WO2012173214A1 - Azepane compound - Google Patents

Azepane compound Download PDF

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Publication number
WO2012173214A1
WO2012173214A1 PCT/JP2012/065294 JP2012065294W WO2012173214A1 WO 2012173214 A1 WO2012173214 A1 WO 2012173214A1 JP 2012065294 W JP2012065294 W JP 2012065294W WO 2012173214 A1 WO2012173214 A1 WO 2012173214A1
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group
ring
compound
substituent
dichlorophenyl
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PCT/JP2012/065294
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French (fr)
Japanese (ja)
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昌美 山田
雄二 石地
▲琢▼ 亀井
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武田薬品工業株式会社
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Publication of WO2012173214A1 publication Critical patent/WO2012173214A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
    • C07D223/08—Oxygen atoms

Definitions

  • the present invention has an excellent monoamine reuptake inhibitory activity, and is associated with depression, anxiety, attention deficit / hyperactivity disorder, menopause, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, and cachexia
  • the present invention relates to a heterocyclic compound useful as a preventive or therapeutic agent for muscle atrophy and stress urinary incontinence.
  • 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. .
  • SERT serotonin transporter
  • NET norepinephrine transporter
  • DAT dopamine transporter
  • Compounds exhibiting monoamine reuptake inhibitory activity 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 literature 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.
  • monoamine reuptake inhibitors are effective as therapeutic agents for lower urinary tract diseases such as overactive bladder and stress urinary incontinence, particularly stress urinary incontinence.
  • Stress urinary incontinence is a disease characterized by symptoms of urine leaking due to an increase in intravesical pressure accompanying a transient increase in abdominal pressure caused by coughing, sneezing, light exercise, and the like. This disease is common in women, and is caused by weakening of the pelvic floor muscles due to childbirth, aging, etc., and a decrease in urethral resistance (see Non-Patent Document 3).
  • an azabicyclo [3.2.1] octane derivative having a monoamine reuptake inhibitory action useful as an antidepressant is a tropane derivative having a monoamine reuptake inhibitory action useful as a therapeutic agent for obesity and Parkinson's disease.
  • Patent Document 2 is a benzoazepine derivative (Patent Document 3) useful as an antidepressant, anxiolytic and analgesic, and piperidine and azepane derivatives (Patent Document 4) useful for NK1 and 5-HT related diseases are analgesic.
  • An azepane derivative (Patent Document 5) useful as a drug is disclosed as a homopiperazine compound (Patent Document 6) having a monoamine reuptake inhibitory action, and a piperidine compound (Patent Document 7) as a monoamine reuptake inhibitor. . Further, the following compounds are known as azepane compounds.
  • monoamine serotonin, norepinephrine, dopamine, etc.
  • reuptake inhibitory activity depression, anxiety, attention deficit / hyperactivity disorder, menopause, pain, pelvic organ prolapse, fecal incontinence, disuse
  • a compound that is useful as a preventive or therapeutic agent for muscle atrophy, muscle atrophy associated with cachexia and stress urinary incontinence, etc. and has excellent properties in terms of drug efficacy, action time, specificity, low toxicity, etc. It is desired.
  • the present invention is associated with a compound having a monoamine reuptake inhibitory activity, etc., and depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, cachexia
  • the object is to provide a preventive or therapeutic agent for muscle atrophy and stress urinary incontinence.
  • ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent
  • ring B 1 , ring B 2 or ring B 3 may further have a substituent
  • X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or an optionally substituted C 1-6 alkyl group).
  • R 1 is a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, a substituted C 1-6 alkyl A group, an optionally substituted C 1-6 alkoxy group, or an optionally substituted carbamoyl group
  • R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a C 1-6 alkoxy group (C) -S-R 1a , (d) -SO 2 -R 1a , (e) -SO 2 -N (R 1b ) (R 1c ), (f) -N (R 1b ) (R 1c ) (G) —NH—CO—R 1a , (h) —NH—CO—N (R 1b ) (R 1c ), (i) —NH—NH—NH—CO—R 1a , (h) —NH—CO—N (
  • R x1 represents a hydrogen atom or a methyl group
  • R x2 represents —CH 2 —CO—N (CH 3 ) —CHR a1 —R a2 (R a1 represents a hydrogen atom or a methyl group, and R a2 represents a halogen atom) 2 represents a 3,5-substituted phenyl group with two substituents selected from an atom and a trifluoromethyl group.
  • R x3 represents a hydrogen atom or a fluorine atom.
  • ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent
  • ring B 1 or ring B 2 may further have a substituent
  • R 1 represents a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, a substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group.
  • R x1 represents a hydrogen atom or a methyl group
  • R x2 represents —CH 2 —CO—N (CH 3 ) —CHR a1 —R a2 (R a1 represents a hydrogen atom or a methyl group, and R a2 represents a halogen atom) 2 represents a 3,5-substituted phenyl group with two substituents selected from an atom and a trifluoromethyl group.
  • R x3 represents a hydrogen atom or a fluorine atom.
  • ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent
  • X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or an optionally substituted C 1-6 alkyl group).
  • R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a hydroxy group (C) C 1-6 alkoxy group, (d) —S—R 1a , (e) —SO 2 —R 1a , (f) —SO 2 —N (R 1b ) (R 1c ), (g) -N (R 1b ) (R 1c ), (h) -NH-CO-R 1a , (i) -NH-CO-N (R 1b ) (R 1c ), (j) -NH-SO 2 -R 1a , (k) -NH—SO 2 —N (R 1b ) (R 1c ), and (l) 1H— optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group Pyrazol-1-yl (wherein R
  • R 1 is selected from) to C 1-6 alkyl group substituted with three substituents, which may be substituted C 1-6 alkoxy group Or an optionally substituted carbamoyl group
  • R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a C 1-6 alkoxy group (C) -S-R 1a , (d) -SO 2 -R 1a , (e) -SO 2 -N (R 1b ) (R 1c ), (f) -N (R 1b ) (R 1c ) (G) —NH—CO—R 1a , (h) —NH—CO—N (R 1b ) (R 1c ), (i) —NH—SO 2 —R 1a , (j) —NH—SO 2 —N (R 1b ) (R 1c ) and (k) 1H
  • Ring B 1 or ring B 3 has no substituent other than ring A and R 1
  • ring B 2 is any of ring A, R 1 , X 1 , X 2 and X 3 .
  • ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent
  • X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or an optionally substituted C 1-6 alkyl group).
  • R 1 is a cyano group, optionally carboxy group which may be substituted, an optionally substituted amino group, (a) a halogen atom, (b) a hydroxy group, (c) C 1-6 alkoxy group, (d) —S—R 1a , (e) —SO 2 —R 1a , (f) —SO 2 —N (R 1b ) (R 1c ), (g) —N (R 1b ) (R 1c ), (h) -NH-CO-R 1a , (i) -NH-CO-N (R 1b ) (R 1c ), (j) -NH-SO 2 -R 1a , (k) -NH-SO 2 -N (R 1b ) (R 1c ) and (l) 1H-pyrazol-1-yl optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group (wherein R 1a is C 1 -6 alkyl
  • Ring B 1 has no substituent other than ring A and R 1
  • ring B 2 is a ring A, R 1
  • any one of X 1 , X 2 and X 3 is a substituent When it has, it has no substituent other than the substituent.
  • Ring A is a benzene ring substituted with 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group
  • R 1 is (1) a hydroxy group, (2) a C 1-6 alkoxy-carbonyl group, (3) (a) a halogen atom, (B) a hydroxy group, (C) a C 1-6 alkoxy group, (D) -S-R 1a, (E) —SO 2 —R 1a , (F) —SO 2 —N (R 1b ) (R 1c ), (G) -N (R 1b ) (R 1c ), (H) -NH-CO-R 1a , (I) —NH—CO—N (R 1b ) (R 1c ), (J) —NH—SO 2 —R 1a , (K) —NH—SO 2 —N (R 1b ) (R 1c ), (J) —NH—SO 2 —R 1
  • a C 1-6 alkoxy group substituted with one substituent, (4) (a) a halogen atom, (B) hydroxy groups, and (c) C 1-6 to 1 is selected from an alkoxy group which may be substituted with 1-3 substituents mono - or di - (C 1-6 alkyl - carbonyl) amino group, (5) a C 1-6 alkylsulfonylamino group, (6) a sulfamoylamino group, or (7) (a) a halogen atom, (B) a hydroxy group, (C) a C 1-6 alkoxy group, (D) -SR 1a , (E) —SO 2 —R 1a , (F) —SO 2 —N (R 1b ) (R 1c ), (G) -N (R 1b ) (R 1c ), (H) -NH-CO-R 1a , (I) —NH—CO—N (R 1b ) (R
  • Ring B 1 or Ring B 3 has no substituents other than Ring A and R 1
  • Ring B 2 is a ring A, R 1
  • any one of X 1 , X 2 and X 3 is a substituent
  • Ring A is a benzene ring substituted with 1 to 3 halogen atoms
  • R 1 is (1) (a) a hydroxy group
  • (B) —SO 2 —R 1a and (c) —NH—SO 2 —R 1a (Wherein, R 1a is, C 1-6 alkyl group.) 1 is selected from to three substituted with a substituent a C 1-6 alkyl group or (2) C 1-6 alkylsulfonyl,
  • An amino group, Ring B 1 or Ring B 3 has no substituents other than Ring A and R 1
  • Ring B 2 is a ring A
  • the present invention also provides [1A] Formula (I)
  • ring A represents a benzene ring having a substituent, or a 5- to 6-membered aromatic heterocycle optionally having a substituent
  • ring B 1 and ring B 2 may further have a substituent
  • R x1 represents a hydrogen atom or a methyl group
  • R x2 represents —CH 2 —CO—N (CH 3 ) —CHR a1 —R a2 (R a1 represents a hydrogen atom or a methyl group, and R a2 represents a halogen atom) And a phenyl group which is 3,5-substituted with two substituents selected from an atom and a trifluoromethyl group.
  • R x3 represents a hydrogen atom or a fluorine atom.
  • a compound that is a group represented by (R 1 is as defined above); (3) [4- (4-Fluorophenyl) azepan-4-yl] acetic acid, (4) 3-amino-N- ⁇ [4- (3-fluorophenyl) azepan-4-yl] methyl ⁇ pyrazine-2-carboxamide; (5) N- ⁇ [4- (3-fluorophenyl) azepan-4-yl] methyl ⁇ -2-methoxybenzamide, (6) 4- (1H-imidazo [4,5-b] pyridin-2-yl) azepan-4-ol, (7) 4- [1- (4-Fluorobenzyl) -1H-imidazo [4,5-b] pyridin-2-yl] azepan-4-ol, (8) 4- (4-chlorophenyl) azepan-4-ol, (9) 2- [3- (3,4-dichlorophenyl) azepan-3-y
  • [2A] A medicament containing the compound or salt thereof according to [1A], [3A] The medicament according to [2A], which is a monoamine reuptake inhibitor [4A] The medicament according to [2A], which is a prophylactic or therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain or stress urinary incontinence, Is to provide.
  • the compound of the present invention has an excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, for example, depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, Prophylactic or therapeutic agents for fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia and stress urinary incontinence can be provided.
  • monoamine serotonin, norepinephrine, dopamine, etc.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples of the “C 1-6 alkyl group” include linear or branched C 1-6 alkyl groups 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.
  • examples of the “C 1-6 alkoxy group” include linear or branched C 1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec -Butoxy, tert-butoxy, 1-methylpropoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy, hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, Examples include 1,2-dimethylbutoxy and 1,2,2-trimethylpropoxy.
  • examples of the “cyclic amino” of the “optionally substituted cyclic amino” include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl, 1-pyrrolyl, 1-pyrrolyl, Examples thereof include 3- to 8-membered (preferably 5- or 6-membered) cyclic amino such as imidazolyl.
  • C 6-10 aryl examples include phenyl, 1-naphthyl, 2-naphthyl and the like.
  • C 7-12 aralkyl examples include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.
  • C 3-6 cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the “5- to 6-membered aromatic heterocycle” of the “optionally substituted 5- to 6-membered aromatic heterocycle” represented by ring A includes 1 to 3 nitrogen atoms, sulfur atoms, or Examples include 5- to 6-membered aromatic heterocycles containing oxygen atoms (eg, pyridine, pyrazine, pyrimidine, pyridazine, triazine, pyrrole, pyrazole, thiazole, oxazole, imidazole).
  • 5- to 6-membered aromatic heterocycles containing oxygen atoms eg, pyridine, pyrazine, pyrimidine, pyridazine, triazine, pyrrole, pyrazole, thiazole, oxazole, imidazole.
  • the substituent that the 5- to 6-membered aromatic heterocycle represented by ring A may have, (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (2) cyano, (3) hydroxy, (4) Select an optionally substituted C 1-6 alkyl group, and (5) 1 to the three a C 1-6 alkoxy group optionally substituted with a halogen atom 1 to 3 halogen atoms
  • the substituent which is made is mentioned.
  • the number of the substituent is 1 to 5, preferably 1 to 3, and more preferably 1 or 2. When a plurality of substituents are present, each substituent may be the same or different.
  • the “benzene ring having a substituent” represented by ring A has 1 to 5 substituents, and when a plurality of substituents are present, each substituent may be the same or different.
  • the “substituent benzene ring” is 1 to 3 selected from a halogen atom (eg, fluorine atom, chlorine atom), a C 1-6 alkyl group (eg, methyl) and a C 1-6 alkoxy group.
  • a benzene ring substituted with (preferably 2) substituents is preferred, and 1 to 3 (selected from a halogen atom (eg, fluorine atom, chlorine atom) and a C 1-6 alkyl group (eg, methyl) ( A benzene ring substituted with 2) substituents is more preferred, and a benzene ring substituted with 1 to 3 (especially 2) halogen atoms (eg, fluorine atom, chlorine atom) is particularly preferred.
  • a halogen atom eg, fluorine atom, chlorine atom
  • a C 1-6 alkyl group eg, methyl
  • the “8 to 10-membered aromatic condensed ring” of the “optionally substituted 8- to 10-membered aromatic condensed ring” formed by combining the substituents on the ring A together with the ring A Naphthalene, benzofuran, indazole and the like can be mentioned.
  • the substituent that the “8 to 10-membered aromatic condensed ring” may have is the same as the substituent that the 5 to 6-membered aromatic heterocyclic ring represented by ring A may have. Is mentioned.
  • the number of the substituent is 1 to 5, preferably 1 to 3, and more preferably 1 or 2. When a plurality of substituents are present, each substituent may be the same or different.
  • ring A a “benzene ring having a substituent” is preferable.
  • ring A preferably,
  • Ring B 1 , ring B 2 or ring B 3 may further have a substituent. However, it is preferable that the hydrogen atom bonded to the nitrogen atom constituting Ring B 1 , Ring B 2 or Ring B 3 is not substituted.
  • ring B, ring B 2 or ring B 3 may further have, (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (2) a cyano group, (3) a hydroxy group, (4) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (5) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and (6) a substituent selected from an oxo group.
  • the number of the substituent is 1 to 5, preferably 1 to 3, and more preferably 1 or 2. When a plurality of substituents are present, each substituent may be the same or different.
  • Ring B 1 , ring B 2 or ring B 3 preferably has no substituent other than ring A and R 1 .
  • Any one of X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or a C 1-6 alkyl group which may be substituted.).
  • R 1 is a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, a substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or an optionally substituted carbamoyl group,.
  • R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a C 1-6 alkoxy group (C) -S-R 1a , (d) -SO 2 -R 1a , (e) -SO 2 -N (R 1b ) (R 1c ), (f) -N (R 1b ) (R 1c ) (G) —NH—CO—R 1a , (h) —NH—CO—N (R 1b ) (R 1c ), (i) —NH—SO 2 —R 1a , (j) —NH—SO 2 —N (R 1b ) (R 1c ) and (k) 1H-pyrazol-1-yl optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group (wherein R 1a Is a C 1-6 alkoxy group (C) -S-
  • the combination of X 1 , X 2 and X 3 is (—NH—, —CH 2 —, —CH 2 —) or (-CH 2 -, - CH 2 -, - NH-) and is, ring B 2 does not have a ring a and R 1 substituent other than.
  • the “C 1-6 alkyl group” of the “ optionally substituted C 1-6 alkyl group” may have a substituent, and the “substituted C 1-6 alkyl group” As the substituent of the “C 1-6 alkyl group” of (1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (2) a cyano group, (3) a hydroxy group, (4) Nitro group, (5) formyl group, (6) amino group, (7) mono- or di-C 1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino), (8) C 1-6 alkyl-carbonylamino group (eg, acetylamino, ethylcarbonylamino), (9) C 1-6 alkoxy-carbonylamino
  • the substituent that the “C 1-6 alkoxy group” of the “optionally substituted C 1-6 alkoxy group” may have is the above-mentioned “optionally substituted C 1 Examples thereof include the same substituents that the “ 1-6 alkyl group” may have.
