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WO2010123006A1 - Composé de pyrrolidine - Google Patents

Composé de pyrrolidine Download PDF

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Publication number
WO2010123006A1
WO2010123006A1 PCT/JP2010/057017 JP2010057017W WO2010123006A1 WO 2010123006 A1 WO2010123006 A1 WO 2010123006A1 JP 2010057017 W JP2010057017 W JP 2010057017W WO 2010123006 A1 WO2010123006 A1 WO 2010123006A1
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Prior art keywords
alkyl
atom
optionally substituted
compound
alkoxy
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Japanese (ja)
Inventor
真人 吉川
琢 亀井
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to a pyrrolidine 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.
  • cycloalkylamine derivatives see Patent Documents 1 and 2
  • pyrrolidine derivatives see Patent Documents 3 and 4
  • bicycloamine derivatives Patent Documents 5 and 6
  • indole derivatives see Patent Document 7
  • bicyclo derivatives Patent Documents 8-10 and the like are known.
  • Patent Document 11 discloses a compound useful as a therapeutic agent for central nervous disease such as depression and anxiety caused by monoamine reuptake inhibitory action.
  • Ar represents a disubstituted phenyl group
  • R 1 and R 2 independently represent hydrogen, C 1-10 alkyl, and the like
  • R 3 represents hydrogen, C 1-6 alkyl, and the like.
  • Patent Document 12 includes, for example, formulas as therapeutic agents for diabetes, obesity, and metabolic diseases by 11- ⁇ -hydroxysteroid dehydrogenase (11 ⁇ HSD) inhibitory action.
  • 11 ⁇ HSD 11- ⁇ -hydroxysteroid dehydrogenase
  • Patent Document 13 describes, as an anti-obesity drug based on melanocortin receptor agonist activity, for example, a formula
  • Patent Document 14 discloses an intermediate of a compound useful as a therapeutic agent for diabetic complications due to laminin / nidogen interaction inhibitory activity.
  • Patent Document 15 discloses a compound useful as a therapeutic agent for central nervous system diseases caused by increased brain levels of catecholamine, dopamine, and norepinephrine.
  • Patent Document 16 discloses a compound useful as a therapeutic agent for central nervous system diseases due to an increase in brain levels of catecholamine, dopamine, and norepinephrine.
  • Ar represents phenyl, thiophenyl, furanyl, etc.
  • R 1 and R 2 independently represent fluorine or chlorine
  • R 3 represents hydrogen, methyl, etc.
  • X represents fluorine or hydroxy.
  • 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 is optionally substituted lower alkylene, —CO—, —CH 2 CO— or an optionally substituted 5-membered heterocyclic ring
  • R 1 is hydroxy, cyano, optionally substituted amino, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted phenyl, optionally substituted mercapto, Substituted sulfonyl or optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group
  • R 2 represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl, or an optionally substituted alkoxycarbonyl
  • R 3 is a hydrogen atom or lower alkyl
  • R 4 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, In this case, At least one group of R 9 to R 13 represents a halogen atom or lower alkyl, or R 4 to R 9, R 12 and R 13 are the same
  • R 2 is a hydrogen atom and X—R 1 is —COOH
  • R 2 is a hydrogen atom, X is —CO—
  • R 1 is optionally substituted lower alkoxy
  • trans-N-2-adamantyl -3- (4-chlorophenyl) -prolinamide and
  • (3R) -3- (2-naphthalenyl) -L-prolyl-L-asparaginyl-L-alanyl-L-valineamide) ].
  • R 10 and R 11 are the same or different and are a hydrogen atom or a halogen atom (provided that at least one of R 10 and R 11 is a halogen atom), R 9 , R 12 and R 13 are all hydrogen atoms, the compound according to the above [1] or a salt thereof, [3] The compound or a salt thereof according to the above [1], wherein R 10 and R 11 are chlorine atoms, and R 9 , R 12 and R 13 are all hydrogen atoms, [4] X represents C 1-6 alkylene optionally substituted with 1 to 4 C 1-6 alkyl, —CO—, —CH 2 CO—, or a nitrogen atom, a sulfur atom and A 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from oxygen atoms, R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino, (4) C 3-6 cycl
  • R 1 is (1) a nitrogen atom other than a carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl, oxo, hydroxy and hydroxy C 1-6 alkyl; A 5- or 6-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom selected from oxygen atoms, or (2) C 1-6 alkyl, amino, C 3-6 cycloalkyl, C 1 -6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl and C 1 Represents an amino optionally substituted with 1 or 2 substituents selected from -6 alkoxycarbamoyl; R 2 to R 9 represent a hydrogen atom, R 10 represents a halogen atom, R 11 represents a hydrogen
  • R 1 is (1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1- It represents alkyl kill, aminosulfonyl, an amino substituted with 1 or 2 substituents selected from carbamoyl and mono- -C 1-6 alkoxy carbamoyl, R 2 to R 9 represent a hydrogen atom, R 10 and R 11 represent a halogen atom, R 12 and R 13 represent a hydrogen atom, The compound or a salt thereof according to the above [1], [7] ( ⁇ )-2,3-cis-3- (3,4-dichlorophenyl) -N, N-dimethylpyrrolidine-2-carboxamide or a salt thereof, [8] [(2R, 3R) -3- (3,4-dichlorophenyl) pyrrolidin-2-yl] [(3S) -3-hydroxypyrroli
  • 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.
  • lower alkyl includes linear or branched alkyl, for example, C 1-6 alkyl (eg, 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 etc.), preferably C 1-4 alkyl.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl.
  • Tert-butyl 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-
  • lower alkoxy includes linear or branched alkoxy, for example, C 1-6 alkoxy (eg, 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 , 2-dimethylbutoxy, 1,2,2-trimethylpropoxy, etc.), preferably C 1-4 alkoxy.
  • C 1-6 alkoxy eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- Butoxy, tert-butoxy, 1-methylpropoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylprop
  • alkoxycarbonyl includes linear or branched alkoxycarbonyl, for example, C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl) , Butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), preferably C 1-4 alkoxy-carbonyl.
  • lower alkylene includes linear alkylene, for example, C 1-6 alkylene (eg, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene), preferably C 1-4 alkylene is mentioned.
  • C 1-6 alkylene eg, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene
  • examples of the “cyclic amino” of “optionally substituted cyclic amino” include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl, 1-pyrrolyl, 1- Examples thereof include 3- to 8-membered (preferably 5- or 6-membered) cyclic amino such as imidazolyl.
  • the “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle” includes 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom ( 5- to 5-membered heterocyclic ring is preferable.
  • Aromatic heterocycles eg, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, oxadiazolidine (eg, 1,2,4-oxadiazolidine, 1,3,4) -Oxadiazolidine), thiadiazolidine (eg, 1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine), pyrroline, oxazoline, isoxazoline, thiazoline, isothiazoline, imidazoline, pyrazoline, oxadiazo Phosphorus (e
  • the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” includes a nitrogen atom in addition to the carbon atom and one nitrogen atom, Examples thereof include a 4- to 10-membered nitrogen-containing heterocyclic group which may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from a sulfur atom and an oxygen atom.
  • the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom 4- to 10-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) nitrogen-containing heterocyclic group (preferably non-aromatic nitrogen-containing heterocyclic group) (for example, azetidinyl, pyrrolidinyl, piperidinyl) , Morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl (eg, 1,4-diazepanyl), oxazepanyl (eg, 1,4-oxazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl
  • the “fused heteroaromatic ring” of the “optionally substituted fused heteroaromatic ring” formed by R 10 and R 11 together with the adjacent benzene ring includes a nitrogen atom, sulfur other than the carbon atom 9- to 14-membered (preferably 9- or 10-membered) condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from atoms and oxygen atoms (for example, benzofuran, isobenzofuran, benzo [b] thiophene, benzo [c] Thiophene, indole, isoindole, benzimidazole, indazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnoline, phenanthridine, acridine, phenazine and the like.
  • the “lower alkyl” of the “optionally substituted lower 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 (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, Ethylmethylamino), (8) C 1-6 alkyl-carbonylamino (preferably C 1-4 alkyl-carbonylamino) (eg, acetylamino, ethylcarbonylamino, etc.), (9) C 1-6 alkoxy-carbonylamino (preferably C 1-4 alkoxy-carbonylamino) (eg,
  • the “lower alkyl” of the “optionally substituted lower alkyl” may have The thing similar to a good substituent is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • the “alkoxycarbonyl” of the “optionally substituted alkoxycarbonyl” may have, the “lower alkyl” of the “optionally substituted lower alkyl” may have The thing similar to a good substituent is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • the “lower alkylene” of the “lower alkylene which may be substituted” may have, (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (2) cyano, (3) hydroxy, (4) Nitro, (5) optionally substituted lower alkyl (preferably C 1-6 alkyl, more preferably C 1-4 alkyl) Substituents selected from the above and the like. The number of substituents is 1 to 4, preferably 1 to 3.
  • the “mercapto” of the “optionally substituted mercapto” may have, (1) C 1-6 alkyl (preferably C 1-4 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), (2) C 2-6 alkenyl (eg, ethenyl, 1-propenyl, 2-propenyl), (3) C 2-6 alkynyl (eg, ethynyl, 1-propynyl, 2-propynyl), (4) C 6-14 aryl (eg, phenyl, 1-na
  • Examples of the substituent that the “sulfonyl” of the “substituted sulfonyl” may have include the same substituents as the substituent that the “mercapto” of the “optionally substituted mercapto” may have. It is done.
