg, 1.71 mmol). This gave the title compound as colorless crystals (487 mg, 85%) with a melting point of 210-212 ° C.
  • Example 41 The same operation as in Example 1 was carried out using tert-butyl 4- [1- (3,4-dichlorophenyl) -2-oxopentyl] piperidine-1-carboxylate obtained in Reference Example 41 (800 mg, 1.93 mmol).
  • the title compound was obtained as colorless crystals (535 mg, 79%) with a melting point of 196-197 ° C.
  • Example 45 The same operation as in Example 1 is performed using tert-butyl 4-[(acetylamino) (3,4-dichlorophenyl) methyl] piperidine-1-carboxylate (320 mg, 0.80 mmol) obtained in Reference Example 45. This gave the title compound as colorless crystals (234 mg, 86%) with a melting point of 241-243 ° C.
  • Example 1 Using tert-butyl 4-[(3,4-dichlorophenyl) (2-oxopyrrolidin-1-yl) methyl] piperidine-1-carboxylate obtained in Reference Example 47 (794 mg, 0.80 mmol) The title compound was obtained as colorless crystals (626 mg, 93%) having a melting point of 241 ° -243 ° C. by performing the same operation as in Example 1.

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Abstract

L'invention porte sur un composé représenté par la formule (Ia) [dans laquelle chaque symbole est tel que défini dans la description] ou sur un sel de celui-ci. Le composé a une activité inhibitrice sur la réabsorption d'une monoamine, et est donc utile en tant qu'agent thérapeutique/prophylactique pour la dépression, l'anxiété, le trouble de l'hyperactivité avec déficit de l'attention/hyperactivité, l'incontinence urinaire d'effort et autres, ou similaire.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012046882A1 (fr) 2010-10-07 2012-04-12 Takeda Pharmaceutical Company Limited Dérivés de 1,4-oxazépane
US20120122927A1 (en) * 2008-06-06 2012-05-17 Ki-Ho Lee 3 or 4-substituted piperidine compounds
WO2013038429A3 (fr) * 2011-09-13 2013-11-28 Panacea Biotec Ltd. Nouveaux inhibiteurs de sglt
CN110467597A (zh) * 2018-05-11 2019-11-19 上海医药工业研究院 芳烷环胺类衍生物及其在多靶点抗抑郁症药物中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050234058A1 (en) * 2003-10-14 2005-10-20 Wyeth Secondary amino-and cycloamino-cycloalkanol derivatives and methods of their use
WO2007002057A1 (fr) * 2005-06-20 2007-01-04 Schering Corporation Pipéridines substituées liées à un atome de carbone et leurs dérivés utiles en tant qu’antagonistes de l'histamine h3
JP2007508393A (ja) * 2003-10-14 2007-04-05 ワイス 縮合アリールおよびヘテロアリール誘導体およびその使用方法
JP2007509073A (ja) * 2003-10-14 2007-04-12 ワイス アルカノールおよびシクロアルカノール−アミン誘導体およびその使用方法
WO2009089462A1 (fr) * 2008-01-09 2009-07-16 Array Biopharma Inc. 5h-cyclopenta[d]pyrimidines en tant qu'inhibiteurs de protéine kinase akt

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050234058A1 (en) * 2003-10-14 2005-10-20 Wyeth Secondary amino-and cycloamino-cycloalkanol derivatives and methods of their use
JP2007508393A (ja) * 2003-10-14 2007-04-05 ワイス 縮合アリールおよびヘテロアリール誘導体およびその使用方法
JP2007509073A (ja) * 2003-10-14 2007-04-12 ワイス アルカノールおよびシクロアルカノール−アミン誘導体およびその使用方法
WO2007002057A1 (fr) * 2005-06-20 2007-01-04 Schering Corporation Pipéridines substituées liées à un atome de carbone et leurs dérivés utiles en tant qu’antagonistes de l'histamine h3
WO2009089462A1 (fr) * 2008-01-09 2009-07-16 Array Biopharma Inc. 5h-cyclopenta[d]pyrimidines en tant qu'inhibiteurs de protéine kinase akt

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"THE MERCK MANUAL OF DIAGNOSIS AND THERAPY", SEVENTEENTH EDITION, MERCK RESEARCH LABORATORIES, 1999, pages 1531 - 1538 *
CAVALLINI, G. ET AL.: "Basic 4-chlorophenyl- 4-pyridylcarbinol ethers new synthetic antihistaminics", FARMACO, EDIZIONE SCIENTIFICA, vol. 12, 1957, pages 887 - 891 *
DAVIDSON ET AL.: "New tissue schizontocidal antimalarial drugs", BULLETIN OF THE WORLD HEALTH ORGANIZATION, vol. 59, no. 3, 1981, pages 463 - 479 *
GAUTAM, B. C. ET AL.: "Agents acting on the central nervous system. VI. 2-Tertiary- aminophenylacetic acid esters and 2-tertiary- amino-2-phenylethanols", INDIAN JOURNAL OF CHEMISTRY, vol. 4, no. 5, 1966, pages 239 - 243 *
MCCAUSTLAND ET AL.: "Structural modification study of the antimalarial 2- (p-chlorophenyl)-2-(4-piperidyl) tetrahydrofuran", JOURNAL OF MEDICINAL CHEMISTRY, vol. 17, no. 9, 1974, pages 993 - 1000 *
PETERS, W. ET AL.: "The chemotherapy of rodent malaria. XXIII. Causal prophylaxis. II. Practical experience with Plasmodium yoelii nigeriensis in drug screening", ANNALS OF TROPICAL MEDICINE & PARASITOLOGY, vol. 69, no. 3, 1975, pages 311 - 328 *
SATO, YASUNOBU ET AL.: "Syntheses and pharmacology of 1-[2-(2-hydroxyethoxy)ethyl]-4- p- chlorobenzylpiperidine hydrochloride (piclobetol), and related compounds", ANN. SANKYO RES. LAB., vol. 23, 1971, pages 104 - 116 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120122927A1 (en) * 2008-06-06 2012-05-17 Ki-Ho Lee 3 or 4-substituted piperidine compounds
US8513285B2 (en) * 2008-06-06 2013-08-20 Sk Biopharmaceuticals Co., Ltd. 3 or 4-substituted piperidine compounds
WO2012046882A1 (fr) 2010-10-07 2012-04-12 Takeda Pharmaceutical Company Limited Dérivés de 1,4-oxazépane
US8722662B2 (en) 2010-10-07 2014-05-13 Takeda Pharmaceutical Company Limited Heterocyclic compounds
WO2013038429A3 (fr) * 2011-09-13 2013-11-28 Panacea Biotec Ltd. Nouveaux inhibiteurs de sglt
US9018249B2 (en) 2011-09-13 2015-04-28 Panacea Biotec Limited SGLT inhibitors
CN110467597A (zh) * 2018-05-11 2019-11-19 上海医药工业研究院 芳烷环胺类衍生物及其在多靶点抗抑郁症药物中的应用
CN110467597B (zh) * 2018-05-11 2022-07-12 上海医药工业研究院 芳烷环胺类衍生物及其在多靶点抗抑郁症药物中的应用

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