  • the number of the substituent is 1 to 4, preferably 1 to 3, and more preferably 1. When a plurality of substituents are present, each substituent may be the same or different.
  • the “optionally substituted carboxy group” (1) a carboxy group, (2) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl), (3) C 6-10 aryloxy-carbonyl group (eg, phenoxycarbonyl, naphthoxycarbonyl), (4) C 7-12 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 2-phenylethyloxycarbonyl) Is mentioned.
  • C 1-6 alkoxy-carbonyl group eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl
  • C 6-10 aryloxy-carbonyl group eg, phenoxycarbonyl, naphthoxycarbonyl
  • C 7-12 aralkyloxy-carbonyl group eg, benz
  • the “optionally substituted amino group” (1) an amino group, (2) mono- or di-C 1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino), (3) C 3-6 cycloalkylamino group (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino), (4) C 6-10 arylamino group (eg, phenylamino, 1-naphthylamino, 2-naphthylamino), (5) C 7-12 aralkylamino group (eg, benzylamino, 2-phenylethylamino, 1-phenylethylamino), (6) hydrazino group, (7) mono- or di- (C 1-6 alkylsulfonine,
  • the substituent that the “cyclic amino group” of the “optionally substituted cyclic amino group” may have, (1) an oxo group, (2) the substituent which the “C 1-6 alkyl group” of the “ optionally substituted C 1-6 alkyl group” may have, (3) C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl) optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group and a C 1-6 alkoxy group , Isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethyl Butyl, 1,2,2-trimethylpropyl, trifluoromethyl, hydroxyethy
  • the “optionally substituted carbamoyl group” (1) a carbamoyl group, (2) mono- or di- (C 1-6 alkyl) carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl), (3) mono- or di- (C 6-10 aryl) carbamoyl group (eg, phenylcarbamoyl, naphthylcarbamoyl, diphenylcarbamoyl, dinaphthylcarbamoyl), (4) Mono- or di- (C 7-12 aralkyl) carbamoyl group (eg, benzylcarbamoyl, dibenzylcarbamoyl) Is mentioned.
  • C 1-6 alkyl
  • Preferred examples of the “substituted C 1-6 alkyl group” represented by R 1 include (A) a halogen atom, (B) a hydroxy group, (C) a C 1-6 alkoxy group (eg, methoxy), (D) -S-R 1a , (E) —SO 2 —R 1a (eg, —SO 2 -methyl), (F) —SO 2 —N (R 1b ) (R 1c ) (eg, —SO 2 —N (H) (methyl)), (G) -N (R 1b ) (R 1c ), (H) -NH-CO-R 1a , (I) —NH—CO—N (R 1b ) (R 1c ) (eg, —NH—CO—NH 2 , —NH—CO—N (H) (ethyl)), (J) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl) or
  • a C 1-6 alkyl group (eg, methyl, ethyl) substituted with 1 to 4 (preferably 1 to 3, more preferably 1) substituents selected from: (A) a hydroxy group, (B) —SO 2 —R 1a (eg, —SO 2 -methyl), and (c) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl) (Wherein R 1a is as defined above.)
  • R 1 As preferable examples of the “optionally substituted C 1-6 alkoxy group” represented by R 1 , (A) a halogen atom, (B) a hydroxy group, (C) a C 1-6 alkoxy group (eg, methoxy), (D) -SR 1a , (E) —SO 2 —R 1a , (F) —SO 2 —N (R 1b ) (R 1c ), (G) -N (R 1b ) (R 1c ), (H) -NH-CO-R 1a , (I) —NH—CO—N (R 1b ) (R 1c ), (J) —NH—SO 2 —R 1a , (K) —NH—SO 2 —N (R 1b ) (R 1c ), and (1) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group 1-yl (wherein R 1a , R 1b and
  • a C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with 1 to 3 substituents selected from And more preferably, a C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with a C 1-6 alkoxy group (eg, methoxy), and more preferably a substituent group.
  • substituent group examples thereof include C 1-6 alkoxy groups which are not present (eg, methoxy, ethoxy).
  • the “optionally substituted carboxy group” represented by R 1 (1) a carboxy group, (2) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl) More preferred is a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl), and even more preferred is ethoxycarbonyl.
  • C 1-6 alkoxy-carbonyl group eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl
  • ethoxycarbonyl ethoxycarbonyl
  • Preferred examples of the “optionally substituted amino group” represented by R 1 include (1) (a) a halogen atom, (B) a hydroxy group, and (c) a C 1-6 alkoxy group (eg, methoxy) A mono- or di- (C 1-6 alkyl-carbonyl) amino group (eg, methylcarbonylamino) which may be substituted with 1 to 3 substituents selected from (2) C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino), (3) A sulfamoylamino group is exemplified, and a C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino) is more preferred.
  • a C 1-6 alkoxy group eg, methoxy
  • a mono- or di- (C 1-6 alkyl-carbonyl) amino group eg, methylcarbonylamino
  • Preferable examples of the “optionally substituted carbamoyl group” represented by R 1 include a mono- or di- (C 1-6 alkyl) carbamoyl group (eg, methylcarbamoyl), more preferably And methylcarbamoyl.
  • R 1 include (1) a hydroxy group, (2) C 1-6 alkoxy-carbonyl group, (3) a C 1-6 alkoxy group, or (4) (a) a halogen atom, (B) a hydroxy group, (C) a C 1-6 alkoxy group, (D) -S-R 1a , (E) -SO 2 -R 1a , (F) -N (R 1b ) (R 1c ), (G) -NH-CO-R 1a , (H) -NH-CO-N (R 1b ) (R 1c ), (I) —NH—SO 2 —R 1a , and (j) —NH—SO 2 —N (R 1b ) (R 1c ) (Wherein R 1a represents a C 1-6 alkyl group, and R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group) A substituted C 1-6 alkyl group can be mentioned.
  • R 1 (1) a hydroxy group, (2) C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), (3) (a) a halogen atom, (B) a hydroxy group, (C) a C 1-6 alkoxy group (eg, methoxy), (D) -SR 1a , (E) —SO 2 —R 1a , (F) —SO 2 —N (R 1b ) (R 1c ), (G) -N (R 1b ) (R 1c ), (H) -NH-CO-R 1a , (I) —NH—CO—N (R 1b ) (R 1c ), (J) —NH—SO 2 —R 1a , (K) —NH—SO 2 —N (R 1b ) (R 1c ), and (l) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group
  • R 2 and R 3 are both hydrogen atoms. That, X 1, preferred combinations of X 2 and X 3 (X 1, X 2 , X 3) is, (- NH -, - CH 2 -, - CH 2 -), (- CH 2 -, - NH- , -CH 2 -) or (-CH 2 -, - CH 2 -, - is NH-).
  • Ring A is a benzene ring substituted with two halogen atoms
  • R 1 is (1) a hydroxy group, (2) C 1-6 alkoxy-carbonyl group, (3) a C 1-6 alkoxy group, or (4) (a) a halogen atom, (B) a hydroxy group, (C) a C 1-6 alkoxy group, (D) -S-R 1a , (E) -SO 2 -R 1a , (F) -N (R 1b ) (R 1c ), (G) -NH-CO-R 1a , (H) -NH-CO-N (R 1b ) (R 1c ), (I) —NH—SO 2 —R 1a , and (j) —NH—SO 2 —N (R 1b )
  • Ring A is a benzene ring substituted with 1 to 3 substituents selected from a halogen atom (eg, fluorine atom, chlorine atom) and a C 1-6 alkyl group (eg, methyl);
  • R 1 is (1) a hydroxy group, (2) C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), (3) (a) a halogen atom, (B) a hydroxy group, (C) a C 1-6 alkoxy group (eg, methoxy), (D) -SR 1a ,
  • E —SO 2 —R 1a ,
  • F —SO 2 —N (R 1b ) (R 1c ),
  • G -N (R 1b ) (R 1c )
  • H -NH-CO-R 1a
  • Ring A is a benzene ring substituted with 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom), R 1 is (1) (a) a hydroxy group, (B) —SO 2 —R 1a (eg, —SO 2 -methyl), and (c) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl) (Wherein R 1a is as defined above) a C 1-6 alkyl group (eg, methyl, ethyl) substituted with 1 to 3 substituents selected from (2) C 1-6 alkylsulfonylamino groups (eg, methylsulfonylamino) And Ring B 1 or Ring B 3 has no substituents other than Ring A and R 1 , and Ring B 2 is a ring A, R 1 , and any one of X 1 , X 2 and X 3 is a substituent Compound (I) having no substituent other than
  • compound (I) include the compounds of Examples 1 to 43. Among them, (3R, 4R) -3- (3-chloro-4-fluorophenyl) -4-[(methylsulfonyl) methyl] azepane or a salt thereof (Example 25), (3RS, 4RS) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane optically active substance or salt thereof (Example 29 ((3R * , 4R * )-3- (3 , 4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane hydrochloride (derived from the Boc form with a smaller retention time) or Example 30 ((3R * , 4R * )-3- (3, 4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride (derived from the Boc form having a larger
  • 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 Examples include salts with acidic 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.
  • salts with organic acids 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) may form a hydrate or / and a solvate, and any case is included in the present invention, and the hydrate or / and solvate is a hydrate or a solvent. Any of a Japanese product and a mixture thereof may be used.
  • each compound in the reaction formula may form a salt.
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the metal salt 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.
  • Salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. Can be mentioned.
  • Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene And salts with sulfonic acid and the like.
  • Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like. Of these, pharmaceutically acceptable salts are preferred.
  • each compound in the reaction formula may be either a hydrate or / and a solvate.
  • the hydrate include 0.23 hydrate, 0.5 hydrate, monohydrate, monohydrate 1 solvate, 2 solvate and the like.
  • the compound obtained in each step can be used as a crude product directly in the next reaction as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be isolated by a means known per se, for example, extraction. It can be easily purified by separation means such as concentration, neutralization, filtration, distillation, recrystallization and chromatography. Or when the compound in reaction formula is marketed, a commercial item can also be used as it is.
  • Compound (I) contains the following compounds (Ia)-(Ig) depending on the position of ring A and substituent R 1 and the presence or absence of a double bond.
  • a method for producing compounds (Ia)-(Ig) will be described.
  • the corresponding compound can be synthesized using the corresponding compound according to the production method shown below. .
  • Compound (Ia) can be produced, for example, by deprotecting compound (IIa) in Step 1.
  • the "protecting group” represented by PRG for example, Greene's protective groups in organic synthesis 4 th edition , but are used those described in (Wiley-International Publication), preferably tert- butoxycarbonyl (Boc) group, a benzyloxy Carbamate protecting groups such as carbonyl (Cbz) group, 9-fluorenylmethyloxycarbonyl (Fmoc) group, amide protecting groups such as acetyl (Ac) group, trifluoroacetyl group, or benzyl (Bzl) group, methyl And alkyl-based protecting groups such as a group.
  • the "protecting group” represented by PRG for example, Greene's protective groups in organic synthesis 4 th edition , but are used those described in (Wiley-International Publication), preferably tert- butoxycarbonyl (Boc) group,
  • the deprotection method in Step 1 for example, the method described in Greene's protective groups in organic synthesis 4 th edition is used.
  • the protective group is a tert-butoxycarbonyl group, hydrochloric acid, trifluoroacetic acid, etc.
  • a benzyl group a method using acid treatment or the like, a catalytic reduction using a metal catalyst such as palladium, an alkyl chloroformate or the like is preferable.
  • the “acid” used in the acid treatment is preferably an organic solvent solution of hydrogen chloride, hydrochloric acid or trifluoroacetic acid.
  • the “organic solvent” is preferably an alcohol solvent such as ethanol or methanol, or an ester solvent such as ethyl acetate.
  • the equivalent amount of the “acid” to be used is generally 1 equivalent to a solvent amount, preferably 1 equivalent to 100 equivalents, relative to compound (IIa).
  • the reaction solvent for example, alcohol solvents such as ethanol and methanol, and ester solvents such as ethyl acetate are preferably used.
  • the reaction temperature is usually -78 ° C to 200 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time is usually 1 minute to 48 hours, preferably 5 minutes to 24 hours.
  • Compound (IIa 1 ) (R 1 represents —OH) and Compound (IIa 2 ) (compound in which R 1 of compound (IIa 1 ) is —O—Alkyl 1 ) included in Compound (IIa) are: For example, it can be produced by the following method.
  • Alkyl 1 is an optionally substituted C 1-6 alkyl group, and other symbols are as defined above.
  • Alkyl 1 "C 1-6 alkyl group” and the "C 1-6 alkyl group” substituent optionally possessed by the "optionally substituted C 1-6 alkyl group” The meaning is the same as above.
  • Compound (IIa 1 ) (R 1 represents —OH), for example, in Step 2, compound (III) and compound (IV) (PRG 1 described in International Publication No. 2009/012125 pamphlet) It can be produced by the addition reaction of “M 1 ” of the compound (III) is preferably an alkali metal, an alkaline earth metal or a salt thereof, and lithium or magnesium halide is particularly preferable.
  • the compound (IIa 1 ) thus obtained can be further converted into a compound (IIa 2 ) (R 1 represents —O-Alkyl 1 ) by introducing an alkyl group in Step 3.
  • R 1 represents —O-Alkyl 1
  • “O-alkylation” can be performed according to the method described in Tetrahedron Lett., 30, 641 (1989), for example. [Production Method of Compound (Ib)]
  • Compound (Ib) can be produced, for example, by deprotecting compound (IIb) in Step 4.
  • the “protecting group” represented by PRG 1 for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group and the like are preferable.
  • Step 4 can be performed under the same reaction conditions as in step 1 or conditions similar thereto.
  • Compound (IIb 1 ) (compound in which R 1 of compound (IIb) is —CO 2 Alkyl 2 ) contained in compound (IIb) can be produced, for example, by the following method.
  • Alkyl 2 represents a C 1-6 alkyl group
  • X 1 represents a halogen atom
  • Tf represents a trifluoromethanesulfonyl group
  • M 2 represents a metal or a derivative thereof, and other symbols are as defined above.
  • the “C 1-6 alkyl group” represented by Alkyl 2 has the same meaning as described above.
  • Compounds (VI) and (VII) can be produced by ring expansion of compound (V) in step 5.
  • Compounds (VI) and (VII) are in a positional isomer relationship with each other and exist in a mixture of both or in a biased form.
  • the “ring expansion” can be performed according to the method described in, for example, Bioorganic “and Medicinal” Chemistry “Letters”, “18”, “2103” -2108 (2008). These can be separated by a purification method such as silica gel column chromatography or recrystallization.
  • Compound (VIII) can be produced by triflating or halogenating compound (VI) in Step 6.
  • the “triflating” can be carried out according to the method described in, for example, Comprehensive Organic Functional Group Transformations II (Elsevier Pergamon), vol.2, 633-634.
  • the “halogenation” can be performed according to the method described in, for example, Journal of American Chemical Society, 65, 2208 (1943).
  • the “halogen” in the “halogenated” is preferably chlorine, bromine or iodine.
  • Compound (IIe 1 ) can be produced by cross-coupling of compound (VIII) or (IX) and compound (X) in Step 7.
  • This step is performed according to the Suzuki-Miyaura coupling reaction described in, for example, Tetrahedron, 58, 9633-9695 (2002), or the Stille coupling reaction described in, for example, Organic Reactions, 50, 1-652 (1997). be able to.
  • Compound (X) is an organic boronic acid compound (M 2 represents a boronic acid or a boronic acid ester) for the Suzuki-Miyaura coupling reaction, and an organic tin compound (M 2 is a trialkyl) for the Stille coupling reaction. Tin is shown.)
  • This step preferably uses the Suzuki-Miyaura coupling reaction.
  • Compound (XI) can be produced by reducing compound (IIe 1 ) in Step 8.
  • the “reduction” can be performed by a method known to those skilled in the art, such as sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, cyanohydrogenation.
  • the compound obtained in this step may give a diastereomeric mixture based on stereoisomerism, and these can be separated and purified by a method such as silica gel column chromatography or recrystallization, if necessary.
  • Compound (IIb 1 ) can be produced by isomerization of compound (XI) in Step 9.
  • the “isomerization” is carried out in the presence of a “base”, and as the “base”, for example, 1) Alkali metal or alkaline earth metal hydrides (e.g. lithium hydride, sodium hydride, potassium hydride, calcium hydride), alkali metal or alkaline earth metal amides (e.g.
  • lithium amide, sodium amide) Lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide), alkali metal or alkaline earth metal C 1-6 alkoxide (eg, sodium methoxide) Strong base such as sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide); 2) Alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, carbonate) Potassium, cesium carbonate), inorganic bases such as alkali metal or alkaline earth metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate); and 3) amines such as triethylamine, diisopropylethylamine
  • Alkyl 3 and Alkyl 4 are each an optionally substituted C 1-6 alkyl group
  • Alkyl 5 and Alkyl 6 are each a hydrogen atom or an optionally substituted C
  • the 1-6 alkyl group and other symbols are as defined above.