  • phenyl of “optionally substituted phenyl” may have, (A) the substituent which the “lower alkyl” of the “optionally substituted lower alkyl” may have, and (b) (1) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom) , iodine), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy) (e.g., methoxy, ethoxy, to 1 selected from propoxy) optionally substituted with 1-3 substituents C 1 -6 alkyl (preferably C 1-4 alkyl) (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl,
  • the substituent that the “cyclic amino” of the “optionally substituted cyclic amino” may have the oxo and the “phenyl” of the “optionally substituted phenyl” may have The thing similar to a good substituent is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • the “phenyl” of the above-mentioned “optionally substituted phenyl” has.
  • the thing similar to the substituent which may be mentioned is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3, and more preferably 1 or 2.
  • Examples of the substituent that the “4- to 10-membered nitrogen-containing heterocyclic group” in the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” may have include oxo and the above-mentioned “substituted” Examples thereof include the same substituents that the “phenyl” of “may be phenyl” may have.
  • 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 “fused heteroaromatic ring” of the “optionally substituted condensed heteroaromatic ring” may have, the above-mentioned “ The thing similar to the substituent which "phenyl” of "the phenyl which may be substituted” may have is mentioned.
  • the number of substituents is 1 to 4, preferably 1 to 3.
  • Saturated non-aromatic nitrogen-containing heterocyclic group eg, thiomorpholinyl, piperazinyl, morpholinyl
  • a sulfonylamino substituted with one substituent selected from (14) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, For example, amino, ethylamino, ethylmethylamino), (Ii) oxo, (Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazin
  • C 1-6 alkoxycarbamoyl means mono- or di-C 1-6 alkoxycarbamoyl.
  • the “optionally substituted lower alkylene” represented by X is 1 to 4 selected from lower alkyl (preferably C 1-6 alkyl, more preferably C 1-4 alkyl), halogen atom and hydroxy And C 1-6 alkylene (preferably C 1-4 alkylene) which may be substituted with these substituents.
  • Another preferred embodiment of the “optionally substituted lower alkylene” represented by X is C 1-6 alkylene.
  • the “optionally substituted 5-membered heterocyclic ring” represented by X may further have a substituent at a substitutable position in addition to R 1 .
  • the “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle” represented by X includes 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom ( A 5-membered aromatic heterocycle containing 1 to 3 is preferred.
  • Examples include azole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole and the like.
  • oxadiazole eg, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane
  • thiadiazole eg, 1,2 , 3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, and more preferably oxadiazole (eg, 1,2,4-oxadiazole, 1,3,4-).
  • the “5-membered heterocycle” of the “optionally substituted 5-membered heterocycle” represented by X may have, (1) a halogen atom, (2) hydroxy, and (3) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1-4 alkyl) 1 to 3 (preferably 1 or 2) substituents selected from
  • the “optionally substituted 5-membered heterocycle” represented by X is a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Is preferred.
  • the X, 1 to the four C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, optionally substituted with one to four C 1-4 alkyl C 1- 4- alkylene), —CO—, —CH 2 CO— or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, 1, 2 , 4-oxadiazole, 1,3,4-oxadiazole).
  • Another preferred example of X is C 1-6 alkylene (preferably C 1-4 alkylene), —CO—, —CH 2 CO—, and among them, C 1-6 alkylene (preferably, C 1-4 alkylene), —CO—.
  • R 1 As the “optionally substituted amino” represented by R 1 , (1) amino, (2) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (3) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino), (4) Hydrazino, (5) mono- or di- (C 1-6 alkylsulfonyl) amino (preferably mono- or di- (C 1-4 alkylsulfonyl) amino, eg methylsulfonylamino), (6) mono- or di- (C 1-6 alkyl-carbonyl
  • Saturated non-aromatic nitrogen-containing heterocyclic group eg, thiomorpholinyl, piperazinyl, morpholinyl
  • a sulfonylamino substituted with one substituent selected from (12) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, For example, amino, ethylamino, ethylmethylamino), (Ii) oxo, (Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Piperazin
  • R 1 As another preferred embodiment of the “optionally substituted amino” represented by R 1 , (1) mono- or di-C 1-6 alkylamino, (2) C 3-6 cycloalkylamino, (3) Hydrazino, (4) C 1-6 alkoxy C 1-6 alkyl, Halogen atoms, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, Aminosulfonyl, C 1-6 alkylaminosulfonyl, Examples include carbamoyl and amino optionally substituted with one or two substituents selected from C 1-6 alkoxycarbamoyl.
  • R 1 As still another preferred embodiment of the “optionally substituted amino” represented by R 1 , C 1-6 alkyl, amino, C 3-6 cycloalkyl, C 1-6 alkoxy C 1-6 alkyl, Halogen atoms, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, Aminosulfonyl, C 1-6 alkylaminosulfonyl, And amino optionally substituted with one or two substituents selected from carbamoyl and C 1-6 alkoxycarbamoyl.
  • R 1 As the “optionally substituted amino” represented by R 1 , (1) amino, (2) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (3) Hydrazino, (4) mono- or di- (C 1-6 alkylsulfonyl) amino (preferably mono- or di- (C 1-4 alkylsulfonyl) amino, eg methylsulfonylamino), (5) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino), (6) mono- or di- (C 1-6 alkoxy-carbonyl) amino
  • Saturated) non-aromatic nitrogen-containing heterocyclic group (eg, thiomorpholinyl, piperazinyl, morpholinyl) Sulfonylamino substituted with one substituent selected from: and (11) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably C 1 Amino optionally mono- or di-substituted with -4 alkyl, such as amino, ethylamino, ethylmethylamino), (Ii) oxo, (Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Pipe
  • the “optionally substituted lower alkyl” represented by R 1 is C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy (preferably C 1 -4 alkyl, such as methyl, ethyl, isopropyl).
  • the “optionally substituted lower alkoxy” represented by R 1 is C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the following (a) to (f): (Preferably C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.) (A) a halogen atom, (B) hydroxy, (C) oxo, (D) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino, such as ethylamino), (E) a 4- to 10-membered saturated heterocyclic group (eg, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl), and (f) 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom)
  • phenyl represented by R 1 , (1) a halogen atom, (2) cyano, (3) hydroxy, (4) Nitro, (5) Formyl, (6) amino, (7) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino), (8) C 1-6 alkyl-carbonylamino (preferably C 1-4 alkyl-carbonylamino), (9) C 1-6 alkoxy-carbonylamino (preferably C 1-4 alkoxy-carbonylamino), (10) C 1-6 alkoxy (preferably C 1-4 alkoxy) optionally substituted by 1 to 3 halogen atoms, (11) C 1-6 alkyl-carbonyloxy (preferably C 1-4 alkyl-carbonyloxy), (12) Carboxy, (13) C 1-6 alkoxy - carbonyl (preferably C 1-4 alkoxy - carbonyl), and (14) 1 to 3 halogen atoms optionally substituted by a C 1-6 alky
  • the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” represented by R 1 is a nitrogen atom in addition to a carbon atom and one nitrogen atom.
  • a 4- to 10-membered saturated non-aromatic nitrogen-containing heterocycle which may contain 1 to 3 (preferably 1 or 2, more preferably 1) heteroatoms selected from sulfur atom and oxygen atom Groups as well as phthalimide are preferred.
  • Examples of the 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl (eg, 1,4-diazepanyl), oxazepanyl (eg, 1, 4-oxazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, pyrazolidinyl, oxadiazolidinyl (eg, 1,2,4-oxadiazolidinyl, 1,3,4-oxadiazinyl) Lysinyl), thiadiazolidinyl (eg, 1,2,4-thiadiazolidinyl, 1,3,4-thiadiazolidinyl), 1,3,8-triazaspir
  • the saturated non-aromatic nitrogen-containing heterocyclic group may contain one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom and one nitrogen atom.
  • 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group more preferably 1,3,8-triazaspiro [4.5] decanyl, azetidinyl, thiazolidinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl .
  • the 4- to 10-membered saturated non-aromatic nitrogen-containing heterocyclic group and phthalimide are preferably bonded to X through a nitrogen atom.
  • the “4- to 10-membered nitrogen-containing heterocyclic group” of the “optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group” represented by R 1 may have, (1) a halogen atom (eg, fluorine atom), (2) hydroxy, (3) hydroxy, and C 1-6 alkoxy (preferably C 1-4 alkoxy) 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from (preferably C 1-4 alkyl, Eg methyl), (4) optionally substituted C 1-6 alkoxy (preferably C 1-4 alkoxy, such as methoxy), (5) an optionally substituted carbamoyl (preferably mono or di-C 1-6 alkyl-carbamoyl, more preferably mono or di-C 1-4 alkyl-carbamoyl, eg dimethylcarbamoyl), and (6) oxo 1 to 3 substituents selected from
  • Examples of the “optionally substituted mercapto” represented by R 1 include a mercapto optionally substituted with C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl). , Ethylthio, propylthio, isopropylthio, butylthio.
  • “Substituted sulfonyl” represented by R 1 includes sulfonyl substituted with C 1-6 alkyl (preferably C 1-4 alkyl, such as methyl), and examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, Examples include isopropylsulfonyl and butylsulfonyl.
  • R 1 (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (4) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino), (5) Hydrazino, (6) C 1-6 alkyl (preferably C 1-4 alkyl such as methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (7) C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the following (a)
  • Saturated non-aromatic nitrogen-containing heterocyclic group eg, thiomorpholinyl, piperazinyl, morpholinyl
  • R 1 As another preferred embodiment of R 1 , (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino, (4) C 3-6 cycloalkylamino, (5) Hydrazino, (6) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (7) C 1-6 alkoxy optionally substituted by 1 to 3 substituents selected from a halogen atom and hydroxy, (8) phenyl, (9)
  • substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom, (A) a halogen atom, (B) hydroxy, (C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from alkoxy, (D) C 1-6 alk
  • R 1 (1) C 1-6 alkyl, Oxo, One heteroatom selected from a nitrogen atom and an oxygen atom, in addition to a carbon atom and one nitrogen atom, optionally substituted by 1 to 3 substituents selected from hydroxy and hydroxy C 1-6 alkyl A 5- or 6-membered saturated nitrogen-containing heterocyclic group which may be contained, and (2) C 1-6 alkyl, amino, C 3-6 cycloalkyl, C 1-6 alkoxy C 1-6 alkyl, Halogen atoms, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, Aminosulfonyl, C 1-6 alkylaminosulfonyl, And amino optionally substituted with one or two substituents selected from carbamoyl and C 1-6 alkoxycarbamoyl.
  • Halogen atom represented by R 2 include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.
  • the “optionally substituted lower alkyl” represented by R 2 is 1 selected from a halogen atom (for example, a chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, for example, methoxy). C 1-6 alkyl (preferably C 1-4 alkyl such as methyl) which may be substituted with 3 substituents.
  • a halogen atom for example, a chlorine atom
  • C 1-6 alkoxy preferably C 1-4 alkoxy, for example, methoxy
  • C 1-6 alkyl preferably C 1-4 alkyl such as methyl
  • the “optionally substituted alkoxycarbonyl” represented by R 2 is substituted with 1 to 3 substituents selected from hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy). And C 1-6 alkoxy-carbonyl (preferably C 1-4 alkoxy-carbonyl). Of these, C 1-6 alkoxy-carbonyl is preferable.
  • alkoxycarbonyl represented by R 2
  • C 1-6 alkoxy-carbonyl is preferable, and C 1-4 alkoxy-carbonyl is more preferable.
  • R 2 (1) a hydrogen atom, (2) C 1 -C 1 which may be substituted with 1 to 3 substituents selected from halogen atom (eg chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy) 6 alkyl (preferably C 1-4 alkyl, such as methyl) or (3) C 1-6 alkoxy-carbonyl (preferably C 1-4 alkoxy-carbonyl) is preferred, Substituted with 1 to 3 substituents selected from (1) a hydrogen atom, or (2) a halogen atom (eg chlorine atom), hydroxy and C 1-6 alkoxy (preferably C 1-4 alkoxy, eg methoxy) More preferably C 1-6 alkyl (preferably C 1-4 alkyl, eg methyl), More preferred is a hydrogen atom.
  • halogen atom eg chlorine atom
  • hydroxy and C 1-6 alkoxy preferably C 1-4 alkoxy, eg methoxy
  • 6 alkyl
  • R 3 represents a hydrogen atom or lower alkyl.
  • C 1-6 alkyl is preferable, and C 1-4 alkyl is more preferable.
  • R 3 is preferably a hydrogen atom or C 1-6 alkyl (preferably methyl, ethyl). R 3 is more preferably a hydrogen atom.
  • R 4 to R 8 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl.
  • the “halogen atom” represented by R 4 to R 8 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “lower alkyl” represented by R 4 to R 8 is preferably C 1-6 alkyl, more preferably C 1-4 alkyl.
  • R 4 to R 8 are the same or different and are preferably a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), more preferably a hydrogen atom.
  • R 9 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, and in this case, at least one group of R 9 to R 13 represents a halogen atom or a lower alkyl group, or R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or lower alkyl, and each of R 10 and R 11 may be substituted together with the adjacent benzene ring. It forms a naphthalene ring or an optionally substituted fused heteroaromatic ring. Particularly preferably, R 9 to R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl.
  • At least one group of R 9 to R 13 is a halogen atom or C 1 1-6 alkyl, or, R 9, R 12 and R 13 are the same or different, a hydrogen atom, a halogen atom or C 1-6 alkyl, R 10 and R 11 are, benzene, each of which adjacent Together with the ring, it forms a naphthalene ring.
  • halogen atom represented by R 9 to R 13
  • examples of the “halogen atom” represented by R 9 to R 13 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably they are a fluorine atom or a chlorine atom, More preferably, it is a chlorine atom.
  • the “lower alkyl” represented by R 9 to R 13 is preferably C 1-6 alkyl, more preferably C 1-4 alkyl.
  • the optionally substituted naphthalene ring formed by R 10 and R 11 together with the adjacent benzene ring is 1 to 3 substituents selected from halogen atoms (for example, fluorine atoms). An optionally substituted naphthalene ring is exemplified.
  • the optionally substituted condensed heteroaromatic ring formed by R 10 and R 11 together with the adjacent benzene ring is 1 to 3 substituents selected from halogen atoms (for example, chlorine atoms) 9- to 14-membered (preferably 9- or 10-membered) condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, optionally substituted by a group ( Preferably, indazole is used.
  • R 10 and R 11 are the same or different and are a hydrogen atom or a halogen atom (provided that at least one of R 10 and R 11 is a halogen atom), and R 9 , R 12 and R 13 are all hydrogen An atom is preferred.
  • R 10 and R 11 are chlorine atoms
  • R 9 , R 12 and R 13 are all hydrogen atoms.
  • Examples of the optionally substituted naphthalene ring or the optionally substituted condensed heteroaromatic ring formed by R 10 and R 11 together with the adjacent benzene ring include (1) a halogen atom, (2) hydroxy, (3) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms (preferably C 1-4 alkyl), and (4) optionally substituted with 1 to 3 halogen atoms C 1-6 alkoxy (preferably C 1-4 alkoxy)
  • the condensed heteroaromatic ring is preferably a 9- to 14-membered (preferably 9- or 10-membered) condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
  • Examples include benzofuran, isobenzofuran, benzo [b] thiophene, benzo [c] thiophene, indole, isoindole, indazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnoline and the like.
  • R 4 to R 9, R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl (preferably C 1-4 alkyl), and R 10 and R 11 are each It is preferable to form a naphthalene ring or a condensed heteroaromatic ring together with an adjacent benzene ring.
  • R 4 to R 9, R 12 and R 13 all represent a hydrogen atom, and R 10 and R 11 together with an adjacent benzene ring form a naphthalene ring or a condensed heteroaromatic ring. Is more preferable.
  • Preferred examples of compound (I) include X is 1 to 4 amino C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, one to four C 1-4 optionally C 1-4 optionally substituted by alkyl Alkylene), —CO—, —CH 2 CO—, or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, 1, 2, 4-oxadiazole, 1,3,4-oxadiazole)
  • R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (4) C 3-6 cycloalkyla
  • Saturated non-aromatic nitrogen-containing heterocyclic group eg, thiomorpholinyl, piperazinyl, morpholinyl
  • compound (I) examples include X is 1 to 4 amino C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, one to four C 1-4 optionally C 1-4 optionally substituted by alkyl Alkylene), —CO—, —CH 2 CO—, or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, 1, 2, 4-oxadiazole, 1,3,4-oxadiazole)
  • R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino), (4) C 3-6 cycloalkylamino, (5) Hydrazino, (6) C 1-6 alkyl (preferably C 1-4 alkyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (7) C 1-6 alkoxy (preferably C 1-4 alkoxy) optionally
  • X and R 1 include the following embodiments.
  • X is 1 to 4 amino C 1-6 alkyl optionally substituted by C 1-6 alkylene (preferably, one to four C 1-4 optionally C 1-4 optionally substituted by alkyl Alkylene)
  • R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.),
  • C 1-6 alkyl preferably C 1-4 alkyl such as methyl, ethyl, isopropyl
  • C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from the
  • methylsulfonylamino (8) mono- or di- (C 1-6 alkyl-carbonyl) amino (preferably mono- or di- (C 1-4 alkyl-carbonyl) amino, eg methylcarbonylamino), (9) mono- or di- (C 1-6 alkoxy-carbonyl) amino (preferably mono- or di- (C 1-4 alkoxy-carbonyl) amino, such as methoxycarbonylamino, ethoxycarbonylamino), (10) amino, (11) cyclic amino, (12) phthalimide, (13) (a) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably a heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) Or 4 to 10-membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group which may be contained (preferably 1 or 2, more preferably 1)), (B) aminocarbonylimino
  • Saturated non-aromatic nitrogen-containing heterocyclic group (eg, thiomorpholinyl, piperazinyl, morpholinyl)
  • a sulfonylamino substituted with one substituent selected from (16) (a) (i) amino optionally mono- or di-substituted with C 1-6 alkyl (preferably amino optionally mono- or di-substituted with C 1-4 alkyl, More preferably, amino, ethylamino, ethylmethylamino), (Ii) oxo, (Iii) an optionally substituted 4- to 10-membered nitrogen-containing heterocyclic group (preferably having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom) (Preferably 1 or 2, more preferably 1) 4 to 10 membered saturated or unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocyclic group such as morpholinyl, Pipe
  • X is —CO— or —CH 2 CO—;
  • R 1 is (1) Mono- or di-C 1-6 alkylamino (preferably mono- or di-C 1-4 alkylamino) (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-) Propylamino, ethylmethylamino, etc.), (2) C 3-6 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino), (3) Hydrazino, (4) C 1-6 alkyl (preferably C 1-4 alkyl such as methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (5) C 1-6 alkoxy optionally substituted with 1 to 3 substituents selected from
  • X is a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (eg, 1,2,4-oxadiazole, 1,3,3 4-oxadiazole),
  • R 1 is (1) Compound (I) which is C 1-6 alkyl (preferably C 1-4 alkyl) optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, or (2) phenyl .
  • suitable examples of compound (I) include the following compounds (I-1), (I-2), (I-3), (I-4) and (I-5) ).