  • “C 1-6 alkyl group” and “C 1-6 alkyl group” of “optionally substituted C 1-6 alkyl group” represented by Alkyl 3 , Alkyl 4 , Alkyl 5 and Alkyl 6 are The substituents that may be present have the same meaning as described above. ]
  • Compound (IIb 2 ) can be produced by reducing compound (IIb 1 ) in Step 10.
  • the “reduction” can be performed by a method according to “reduction” in step 8, but among them, a method using a metal hydride such as sodium borohydride, lithium borohydride, lithium aluminum hydride or the like is preferable.
  • Compound (IIb 3 ) can be produced by converting the hydroxyl group of compound (IIb 2 ) to leaving group L 1 in step 11.
  • the leaving group L 1 include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy) optionally substituted with a halogen atom.
  • Trifluoromethanesulfonyloxy C 6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy) optionally substituted with C 1-6 alkyl is used.
  • arylsulfonyloxy eg, benzenesulfonyloxy, p-toluenesulfonyloxy
  • C 1-6 alkyl is used.
  • a halogen atom and methanesulfonyloxy are preferred.
  • the leaving group L 1 is a halogen atom, for example, the method described in Journal of the American Chemical Society, 107, 3950-3955 (1985)
  • methanesulfonyloxy for example, Synthesis, 6 , 627-629 (1995).
  • Compound (IIb 4 ) can be produced by replacing the leaving group L 1 of compound (IIb 3 ) with the corresponding thiol in Step 12.
  • a base may be used as appropriate.
  • the “base”, for example, the “base” used in Step 9 is used, and among them, an alkali metal hydride such as sodium hydride is preferable. Moreover, you may use the alkali metal salt of thiol instead of thiol.
  • This step can be performed, for example, according to the method described in Journal of Medicinal Chemistry, (48), 4679-4689 (2005).
  • Compound (IIb 5 ) can be produced by oxidation of compound (IIb 4 ) in Step 13.
  • the “oxidation” can be performed using an oxidizing agent such as 3-chlorophenyl perbenzoic acid, sodium periodate, hydrogen peroxide solution, peracetic acid, Oxone (registered trademark), among others 3-chlorophenyl perbenzoic acid.
  • An acid or the like is preferable. This step can be performed according to the method described in, for example, Journal of Organic Chemistry, 68, 5075-5083 (2003).
  • Compound (IIb 6 ) can be produced by replacing the leaving group L 1 of compound (IIb 3 ) with the corresponding alkylthiocarboxylic acid in Step 14.
  • a base may be used as appropriate.
  • the “base”, for example, the “base” used in Step 9 is used, and among them, an organic base, an alkali metal hydride such as sodium hydride or potassium hydride, or an alkali metal carbonate such as cesium carbonate is preferable.
  • This step can be performed, for example, according to the method described in International Publication No. 2005/013975 pamphlet.
  • Compound (IIb 7 ) can be produced by chlorosulfonylation (conversion to sulfonyl chloride) of compound (IIb 6 ) in Step 15.
  • the “chlorosulfonylation” is exemplified by chlorine gas, sulfuryl chloride, N-chlorosuccinimide, etc. Although it can be carried out by a method using a chlorinating agent or a method of treating with thionyl chloride after oxidation with hydrogen peroxide, N-chlorosuccinimide is particularly preferred. This step can be performed, for example, according to the method described in Synthesis, 24, 4131-4134 (2006).
  • Compound (IIb 8 ) can be produced by sulfonamidation of compound (IIb 7 ) in Step 16.
  • the “sulfonamidation” can be carried out by a method known per se, for example, by reaction with sulfonyl chloride in the presence of a base.
  • the base for example, the base in Step 9 can be used, among which a tertiary amine such as triethylamine is preferable.
  • Compound (Ic) can be produced, for example, by deprotecting compound (IIc) in Step 17.
  • the “protecting group” represented by PRG 1 for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group is preferable.
  • Step 17 can be carried out under the same reaction conditions as in Step 1 or conditions analogous thereto.
  • Compound (IIc 1 ) (compound in which R 1 of compound (IIc) is —CO 2 Alkyl 7 ) contained in compound (IIc) can be produced, for example, by the following method.
  • Alkyl 7 represents an optionally substituted C 1-6 alkyl group, and other symbols are as defined above. Here, shown is and Alkyl 7 "C 1-6 alkyl group” and the “C 1-6 alkyl group” substituent optionally possessed by the "optionally substituted C 1-6 alkyl group” The meaning is the same as above. ]
  • Compound (XIII) can be produced by ring expansion of compound (XII) in Step 18. This step can be carried out under the same reaction conditions as in step 5 or conditions analogous thereto.
  • Compound (IIc 1 ) can be produced from compound (XIII) through compound (XIV) or (XV), (IIf 1 ) and (XVII), for example, by sequentially performing steps 19, 20, 21 and 22. it can.
  • the “steps 19, 20, 21 and 22” can be carried out according to the aforementioned steps 6, 7, 8 and 9, respectively.
  • Compound (Id) can be produced, for example, by deprotecting compound (IId) in Step 23.
  • the “protecting group” represented by PRG 1 for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group is preferable.
  • Step 23 can be carried out under the same reaction conditions as in Step 1 or conditions analogous thereto.
  • Compound (IId 1 ) (compound in which R 1 of compound (IId) is —CO 2 Alkyl 2 ) contained in compound (IId) can be produced, for example, by the following method.
  • Compound (VII) can be obtained by purifying the regioisomer generated together with compound (VI) in Step 5 by silica gel column chromatography. Further, the steps 24, 25, 26 and 27 shown here can be carried out according to the steps 6, 7, 8 and 9, respectively.
  • Alkyl 8 and Alkyl 11 are each an optionally substituted C 1-6 alkyl group
  • Alkyl 9 , Alkyl 10 , Alkyl 12 and Alkyl 13 are hydrogen atoms or substituted, respectively.
  • C 1-6 alkyl group which may be substituted other symbols are as defined above.
  • Alkyl 8, Alkyl 9, Alkyl 10, Alkyl 11, Alkyl 12 and and Alkyl 13 are "C 1-6 alkyl group" of the "optionally substituted C 1-6 alkyl group” shown and the "C 1
  • the substituent which the “ -6 alkyl group” may have has the same meaning as described above.
  • Compound (IId 2 ) can be produced by reducing compound (IId 1 ) in step 28.
  • the “reduction” can be performed, for example, according to the method of Step 10 described above.
  • Compound (IId 3 ) can be produced by converting the side chain hydroxyl group of compound (IId 2 ) to a sulfone group (conversion to a side chain sulfone) in Step 29.
  • the “conversion to a sulfone group” can be carried out, for example, according to the method of Step 11-13.
  • Compound (IId 5 ) can be produced by converting the side chain hydroxyl group of compound (IId 2 ) into a leaving group L 2 in Step 30 and then azidating in Step 31.
  • the leaving group L 2 those similar to the above L 1 can be used, and for example, a methanesulfonyloxy group, a chlorine atom and the like are preferable.
  • an azidating agent such as sodium azide or trimethylsilyl azide is used.
  • Compound (IId 6 ) can be produced by reducing the azide group of the azide derivative (IId 5 ) in step 32.
  • the “reduction of the azide group” can be carried out by the Staudinger reaction described in, for example, Tetrahedron, 48, 1353-1406 (1992) in addition to the reduction conditions used in Step 8.
  • Compound (IId 7 ) can be produced by urea formation of compound (IId 6 ) in Step 33.
  • the “urea” can be carried out according to a method known per se, for example, a reaction with an alkyl isocyanate, a method via a phenyl carbamate described in Journal of Medicinal Chemistry, 36, 2984-2997 (1993). Can be manufactured. Among these, the use of trimethylsilyl isocyanate is preferred for the production of terminal-unsubstituted urea.
  • Compound (IId 8 ) can be produced by sulfonamidation of compound (IId 6 ) in Step 34.
  • the “sulfonamidation” can be carried out according to a method known per se, for example, by reaction with sulfonyl chloride in the presence of a base.
  • a base for example, the base in Step 9 can be used, but a tertiary amine such as triethylamine is preferable.
  • Compound (IId 9 ) can be produced by sulfamidation of compound (IId 6 ) in Step 35.
  • the “sulfamidation” is, for example, a method by condensation with sulfamoyl chloride described in International Publication No. 2007/049041, Pamphlet N- (tert) described in Organic Letters, 3 (14), 2241-2243 (2001). It can be carried out by a method using -butoxycarbonyl) -N- [4- (dimethylazanimilidene) -1,4-dihydropyridin-1-ylsulfonyl] azanide. [Production Method of Compound (Ie)]
  • Compound (Ie) can be produced, for example, by deprotecting compound (IIe) in Step 36.
  • the “protecting group” represented by PRG 1 for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group is preferable.
  • Step 36 can be performed under the same reaction conditions as in step 1 or conditions similar thereto.
  • Compound (IIe 1 ) (compound in which R 1 of compound (IIe) is —CO 2 Alkyl 2 ) contained in compound (IIe) is obtained from Step 7 above, and compound (IIe 2 ) (compound (IIe) A compound in which R 1 is —CH 2 OH.) And a compound (IIe 3 ) (a compound in which R 1 of compound (IIe) is —CH 2 O—Alkyl 14 ) are obtained by, for example, 1 ) can be derived from.
  • Alkyl 14 represents an optionally substituted C 1-6 alkyl group, and other symbols are as defined above. Here, shown is and Alkyl 14 "C 1-6 alkyl group” and the “C 1-6 alkyl group” substituent optionally possessed by the "optionally substituted C 1-6 alkyl group” The meaning is the same as above. ]
  • Compound (IIe 2 ) can be produced by reduction of compound (IIe 1 ) in Step 37.
  • the “reduction” can be performed, for example, according to the method of Step 10 described above.
  • Compound (IIe 3 ) can be produced in step 38 by “O-alkylation” of compound (IIe 2 ).
  • the “O-alkylation” can be carried out, for example, according to the method of Step 3. [Production Method of Compound (If)]
  • Compound (If) can be produced, for example, by deprotecting compound (IIf) in Step 39.
  • the “protecting group” represented by PRG 1 for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group is preferable.
  • Step 39 can be performed under the same reaction conditions as in step 1 or conditions similar thereto.
  • Compound (Ig) can be produced, for example, by deprotecting compound (IIg) in Step 40.
  • the “protecting group” represented by PRG 1 for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group and the like are preferable.
  • Step 40 can be performed under the same reaction conditions as in step 1 or conditions similar thereto.
  • the compound (IIg 1 ) (compound in which R 1 of the compound (IIg) is —CO 2 Alkyl 2 ) contained in the compound (IIg) is obtained from the step 25, and the compound (IIg 2 ) (compound (IIg) In which R 1 is —CH 2 OH.) Can be derived from compound (IIe 1 ) by the following method, for example.
  • Compound (IIg 2 ) can be produced by reducing compound (IIg 1 ) in Step 41.
  • the “reduction” can be performed, for example, according to the method of Step 10 described above.
  • 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 mixtures thereof are also included in compound (I).
  • Each can be obtained as a single product by a synthesis method and a separation method known per se (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • optical isomers 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.
  • optical resolution method methods known per se, for example, fractional recrystallization method, chiral column method, diastereomer method are used.
  • Chiral column method A method in which a racemate or a salt thereof is separated by applying to an optical isomer separation column (chiral column).
  • an optical isomer separation column 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 buffer solutions (phosphate buffer solutions) Etc.) and an organic solvent (ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) are developed as a single or mixed solution to separate optical isomers.
  • Diastereomer method A racemic mixture is converted into a diastereomer mixture by a chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (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 hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( ⁇ ) -Mentoxyacetic acid or the like) is subjected to a condensation reaction to obtain an ester or amide diastereomer, respectively.
  • MTPA optically active organic acid
  • an amide or ester diastereomer when the compound (I) has a carboxylic acid group, an amide or ester diastereomer can be 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.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • a co-crystal or co-crystal salt is two or more unique solids each having different physical properties (structure, melting point, heat of fusion, hygroscopicity, solubility and stability, etc.) at room temperature.
  • Means a crystalline substance composed of The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the crystal of compound (I) can be produced by crystallization by applying a crystallization method known per se to compound (I).
  • examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.
  • the “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent.
  • a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method.
  • solvent used examples include aromatic hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), saturated hydrocarbons (hexane, heptane, cyclohexane, etc.), ethers ( Diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (acetonitrile, etc.), ketones (acetone, etc.), sulfoxides (dimethyl sulfoxide, etc.), acid amides (N, N-dimethylformamide, etc.), esters ( Ethyl acetate), alcohols (methanol, ethanol, isopropyl alcohol, etc.), and water. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)).
  • a seed crystal can also be used as
  • Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, and a chemical transport method.
  • 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).
  • compound (I) is dissolved in an appropriate solvent (alcohol such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is below the temperature at the time of dissolution.
  • solvent such as methanol, ethanol, etc.
  • examples thereof include a method of cooling to 0 to 50 ° C. (preferably 0 to 20 ° C.).
  • the crystals of compound (I) thus obtained can be isolated by, for example, filtration.
  • a crystal analysis method by powder X-ray diffraction is common.
  • examples of the method for determining the crystal orientation include a mechanical method and an optical method.
  • the crystals of compound (I) obtained by the above production method have high purity and high quality, low hygroscopicity, do not change even when stored for a long time under normal conditions, and are extremely excellent in stability. In addition, it has excellent biological properties (pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of medicinal effects, etc.) and is extremely useful as a medicine.
  • Compound (I) labeled with an isotope eg, 3 H, 14 C, 35 S, 125 I, etc.
  • a deuterium converter of compound (I) are also included in the present invention.
  • Compound (I) may be a prodrug, and 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, enzymatically.
  • 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, enzymatically.
  • Compounds that undergo oxidation, reduction, hydrolysis, etc. to change to compound (I), and compounds that undergo hydrolysis, etc. by gastric acid, etc. to change to compound (I) are shown, and these are also included in the present invention.
  • 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.
  • the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990 “Pharmaceutical Development”, Volume 7, pages 163 to 198 of molecular design. It may be.
  • Compound (I) or a prodrug thereof (hereinafter abbreviated as compound (I ′)) has an excellent monoamine (such as serotonin, norepinephrine, dopamine) reuptake inhibitory activity.
  • compound (I ′) has low toxicity and is safe. In particular, it is useful in that it does not exhibit phototoxicity.
  • Compound (I ′) is reuptaked into mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human) by brain monoamines (serotonin, norepinephrine, dopamine, etc.) As a substance having an inhibitory activity, it inhibits reuptake of monoamines in the brain and improves symptoms of neuropsychiatric diseases such as depression and anxiety.
  • mammals eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human
  • brain monoamines serotonin, norepinephrine, dopamine, etc.
  • Compound (I ′) is reuptaked by monoamines (serotonin, norepinephrine, dopamine, etc.) to mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human). As a substance having inhibitory activity, it inhibits reuptake of monoamines and improves lower urinary tract symptoms such as stress urinary incontinence.
  • An embodiment of the present invention is characterized in that an effective amount of Compound (I ′) is administered to a mammal (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human).
  • a mammal eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human.
  • depression anxiety, attention deficit / hyperactivity disorder, menopause, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia and stress urinary incontinence Can be mentioned.
  • the embodiments of the present invention include depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia and stress urine
  • compound (I ′) for producing a prophylactic or therapeutic drug for incontinence is mentioned.
  • compound (I ′) Since compound (I ′) has excellent properties as a pharmaceutical product with low toxicity and few side effects, mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans) For example, it is useful for the prevention and treatment of the following diseases.
  • mammals eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans.
  • Psychiatric and neurological diseases eg, depression (eg, major depression, cerebrovascular disorder depression, seasonal depression, drug-induced depression, HIV depression), anxiety (eg, generality) Anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder), attention deficit / hyperactivity disorder (ADHD), menopause, bipolar disorder, mania, recurrent depression, persistent mood emotion disorder (Eg, mood circulatory disorder, dysthymia), depressive neurosis, sleep disorders, diurnal rhythm disorders, eating disorders, drug addiction, premenstrual tension, autism, mood disorders due to menopause, senile dementia , Mild cognitive impairment, hypersomnia, psychosomatic disorder, manic depression, posttraumatic stress disorder (PTSD), schizophrenia, anxiety, obsessive compulsive disorder, stroke and cerebrovascular disorder Accompanying mood disorders and movement disorders)
  • Neurodegenerative diseases eg, myofibrosis, Alzheimer's disease, Parkinson'
  • Compound (I ′) is useful as a monoamine reuptake inhibitor, and is particularly useful as a prophylactic / therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence.