  • Compound (I-1) The compound (I), X is C 1-6 alkylene optionally substituted with 1 to 4 C 1-6 alkyl, —CO—, —CH 2 CO—, or a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
  • R 1 is (1) hydroxy, (2) cyano, (3) mono- or di-C 1-6 alkylamino, (4) C 3-6 cycloalkylamino, (5) Hydrazino, (6) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (7) C 1-6 alkoxy optionally substituted by 1 to 3 substituents selected from a halogen atom and hydroxy, (8) phenyl, (9)
  • substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom
  • a 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom, (A) a halogen atom, (B) hydroxy, (C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6
  • R 1 is (1) cyano, (2) mono- or di-C 1-6 alkylamino, (3) C 3-6 cycloalkylamino, (4) Hydrazino, (5) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from a halogen atom and hydroxy, (6) phenyl, (7)
  • substituents selected from the following (a) to (e), selected from nitrogen atom, sulfur atom and oxygen atom A 4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one heteroatom, (A) a halogen atom, (B) hydroxy, (C) hydroxy, and C 1-6 1 to 3 substituents optionally substituted by C 1-6 alkyl selected from alkoxy, (D) C 1-6 alkoxy, and (e) oxo, or (8) Amino, C 1-6 alkoxy C 1-6 alkyl, halogen
  • the “5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom” in the definition of X of the compound (I-1) is preferably 1, 2,4-oxadiazole and 1,3,4-oxadiazole, and in the definition of R 1 , a hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and one nitrogen atom
  • the “4- to 10-membered saturated nitrogen-containing heterocyclic group which may contain one atom” is preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.
  • R 1 is (1) a nitrogen atom other than a carbon atom and one nitrogen atom, which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl, oxo, hydroxy and hydroxy C 1-6 alkyl; A 5- or 6-membered saturated non-aromatic nitrogen-containing heterocyclic group which may contain one heteroatom selected from oxygen atoms, or (2) C 1-6 alkyl, amino, C 3-6 cycloalkyl C 1-6 alkoxy C 1-6 alkyl, halogen atom, C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl And an amino optionally substituted with 1 or 2 substituents selected from C 1-6 alkoxycarbam
  • a hetero atom selected from a nitrogen atom and an oxygen atom may be contained in addition to the carbon atom and one nitrogen atom.
  • the “aromatic nitrogen-containing heterocyclic group” is preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.
  • R 1 is (1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1-6 Represents an amino substituted with one or two substituents selected from alkylkylsulfonyl, aminosulfonyl, carbamoyl and mono-C 1-6 alkoxycarbamoyl;
  • R 2 to R 9 represent a hydrogen atom
  • R 10 and R 11 represent a halogen atom
  • R 12 and R 13 represent a hydrogen atom, Compound.
  • R 1 is (1) pyrrolidinyl optionally substituted with one substituent selected from hydroxy and hydroxy C 1-6 alkyl, or (2) C 1-6 alkyl-carbonyl, C 1-6 alkylkylsulfonyl, aminosulfonyl And a compound representing amino substituted with one substituent selected from carbamoyl and mono-C 1-6 alkoxycarbamoyl.
  • the compounds described in Examples 1 to 232 and the like are preferable.
  • the compound (I) the following compounds or salts thereof are particularly preferable.
  • examples of such a salt include a salt with an inorganic base, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic or acidic Examples include salts with amino acids.
  • 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.
  • pharmaceutically acceptable salts include, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, phthalic acid, etc., when the compound has a basic functional group.
  • salts with organic acids such as acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.) And ammonium salts.
  • Compound (I) includes within its scope solvates (eg hydrates) and non-solvates.
  • compound (I) may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.).
  • Compound (I) may be a deuterium converter. Further, a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • 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 or tautomerism may be produced, and such isomers or mixtures thereof are also included in the compound (I) of the present invention.
  • a compound represented by the following formula (I) or a salt thereof and a raw material compound thereof can be produced by a method known per se, for example, by a method shown in the following scheme.
  • room temperature usually indicates 0 to 30 ° C.
  • each symbol in the chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified.
  • the compound in a formula also includes the case where it forms the salt, As such a salt, the thing similar to the salt of compound (I) etc. are mentioned, for example.
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method. At that time, it can be purified by separation means such as recrystallization, distillation, chromatography and the like.
  • the protecting group PRG refers to a protecting group for the nitrogen atom of an amine or amide.
  • Green's Protective Groups in Organic Synthesis 4th Edition 4 th Edition it can be used protecting groups described in 2006. Moreover, when introduction
  • preferred PRG includes tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, acetyl and the like.
  • LG includes, for example, a halogen atom (eg, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methane) optionally substituted with a halogen atom.
  • a halogen atom eg, chlorine atom, bromine atom, iodine atom
  • C 1-6 alkylsulfonyloxy eg, methane
  • C 6-10 arylsulfonyloxy eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.
  • reaction when performing alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, etherification reaction, oxidation reaction, reduction reaction, reductive amination reaction, etc.
  • the reaction is carried out according to a method known per se.
  • a method for example, Organic Functional Group Preparations (ORGANIC FUNCTIONAL GROUP PREPARATIONS), 2nd edition, Academic Press, Inc., published in 1989; Comprehensive Organic Transformation (Comprehensive Organics) Transformations), VCH Publishers Inc. And the method described in 1989.
  • solvent examples include hydrocarbon solvents, alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents, ketone solvents, esters. It refers to a system solvent, a carboxylic acid solvent, water, etc., and these may be used in a mixture of two or more at an appropriate ratio.
  • Compound (Ia) can be produced by deprotection of compound (II).
  • Deprotection for example Greens Protective Groups in Organic Synthesis, 4th edition (Greene's Protective Groups in Organic Synthesis 4 th Edition), can be carried out according to the method described in 2006. Specifically, it can be carried out by acid treatment, alkali hydrolysis, catalytic hydrogenation reaction or the like.
  • the protecting group PRG a general amine protecting group can be used, and preferred examples include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, acetyl, methyl and the like.
  • the protecting group PRG is tert-butoxycarbonyl or acetyl
  • deprotection using an acid is preferred.
  • 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 include alcohol solvents (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ether solvents (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, Diisopropyl ether, ethylene glycol-dimethyl ether, etc.), ester solvents (eg, ethyl formate, ethyl acetate, n-butyl acetate, etc.), carboxylic acid solvents (eg, formic acid, acetic acid, propionic acid, etc.), halogenated hydrocarbons Solvent (eg, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-d
  • the “solvent” is preferably an ester solvent (for example, ethyl acetate), an alcohol solvent (for example, ethanol) or the like, and the protecting group PRG is an acetyl group.
  • the “solvent” is preferably an alcohol solvent (eg, ethanol).
  • Preferred examples of the “acid” include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like.
  • the amount of the “acid” to be used is generally 1 to 100 molar equivalents, preferably 1 to 50 molar equivalents, per 1 mol of compound (II).
  • the reaction temperature is usually about 0 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
  • deprotection can also be performed by a catalytic hydrogenation reaction or the like.
  • the “catalytic hydrogenation reaction” can be performed in a hydrogen atmosphere in the presence of a catalyst.
  • the “catalyst” include palladium (eg, palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel (eg, developed nickel catalyst, etc.), platinum (eg, platinum oxide, platinum carbon, etc.), rhodium.
  • the amount of the “catalyst” to be used is generally 0.001 to 1 molar equivalent, preferably 0.01 to 0.2 molar equivalent, per 1 mol of compound (II).
  • the “solvent” is preferably an alcohol solvent (eg, methanol, ethanol, propanol, butanol, etc.), an ether solvent (eg, diethyl ether, dioxane, tetrahydrofuran, etc.), an ester solvent (eg, ethyl acetate, etc.), An acid solvent (for example, acetic acid etc.), water, or mixtures thereof are mentioned.
  • the hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.
  • Compound (I) can be produced by reductive alkylation of compound (Ia).
  • the reaction is described, for example, in Organic Reactions, vol. 59, 1-714 (2002), and can be carried out by subjecting compound (Ia) and an imine intermediate produced from the corresponding aldehyde or ketone to a reduction reaction.
  • the amount of aldehyde or ketone to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (Ia).
  • Examples of the reducing agent used include aluminum reagents (eg, lithium aluminum hydride (LiAlH 4 ), diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), and alane. (AlH 3 )), boron reagents (eg, borane (BH 3 ), 9-borabicyclo [3.3.1] nonane (9-BBN), sodium borohydride (NaBH 4 ), sodium cyanoborohydride ( NaBH 3 CN), sodium triacetoxyborohydride (NaBH (OAc) 3 ) and the like).
  • aluminum reagents eg, lithium aluminum hydride (LiAlH 4 ), diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), and alane. (AlH 3 )
  • the amount of the “reducing agent” to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (Ia).
  • an acid may be added to promote the reaction.
  • Preferred examples of the “acid” include acetic acid.
  • the amount of the “acid” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (Ia).
  • reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C.
  • reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Compound (II) can be produced by the following [Production Method A] to [Production Method G].
  • [Production Method A] is Compound (IIa)
  • [Production Method B] is Compound (IIb) and (IIc)
  • [Production Method C] is Compound (IId)
  • [Production Method D] is Compound (IIe), (IIf) ) And (IIg)
  • [Production E] is compound (IIh) (IIi) and (IIj)
  • [Production F] is compound (IIk) and (IIl)
  • [Production G] is compound (IIm). A manufacturing method is shown.
  • R 14 and R 15 are the same or different and each represents a hydrogen atom or an optionally substituted lower alkyl, or R 14 and R 15 are substituted together with the nitrogen atom to which they are bonded. It may also form a 3- to 8-membered cyclic amino. ]
  • Step 3 Compound (IIa) can be produced by amidation of compound (III).
  • Step 3 can be performed, for example, by the method described in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), and the corresponding amine or a hydrochloride thereof and a condensing agent (for example, Carbodiimides (eg, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, etc.), phosphoric acid derivatives (diethyl cyanophosphate, diphenylphosphoryl azide, etc.), 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM: Kunishima et al., Tetrahedron, 55, 13159, (1999)) is used.
  • DMT-MM Kunishima et al
  • a condensing agent carbodiimide or a salt thereof
  • an appropriate condensation accelerator eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxy is used as necessary.
  • the amount of “amine or its hydrochloride” to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (III).
  • the amount of the “agent” is usually 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, preferably 1 to 2 molar equivalents relative to 1 mol of the compound (III).
  • 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
  • Amides lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • alkali metal or alkaline earth metal lower alkoxides eg, sodium methoxide, Strong bases such as sodium ethoxide, potassium tert-butoxide and the like
  • Alkali metal or alkaline earth metal hydroxides eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.
  • alkali metal or alkaline earth metal carbonates eg, sodium carbonate, Inorganic bases such as potassium carbonate, cesium carbonate,
  • 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 (III).
  • 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.
  • R 16 represents an optionally substituted lower alkyl.
  • Compound (IIb) can be produced by reduction of the carboxy group of compound (III). Moreover, this process can also be performed without using a protecting group (PRG).
  • the reducing agent is used in an amount of 0.1 molar equivalent to a large excess (preferably 0.3 to 10 molar equivalents) per mole of compound (III).
  • the “reducing agent” the same as the “reducing agent” described in the above (Step 2) can be used, and among them, lithium aluminum hydride, borane complex (such as borane-THF complex) and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and ether solvents 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 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 5 Compound (IIc) can be produced by O-alkylation of compound (IIb).
  • Step 5 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).
  • a base those similar to the “base” described in (Step 3) can be used.
  • alkali metal such as sodium hydride or alkaline earth metal hydride, alkali metal such as sodium amide, etc.
  • alkaline earth metal amides or alkali metal or alkaline earth metal lower alkoxides such as potassium tert-butoxide are preferred.
  • the “alkylating agent” is selected depending on R 16 to be introduced, and is a lower alkyl chloride such as methyl chloride, ethyl chloride, propyl chloride, butyl chloride, the corresponding lower alkyl bromide, the corresponding lower alkyl iodide, the corresponding methane And a lower alkyl sulfonate and a corresponding lower alkyl p-toluenesulfonate.
  • lower alkyl halides such as methyl iodide and ethyl bromide
  • the amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIb).
  • the amount of the “alkylating agent” to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIb).
  • As the solvent those similar to the “solvent” described in the above (Step 1) can be used, but ether solvents such as tetrahydrofuran and amide solvents such as N, N-dimethylformamide are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • R 17 represents lower alkyl
  • Step 6 Compound (IId) can be produced by stereoselective reduction of compound (IV).
  • the reducing agent is used in an amount of 0.1 to 100 molar equivalents (preferably 0.3 to 10 molar equivalents) per 1 mol of compound (IV).
  • the “reducing agent” the same “reducing agent” as described in the above (Step 2) can be used, and among them, sodium borohydride and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as ethanol are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ⁇ About 24 hours.
  • R 16 represents an optionally substituted lower alkyl
  • R 17 represents a lower alkyl
  • R 18 represents an optionally substituted lower alkyl or an optionally substituted aromatic ring group. (Eg, phenyl, aromatic nitrogen-containing heterocyclic group). ]
  • Step 7 Compound (IIe) can be produced by reacting compound (IIr) with a carbon nucleophile. Depending on conditions, compound (IIf) may be obtained. Moreover, this process can also be performed without using a protecting group (PRG).
  • PRG protecting group
  • carbon nucleophile examples include organolithium reagents such as alkyllithium and aryllithium, organomagnesium reagents such as alkylmagnesium halide and arylmagnesium bromide (for example, methylmagnesium bromide, ethylmagnesium bromide, propylmagnesium bromide, etc.), nitromethane And enol ether compounds such as alkyl enol ethers and alkyl silyl enol ethers, and active methylene compounds such as alkyl or aryl sulfones, malonic acid esters, acetoacetic acid esters, and 1,3-dithiane.
  • organolithium reagents such as alkyllithium and aryllithium
  • organomagnesium reagents such as alkylmagnesium halide and arylmagnesium bromide (for example, methylmagnesium bromide, eth
  • organic magnesium reagents such as alkyl magnesium bromide or aryl magnesium bromide (for example, methyl magnesium bromide, ethyl magnesium bromide, propyl magnesium bromide, etc.) are preferable.
  • the amount of the “carbon nucleophile” to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (IIr).
  • (Step 7) is performed in the presence of a base as necessary.
  • the “base” those similar to the “base” described in (Step 3) can be used.
  • alkali metal such as sodium hydride or alkaline earth metal hydride, alkali metal such as sodium amide, etc.
  • alkaline earth metal amides or alkali metal or alkaline earth metal lower alkoxides such as potassium tert-butoxide are preferred.
  • the amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, per 1 mol of compound (IIr).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and ether solvents 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 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 8 Compound (IIg) can be produced by O-alkylation of compound (IIe) according to (Step 5).
  • the base those similar to the “base” described in (Step 3) can be used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkali such as sodium amide, etc.
  • An earth metal amide or an alkali metal or alkaline earth metal lower alkoxide such as potassium tert-butoxide is preferred.
  • alkylating agent those similar to the “alkylating agent” described in (Step 5) can be used, and among them, lower alkyl halides (methyl iodide, ethyl bromide, etc.) are preferable.
  • the amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIe).
  • the amount of the “alkylating agent” to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IIe).
  • reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C.
  • reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • R 14 and R 15 are the same or different and each represents a hydrogen atom or an optionally substituted lower alkyl, or R 14 and R 15 are substituted together with the nitrogen atom to which they are bonded. It may also form a 3- to 8-membered cyclic amino. ]
  • Step 9 The hydroxy group of compound (IIb) is converted to a leaving group LG to produce compound (V).
  • a method for converting a hydroxy group into a leaving group LG for example, Organic Functional Group PREPARATIONS, 2nd edition, Academic Press, Inc., published in 1989; Comprehensive Organic Transformation (Comprehensive Organic Transformations), VCH Publishers Inc. 1989, etc., and the like.
  • the leaving group LG preferably, methanesulfonyloxy, a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.) and the like can be mentioned.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but ether solvents such as tetrahydrofuran and hydrocarbon solvents such as toluene 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.
  • this process can also be performed without using a protecting group (PRG).
  • PRG protecting group
  • the leaving group LG of compound (V) is substituted with a cyano group to produce compound (IIh).
  • Examples of the method for substituting the leaving group LG with a cyano group include the methods described in ADVANCED ORGANIC CHEMISTRY, 4th edition, Wiley-InterScience, 1992, and the like.
  • Preferred examples of the cyanating agent include sodium cyanide and potassium cyanide.
  • As the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, an amide solvent such as N, N-dimethylformamide, an ether solvent such as tetrahydrofuran and the like are preferable.
  • the reaction temperature is generally about ⁇ 50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • Step 11 Compound (IIi) can be produced by hydrolysis of compound (IIh).
  • the hydrolysis can be performed by selecting from alkaline conditions and acidic conditions. Hydrolysis under alkaline conditions is performed in the presence of a base in 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” to be used is preferably about 1 to about 5 molar equivalents relative to 1 mol of compound (IIh).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used.
  • reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C.
  • reaction time is usually about 0.1 hour to about 48 hours.
  • Hydrolysis under acidic conditions is performed in the presence of an acid in a solvent that does not affect the reaction.
  • an acid hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent such as acetic acid or water is preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 to about 48 hours.
  • the hydrolysis reaction does not proceed under such 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.
  • an amino protecting group (PRG) is cut
  • Step 12 Compound (IIj) can be produced by amidation of compound (IIi) according to (Step 3), for example, in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990). It can be performed by the method described.
  • the condensing agent the same “condensing agent” as described in (Step 3) can be used, and among them, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or 4- (4, 6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride is preferred.
  • the condensation accelerator 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole and the like are preferable.
  • the amount of amine or its hydrochloride to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IIi).
  • the amount of the “condensing agent” to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IIi).
  • the amount of the “condensation accelerator” to be used is generally 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, per 1 mol of compound (IIi).
  • reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C.
  • reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • R 17 represents lower alkyl
  • R 18 represents optionally substituted lower alkyl or an optionally substituted aromatic ring group (eg, phenyl, aromatic nitrogen-containing heterocyclic group).
  • Step 13 Compound (IIk) can be produced by esterification of compound (IIi).
  • Examples of the esterification method include the method described in New Experimental Chemistry Course 14 (Edited by Chemical Society of Japan), pages 1002 to 1027, and the like.
  • the ester methyl ester or ethyl ester is preferable.
  • the acid catalyst used preferably includes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable.
  • the reaction temperature is generally about ⁇ 50 ° C.
  • reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • compound (IIk) can also be produced via an acid halide.
  • a reagent to be used thionyl chloride, oxalyl chloride and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable.
  • the reaction temperature is generally about ⁇ 50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • methyl ester can be produced using diazomethane.
  • diazomethane trimethylsilyldiazomethane may be used.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol, ether solvents such as diethyl ether and the like are preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 50 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • Step 14 Compound (IIl) can be produced from compound (IIk) according to (Step 7).
  • the carbon nucleophile methylmagnesium bromide and the like are particularly preferable, and as the solvent, the same solvents as the “solvent” described in the above (Step 1) can be used, and among them, ether solvents such as tetrahydrofuran are preferable. .
  • the amount of the “carbon nucleophile” to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (IIk).
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • LG represents a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.).
  • Step 15 Compound (IIm) can be produced by dehalogenation of compound (V). This reaction is also carried out by the reduction reaction using the “reducing agent” described in (Step 2) for compound (V) or the “catalytic hydrogenation reaction” described in (Step 1). A reduction reaction is particularly preferred.