  • compound (I ′) is useful as a triple reuptake inhibitor because it has serotonin, norepinephrine and dopamine reuptake inhibitory activity.
  • compound (I ′) has a norepinephrine reuptake inhibitory activity, and is therefore useful as a norepinephrine reuptake inhibitor.
  • Compound (I ′) is a positron emission tomography (PET) that emits positrons such as carbon 11 ( 11 C), fluorine 18 ( 18 F), oxygen 15 ( 15 O), nitrogen 13 ( 13 N), etc. It can be used as a tracer by labeling with nuclides.
  • PET positron emission tomography
  • “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.
  • a pharmaceutical containing compound (I ′) is compound (I ′) alone or pharmacologically acceptable according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia, etc.).
  • tablets including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
  • pills pills, powders, granules, capsules (soft capsules, microcapsules) ), Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, oral cavity) Internal disintegration film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), instillation, transdermal preparation, ointment, lotion, Patches, suppositories (eg, anal suppositories, vagina Agents), pellets, nasal agents, pulmonary agents (inhalants), eye drops, etc., orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermatiti
  • the content of the compound (I ′) varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight as the amount of the compound (I) relative to the whole preparation, More preferably, it is about 0.5 to 20% by weight.
  • the dose varies depending on the type of compound (I '), administration route, symptoms, patient age, etc., but for example, depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain or stress urine
  • 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 doses. it can.
  • 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, and pigs), which vary depending on the purpose of administration.
  • animal to be administered eg, human, rat, mouse, Mammals such as cats, dogs, rabbits, cows, and pigs
  • animal to be administered eg, human, rat, mouse, Mammals such as cats, dogs, rabbits, cows, and pigs
  • animal to be administered eg, human, rat, mouse, Mammals such as cats, dogs, rabbits, cows, and pigs
  • about 0.1 to about 100 mg of compound (I ′) is administered per week. May be released from the.
  • the pharmacologically acceptable carrier examples include excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, Crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone), lubricant (eg, stearic acid, magnesium stearate, calcium stearate, talc), disintegrant (eg, carboxymethylcellulose calcium, talc), diluent (eg, water for injection, Physiological saline) and additives (for example, stabilizers, preservatives, colorants, fragrances, solubilizers, emulsifiers, buffers, isotonic agents).
  • excipients eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate
  • binders eg, starch, gum arabic, carboxymethylcellulose, hydroxypropy
  • compound (I ′) is used as a dispersant (eg, surfactants such as Tween 80, HCO-60, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, polysorbate), preservatives (Eg, methylparaben, propylparaben), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose), buffers (eg, calcium carbonate), pH adjusters (eg, sodium phosphate, potassium phosphate), etc.
  • a practical injectable preparation can be obtained by preparing an aqueous suspension together.
  • vegetable oils such as sesame oil and corn oil or those mixed with phospholipids such as lecithin or dispersed with medium-chain fatty acid triglycerides (eg, Miglyol 812) to make an injection that can actually be used as an oily suspension.
  • medium-chain fatty acid triglycerides eg, Miglyol 812
  • the preventive / 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 the compound (I ′) include the following.
  • central nervous disease prophylactic / therapeutic drugs Depressant drugs, anxiety drugs (eg, chlordiazepoxide, diazepam, potassium chlorazepate, lorazepam, clonazepam, benzodiazepane such as alprazolam), mood stabilizers (eg, carbonic acid carbonate) Lithium), 5-HT2 antagonists (eg, nefazodone), 5-HT1A agonists (eg, tandospirone, buspirone, Gepiron), CRF antagonists (eg, Pexacerfont), ⁇ 3 agonists (eg, Amibegron), melatonin agonists (Eg, ramelteon, agomelatine), ⁇ 2 antagonist (eg, mirtazapine, cetipitrine), NK2 antagonist (eg, Saredutant), GR antagonist (eg, Mifepristone), NK-1 antagonist (eg, Casopitant, Orvepitant), Drugs for treating
  • ⁇ -amyloid vaccine ⁇ -amyloid-degrading enzyme etc.
  • brain function activator Eg, aniracetam, nicergoline
  • Parkinson's disease drug eg, dopamine receptor agonist (eg, L-dopa, bromocriptene, pergolide, talipexol, prasipexol, cabergoline, adamantazine), COMT inhibitor (eg, entacapone) ], Attention deficit / hyperactivity disorder (eg, modafinil), amyotrophic lateral sclerosis (eg, riluzole, neurotrophic factor), insomnia (eg, etizolam, zopiclone, triazolam, zolpidem , Indiplon), hypersomnia drug (eg, modafinil), anti-cytokine drug (TNF inhibitor, MAP kinase inhibitor), steroid drug (eg, de
  • Adrenaline ⁇ 1 receptor agonist eg, ephedrine hydrochloride, mitodrine hydrochloride
  • Adrenaline ⁇ 2 receptor agonist eg, Clenbuterol
  • tricyclic antidepressants eg, imipramine hydrochloride
  • anticholinergic drugs or smooth muscle stimulants eg, oxybutynin hydrochloride, propiverine hydrochloride, serimevelin hydrochloride
  • female hormone drugs eg, Conjugated estrogens (premarin), estriol
  • 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, D-caylinositol)], insulin sensitivity enhancers (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, leglitazar, isaglitazone, 2,2 '-[2 (Z) -butene-1 , 4-Diyl] dioxybis (1,4-phenylene) bis (methylene) bis [1,2,4-oxadiazole-3,5 (2H, 4H) -dione], farglitazar, 5- (2,4- Dioxothiazolidine-5-ylmethyl) -2-methoxy-N- [4- (trifluoromethyl) benzyl] benzamide, 1- (2,4-dich
  • Antidiabetic complications aldose reductase inhibitors eg, torrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minalrestat (ARI-509), lisarestat
  • neurotrophic factor Eg, NGF, NT-3
  • AGE inhibitor eg, ALT-945, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (N-phenacylthiazolium bromide), EXO-226)
  • active oxygen scavenging examples thereof include drugs (eg, thioctic acid), cerebral vasodilators (eg, thioprid) and the like.
  • Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt)), squalene synthase inhibition Or a fibrate compound having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate) and the like.
  • cholesterol synthesis inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt)
  • squalene synthase inhibition Or a fibrate compound having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate) and the like.
  • Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril), angiotensin II antagonist (eg, losartan, candesartan cilexetil), calcium antagonist (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine), And clonidine.
  • Angiotensin converting enzyme inhibitor eg, captopril, enalapril, delapril
  • angiotensin II antagonist eg, losartan, candesartan cilexetil
  • calcium antagonist eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine
  • Anti-obesity drugs Central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex), pancreatic lipase inhibitor ( Eg, orlistat), ⁇ 3 agonist (eg, (R, R) -5- [2- [2- (3-chlorophenyl) -2-hydroxyethylamino] propyl] -1,3-benzodioxole-2, 2-dicarboxylic acid disodium salt, amibegron hydrochloride, UL-TG-307, rafabegron, AZ40140), peptidic appetite suppressant (eg, leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonist (eg , Lynchtripto, FPL-15849), 5-HT
  • Diuretics Xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclothiad ), Anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide), azosemides, isosorbide, ethacrynic acid, piretanide, bumetanide And furosemide.
  • thiazide preparations eg, eti
  • Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil), anticancer antibiotics (eg, mitomycin, adriamycin), plant-derived anticancer agents ( For example, vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide and the like, among others, 5-fluorouracil derivative flurtulon or neoflutulon can be mentioned.
  • antimetabolites eg, methotrexate, 5-fluorouracil
  • anticancer antibiotics eg, mitomycin, adriamycin
  • plant-derived anticancer agents For example, vincristine, vindesine, taxol
  • cisplatin carboplatin, etoposide and the like, among others, 5-fluorouracil derivative flurtulon or neoflutulon can be
  • Immunotherapeutic agents Microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil), immunopotentiating polysaccharides (eg, lentinan, schizophyllan, krestin), cytokines obtained by genetic engineering techniques (eg, interferon) , Interleukin (IL)), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin), among others, IL-1, IL-2 and IL-12.
  • IL-1 Interleukin
  • IL-12 Interleukin
  • Anti-inflammatory agents Steroid agents (eg, dexamethasone), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib) and the like.
  • cyclooxygenase inhibitors eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib
  • Glycation inhibitors eg, allagebrium chloride
  • nerve regeneration promoters eg, Y-128, thymcodar dimesylate, prosaptide
  • central nervous system drugs eg, desipramine, amitriptyline, imipramine, floxetine, paroxetine, doxepin
  • Antidepressants antiepileptic drugs (eg, lamotrigine, carbamazepine), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, evaniculin), endothelin receptor antagonists (eg, atrasentan), monoamines
  • Uptake inhibitors eg, tramadol
  • indoleamine uptake inhibitors eg, floxetine, paroxetine
  • narcotic analgesics eg, morphine
  • GABA receptor agonists eg, gabapentin
  • GABA uptake inhibitors
  • 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) are used, among which oxybutynin, propiverine, dar
  • NK-2 receptor antagonist examples include (S) -5-fluoro-3- [2- [4-methoxy-4- (phenylsulfinylmethyl) piperidin-1-yl] ethyl] -1H-indole, GR149861.
  • the administration time of the compound (I ′) and the concomitant drug is not limited, and the compound (I ′) or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are administered simultaneously to the administration subject. Alternatively, 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, and it is sufficient that the 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
  • 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 the concomitant drug is administered first, compound (I ′) may be administered, (I ′) may be administered first, followed by administration of the concomitant drug.
  • the time difference varies depending on the active ingredient to be administered, dosage form, and administration method.
  • 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 the administration of the compound (I ′).
  • the method of administration is mentioned.
  • the compounding ratio of the compound (I ′) and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of compound (I ′) 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 based on the whole preparation. Is 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 0.5 to 20%, based on the whole preparation. It is about wt%.
  • the content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
  • the dose when compound (I ′) and a concomitant drug are separately formulated varies depending on the type of compound (I ′), administration route, symptoms, patient age, etc., for example, depression, anxiety,
  • Up to 4 mg can be divided into 1 to 3 doses.
  • the dosage is the type and content of the compound (I ′), the dosage form, It varies depending on the duration of drug release, the animal to be administered (eg, mammals such as humans, rats, mice, cats, dogs, rabbits, cows, pigs, etc.) and the purpose of administration. For example, when applied by parenteral administration About 0.1 to about 100 mg of compound (I ′) may be released from the administered preparation per week.
  • 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, 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 a mammal, for example, by oral administration. Divide into 4 doses.
  • 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.
  • Root temperature in the following examples usually indicates about 10 ° C. to about 35 ° C.
  • the ratio shown in the mixed solvent is a volume ratio unless otherwise specified.
  • “%” Indicates wt% unless otherwise specified.
  • silica gel column chromatography when described as NH, aminopropylsilane-bonded silica gel was used.
  • the ratio of elution solvent indicates a volume ratio unless otherwise specified.
  • MS mass spectrum
  • LC / MS liquid chromatograph mass spectrometer
  • a peak from which H 2 O is eliminated may be observed as a fragment ion.
  • a peak from which H 2 O is eliminated may be observed as a fragment ion.
  • a salt a free molecular ion peak or a fragment ion peak is usually observed.
  • 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) device (SEIKO, EXSTAR6000).
  • a trace melting point measuring device Yanako, MP-500D type
  • a DSC Density Scanning Calorimetry device
  • Example 1 4- (3,4-Dichlorophenyl) azepan-4-ol hydrochloride A) tert-butyl 4- (3,4-dichlorophenyl) -4-hydroxyazepane-1-carboxylate tert-butyl 4-oxoazepane-1-carboxylate (5.0 g) prepared according to the method described in WO2003-103669 ) In diethyl ether (10 mL) was added separately prepared 3,4-dichlorophenylmagnesium bromide-diethyl ether solution (about 25.7 mmol) under ice cooling. The reaction mixture was stirred for 30 minutes under ice-cooling, water was added, and the mixture was extracted with ethyl acetate.
  • Example 2 4- (3,4-Dichlorophenyl) -4-methoxyazepane hydrochloride A) tert-butyl 4- (3,4-dichlorophenyl) -4-methoxyazepane-1-carboxylate tert-butyl 4- (3,4-dichlorophenyl) -4-hydroxyazepane-1-carboxylate (850 mg) in DMF (10 mL) at room temperature was added 60% sodium hydride (142 mg) and methyl iodide (0.22 mL), and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, and the solvent was distilled off under reduced pressure.
  • Example 3 4- (3,4-Dichlorophenyl) -4-ethoxyazepane hydrochloride A) tert-butyl 4- (3,4-dichlorophenyl) -4-ethoxyazepane-1-carboxylate In the same manner as in Step A of Example 2, tert-butyl 4- (3,4-dichlorophenyl)- The title compound (480 mg) was obtained from 4-hydroxyazepane-1-carboxylate (510 mg) and ethyl iodide (0.17 mL).
  • Example 4 4- (3,4-Dichlorophenyl) -4- (2-methoxyethoxy) azepane hydrochloride A) tert-butyl 4- (3,4-dichlorophenyl) -4- (2-methoxyethoxy) azepane-1-carboxylate In the same manner as in step A of Example 2, tert-butyl 4- (3,4 The title compound (725 mg) was obtained from -dichlorophenyl) -4-hydroxyazepane-1-carboxylate (700 mg) and 2-methoxyethyl methanesulfonate (378 mg).
  • Example 5 4- (2-Methylphenyl) azepan-4-ol hydrochloride A) tert-butyl 4-hydroxy-4- (2-methylphenyl) azepan-1-carboxylate In the same manner as in Step A of Example 1, tert-butyl 4-oxoazepane-1-carboxylate (1.0 g) The title compound (661 mg) was obtained from a 1.0 M 2-methylphenylmagnesium bromide / THF (6.6 mL) solution.
  • Example 6 4-Methoxy-4- (2-methylphenyl) azepan hydrochloride A) tert-butyl 4-methoxy-4- (2-methylphenyl) azepan-1-carboxylate In the same manner as in Step A of Example 2, tert-butyl 4-hydroxy-4- (2-methylphenyl) The title compound (232 mg) was obtained from azepane-1-carboxylate (230 mg), 60% sodium hydride (45 mg) and methyl iodide (0.07 mL).
  • Example 7 4-Ethoxy-4- (2-methylphenyl) azepane hydrochloride A) tert-butyl 4-ethoxy-4- (2-methylphenyl) azepan-1-carboxylate In the same manner as in Step A of Example 2, tert-butyl 4-hydroxy-4- (2-methylphenyl) The title compound (178 mg) was obtained from azepan-1-carboxylate (190 mg), 60% sodium hydride (136 mg) and ethyl iodide (0.28 mL).
  • Example 8 Ethyl 3- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-4-carboxylate fumarate A) 1-tert-butyl 4-ethyl 3- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate 60% sodium hydride (350 mg) And 1-tert-butyl 4-ethyl 3-oxoazepane-1,4 prepared according to the method described in J. Med. Chem. 29, 224-229 (1986).
  • Example 9 (3,4-Dichlorophenyl) -5- (methoxymethyl) -2,3,4,7-tetrahydro-1H-azepine hydrochloride
  • Example 10 Ethyl (3RS, 4RS) -3- (3,4-dichlorophenyl) azepan-4-carboxylate fumarate A) 1-tert-butyl 4-ethyl (3RS, 4SR) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate 1-tert-butyl 4-ethyl obtained in Step A of Example 8 Ethyl 3- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (1.34 g) in methanol (30 mL) in 3% platinum-sulfite Dead carbon (300 mg) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere.
  • Example 11 [(3RS, 4RS) -3- (3,4-dichlorophenyl) azepan-4-yl] methanol hydrochloride A) tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4- (hydroxymethyl) azepan-1-carboxylate sodium borohydride (214 mg) in THF (4.8 mL) -ethanol ( 3.2 mL) solution was added with calcium chloride (314 mg) and stirred at room temperature for 20 minutes.
  • Example 12 (3RS, 4RS) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride A) tert-Butyl (3RS, 4RS) -3- (3,4-Dichlorophenyl) -4-[(methylsulfanyl) methyl] azepan-1-carboxylate tert-Butyl obtained in Step A of Example 11 ( 3RS, 4RS) -3- (3,4-dichlorophenyl) -4- (hydroxymethyl) azepane-1-carboxylate (252 mg) in THF (5.0 mL) was added to triethylamine (0.14 mL) and methanesulfonyl under ice-cooling.
  • the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (65 mg).
  • Example 13 1-[(3RS, 4RS) -3- (3,4-Dichlorophenyl) azepan-4-yl] -N-methylmethanesulfonamide hydrochloride A) tert-Butyl (3RS, 4RS) -4-[(acetylsulfanyl) methyl] -3- (3,4-dichlorophenyl) azepan-1-carboxylate tert-Butyl obtained in Step A of Example 11 ( 3RS, 4RS) -3- (3,4-dichlorophenyl) -4- (hydroxymethyl) azepane-1-carboxylate (1.0 g) in THF (20 mL) was added to triethylamine (1.12 mL) and methane under ice-cooling.
  • reaction mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (42 mg).
  • Example 14 Ethyl 4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-3-carboxylate hydrochloride A) 1-tert-butyl 3-ethyl 4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,3-dicarboxylate Similar to step A of Example 8. By the method, the title compound (44 mg) was obtained from 1-tert-butyl 3-ethyl 4-oxoazepane-1,3-dicarboxylate (143 mg).
  • Example 15 [4- (3,4-Dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methanol hydrochloride A) tert-butyl 5- (3,4-dichlorophenyl) -6- (hydroxymethyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate The same method as in step A of Example 9 1-tert-butyl 3-ethyl 4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,3-dicarboxylate (2.50 g) to give the title compound (1.75 g) was obtained.
  • Example 16 Ethyl (3RS, 4SR) -4- (3,4-dichlorophenyl) azepane-3-carboxylate hydrochloride A) 1-tert-butyl 3-ethyl (3RS, 4RS) -4- (3,4-dichlorophenyl) azepane-1,3-dicarboxylate 1-tert-butyl 3 obtained in Step A of Example 14 -Platinum 4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,3-dicarboxylate (350 mg) in methanol (8.0 mL) in platinum oxide (39 mg ) was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere.
  • Example 17 (3RS, 4SR) -4- (3,4-Dichlorophenyl) -3-[(methylsulfonyl) methyl] azepan hydrochloride A) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3- (hydroxymethyl) azepane-1-carboxylate In the same manner as in Step 9 of Example 9, 1-tert-butyl The title compound (1.3 g) was obtained from 3-ethyl (3RS, 4SR) -4- (3,4-dichlorophenyl) azepane-1,3-dicarboxylate (1.6 g).
  • Example 18 1- ⁇ [(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl ⁇ -3-ethylurea hydrochloride A) tert-butyl (3RS, 4SR) -3- (azidomethyl) -4- (3,4-dichlorophenyl) azepan-1-carboxylate tert-butyl (3RS, 4SR) obtained in Step 17 of Example 17 To a solution of -4- (3,4-dichlorophenyl) -3-[(methylsulfonyl) methyl] azepane-1-carboxylate (1.28 g) in dichloromethane (25 mL), triethylamine (1.05 g), methanesulfonyl chloride (0.7 g) in dichloromethane (2.0 mL) was added and stirred at room temperature overnight.
  • the reaction mixture was diluted with ethyl acetate and water and separated.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale-yellow oil (1.54 g). .
  • the product was used in the next reaction without further purification.
  • To a solution of the oil (1.54 g) obtained above in DMF (15 mL) was added sodium azide (0.68 g), and the mixture was stirred at 60 ° C. overnight.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and separated.
  • Example 19 N- ⁇ [(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl ⁇ -1,1,1-trifluoromethanesulfonamide hydrochloride A) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-( ⁇ [(trifluoromethyl) sulfonyl] amino ⁇ methyl) azepan-1-carboxylate In step B of Example 18 The obtained tert-butyl (3RS, 4RS) -3- (aminomethyl) -4- (3,4-dichlorophenyl) azepan-1-carboxylate (546 mg) in dichloromethane (6.0 mL) was added to N-phenyl trifluoro L-methanesulfonimide (574 mg) and triethylamine (178 mg) were added, and the mixture was heated to reflux for 18 hours.
  • Example 20 N- ⁇ [(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl ⁇ -N'-methylsulfuric acid diamide hydrochloride A) tert-Butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3- ⁇ [(methylsulfamoyl) amino] methyl ⁇ azepan-1-carboxylate obtained in Step B of Example 18 To a solution of tert-butyl (3RS, 4RS) -3- (aminomethyl) -4- (3,4-dichlorophenyl) azepane-1-carboxylate (546 mg) in dichloromethane (6.0 mL) was added triethylamine (163 mg).
  • Example 21 Ethyl 5- (3,4-dichlorophenyl) -2,3,6,7-tetrahydro-1H-azepine-4-carboxylate hydrochloride A) 1-tert-butyl 4-ethyl 5- (3,4-dichlorophenyl) -2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate Similar to step A of Example 8. The title compound (482 mg) was obtained from 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (465 mg) prepared by the method described in Synthetic Communications, 1992, 22, 1249-1258. Obtained. MS (ESI +): [M + H (-Boc)] + 314.3.
  • Example 22 Ethyl (4RS, 5RS) -5- (3,4-dichlorophenyl) azepane-4-carboxylate hydrochloride A) 1-tert-butyl 4-ethyl (4RS, 5RS) -5- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate Carried out by the same steps as steps A and B of Example 10. 1-tert-Butyl 4-ethyl 5- (3,4-dichlorophenyl) -2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (470) obtained in Step A of Example 21 mg) gave the title compound (65 mg).
  • Example 23 (4RS) -4- (4-Chloro-3-methylphenyl) -4-methoxyazepane hydrochloride The title compound was obtained in the same manner as in Step A of Example 1 and Example 2. MS (ESI +): [M + H] + 254.2.
  • Example 24 (4RS) -4- (4-Chlorophenyl) -4-methoxyazepane hydrochloride The title compound was obtained in the same manner as in Step A of Example 1 and Example 2. MS (ESI +): [M + H] + 240.2.
  • Example 25 (3R, 4R) -3- (3-Chloro-4-fluorophenyl) -4-[(methylsulfonyl) methyl] azepane fumarate
  • the resulting 1-tert-butyl 4-ethyl (3RS, 4RS) -3- (3-chloro-4-fluorophenyl) azepane-1,4-dicarboxylate was optically resolved.
  • Example 28 [(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] methanol hydrochloride A) tert-Butyl (3R, 4R) -3- (3,4-Dichlorophenyl) -4- (hydroxymethyl) azepan-1-carboxylate 1-tert-butyl 4-obtained in Step 27 of Example 27 The title compound was obtained from ethyl (3R, 4R) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate in the same manner as in Step A of Example 11.
  • Example 29 Hydrochloride of optically active form of (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane: (3R * , 4R * ) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride (derived from the Boc form with the smaller retention time) A) tert-butyl (3R * , 4R * )-4- (3,4-dichlorophenyl) -3-[(methylsulfonyl) methyl] azepan-1-carboxylate (low retention time) Tert-Butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan-1-carboxylate (397 mg) obtained in steps A and B of Example 12 Was subjected to optical resolution (
  • Example 30 Hydrochloride of optically active form of (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane: (3R * , 4R * ) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride (derived from the Boc body with the longer retention time) Tert-butyl (3R * , 4R * )-4- (3,4-dichlorophenyl) -3-[(methylsulfonyl) methyl] azepan-1-carboxylate obtained in Example 29, Step A (large retention time) 2N Hydrogen chloride-ethanol solution (4.7 mL) was added to (175 mg), and the mixture was stirred at room temperature for 6 hours.
  • Example 31 N-[(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] methanesulfonamide hydrochloride A) (3R, 4R) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) azepane-4-carboxylic acid 1-tert-butyl 4-ethyl obtained in Step A of Example 27 To a solution of (3R, 4R) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate (2.0 g) in ethanol (50 mL) was added aqueous sodium hydroxide (15 mL) at 50 ° C.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and 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 (108 mg).
  • Example 32 N-[(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] -2-methoxyacetamide hydrochloride A) tert-butyl (3R, 4R) -3- (3,4-dichlorophenyl) -4-[(methoxyacetyl) amino] azepan-1-carboxylate tert-butyl obtained in Step B of Example 31 ( 3R, 4R) -4-amino-3- (3,4-dichlorophenyl) azepane-1-carboxylate (132 mg) in THF (3 mL) was added to triethylamine (0.15 mL) and methoxyacetyl chloride (0.07 mL).
  • Example 33 N-[(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] acetamide hydrochloride A) tert-butyl (3R, 4R) -4- (acetylamino) -3- (3,4-dichlorophenyl) azepan-1-carboxylate tert-butyl (3R, 4R) obtained in Step B of Example 31 ) -4-Amino-3- (3,4-dichlorophenyl) azepane-1-carboxylate (150 mg) in THF (4 mL) was added triethylamine (0.18 mL) and acetyl chloride (0.06 mL) at room temperature.
  • Example 34 (3R, 4R) -3- (3,4-Dichlorophenyl) -N-methylazepan-4-carboxamide hydrochloride A) tert-butyl (3R, 4R) -3- (3,4-dichlorophenyl) -4- (methylcarbamoyl) azepan-1-carboxylate (3R, 4R) -1 obtained in Step A of Example 31
  • a DMF 5 mL
  • solution of-(tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) azepane-4-carboxylic acid 200 mg
  • 40% methylamine-methanol solution 40 mg
  • 1- Hydroxybenzotriazole 77 mg
  • 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 109 mg
  • the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and 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 (179 mg).
  • Example 35 1- ⁇ [(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl ⁇ -3-methyl-1H-pyrazole-5-carboxylic acid hydrochloride A) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3- ⁇ [(methylsulfonyl) oxy] methyl ⁇ azepan-1-carboxylate methanesulfonyl chloride (0.132 mL, 1.71 mmol) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3- (hydroxymethyl) azepane-1-carboxylate (427 mg, 1.14 mmol) and triethylamine (0.318 mL, 2.28 mmol) in THF ( 8 mL) was added to the solution at room temperature and stirred overnight.
  • THF 8 mL
  • reaction mixture was concentrated under reduced pressure, diluted aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (550 mg). This compound was used in the next reaction without purification.
  • Example 36 1- ⁇ [(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl ⁇ -5-methyl-1H-pyrazole-3-carboxylic acid hydrochloride As in Step C of Example 35 Tert-Butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3- ⁇ [3- (ethoxycarbonyl) -5-methyl-1H-- obtained in Step B of Example 35 The title compound (98 mg) was obtained as a white solid from pyrazol-1-yl] methyl ⁇ azepan-1-carboxylate.
  • Example 37 (1RS) -1-[(3RS, 4RS) -3- (3,4-Dichlorophenyl) azepan-4-yl] ethane-1,2-diol hydrochloride A) tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-formylazepane-1-carboxylate tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl)- Dess-Martin reagent (5.4 g) was added to a solution of 4- (hydroxymethyl) azepan-1-carboxylate in acetonitrile (20 mL), and the mixture was stirred at 0 ° C.
  • Example 38 (1RS) -1-[(3SR, 4SR) -3- (3,4-Dichlorophenyl) azepan-4-yl] ethane-1,2-diol hydrochloride A) tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(1SR) -1,2-dihydroxyethyl] azepane-1-carboxylate obtained in Example 36, step C The obtained diastereomeric mixture (56 mg) was fractionated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% ammonium acetate)), and the obtained fraction (highly polar fraction of diastereomers).
  • Example 39 5- (3,4-Dichlorophenyl) -6-((methylsulfonyl) methyl) -2,3,4,7-tetrahydro-1H-azepine hydrochloride
  • step A of Example 15 The resulting tert-butyl 5- (3,4-dichlorophenyl) -6- (hydroxymethyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (220 mg) in THF (4.5 mL )
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was dissolved in DMF (2.5 mL) solution, sodium thiomethoxide (61 mg) was added to the mixture, and the mixture was stirred at room temperature for 18 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (177 mg).
  • the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (167 mg).
  • Example 40 N- ⁇ [4- (3,4-Dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methyl ⁇ methanesulfonamide hydrochloride A) tert-Butyl 6- (azidomethyl) -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate tert obtained in Step A of Example 15 To a solution of -butyl 5- (3,4-dichlorophenyl) -6- (hydroxymethyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (1.0 g) in THF (20 mL), Triethylamine (1.12 mL) and methanesulfonyl chloride (0.42 mL) were added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was dissolved in DMF (20 mL) solution, sodium azide (262 mg) was added to the mixture, and the mixture was stirred at room temperature for 18 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (744 mg).
  • the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine.
  • the extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (140 mg).
  • Example 41 1- ⁇ [4- (3,4-Dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methyl ⁇ urea hydrochloride A) tert-butyl 6-[(carbamoylamino) methyl] -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate In step B of Example 40 Obtained tert-butyl 6- (aminomethyl) -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (105 mg) in THF (1.5 mL) ) Trimethylsilyl isocyanate (0.06 mL) was added to the solution, and the mixture was stirred at room temperature for 3 days.
  • the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine.
  • the extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (107 mg).
  • Example 42 [(4RS) -4- (3,4-Dichlorophenyl) azepan-4-yl] methanol hydrochloride A) 3- (3,4-Dichlorophenyl) cyclohex-2-en-1-one Magnesium (1.04 g) in THF (10 mL) in 4-bromo-1,2-dichlorobenzene (9.67 g) in THF (20 mL) and iodine (3 mg) were added at room temperature, and the mixture was stirred at 40 ° C. for 1 hour under a nitrogen stream.
  • reaction mixture was extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (1.5 g).
  • reaction mixture was extracted with ethyl acetate, the extract was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure, and the residue was chromatographed on silica gel (hexane). / Ethyl acetate) to give the title compound (0.91 g).
  • the diluted solution was washed with distilled water and saturated brine, and then dried over anhydrous magnesium sulfate.
  • the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound.
  • the diluted solution was washed with distilled water and saturated brine, and then dried over anhydrous magnesium sulfate.
  • the solvent was concentrated under reduced pressure.
  • the reaction mixture was diluted with ethyl acetate.
  • the diluted solution was washed with distilled water and saturated brine, and then dried over anhydrous magnesium sulfate.
  • reaction mixture was added 1N aqueous hydrochloric acid (1 mL) at 65 ° C., and the mixture was stirred at 60 ° C. for 1 hr.
  • triethylamine 0.1 mL
  • di-tert-butyl dicarbonate 0.057 mL
  • the reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, and then dried over anhydrous magnesium sulfate.
  • Example 43 [(3RS) -3- (3,4-Dichlorophenyl) azepan-3-yl] methanol hydrochloride A) (6RS) -6- (3,4-Dichlorophenyl) -6- (hydroxymethyl) azepan-2-one (3RS) -3-( ⁇ [tert-butyl ( Titanium (IV) chloride (0.259 mL) and sodium azide (154 mg) were added to a solution of (dimethyl) silyl] oxy ⁇ methyl) -3- (3,4-dichlorophenyl) cyclohexanone (0.459 g) in acetonitrile (10 mL) (10 mL). And stirred at 100 ° C. for 4 hours.
  • Test example 1 Construction of human dopamine transporter expression plasmid
  • the SR ⁇ promoter contained in pTB1411 described in JP-A-5-076385 is cleaved with restriction enzyme HindIII (manufactured by Takara Bio Inc.), blunt-ended, and further subjected to restriction enzyme EcoRI (Takara (Manufactured by Bio Inc.) and fragmented.
  • the pCI vector was cleaved with the restriction enzyme BglII (Takara Bio), blunt-ended with T4 DNA polymerase, and further cleaved with the restriction enzyme EcoRI (Takara Bio).
  • An SR ⁇ promoter fragment was inserted into this site to prepare pCI-SR ⁇ .
  • pMSR ⁇ neo Human dopamine transporter cDNA was amplified by PCR from a human substantia nigra cDNA library and inserted into a pCRII vector (Invitrogen). After confirming and correcting the nucleotide sequence, it was subcloned into pMSR ⁇ neo to construct a human dopamine transporter expression plasmid.
  • Human serotonin transporter cDNA was amplified by PCR from a human brain cDNA library and inserted into a pCRII-TOPO vector (Invitrogen). After confirming and correcting the base sequence, it was subcloned into pcDNA3.1 vector (manufactured by Invitrogen) to construct a human serotonin transporter expression plasmid.
  • Human norepinephrine transporter cDNA was purchased from Invitrogen, and after confirming and correcting the nucleotide sequence, it was subcloned into pcDNA3.1 vector to construct a human norepinephrine transporter expression plasmid.
  • These prepared monoamine transporter expression plasmids were introduced into CHO-K1 cells using FuGENE6 (Roche Diagnostics) according to the attached protocol to establish each expression cell.
  • test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 ⁇ L of the diluted test compound was dispensed into the cell plate.
  • [3H] -5-hydroxytryptamine (GE Healthcare) was diluted to 200 nM with an assay buffer, and 10 ⁇ L was dispensed onto the cell plate. After 20 minutes from the addition of [3H] -5-hydroxytryptamine, the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 ⁇ L per well.
  • Microscinti20 (PerkinElmer) was dispensed at 100 ⁇ L per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer). The 10 ⁇ M inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 10 ⁇ M Paroxetine (serotonin transporter inhibitor) as 100%. The results are shown in Table 2-1 below.