  • the hydride agent is used in an amount of 0.1 molar equivalent to large excess (preferably 0.3 to 10 molar equivalents) per mole of compound (V). Further, the radical initiator is used in an amount of 0.001 to 10 molar equivalents (preferably 0.01 to 1 molar equivalents) relative to 1 mol of Compound (V). At this time, as the “hydride agent”, tri-n-butyltin hydride and the like are preferable.
  • the “radical initiator” 2,2 ′-(E) -diazene-1,2-diylbis (2-methylpropanenitrile) and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and hydrocarbon solvents such as toluene are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about 0 ° C. to about 110 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ⁇ About 24 hours.
  • Compound (IIn) and Compound (IIo) can be produced by [Production Method H] or [Production Method I] shown below.
  • R 2 represents a hydrogen atom or optionally substituted lower alkyl
  • R 8 represents a hydrogen atom or lower alkyl
  • R 17 represents lower alkyl.
  • Compound (cis-IIn) represents a cis form of compound (IIn)
  • compound (trans-IIn) represents a trans form of compound (IIn)
  • Compound (trans-IIo) represents a trans form of compound (IIo).
  • Step 16 Compound (VIII) can be produced by subjecting compound (VI) and compound (VII) to a cycloaddition reaction in the presence of a base.
  • Step 16 is performed in accordance with, for example, the description of Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chem. Letters, 7, 943, (1998). be able to.
  • the base those similar to the “base” described in (Step 3) can be used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkali such as sodium amide, etc.
  • An earth metal amide or an alkali metal or alkaline earth metal lower alkoxide such as potassium tert-butoxide is preferred.
  • the amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (VI).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as ethanol are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 17 Compound (IIn) can be produced by reduction of compound (VIII).
  • the reducing agent is preferably triethylsilane, and the amount used is usually 0.1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (VIII).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, halogenated hydrocarbon solvents such as dichloromethane and chloroform or nitrile solvents such as acetonitrile are 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 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 18 Compound (cis-IIn) and compound (trans-IIo) can be produced by hydrolysis of compound (IIn).
  • Step 18 is, for example, a method described in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chemistry Letters (Chem. Lett.), 7, 943, (1998) It can be carried out according to step 11).
  • Hydrolysis under alkaline conditions is particularly preferred. Hydrolysis under alkaline conditions is performed in the presence of a base in 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” to be used is preferably about 1 to about 5 molar equivalents relative to 1 mol of compound (IIn).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, alcohol solvents such as ethanol, ethers such as tetrahydrofuran, water, and the like are preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 48 hours.
  • the ester at the trans position is preferentially hydrolyzed to obtain the compound (trans-IIo).
  • the amino protecting group (PRG) is cleaved during hydrolysis, the amino protecting group (PRG) can be introduced again.
  • R 8 represents a hydrogen atom or lower alkyl
  • R 17 represents lower alkyl
  • Step 19 Compound (cis-IIo) can be produced by hydrolysis of compound (cis-IIn).
  • Step 19 is, for example, a method described in Journal of Organic Chemistry (J. Org. Chem.), 55, 270, (1990), Chemistry Letters (Chem. Lett.), 7, 943, (1998) It can be carried out according to step 11).
  • the hydrolysis can be carried out by selecting from alkaline conditions and acidic conditions, but hydrolysis under acidic conditions is particularly preferred. Hydrolysis under acidic conditions is performed in the presence of an acid in a solvent that does not affect the reaction. As such an acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent such as acetic acid or water is preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C. to about 150 ° C., and the reaction time is usually about 0.1 hour to about 48 hours.
  • an amino protecting group (PRG) is cut
  • R 8 represents a hydrogen atom or lower alkyl
  • R 17 represents lower alkyl.
  • Compound (cis-IIp) represents a cis form of compound (IIp).
  • Compound (trans-IIq) represents a trans form of compound (IIq), and compound (cis-IIq) represents a cis form of compound (IIq).
  • Compound (cis-IIp) represents a cis form of compound (IIp).
  • trans-IIq represents a trans form of compound (IIq)
  • compound (cis-IIq) represents a cis form of compound (IIq).
  • Step 20 Compound (X) can be produced by subjecting compound (VI) and compound (IX) to a cycloaddition reaction in the presence of a base according to (Step 16).
  • a base those similar to the “base” described in (Step 3) can be used, and among them, alkali metal or alkaline earth metal hydride such as sodium hydride, alkali metal or alkali such as sodium amide, etc.
  • An earth metal amide or an alkali metal or alkaline earth metal lower alkoxide such as potassium tert-butoxide is preferred.
  • the amount of the “base” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (VI).
  • 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 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 21 Compound (XI) can be produced by reduction of compound (X) according to (Step 17).
  • the reducing agent is preferably triethylsilane, and the amount used is usually 0.1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (X).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, halogenated hydrocarbon solvents such as dichloromethane and chloroform or nitrile solvents such as acetonitrile are preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 150 ° C., preferably about ⁇ 30 ° C. to about 100 ° C., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 22 Compound (IIq) can be produced by hydrolyzing compound (XI) under acidic conditions according to (Step 11).
  • the hydrolysis proceeds with decarboxylation.
  • Hydrolysis under acidic conditions is performed in the presence of an acid in a solvent that does not affect the reaction.
  • an acid hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent such as acetic acid or water is preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 250 ° C., preferably about 0 ° C.
  • an amino protecting group (PRG) when cut
  • PRG tert-butoxycarbonyl, benzyloxycarbonyl and the like are preferable as the protecting group PRG.
  • Step 23 Compound (IIp) can be produced by esterification of compound (IIq) according to (Step 13).
  • the ester methyl ester, ethyl ester and the like are particularly preferable.
  • the acid catalyst used preferably includes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable.
  • the reaction temperature is generally about ⁇ 50 ° C. to about 200 ° C., preferably about 0 ° C. to about 150 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • An ester can also be produced via an acid halide.
  • a reagent to be used thionyl chloride, oxalyl chloride and the like are preferable.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, but alcohol solvents such as methanol and ethanol are particularly preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 50 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • methyl ester can be produced using diazomethane.
  • trimethylsilyldiazomethane may be used.
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, alcohol solvents such as methanol and ethanol, or ether solvents such as diethyl ether are preferable.
  • the reaction temperature is usually about ⁇ 80 ° C. to about 200 ° C., preferably about ⁇ 20 ° C. to about 50 ° C.
  • the reaction time is usually about 1 minute to about 10 days, preferably about 0.5 hour to about 24 hours.
  • the amino protecting group (PRG) is cleaved during esterification, the amino protecting group (PRG) can be introduced again by the method described above. Of these, tert-butoxycarbonyl, benzyloxycarbonyl and the like are preferable as the protecting group PRG.
  • Step 24 Compound (cis-IIp), compound (trans-IIq) and compound (cis-IIq) can be produced by hydrolysis of compound (IIp) according to (Step 11).
  • (Step 24) is particularly preferably hydrolysis under alkaline conditions. Hydrolysis under alkaline conditions is performed in the presence of a base in a solvent that does not affect the reaction.
  • a 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” to be used is preferably about 1 to about 5 molar equivalents relative to 1 mol of compound (IIp).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used. Among them, an alcohol solvent such as ethanol, an ether solvent 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., and the reaction time is usually about 0.1 hour to about 72 hours, preferably about 0.3 hour. ⁇ About 24 hours. Note that the ester at the trans position is preferentially hydrolyzed due to steric hindrance between the amino protecting group (PRG) and the benzene ring at the 3-position of pyrrolidine.
  • PRG amino protecting group
  • an amino protecting group (PRG) when cut
  • PRG amino protecting group
  • tert-butoxycarbonyl, benzyloxycarbonyl and the like are preferable as the protecting group PRG.
  • compound (I-1) a compound in which R 4 and R 5 are hydrogen atoms (referred to as compound (I-1)) can also be produced by [Production Method K] shown below.
  • R 17 represents lower alkyl
  • Step 25 Compound (XIV) can be produced by addition reaction of compound (XIII) to compound (XII).
  • Step 25 is, for example, Angewante Chemie International Edition (Angew. Chem. Int. Ed.), 46, 2124, (2007), Australian Journal of Chemistry (Aust. J. Chem.), 47, 1441, (1994).
  • base those similar to the “base” described in (Step 3) can be used, and among them, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 Amidines such as diazabicyclo [4.3.0] non-5-ene (DBN) are preferred.
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • DBN 1,5 Amidines such as diazabicyclo [4.3.0] non-5-ene
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a nitrile solvent such as acetonitrile and an ether solvent such as tetrahydrofuran are 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 hour to about 72 hours, preferably about 0.3 hour. ⁇ About 24 hours.
  • Compound (XV) can be produced by a reduction reaction of the nitro group of compound (XIV) followed by a cyclization reaction.
  • Examples of the method for reducing the nitro group include the methods described in New Experimental Chemistry Course 14 (Edited by The Chemical Society of Japan), pages 1333 to 1335, and the like.
  • zinc, iron, tin, tin (II) chloride, and the like are often used, and zinc is particularly preferable.
  • the reaction can be carried out even under neutral or alkaline conditions.
  • the amount of zinc used is usually 0.1 to a large excess, preferably 1 to 100 molar equivalents, relative to 1 mole of compound (XIV).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and among them, a carboxylic acid solvent (for example, acetic acid and the like) is preferable.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 150 hours, preferably about 0.5 hours to about 72 hours. It's time.
  • the catalytic hydrogenation reaction can be performed in a hydrogen atmosphere in the presence of a catalyst.
  • Catalyst examples include palladium (eg, palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel (eg, developed nickel catalyst), platinum (eg, platinum oxide, platinum carbon, etc.), Rhodiums (for example, rhodium carbon) and the like can be mentioned.