  • Test Example 2 Inhibitory Action on Human Norepinephrine Transporter
  • CHO cells stably expressing human norepinephrine transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE). Cells cultured until almost confluent were rinsed with PBS (Invitrogen), then detached with Trypsin / EDTA (Invitrogen), and collected by centrifugation.
  • test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 ⁇ L of the diluted test compound was dispensed into the cell plate.
  • [3H] -norepinephrine GE Healthcare
  • Microscinti20 (PerkinElmer) was dispensed at 100 ⁇ L per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer). The 10 ⁇ M inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 10 ⁇ M DMI (norepinephrine transporter inhibitor) as 100%. The results are shown in Table 3-1 below.
  • the 1 ⁇ M inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 10 ⁇ M DMI (norepinephrine transporter inhibitor) as 100%.
  • the results are shown in Table 3-2 below.
  • Test Example 3 Inhibitory action on human dopamine transporter
  • CHO cells stably expressing human dopamine transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE). On the day before the assay, the cells cultured until they were almost confluent were rinsed with PBS (Invitrogen), detached with Trypsin / EDTA (Invitrogen), and collected by centrifugation.
  • PBS Invitrogen
  • Trypsin / EDTA Invitrogen
  • Count the number of cells obtained dilute to contain 3 ⁇ 10 5 cells per mL of medium, dispense 100 ⁇ L per well into a 96 well white plate (Corning), and culture with CO 2 Incubated overnight in a vessel.
  • Prepare assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH 2 PO 4 , 1.26 mM MgSO 4 , 10 mM HEPES, 2.32 mM CaCl 2 , 5.52 mM Glucose, 0.5% BSA) on the day of the test. After removing the medium, 80 ⁇ L of assay buffer was added.
  • test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 ⁇ L of the diluted test compound was dispensed into the cell plate.
  • [3H] -Dopamine GE Healthcare
  • the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 ⁇ L per well.
  • Microscinti20 (PerkinElmer) was dispensed at 100 ⁇ L per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer). The 10 ⁇ M inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 100 ⁇ M Nomifensine (dopamine transporter inhibitor) as 100%. The results are shown in Table 4-1 below.
  • Test Example 4 Measurement of urethral resistance increasing action
  • the measurement of urethral resistance increasing action using rats was carried out as follows in accordance with the method of Matsumoto et al. (PCT / JP2008 / 70809). That is, SD female rats (CLEA Japan) were anesthetized with isoflurane (1.0%; Abbott), and the spinal cord was cut with Th8-9 to eliminate the micturition reflex. After laparotomy, a catheter (PE-100; Clay Adams) for measuring intravesical pressure and injecting physiological saline was inserted into the bladder. The rat laparotomy was then closed using Aron Alpha A “Sankyo” (Daiichi Sankyo).
  • the rat with the inserted catheter was fixed to a ball man cage (KN-326 ball man cage type III; Natsume).
  • the intravesical pressure measurement catheter is connected to a computer via a pressure transducer (REF 695640; Nihon Koden), an amplifier (RPM-6008M; Nihon Koden), and a multi-channel data analyzer (MP150; Biopack) to change the intravesical pressure.
  • REF 695640 Nihon Koden
  • RPM-6008M Nihon Koden
  • MP150 multi-channel data analyzer
  • the saline injection catheter was connected to a 50 mL syringe (Terumo) filled with colored saline using Evans Blue (Wako).
  • the infusion pump Kds100; KD Scientific
  • Kds100 KD Scientific
  • the infusion pump Kds100; KD Scientific
  • the infusion pump was stopped and saline in the bladder was drained.
  • the maximum pressure until physiological saline was injected into the bladder and leaked was defined as an LPP (Leak point pressure) value.
  • the measurement was repeated until the LPP value was stabilized, and the result was an average of three consecutive LPP values that were stable.
  • the action of the drug was measured 1 hour after the animal was fixed to the Ballman cage, the LPP value (Pre value) was measured, the drug was administered intravenously, 10 minutes later, the LPP value (Post) Value) was measured, and the urethral resistance increasing action by the drug was expressed by the difference between the LPP value (Post value) and the LPP value (Pre value).
  • the drug was intravenously administered at a rate of 1.0 mL / kg using physiological saline as a solvent.
  • the Williams test was used for the significant difference test of the urethral resistance increasing action by the drug compared to the solvent.
  • the compound of Example 12 (0.3 mg / kg), the compound of Example 12 (1.0 mg / kg) and a solvent were administered to rats, and the effect of increasing urethral resistance was measured by the method described above. As shown in Table 5-1 below, the rats administered with the compound of Example 12 showed a dose-dependent and significant effect of increasing urethral resistance as compared with the solvent administration.
  • Example 29 the compound of Example 29, 0.3 mg / kg, 1.0 mg / kg, 3.0 mg / kg, and a solvent were administered to rats, and the urethral resistance increasing action was measured by the method described above. As shown in Table 5-2 below, the rat administered with the compound of Example 29 showed a dose-dependent and significant effect of increasing urethral resistance as compared with the solvent administration.
  • Example 40 1.0 mg / kg, 3.0 mg / kg
  • a solvent 1.0 mg / kg, 3.0 mg / kg
  • the effect of increasing urethral resistance was measured by the method described above.
  • Table 5-3 the rats administered with the compound of Example 40 showed a dose-dependent and significant effect of increasing urethral resistance as compared with vehicle administration.
  • Formulation Example 1 The pharmaceutical containing compound (I ') can be manufactured by the following prescription, for example. 1. Capsule (1) 40 mg of the compound obtained in Example 1 (2) Lactose 70mg (3) Microcrystalline cellulose 9mg (4) Magnesium stearate 1mg 1 capsule 120mg After mixing 1/2 of (1), (2), (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
  • Tablet (1) Compound obtained in Example 1 40 mg (2) Lactose 58mg (3) Corn starch 18mg (4) Microcrystalline cellulose 3.5mg (5) Magnesium stearate 0.5mg 1 tablet 120mg After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
  • the compound of the present invention or a prodrug thereof has an excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, for example, depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, It is useful as a safe preventive or therapeutic agent for pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia and stress urinary incontinence.
  • monoamine serotonin, norepinephrine, dopamine, etc.

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Abstract

The purpose of the present invention is to provide: a compound having a monoamine reuptake inhibition activity or the like; and a prophylactic or therapeutic agent for depression, anxiety, attention deficit-hyperactivity disorder, postmenopausal syndrome, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, atrophy associated with cachexia, stress urinary incontinence and so on. A compound represented by formula (I) [wherein each symbol is as defined in the description] or a salt thereof; and a medicinal agent comprising the compound or a salt thereof.

Description

アゼパン化合物Azepan compound
　本願発明は、優れたモノアミン再取り込み阻害活性を有し、うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮及び腹圧性尿失禁等の予防又は治療薬等として有用な複素環化合物に関する。 The present invention has an excellent monoamine reuptake inhibitory activity, and is associated with depression, anxiety, attention deficit / hyperactivity disorder, menopause, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, and cachexia The present invention relates to a heterocyclic compound useful as a preventive or therapeutic agent for muscle atrophy and stress urinary incontinence.
（発明の背景）
　モノアミン神経伝達物質であるセロトニン（5-HT）、ノルエピネフリン（NE）及びドーパミン（DA）は、脳内に広範囲に存在し、それらの受容体を介する神経伝達など、様々な機能を有している。これらのモノアミンが神経終末から放出された後に、それぞれのトランスポーター（セロトニントランスポーター：SERT、ノルエピネフリントランスポーター：NETおよびドーパミントランスポーター：DAT）により、神経間隙から速やかに再取り込みされると、神経伝達が終結する。モノアミンの再取り込みの阻害活性を示す化合物は、うつ病などの精神神経疾患を始めとする様々な疾患で有効性が知られており、治療薬として広く用いられている。セロトニン、ノルエピネフリン及びドーパミンの３種類の再取り込みを阻害する化合物は、Triple Reuptake Inhibitorと呼ばれ、精神神経疾患等の治療薬としての用途が期待されている。 (Background of the Invention)
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. . When these monoamines are released from the nerve endings and are rapidly re-incorporated from the nerve gap by the respective transporters (serotonin transporter: SERT, norepinephrine transporter: NET and dopamine transporter: DAT), neurotransmission Ends. Compounds exhibiting monoamine reuptake inhibitory activity are known to be effective in various diseases including neuropsychiatric diseases such as depression, and are widely used as therapeutic agents. 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.
　うつ病治療薬としては、イミプラミンに代表される三環性抗うつ薬（TCA）、フルオキセチンに代表される選択的セロトニン再取り込み阻害薬（SSRI）、ベンラファキシンに代表される選択的セロトニン・ノルエピネフリン再取り込み阻害薬（SNRI）やブプロピオンなどのノルエピネフリン・ドーパミン再取り込み阻害薬あるいはモノアミンオキシダーゼ阻害薬などが用いられているが、いずれも効果発現に数週間を要する点、有効性や改善率あるいは副作用の点などから、必ずしも充足度が高いとは言えない（非特許文献1、2参照）。 Depressive drugs include tricyclic antidepressants (TCA) typified by imipramine, selective serotonin reuptake inhibitors (SSRI) typified by fluoxetine, and selective serotonin norepinephrine typified by venlafaxine. 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 literature 1 and 2).
　また、TCA、SSRIおよびSNRIは、うつ病のみならず不安症や注意欠陥・多動性障害などの精神神経疾患や、アルツハイマー病などの神経変性疾患における症状改善、糖尿病性疼痛や筋線維症などの疼痛治療、あるいは過敏性腸症候群などの消化器疾患の治療薬としても有用であるとの報告もある。 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.
　また、モノアミン再取り込み阻害薬は、過活動膀胱や腹圧性尿失禁などの下部尿路疾患、とりわけ腹圧性尿失禁の治療薬としても有効であるとの報告がある。腹圧性尿失禁とは、咳やくしゃみ、軽い運動などによっておこる一過的な腹圧の上昇に伴った膀胱内圧の上昇により、尿が漏れる症状を特徴とする疾患である。この疾患は、女性に多く、出産や加齢などにより骨盤底筋群が弱体し、尿道抵抗が低下するためにおこるとされている（非特許文献3参照）。一方、腹圧の一過的な上昇に伴い膀胱内圧が上昇する際に、一連の神経反射を介して骨盤底筋および尿道括約筋が能動的に収縮し、尿禁性が維持される尿禁性反射機構が存在することが明らかとなっている（非特許文献4-7参照）。近年、この尿禁性反射にモノアミン神経伝達物質であるセロトニンとノルエピネフリンが関与することが示された（非特許文献6-8参照）。さらに、セロトニン及びノルエピネフリン再取り込み阻害薬であるデュロキセチン（Duloxetine）やノルエピネフリン再取り込み阻害薬であるエスレボキセチン（Esreboxetine）などを用いて、それぞれ、或いは両トランスポーターを阻害し神経伝達を増強することによって、腹圧性尿失禁の予防・治療効果があることが明らかとされた（非特許文献9-11参照）。 In addition, it has been reported that monoamine reuptake inhibitors are effective as therapeutic agents for lower urinary tract diseases such as overactive bladder and stress urinary incontinence, particularly stress urinary incontinence. Stress urinary incontinence is a disease characterized by symptoms of urine leaking due to an increase in intravesical pressure accompanying a transient increase in abdominal pressure caused by coughing, sneezing, light exercise, and the like. This disease is common in women, and is caused by weakening of the pelvic floor muscles due to childbirth, aging, etc., and a decrease in urethral resistance (see Non-Patent Document 3). On the other hand, when intravesical pressure rises with a transient increase in abdominal pressure, the pelvic floor muscles and urethral sphincters actively contract through a series of nerve reflexes, and urinary incontinence is maintained It is clear that there is a reflection mechanism (see Non-Patent Documents 4-7). In recent years, it has been shown that serotonin and norepinephrine, which are monoamine neurotransmitters, are involved in this urinary reflex (see Non-Patent Documents 6-8). Furthermore, by using serotonin and norepinephrine reuptake inhibitor duloxetine, norepinephrine reuptake inhibitor esreboxetine (Esreboxetine), etc., or by inhibiting both transporters and enhancing nerve transmission, It has been clarified that there is a preventive / therapeutic effect on pressure urinary incontinence (see Non-Patent Document 9-11).
　これまで、抗うつ薬として有用なモノアミン再取り込み阻害作用を有するアザビシクロ［3.2.1］オクタン誘導体（特許文献1）が、肥満、パーキンソン病の治療薬として有用なモノアミン再取り込み阻害作用を有するトロパン誘導体（特許文献2）が、抗うつ、抗不安、鎮痛薬として有用なベンゾアゼピン誘導体（特許文献3）が、NK1および5-HT関連疾患に有用なピペリジン及びアゼパン誘導体（特許文献4）が、鎮痛薬として有用なアゼパン誘導体（特許文献5）が、モノアミン再取り込み阻害作用を有するホモピペラジン化合物（特許文献6）が、また、モノアミン再取り込み阻害剤としてピペリジン化合物（特許文献7）が開示されている。
　さらに、アゼパン化合物として、以下の化合物が公知である。 So far, an azabicyclo [3.2.1] octane derivative having a monoamine reuptake inhibitory action useful as an antidepressant (Patent Document 1) is a tropane derivative having a monoamine reuptake inhibitory action useful as a therapeutic agent for obesity and Parkinson's disease. (Patent Document 2) is a benzoazepine derivative (Patent Document 3) useful as an antidepressant, anxiolytic and analgesic, and piperidine and azepane derivatives (Patent Document 4) useful for NK1 and 5-HT related diseases are analgesic. An azepane derivative (Patent Document 5) useful as a drug is disclosed as a homopiperazine compound (Patent Document 6) having a monoamine reuptake inhibitory action, and a piperidine compound (Patent Document 7) as a monoamine reuptake inhibitor. .
Further, the following compounds are known as azepane compounds.
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　しかし、なお、モノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有し、うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮及び腹圧性尿失禁等の予防または治療薬等として有用であり、かつ、薬効、作用時間、特異性、低毒性等の点で優れた性質を有する化合物の開発が望まれている。 However, monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, depression, anxiety, attention deficit / hyperactivity disorder, menopause, pain, pelvic organ prolapse, fecal incontinence, disuse Development of a compound that is useful as a preventive or therapeutic agent for muscle atrophy, muscle atrophy associated with cachexia and stress urinary incontinence, etc., and has excellent properties in terms of drug efficacy, action time, specificity, low toxicity, etc. It is desired.
国際公開第2009/056520号パンフレットInternational Publication No. 2009/056520 Pamphlet 国際公開第1997/030997号パンフレットInternational Publication No. 1997/030997 Pamphlet 国際公開第2007/137953号パンフレットInternational Publication No. 2007/137953 Pamphlet 国際公開第2004/005256号パンフレットInternational Publication No. 2004/005256 Pamphlet 英国特許出願公開第2056439号明細書UK Patent Application No. 2056439 国際公開第2009/119528号パンフレットInternational Publication No. 2009/119528 Pamphlet 国際公開第2010/016554号パンフレットInternational Publication No. 2010/016554 Pamphlet
　本願発明は、モノアミン再取り込み阻害活性等を有する化合物、及びうつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮および腹圧性尿失禁等の予防または治療薬を提供することを目的とする。 The present invention is associated with a compound having a monoamine reuptake inhibitory activity, etc., and depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, cachexia The object is to provide a preventive or therapeutic agent for muscle atrophy and stress urinary incontinence.
　本願発明者らは、上記課題を解決するために鋭意研究した結果、下記式(I)で表される化合物が、優れたモノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有することを見出し、本願発明を完成するに至った。
　即ち、本願発明は、
［１］式（Ｉ） As a result of diligent research to solve the above problems, the present inventors have found that the compound represented by the following formula (I) has excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity. The present invention has been completed.
That is, the present invention
[1] Formula (I)
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
〔式中、環Ａは、置換基を有するベンゼン環、または置換基を有していてもよい５～６員芳香族複素環を示す； [Wherein, ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent;
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
で表される基は、 The group represented by
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
（式中、環Ｂ１、環Ｂ２または環Ｂ３は、さらに置換基を有していてもよい； (In the formula, ring B 1 , ring B 2 or ring B 3 may further have a substituent;
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
は、単結合または二重結合を示す；
Ｘ１、Ｘ２およびＸ３のいずれか１つは－ＮＨ－を示し、他の２つは各々独立して－ＣＲ２Ｒ３－（Ｒ２およびＲ３は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。）で表される基を示す；
環Ｂが環Ｂ１または環Ｂ２である場合、Ｒ１は、ヒドロキシ基、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示し、
環Ｂが環Ｂ３である場合、Ｒ１は、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、（ａ）ハロゲン原子、（ｂ）Ｃ１－６アルコキシ基、（ｃ）－Ｓ－Ｒ１ａ、（ｄ）－ＳＯ２－Ｒ１ａ、（ｅ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｆ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｇ）－ＮＨ－ＣＯ－Ｒ１ａ、（ｈ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｉ）－ＮＨ－ＳＯ２－Ｒ１ａ、（ｊ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）および（ｋ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル（式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す；
ただし、環Ｂ１、環Ｂ２または環Ｂ３の環構成原子である窒素原子に結合した水素原子は置換されない。）で表される基を示す；
また、環Ａ上の置換基同士が結合して、環Ａと共に、置換基を有していてもよい８～１０員芳香族縮合環を形成してもよい。〕で表される化合物
（ただし、（１）式： Represents a single bond or a double bond;
Any one of X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or an optionally substituted C 1-6 alkyl group).