  • the amount of the “catalyst” to be used is generally 0.001 to 1 molar equivalent, preferably 0.01 to 0.1 molar equivalent, per 1 mol of compound (XIV).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used.
  • the hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.
  • Step 27 Compound (I-1a) can be produced by reduction of compound (XV).
  • the reducing agent the same “reducing agent” as described in the above (Step 2) can be used, and among them, lithium aluminum hydride, borane complex (borane-THF complex and the like) and the like are preferable.
  • the “reducing agent” is generally used in 1 molar equivalent to large excess, preferably 1 to 10 molar equivalents, relative to compound (XV).
  • the solvent those similar to the “solvent” described in the above (Step 1) can be used, and ether solvents 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 hour to about 72 hours, preferably about 0.3 Time to about 24 hours.
  • Step 28 Compound (I-1b) can be produced by reductive alkylation of compound (I-1a).
  • the reaction is described, for example, in Organic Reactions, vol. 59, 1-714 (2002), or according to (Step 2).
  • the compound (I-1a) and an imine intermediate produced from the corresponding aldehyde or ketone are subjected to a reduction reaction. Is done.
  • the amount of aldehyde or ketone to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (I-1a).
  • As the reducing agent those similar to the “reducing agent” described in the above (Step 2) can be used.
  • the amount of the “reducing agent” to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (I-1a).
  • an acid may be added to promote the reaction.
  • Preferred examples of the “acid” include acetic acid.
  • the amount of the “acid” to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (I-1a).
  • reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C.
  • reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Compound (II) may be prepared by a method other than the above by using Tetrahedron Letters, 44, 6779, (2003); Il Pharmaco, 54, 461, (1999); Tetrahedron Letters. (Tetrahedron Lett.), 48, 8695, (2007), and the like.
  • Compound (II) can also be produced by [Production Method L] shown below.
  • R 19 represents C 1-6 alkoxy-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, carbamoyl or C 1-6 alkoxycarbamoyl. Represents. ]
  • Step 29 Compound (IIs) can be produced by aminating the hydroxyl group of compound (IIb).
  • the “amination” is, for example, a method by azidation and subsequent reduction described in Journal of the American Chemical Society (J. Am. Chem. Soc.), 123, 9465, (2001), or tetrahedron. 50, 12713, (1994), followed by substitution with phthalimide and subsequent deprotection.
  • Compound (IIt) can be produced by acylating, carbamoylating, sulfonylating, or sulfamoylating the amino group of compound (IIs).
  • Acylation can be carried out, for example, by condensation of acid chloride, carbamoylation, for example, isocyanate, and sulfonylation, for example, by condensation of sulfonyl chloride with amine (IIs).
  • the sulfamoylation can be carried out, for example, by using the reagent described in Organic Letters, 14, 2241 (2001) and deprotecting the resulting intermediate.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
  • the compound (I) produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and 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.
  • compound (I) has an optical isomer
  • the optical isomer resolved from the compound is also encompassed in compound (I).
  • 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 (I) when the compound (I) has a hydroxy or a primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( -)-Menthoxyacetic acid etc.) are subjected to a condensation reaction to obtain 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 (I) may be a crystal.
  • Compound (I) may have a single crystal form or a mixture of a plurality of crystal forms. Further, the compound (I) may be a co-crystal.
  • Crystals of compound (I) can be produced by crystallization by applying a crystallization method known per se to compound (I).
  • 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 (I) 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.
  • Examples thereof include 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.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • 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).
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated [eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated.
  • prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
  • the compound (I) 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.
  • the compound (I ′) of the present invention is a monoamine (serotonin, norepinephrine, dopamine) for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). Etc.) As a substance having reuptake inhibitory activity, it inhibits reuptake of monoamines and improves lower urinary tract symptoms such as stress urinary incontinence.
  • 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), fecal incontinence, (Digestive system diseases, 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 compound (I ′) of the present invention since the compound (I ′) of the present invention has a norepinephrine reuptake inhibitory activity, it is useful as a norepinephrine 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 medicament containing the compound (I ′) can be obtained by using the compound of the present invention alone or a pharmacologically acceptable carrier according to a method known per se (eg, a method described in the Japanese Pharmacopoeia) as a method for producing a pharmaceutical preparation.
  • a method known per se eg, a method described in the Japanese Pharmacopoeia
  • tablets including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
  • pills powders, granules, capsules (including soft capsules and microcapsules)
  • Lozenges syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, oral disintegration) Film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, ointment, lotion, patch Suppositories (eg, anal suppositories, Vaginal suppositories), pellets, nasal agents, pulmonary agents (inhalants), eye drops and the like.
  • controlled-release preparations eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules
  • aerosols films (e
  • the preparation of sustained-release preparation can be applied in accordance with the method described in JP-A-9-263545.
  • the medicament containing compound (I ′) can be used orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, rectal, intravaginal, Administration to the abdominal cavity, inside the tumor, proximal to the tumor, etc. and direct administration to the lesion).
  • 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 (I) relative to the whole preparation. It is about 50% by weight, more preferably about 0.5 to 20% by weight.
  • pharmacologically acceptable carrier examples include excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose).
  • excipients eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.
  • binders eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose.
  • Crystalline cellulose alginic acid, gelatin, polyvinylpyrrolidone, etc.
  • lubricant eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.
  • disintegrant eg, carboxymethylcellulose calcium, talc, etc.
  • diluent eg, Water for injection, physiological saline, etc.
  • additives for example, stabilizers, preservatives, coloring agents, fragrances, solubilizers, emulsifiers, buffers, isotonic agents, etc.
  • 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 as compound (I) per kg body weight per day is divided into 1 to 3 times. 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 nuclear magnetic resonance spectrum s: singlet d: doublet ddd: double double doublet (double double doublet) dt: Double triplet (double triplet) dq: double quartet t: triplet q: quartet quint: quintet dd: double doublet (double doublet) m: multiplet br: broad brs: broad singlet J: Coupling constant THF: Tetrahydrofuran MeOH: Methanol DMF: N, N-Dimethylformamide DMSO: Dimethyl sulfoxide LC / MS: Liquid chromatography-mass spectrometry spectrum ESI: Electrospray ionization method [M + H] + : Molecular ion peak (LC in this specification) / MS measurements show [M + H] + unless otherwise specified) Me: methyl Et: ethyl Ac: acetyl Boc: tert-butoxycarbonyl TFA: trifluoroace
  • the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (1-15% ethyl acetate / hexane) to give the title compound as a colorless oil (0.65 g, 29%).
  • 3,4-Dichlorobenzaldehyde (10 g, 57 mmol) was dissolved in acetaldehyde (23 mL, 400 mmol). To this was added dropwise a solution of potassium hydroxide (0.42 g, 6.3 mmol) in methanol (5 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hr, acetic anhydride (28 mL) was added, and the mixture was heated under reflux for 1 hr. The mixture was allowed to cool to room temperature, 1N aqueous hydrochloric acid solution (95 mL) was added, and the mixture was heated under reflux for 1 hr.
  • Acetic acid 23 mL
  • 6 N aqueous hydrochloric acid 100 ⁇ mL
  • diethyl 1-acetyl-3- (3,4-dichlorophenyl) pyrrolidine-2,2-dicarboxylate 50 g, 130 ⁇ mmol
  • the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure.
  • the obtained residue was dissolved in methanol (200 mL), thionyl chloride (12 mL, 160 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 4 hr. The solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol and toluene, and the solvent was distilled off again. The obtained residue was dissolved in methanol (200 mL), sodium hydrogen carbonate (49 g, 590 mmol) and di-tert-butyl dicarbonate (35 mL, 150 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure.
  • the extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give 1-tert-butyl 2-methyl (2R * , 3R * )-3- (3,4-dichlorophenyl) pyrrolidine-1,2 -Dicarboxylate was obtained as a colorless oil (17 g, 47%). Further, citric acid was added to the aqueous layer to make it acidic, sodium chloride was added until saturation, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in acetic acid (38 mL), 6N aqueous hydrochloric acid solution (150 mL) was added, and the mixture was heated to reflux overnight.
  • the reaction mixture was cooled to room temperature and concentrated under reduced pressure until the volume became about 1/4.
  • An 8 N aqueous sodium hydroxide solution was added to the resulting suspension to adjust the pH to about 7, and the precipitated solid was collected by filtration.
  • the obtained solid was placed in an eggplant flask, azeotroped with toluene, and dried to give the title compound as a white solid (13 g, 50%).
  • 3-Chloro-4-fluorobenzaldehyde 50 g, 320 mmol was dissolved in acetaldehyde (100 mL, 180 mmol).
  • the reaction mixture was stirred at 0 ° C. for 2 hr, acetic anhydride (30 mL, 320 mmol) was added, and the mixture was heated at 60 ° C. for 1 hr.
  • To the reaction mixture was added 3N aqueous hydrochloric acid (200 mL), and the mixture was heated at 100 ° C. for 1 hr.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in acetonitrile (170 mL), triethylsilane (76 mL, 470 mmol) and trifluoroacetic acid (170 mL, 2.2 mol) were added, and the mixture was stirred at room temperature for 3 hr.
  • the solvent was distilled off under reduced pressure and diluted with ethyl acetate.
  • the obtained residue was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the aqueous layer was adjusted to pH about 3 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure to give 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chloro-4-fluorophenyl) pyrrolidine-2-carboxylic acid. The acid was obtained as a pale yellow oil (1.5 g, 22%).