When Ring B is Ring B 1 or Ring B 2 , R 1 is a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, a substituted C 1-6 alkyl A group, an optionally substituted C 1-6 alkoxy group, or an optionally substituted carbamoyl group,
When ring B is ring B 3 , R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a C 1-6 alkoxy group (C) -S-R 1a , (d) -SO 2 -R 1a , (e) -SO 2 -N (R 1b ) (R 1c ), (f) -N (R 1b ) (R 1c ) (G) —NH—CO—R 1a , (h) —NH—CO—N (R 1b ) (R 1c ), (i) —NH—SO 2 —R 1a , (j) —NH—SO 2 —N (R 1b ) (R 1c ) and (k) 1H-pyrazol-1-yl optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group (wherein R 1a Is a C 1-6 alkyl group, R 1b and R 1c are each independently a hydrogen atom or C 1-6 A C 1-6 alkyl group substituted with 1 to 3 substituents selected from: a C 1-6 alkoxy group which may be substituted, or a carbamoyl group which may be substituted; Indicates;
However, the hydrogen atom bonded to the nitrogen atom which is the ring constituent atom of ring B 1 , ring B 2 or ring B 3 is not substituted. ) Represents a group represented by
In addition, substituents on ring A may be bonded to each other to form an 8- to 10-membered aromatic condensed ring which may have a substituent together with ring A. ] A compound represented by the formula (However, the formula (1):
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（式中、Ｒｘ１は水素原子またはメチル基を示し、Ｒｘ２は－ＣＨ２－ＣＯ－Ｎ（ＣＨ３）－ＣＨＲａ１－Ｒａ２（Ｒａ１は水素原子またはメチル基を、Ｒａ２はハロゲン原子およびトリフルオロメチル基から選択される２個の置換基で３，５－置換されたフェニル基を示す。）で表される基を示し、Ｒｘ３は水素原子またはフッ素原子を示す。）で表される化合物、
（２）式（Ｉ）中、 (Wherein R x1 represents a hydrogen atom or a methyl group, R x2 represents —CH 2 —CO—N (CH 3 ) —CHR a1 —R a2 (R a1 represents a hydrogen atom or a methyl group, and R a2 represents a halogen atom) 2 represents a 3,5-substituted phenyl group with two substituents selected from an atom and a trifluoromethyl group.), And R x3 represents a hydrogen atom or a fluorine atom. The compound represented,
(2) In formula (I),
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
で表される基が、 The group represented by
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
（式中、Ｒ１は上記と同義を表す。）で表される基である化合物、
（３）［４－（４－フルオロフェニル）アゼパン－４－イル］酢酸、
（４）３－アミノ－Ｎ－｛［４－（３－フルオロフェニル）アゼパン－４－イル］メチル｝ピラジン－２－カルボキサミド、
（５）Ｎ－｛［４－（３－フルオロフェニル）アゼパン－４－イル］メチル｝－２－メトキシベンズアミド、
（６）４－（１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル）アゼパン－４－オール、
（７）４－［１－（４－フルオロベンジル）－１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル］アゼパン－４－オール、
（８）４－（４－クロロフェニル）アゼパン－４－オール、
（９）２－［３－（３，４－ジクロロフェニル）アゼパン－３－イル］エタノール、
（１０）４－（３－フルオロフェニル）－７－オキソアゼパン－４－カルボニトリル、
（１１）４－（３－メトキシフェニル）－７－オキソアゼパン－４－カルボニトリル、
（１２）３－（４－フルオロフェニル）アゼパン－３－オール、
（１３）３－（３，４－ジクロロフェニル）－３－［３－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）プロピル］アゼパン、
（１４）３－（３，４－ジクロロフェニル）－３－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］アゼパン、
および
（１５）２－［３－（３－メトキシフェニル）アゼパン－３－イル］エタノール
を除く。）またはその塩（本明細書中、化合物（Ｉ）と称する場合がある）；
［２］式（Ｉ） (Wherein R 1 represents the same meaning as described above),
(3) [4- (4-Fluorophenyl) azepan-4-yl] acetic acid,
(4) 3-amino-N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} pyrazine-2-carboxamide;
(5) N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} -2-methoxybenzamide,
(6) 4- (1H-imidazo [4,5-b] pyridin-2-yl) azepan-4-ol,
(7) 4- [1- (4-Fluorobenzyl) -1H-imidazo [4,5-b] pyridin-2-yl] azepan-4-ol,
(8) 4- (4-chlorophenyl) azepan-4-ol,
(9) 2- [3- (3,4-Dichlorophenyl) azepan-3-yl] ethanol,
(10) 4- (3-Fluorophenyl) -7-oxoazepane-4-carbonitrile,
(11) 4- (3-methoxyphenyl) -7-oxoazepane-4-carbonitrile,
(12) 3- (4-fluorophenyl) azepan-3-ol,
(13) 3- (3,4-Dichlorophenyl) -3- [3- (tetrahydro-2H-pyran-2-yloxy) propyl] azepane,
(14) 3- (3,4-dichlorophenyl) -3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] azepan,
And (15) 2- [3- (3-methoxyphenyl) azepan-3-yl] ethanol. ) Or a salt thereof (sometimes referred to herein as compound (I));
[2] Formula (I)
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
〔式中、環Ａは、置換基を有するベンゼン環、または置換基を有していてもよい５～６員芳香族複素環を示す； [Wherein, ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent;
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
で表される基は、 The group represented by
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
（式中、環Ｂ１または環Ｂ２は、さらに置換基を有していてもよい； (In the formula, ring B 1 or ring B 2 may further have a substituent;
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
は、単結合または二重結合を示す；
Ｘ１、Ｘ２およびＸ３のいずれか１つは－ＮＨ－を示し、他の２つは－ＣＲ２Ｒ３－（Ｒ２およびＲ３は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。）で表される基を示す；
Ｒ１は、ヒドロキシ基、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す；
ただし、環Ｂ１または環Ｂ２の環構成原子である窒素原子に結合した水素原子は置換されない。）で表される基を示す；
また、環Ａ上の置換基同士が結合して、環Ａと共に、置換基を有していてもよい８～１０員芳香族縮合環を形成してもよい。〕で表される［１］記載の化合物
（ただし、（１）式： Represents a single bond or a double bond;
Any one of X 1 , X 2 and X 3 represents —NH—, and the other two represent —CR 2 R 3 — (R 2 and R 3 are the same or different and each represents a hydrogen atom or a substituted Represents an optionally substituted C 1-6 alkyl group).
R 1 represents a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, a substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group. Or an optionally substituted carbamoyl group;
However, the hydrogen atom bonded to the nitrogen atom that is the ring constituent atom of ring B 1 or ring B 2 is not substituted. ) Represents a group represented by
In addition, substituents on ring A may be bonded to each other to form an 8- to 10-membered aromatic condensed ring which may have a substituent together with ring A. The compound of [1] represented by the formula (provided that the formula (1)
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
（式中、Ｒｘ１は水素原子またはメチル基を示し、Ｒｘ２は－ＣＨ２－ＣＯ－Ｎ（ＣＨ３）－ＣＨＲａ１－Ｒａ２（Ｒａ１は水素原子またはメチル基を、Ｒａ２はハロゲン原子およびトリフルオロメチル基から選択される２個の置換基で３，５－置換されたフェニル基を示す。）で表される基を示し、Ｒｘ３は水素原子またはフッ素原子を示す。）で表される化合物、
（２）式（Ｉ）中、 (Wherein R x1 represents a hydrogen atom or a methyl group, R x2 represents —CH 2 —CO—N (CH 3 ) —CHR a1 —R a2 (R a1 represents a hydrogen atom or a methyl group, and R a2 represents a halogen atom) 2 represents a 3,5-substituted phenyl group with two substituents selected from an atom and a trifluoromethyl group.), And R x3 represents a hydrogen atom or a fluorine atom. The compound represented,
(2) In formula (I),
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
で表される基が、 The group represented by
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
（式中、Ｒ１は上記と同義を表す。）で表される基である化合物、
（３）［４－（４－フルオロフェニル）アゼパン－４－イル］酢酸、
（４）３－アミノ－Ｎ－｛［４－（３－フルオロフェニル）アゼパン－４－イル］メチル｝ピラジン－２－カルボキサミド、
（５）Ｎ－｛［４－（３－フルオロフェニル）アゼパン－４－イル］メチル｝－２－メトキシベンズアミド、
（６）４－（１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル）アゼパン－４－オール、
（７）４－［１－（４－フルオロベンジル）－１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル］アゼパン－４－オール、
（８）４－（４－クロロフェニル）アゼパン－４－オール、
（９）４－（３－フルオロフェニル）－７－オキソアゼパン－４－カルボニトリル、および
（１０）４－（３－メトキシフェニル）－７－オキソアゼパン－４－カルボニトリル
を除く。）またはその塩；
［３］式（Ｉ） (Wherein R 1 represents the same meaning as described above),
(3) [4- (4-Fluorophenyl) azepan-4-yl] acetic acid,
(4) 3-amino-N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} pyrazine-2-carboxamide;
(5) N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} -2-methoxybenzamide,
(6) 4- (1H-imidazo [4,5-b] pyridin-2-yl) azepan-4-ol,
(7) 4- [1- (4-Fluorobenzyl) -1H-imidazo [4,5-b] pyridin-2-yl] azepan-4-ol,
(8) 4- (4-chlorophenyl) azepan-4-ol,
(9) 4- (3-Fluorophenyl) -7-oxoazepane-4-carbonitrile and (10) 4- (3-methoxyphenyl) -7-oxoazepane-4-carbonitrile are excluded. ) Or a salt thereof;
[3] Formula (I)
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
〔式中、環Ａは、置換基を有するベンゼン環、または置換基を有していてもよい５～６員芳香族複素環を示す； [Wherein, ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent;
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
で表される基は、 The group represented by
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
（式中、 (Where
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
は、単結合または二重結合を示す；
Ｘ１、Ｘ２およびＸ３のいずれか１つは－ＮＨ－を示し、他の２つは各々独立して－ＣＲ２Ｒ３－（Ｒ２およびＲ３は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。）で表される基を示す；
環Ｂが環Ｂ１または環Ｂ２である場合、Ｒ１は、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、（ａ）ハロゲン原子、（ｂ）ヒドロキシ基、（ｃ）Ｃ１－６アルコキシ基、（ｄ）－Ｓ－Ｒ１ａ、（ｅ）－ＳＯ２－Ｒ１ａ、（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル（式中、Ｒ１ａはＣ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示し、
環Ｂが環Ｂ３である場合、Ｒ１は、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、（ａ）ハロゲン原子、（ｂ）Ｃ１－６アルコキシ基、（ｃ）－Ｓ－Ｒ１ａ、（ｄ）－ＳＯ２－Ｒ１ａ、（ｅ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｆ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｇ）－ＮＨ－ＣＯ－Ｒ１ａ、（ｈ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｉ）－ＮＨ－ＳＯ２－Ｒ１ａ、（ｊ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）および（ｋ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル（式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す；
ただし、環Ｂ１、環Ｂ２または環Ｂ３の環構成原子である窒素原子に結合した水素原子は置換されない。）を示し、環Ｂ１または環Ｂ３は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない。）で表される基を示す〕で表される［１］記載の化合物またはその塩；
［４］式（Ｉ） Represents a single bond or a double bond;
Any one of X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or an optionally substituted C 1-6 alkyl group).
When Ring B is Ring B 1 or Ring B 2 , R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a hydroxy group (C) C 1-6 alkoxy group, (d) —S—R 1a , (e) —SO 2 —R 1a , (f) —SO 2 —N (R 1b ) (R 1c ), (g) -N (R 1b ) (R 1c ), (h) -NH-CO-R 1a , (i) -NH-CO-N (R 1b ) (R 1c ), (j) -NH-SO 2 -R 1a , (k) -NH—SO 2 —N (R 1b ) (R 1c ), and (l) 1H— optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group Pyrazol-1-yl (wherein R 1a is a C 1-6 alkyl group, R 1b and R 1c are Standing and represent a hydrogen atom or a C 1-6 alkyl group. 1 is selected from) to C 1-6 alkyl group substituted with three substituents, which may be substituted C 1-6 alkoxy group Or an optionally substituted carbamoyl group,
When ring B is ring B 3 , R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a C 1-6 alkoxy group (C) -S-R 1a , (d) -SO 2 -R 1a , (e) -SO 2 -N (R 1b ) (R 1c ), (f) -N (R 1b ) (R 1c ) (G) —NH—CO—R 1a , (h) —NH—CO—N (R 1b ) (R 1c ), (i) —NH—SO 2 —R 1a , (j) —NH—SO 2 —N (R 1b ) (R 1c ) and (k) 1H-pyrazol-1-yl optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group (wherein R 1a Is a C 1-6 alkyl group, R 1b and R 1c are each independently a hydrogen atom or C 1-6 A C 1-6 alkyl group substituted with 1 to 3 substituents selected from: a C 1-6 alkoxy group which may be substituted, or a carbamoyl group which may be substituted; Indicates;
However, the hydrogen atom bonded to the nitrogen atom which is the ring constituent atom of ring B 1 , ring B 2 or ring B 3 is not substituted. Ring B 1 or ring B 3 has no substituent other than ring A and R 1 , and ring B 2 is any of ring A, R 1 , X 1 , X 2 and X 3 . When has a substituent, it has no substituent other than the substituent. A compound represented by [1] or a salt thereof;
[4] Formula (I)
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
〔式中、環Ａは、置換基を有するベンゼン環、または置換基を有していてもよい５～６員芳香族複素環を示す； [Wherein, ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent;
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
で表される基は、 The group represented by
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
（式中、 (Where
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
は、単結合または二重結合を示す；
Ｘ１、Ｘ２およびＸ３のいずれか１つは－ＮＨ－を示し、他の２つは各々独立して－ＣＲ２Ｒ３－（Ｒ２およびＲ３は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。）で表される基を示す；
Ｒ１は、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、（ａ）ハロゲン原子、（ｂ）ヒドロキシ基、（ｃ）Ｃ１－６アルコキシ基、（ｄ）－Ｓ－Ｒ１ａ、（ｅ）－ＳＯ２－Ｒ１ａ、（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）および（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル（式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す；
ただし、環Ｂ１または環Ｂ２の環構成原子である窒素原子に結合した水素原子は置換されない。）を示し、環Ｂ１は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない。）で表される基を示す〕で表される［１］記載の化合物またはその塩；
［５］環Ａが、ハロゲン原子およびＣ１－６アルキル基から選択される１ないし３個の置換基で置換されたベンゼン環であり、
Ｒ１が、
（１）ヒドロキシ基、
（２）Ｃ１－６アルコキシ－カルボニル基、
（３）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ１－６アルコキシ基、
　　　（ｄ）－Ｓ－Ｒ１ａ、
　　　（ｅ）－ＳＯ２－Ｒ１ａ、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、
　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルコキシ基、
（４）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、および
　　　（ｃ）Ｃ１－６アルコキシ基
から選択される１ないし３個の置換基で置換されてもよいモノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ基、
（５）Ｃ１－６アルキルスルホニルアミノ基、
（６）スルファモイルアミノ基、または
（７）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ１－６アルコキシ基、
　　　（ｄ）－Ｓ－Ｒ１ａ、
　　　（ｅ）－ＳＯ２－Ｒ１ａ、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、
　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基であり、
環Ｂ１または環Ｂ３は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない［１］に記載の化合物またはその塩；
［６］環Ａが、１ないし３個のハロゲン原子で置換されたベンゼン環であり、
Ｒ１が、
（１）（ａ）ヒドロキシ基、
　　　（ｂ）－ＳＯ２－Ｒ１ａ、および
　　　（ｃ）－ＮＨ－ＳＯ２－Ｒ１ａ
（式中、Ｒ１ａは、Ｃ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、または
　　（２）Ｃ１－６アルキルスルホニルアミノ基
　　であり、
環Ｂ１または環Ｂ３は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない［１］に記載の化合物またはその塩；
［７］（３Ｒ，４Ｒ）－３－（３－クロロ－４－フルオロフェニル）－４－［（メチルスルホニル）メチル］アゼパンまたはその塩；
［８］（３ＲＳ，４ＲＳ）－３－（３，４－ジクロロフェニル）－４－［（メチルスルホニル）メチル］アゼパンの光学活性体またはその塩；
［９］Ｎ－［（３Ｒ，４Ｒ）－３－（３，４－ジクロロフェニル）アゼパン－４－イル］メタンスルホンアミドまたはその塩；
［１０］（１ＲＳ）－１－［（３ＳＲ，４ＲＲ）－３－（３，４－ジクロロフェニル）アゼパン－４－イル］エタン－１，２－ジオールまたはその塩；
［１１］５－（３，４－ジクロロフェニル）－６－［（メチルスルホニル）メチル］－２，３，４，７－テトラヒドロ－１Ｈ－アゼピンまたはその塩；
［１２］［１］記載の化合物またはその塩を含有する医薬；
［１３］モノアミン再取り込み阻害薬である［１２］記載の医薬；
［１４］うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮または腹圧性尿失禁の予防または治療薬である［１２］記載の医薬；
［１５］哺乳動物に対して［１］記載の化合物またはその塩の有効量を投与することを特徴とするうつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮または腹圧性尿失禁の予防・治療方法；
［１６］うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮または腹圧性尿失禁の予防・治療剤を製造するための、［１］記載の化合物またはその塩の使用；
［１７］うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮または腹圧性尿失禁の予防・治療に使用するための、［１］記載の化合物またはその塩
を提供するものである。 Represents a single bond or a double bond;
Any one of X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or an optionally substituted C 1-6 alkyl group).