  • Triethylsilane (12 mL, 75 mmol) and TFA (27 mL, 350 mmol) were added to a solution of the obtained residue in acetonitrile (27 mL), and the mixture was stirred at room temperature for 3.5 hours. After evaporating the solvent under reduced pressure, the resulting residue was diluted with ethyl acetate and washed with an aqueous potassium carbonate solution and an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Triethylamine (2.4 mL, 17 mmol) and di-tert-butyl dicarbonate (3.9 mL, 17 mmol) were added to a solution of the obtained solid in methanol (60 mL), and the mixture was stirred at room temperature for 5 hours. After the reaction solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (25% ethyl acetate / hexane) to give the title compound as a white solid (0.49 g, 91%).
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (5-25% ethyl acetate / hexane) to give the title compound as white crystals (0.23 g, 43%).
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (25% ethyl acetate / hexane) to give the title compound as a white solid (0.39 g, 72%).
  • the obtained residue was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white solid (46 mg, 19%).
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (5-25% ethyl acetate / hexane) to give the title compound as a purple oil (0.48 g, 87%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.50 g, 90%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.47 g, 79%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.28 g, 72%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.35 g, 86%).
  • the extract was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (4.4 g, 95%).
  • the obtained residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (0.14 g, 56%).
  • 1,3-borane-THF complex THF solution in 2,3-trans-1- (tert-butoxycarbonyl) -3- (3-chlorophenyl) pyrrolidine-2-carboxylic acid (0.5 g, 1.53 mmol) in THF (12.5 mL) (3.1 mL, 3.1 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight.
  • Methanol was added to the reaction mixture at 0 ° C., and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate.
  • the extract was washed with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (3-30% ethyl acetate / hexane) to give the title compound as a colorless oil (0.44 g, 92%).
  • the fraction solution containing the optically active substance having the smaller retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidine-2 -Il] propan-2-ol (short retention time) (0.26 g, 98.3% ee) was obtained.
  • LC / MS 274 Further, the fraction containing the optically active substance having the longer retention time was concentrated to give 2,3-cis-2- [3- (3,4-dichlorophenyl) pyrrolidin-2-yl] propane-2- All (long holding time) (0.25 g, 96.5% ee) was obtained.
  • the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (0-10% ethyl acetate / hexane) to give the title compound as a colorless oil (0.50 g, 93%).
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by preparative HPLC, and the obtained fractions containing the two peaks were each concentrated and extracted with ethyl acetate.
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by basic silica gel column chromatography (ethyl acetate) to give a colorless oil.
  • the resulting oil was dissolved in pyridine (3 mL). 4-methylbenzenesulfonyl chloride (0.39 g, 2.0 mmol) was added thereto, and the mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere.
  • the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered over basic silica gel. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (3-40% ethyl acetate / hexane) to give the title compound as a colorless oil (0.090 g, 34%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained oil was crystallized from diisopropyl ether / ethyl acetate to give a white solid.
  • the obtained solid was dissolved in pyridine (6 mL). 4-methylbenzenesulfonyl chloride (0.76 g, 4.0 mmol) was added thereto, and the mixture was stirred at 100 ° C. overnight under a nitrogen atmosphere.
  • the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered over basic silica gel. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (3-40% ethyl acetate / hexane) to give the title compound as a colorless oil (0.36 g, 68%).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (20-100% ethyl acetate / hexane) to give a colorless oil (0.58 g).
  • the obtained oil (0.19 g) was dissolved in toluene (5 mL) and heated to reflux overnight. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.17 g, 94%).
  • the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a colorless oil.
  • the obtained oil was dissolved in DMF (30 mL), sodium cyanide (0.37 g, 7.6 mmol) was added, and the mixture was stirred at 100 ° C. overnight.
  • the reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was washed with diisopropyl ether to give the title compound as white crystals (0.090 g, 56%).
  • 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 1-tert-butyl 2-methyl-2,3-cis-3- (3,4- 26.2 g (99.9% ee) of dichlorophenyl) pyrrolidine-1,2-dicarboxylate (low retention time) were obtained. Further, the fraction containing the optically active substance having the longer retention time was concentrated to give 1-tert-butyl 2-methyl 2,3-cis-3- (3,4-dichlorophenyl) pyrrolidine-1,2 -26.8 g (99.9% ee) of dicarboxylate (long retention time) was obtained.
  • the obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.51 g).
  • the obtained extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained crystals were washed with diisopropyl ether to give the title compound as white crystals (0.30 g, 84%).
  • Acetic acid (3 mL) and 6N aqueous hydrochloric acid (15 mL) were added to diethyl 1-acetyl-3- (3,4-difluorophenyl) pyrrolidine-2,2-dicarboxylate (6.4 g), and heated under reflux overnight. did.
  • the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure.
  • the obtained residue was dissolved in methanol (30 mL), thionyl chloride (1.6 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 4 hr.
  • the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in methanol and toluene, and the solvent was distilled off again.
  • the obtained residue was dissolved in methanol (30 mL), sodium hydrogen carbonate (6.5 g) and di-tert-butyl dicarbonate (4.64 mL) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and washed with water. The obtained extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.37 g).
  • Triethylamine (5.47 mL) and di-tert-butyl dicarbonate (3.36 mL) were added to a THF (40 mL) solution of the obtained (2S, 3S) -3- (3,4-dichlorophenyl) pyrrolidine-2-carboxylic acid monohydrochloride. ) was added and stirred at room temperature for 14 hours.
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the obtained extract was washed with 10% aqueous citric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.23 g).
  • the obtained extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (32.2 g).

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Abstract

L'invention porte sur un composé ayant une activité de blocage de la réabsorption de monoamine, qui est représenté par la formule (I) [dans laquelle X représente un groupe alkylène inférieur facultativement substitué, -CO-, -CH2CO-, ou un noyau hétérocyclique à 5 chaînons facultativement substitué; R1 représente un groupe hydroxy, un groupe cyano ou un groupe amino, alkyle inférieur, alcoxy inférieur, phényle, mercapto, sulfonyle ou hétérocyclique azoté à 4 à 10 chaînons, ces groupes peuvent être substitués; R2 représente un atome d'hydrogène, un atome d'halogène ou un groupe alkyle inférieur ou alcoxycarbonyle facultativement substitué; R3 représente un atome d'hydrogène ou un groupe alkyle inférieur; et R4 à R13 représentent indépendamment un atome d'hydrogène, un atome d'halogène ou un groupe alkyle inférieur, dans lequel au moins l'un de R9 à R13 représente un atome d'halogène ou un groupe alkyle inférieur ou chacun parmi R10 et R11 et un noyau benzène adjacent à celui-ci forment ensemble un noyau naphtalène facultativement substitué ou un noyau hétéroaromatique fusionné], ou un sel du composé.
PCT/JP2010/057017 2009-04-21 2010-04-20 Composé de pyrrolidine Ceased WO2010123006A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018071327A1 (fr) 2016-10-12 2018-04-19 Dow Agrosciences Llc Molécules à usage pesticide et intermédiaires, compositions et procédés associés
EP3578542A1 (fr) 2015-04-17 2019-12-11 Dow AgroSciences LLC Molécules présentant une utilité en tant que pesticide et intermédiaires, compositions et procédés associés

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050192286A1 (en) * 2003-10-22 2005-09-01 Neurocrine Biosciences, Inc. Ligands of melanocortin receptors and compositions and methods related thereto
JP2007536369A (ja) * 2004-05-06 2007-12-13 ファイザー・インク プロリン及びモルホリン誘導体の新規化合物
WO2009011871A2 (fr) * 2007-07-17 2009-01-22 Amgen Inc. Thiadiazoles modulateurs de l'activité de pkb

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050192286A1 (en) * 2003-10-22 2005-09-01 Neurocrine Biosciences, Inc. Ligands of melanocortin receptors and compositions and methods related thereto
JP2007536369A (ja) * 2004-05-06 2007-12-13 ファイザー・インク プロリン及びモルホリン誘導体の新規化合物
WO2009011871A2 (fr) * 2007-07-17 2009-01-22 Amgen Inc. Thiadiazoles modulateurs de l'activité de pkb

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOE A. TRAN ET AL.: "Design and synthesis of 3-arylpyrrolidine-2-carboxamide derivatives as melanocortin-4 receptor ligands", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 6, 2008, pages 1931 - 1938 *
STEPHAN LAABS ET AL.: "Auxiliary controlled enantioselective synthesis of 3-aryl-prolines", TETRAHEDRON, vol. 58, no. 7, 2002, pages 1317 - 1334 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3578542A1 (fr) 2015-04-17 2019-12-11 Dow AgroSciences LLC Molécules présentant une utilité en tant que pesticide et intermédiaires, compositions et procédés associés
EP3578541A1 (fr) 2015-04-17 2019-12-11 Dow AgroSciences LLC Molécules ayant une fonction pesticide et intermédiaires, composition et procédés associés
EP3578543A1 (fr) 2015-04-17 2019-12-11 Dow AgroSciences LLC Molécules ayant une fonction pesticide et intermédiaires, compositions et procédés associés
EP4666856A2 (fr) 2015-04-17 2025-12-24 Corteva Agriscience LLC Molécules présentant une utilité pesticide, et intermédiaires, compositions et procédés associés
WO2018071327A1 (fr) 2016-10-12 2018-04-19 Dow Agrosciences Llc Molécules à usage pesticide et intermédiaires, compositions et procédés associés
EP3964067A1 (fr) 2016-10-12 2022-03-09 Dow AgroSciences LLC Molécules ayant une fonction pesticide et intermédiaires, compositions et procédés associés
EP3964495A1 (fr) 2016-10-12 2022-03-09 Dow AgroSciences LLC Molécules ayant une fonction pesticide et compositions et procédés associés
EP3971166A1 (fr) 2016-10-12 2022-03-23 Corteva Agriscience LLC Molécules ayant une fonction pesticide et compositions et procédés associés

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