R 1 is a cyano group, optionally carboxy group which may be substituted, an optionally substituted amino group, (a) a halogen atom, (b) a hydroxy group, (c) C 1-6 alkoxy group, (d) —S—R 1a , (e) —SO 2 —R 1a , (f) —SO 2 —N (R 1b ) (R 1c ), (g) —N (R 1b ) (R 1c ), (h) -NH-CO-R 1a , (i) -NH-CO-N (R 1b ) (R 1c ), (j) -NH-SO 2 -R 1a , (k) -NH-SO 2 -N (R 1b ) (R 1c ) and (l) 1H-pyrazol-1-yl optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group (wherein R 1a is C 1 -6 alkyl group, R 1b and R 1c are each independently a hydrogen atom or C 1-6 alkyl It 1 is selected from the representative.) Are shown three substituted with a substituent a C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group or an optionally substituted carbamoyl group, ;
However, the hydrogen atom bonded to the nitrogen atom that is the ring constituent atom of ring B 1 or ring B 2 is not substituted. Ring B 1 has no substituent other than ring A and R 1 , and ring B 2 is a ring A, R 1 , and any one of X 1 , X 2 and X 3 is a substituent When it has, it has no substituent other than the substituent. A compound represented by [1] or a salt thereof;
[5] Ring A is a benzene ring substituted with 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group,
R 1 is
(1) a hydroxy group,
(2) a C 1-6 alkoxy-carbonyl group,
(3) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group,
(D) -S-R 1a,
(E) —SO 2 —R 1a ,
(F) —SO 2 —N (R 1b ) (R 1c ),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ),
(J) —NH—SO 2 —R 1a ,
(K) —NH—SO 2 —N (R 1b ) (R 1c ), and (l) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group 1 to 3 selected from 1-yl (wherein R 1a represents a C 1-6 alkyl group, and R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group). A C 1-6 alkoxy group substituted with one substituent,
(4) (a) a halogen atom,
(B) hydroxy groups, and (c) C 1-6 to 1 is selected from an alkoxy group which may be substituted with 1-3 substituents mono - or di - (C 1-6 alkyl - carbonyl) amino group,
(5) a C 1-6 alkylsulfonylamino group,
(6) a sulfamoylamino group, or (7) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group,
(D) -SR 1a ,
(E) —SO 2 —R 1a ,
(F) —SO 2 —N (R 1b ) (R 1c ),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ),
(J) —NH—SO 2 —R 1a ,
(K) —NH—SO 2 —N (R 1b ) (R 1c ), and (l) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group 1 to 3 selected from 1-yl (wherein R 1a represents a C 1-6 alkyl group, and R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group). A C 1-6 alkyl group substituted with one substituent,
Ring B 1 or Ring B 3 has no substituents other than Ring A and R 1 , and Ring B 2 is a ring A, R 1 , and any one of X 1 , X 2 and X 3 is a substituent The compound or a salt thereof according to [1], which has no substituent other than that substituent;
[6] Ring A is a benzene ring substituted with 1 to 3 halogen atoms,
R 1 is
(1) (a) a hydroxy group,
(B) —SO 2 —R 1a , and (c) —NH—SO 2 —R 1a
(Wherein, R 1a is, C 1-6 alkyl group.) 1 is selected from to three substituted with a substituent a C 1-6 alkyl group or (2) C 1-6 alkylsulfonyl, An amino group,
Ring B 1 or Ring B 3 has no substituents other than Ring A and R 1 , and Ring B 2 is a ring A, R 1 , and any one of X 1 , X 2 and X 3 is a substituent The compound or a salt thereof according to [1], which has no substituent other than that substituent;
[7] (3R, 4R) -3- (3-chloro-4-fluorophenyl) -4-[(methylsulfonyl) methyl] azepane or a salt thereof;
[8] (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane optically active substance or a salt thereof;
[9] N-[(3R, 4R) -3- (3,4-dichlorophenyl) azepan-4-yl] methanesulfonamide or a salt thereof;
[10] (1RS) -1-[(3SR, 4RR) -3- (3,4-dichlorophenyl) azepan-4-yl] ethane-1,2-diol or a salt thereof;
[11] 5- (3,4-dichlorophenyl) -6-[(methylsulfonyl) methyl] -2,3,4,7-tetrahydro-1H-azepine or a salt thereof;
[12] A medicament containing the compound or salt thereof according to [1];
[13] The medicament according to [12], which is a monoamine reuptake inhibitor;
[14] Preventive or therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia or stress urinary incontinence [12] The pharmaceutical according to [12];
[15] Depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse characterized by administering an effective amount of the compound or salt thereof according to [1] to a mammal Prevention, treatment of fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia or stress urinary incontinence;
[16] Prevention / treatment agent for depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia or stress urinary incontinence Use of the compound according to [1] or a salt thereof for the production of
[17] For prevention / treatment of depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia or stress urinary incontinence The compound or salt thereof according to [1] for use.
　本願発明はまた、
［１Ａ］式（Ｉ） The present invention also provides
[1A] Formula (I)
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
〔式中、環Ａは、置換基を有するベンゼン環、または置換基を有していてもよい５～６員芳香族複素環を示し、 [Wherein, ring A represents a benzene ring having a substituent, or a 5- to 6-membered aromatic heterocycle optionally having a substituent,
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
で表される基は、 The group represented by
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
または Or
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
（式中、環Ｂ1および環Ｂ2は、さらに置換基を有していてもよい； (In the formula, ring B 1 and ring B 2 may further have a substituent;
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
は、単結合または二重結合を示す；
Ｘ1、Ｘ2およびＸ3のいずれか１つは－ＮＨ－、他の２つは－ＣＲ2Ｒ3－（Ｒ2およびＲ3は、同一または異なって、水素原子または置換されていてもよいＣ1-6アルキル基を示す。）で表される基を示す；
Ｒ1は、ヒドロキシ基、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、置換されたＣ1-6アルキル基、置換されていてもよいＣ1-6アルコキシ基、または置換されていてもよいカルバモイル基を示す；
ただし、環Ｂ1および環Ｂ2の環構成原子である窒素原子に結合した水素原子は置換されない。）を示す；
また、環Ａ上の置換基同士が結合して、環Ａと共に、置換基を有していてもよい８～１０員芳香族縮合環を形成してもよい。〕で表される化合物
（ただし、（１）式： Represents a single bond or a double bond;
Any one of X 1 , X 2 and X 3 is —NH—, and the other two are —CR 2 R 3 — (R 2 and R 3 may be the same or different and may be a hydrogen atom or substituted Represents a good C 1-6 alkyl group.);
R 1 represents a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, a substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group. Or an optionally substituted carbamoyl group;
However, a hydrogen atom bonded to a nitrogen atom that is a ring constituting atom of ring B 1 or ring B 2 is not substituted. );
In addition, substituents on ring A may be bonded to each other to form an 8- to 10-membered aromatic condensed ring which may have a substituent together with ring A. ] A compound represented by the formula (However, the formula (1):
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
（式中、Ｒx1は水素原子またはメチル基を示し、Ｒx2は－ＣＨ２－ＣＯ－Ｎ(ＣＨ3)-ＣＨＲa1-Ｒa2（Ｒa１は水素原子またはメチル基を、Ｒa2はハロゲン原子およびトリフルオロメチル基から選択される２個の置換基で３，５－置換されたフェニル基を示す。）で表される基を示し、Ｒx3は水素原子またはフッ素原子を示す。）で表される化合物、
（２）式（Ｉ）中、 (Wherein R x1 represents a hydrogen atom or a methyl group, R x2 represents —CH 2 —CO—N (CH 3 ) —CHR a1 —R a2 (R a1 represents a hydrogen atom or a methyl group, and R a2 represents a halogen atom) And a phenyl group which is 3,5-substituted with two substituents selected from an atom and a trifluoromethyl group.) And R x3 represents a hydrogen atom or a fluorine atom. The compound represented,
(2) In formula (I),
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
で表される基が、 The group represented by
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
（Ｒ1は上記と同義を表す。）で表される基である化合物、
（３）[4-(4-フルオロフェニル)アゼパン-4-イル]酢酸、
（４）3-アミノ-N-{[4-(3-フルオロフェニル)アゼパン-4-イル]メチル}ピラジン-2-カルボキサミド、
（５）N-{[4-(3-フルオロフェニル)アゼパン-4-イル]メチル}-2-メトキシベンズアミド、
（６）4-(1H-イミダゾ[4,5-b]ピリジン-2-イル)アゼパン-4-オール、
（７）4-[1-(4-フルオロベンジル)-1H-イミダゾ[4,5-b]ピリジン-2-イル]アゼパン-4-オール、
（８）4-(4-クロロフェニル)アゼパン-4-オール、
（９）2-[3-(3,4-ジクロロフェニル)アゼパン-3-イル]エタノール、
（１０）4-(3-フルオロフェニル)-7-オキソアゼパン-4-カルボニトリル、および
（１１）4-(3-メトキシフェニル)-7-オキソアゼパン-4-カルボニトリルを除く。）またはその塩、
［２Ａ］［１Ａ］記載の化合物またはその塩を含有する医薬、
［３Ａ］モノアミン再取り込み阻害薬である［２Ａ］記載の医薬、
［４Ａ］うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛または腹圧性尿失禁の予防または治療薬である［２Ａ］記載の医薬、
を提供するものである。 A compound that is a group represented by (R 1 is as defined above);
(3) [4- (4-Fluorophenyl) azepan-4-yl] acetic acid,
(4) 3-amino-N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} pyrazine-2-carboxamide;
(5) N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} -2-methoxybenzamide,
(6) 4- (1H-imidazo [4,5-b] pyridin-2-yl) azepan-4-ol,
(7) 4- [1- (4-Fluorobenzyl) -1H-imidazo [4,5-b] pyridin-2-yl] azepan-4-ol,
(8) 4- (4-chlorophenyl) azepan-4-ol,
(9) 2- [3- (3,4-dichlorophenyl) azepan-3-yl] ethanol,
(10) 4- (3-Fluorophenyl) -7-oxoazepan-4-carbonitrile and (11) 4- (3-methoxyphenyl) -7-oxoazepan-4-carbonitrile are excluded. ) Or its salt,
[2A] A medicament containing the compound or salt thereof according to [1A],
[3A] The medicament according to [2A], which is a monoamine reuptake inhibitor
[4A] The medicament according to [2A], which is a prophylactic or therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain or stress urinary incontinence,
Is to provide.
　本願発明の化合物は、優れたモノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有するため、例えば、うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮および腹圧性尿失禁等の予防または治療薬を提供することができる。 Since the compound of the present invention has an excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, for example, depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, Prophylactic or therapeutic agents for fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia and stress urinary incontinence can be provided.
（発明の詳細な説明）
　本願発明について以下詳細に説明する。
　本明細書中、「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 (Detailed description of the invention)
The present invention will be described in detail below.
In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
　本明細書中、「Ｃ1-6アルキル基」としては、直鎖状もしくは分岐鎖状のＣ1-6アルキル基が挙げられ、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、1-メチルプロピル、ペンチル、イソペンチル、ネオペンチル、tert-ペンチル、1,2-ジメチルプロピル、ヘキシル、2-メチルペンチル、3-メチルペンチル、1,2-ジメチルブチル、1,2,2-トリメチルプロピルが挙げられる。 In the present specification, examples of the “C 1-6 alkyl group” include linear or branched C 1-6 alkyl groups 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.
　本明細書中、「Ｃ1-6アルコキシ基」としては、直鎖状もしくは分岐鎖状のＣ1-6アルコキシ基が挙げられ、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ、1-メチルプロポキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、tert-ペンチルオキシ、1,2-ジメチルプロポキシ、ヘキシルオキシ、2-メチルペンチルオキシ、3-メチルペンチルオキシ、1,2-ジメチルブトキシ、1,2,2-トリメチルプロポキシが挙げられる。 In the present specification, examples of the “C 1-6 alkoxy group” include linear or branched C 1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec -Butoxy, tert-butoxy, 1-methylpropoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy, hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, Examples include 1,2-dimethylbutoxy and 1,2,2-trimethylpropoxy.
　本明細書中、「置換されていてもよい環状アミノ」の「環状アミノ」としては、例えば、1-アゼチジニル、1-ピロリジニル、ピペリジノ、チオモルホリノ、モルホリノ、1-ピペラジニル、1-ピロリル、1-イミダゾリル等の３ないし８員（好ましくは５または６員）の環状アミノが挙げられる。 In the present specification, examples of the “cyclic amino” of the “optionally substituted cyclic amino” include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl, 1-pyrrolyl, 1-pyrrolyl, Examples thereof include 3- to 8-membered (preferably 5- or 6-membered) cyclic amino such as imidazolyl.
　本明細書中、「Ｃ6-10アリール」としては、フェニル、1-ナフチル、2-ナフチル等が挙げられる。 In the present specification, examples of “C 6-10 aryl” include phenyl, 1-naphthyl, 2-naphthyl and the like.
　本明細書中、「Ｃ7-12アラルキル」としては、ベンジル、2-フェニルエチル、1-フェニルエチル、3-フェニルプロピル、4-フェニルブチル、1-ナフチルメチル、2-ナフチルメチル等が挙げられる。 In the present specification, examples of “C 7-12 aralkyl” include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. .
　本明細書中、「Ｃ3-6シクロアルキル」としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等が挙げられる。 In the present specification, examples of “C 3-6 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
　環Ａで表される「置換基を有していてもよい５～６員芳香族複素環」の「５～６員芳香族複素環」としては、1ないし3個の窒素原子、硫黄原子又は酸素原子を含有する５～６員芳香族複素環（例、ピリジン、ピラジン、ピリミジン、ピリダジン、トリアジン、ピロール、ピラゾール、チアゾール、オキサゾール、イミダゾール）などが挙げられる。 The “5- to 6-membered aromatic heterocycle” of the “optionally substituted 5- to 6-membered aromatic heterocycle” represented by ring A includes 1 to 3 nitrogen atoms, sulfur atoms, or Examples include 5- to 6-membered aromatic heterocycles containing oxygen atoms (eg, pyridine, pyrazine, pyrimidine, pyridazine, triazine, pyrrole, pyrazole, thiazole, oxazole, imidazole).
　環Ａで表される５～６員芳香族複素環が有していてもよい置換基としては、
（１）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、
（２）シアノ、
（３）ヒドロキシ、
（４）1ないし3個のハロゲン原子で置換されていてもよいＣ1-6アルキル基、および
（５）1ないし3個のハロゲン原子で置換されていてもよいＣ1-6アルコキシ基
から選択される置換基が挙げられる。該置換基の数は1ないし5個、好ましくは1ないし3個、より好ましくは1または2個である。置換基が複数存在する場合、各置換基は同一であっても異なっていてもよい。 As the substituent that the 5- to 6-membered aromatic heterocycle represented by ring A may have,
(1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom),
(2) cyano,
(3) hydroxy,
(4) Select an optionally substituted C 1-6 alkyl group, and (5) 1 to the three a C 1-6 alkoxy group optionally substituted with a halogen atom 1 to 3 halogen atoms The substituent which is made is mentioned. The number of the substituent is 1 to 5, preferably 1 to 3, and more preferably 1 or 2. When a plurality of substituents are present, each substituent may be the same or different.
　環Ａで表される「置換基を有するベンゼン環」は、１～５個の置換基を有し、置換基が複数存在する場合、各置換基は同一であっても異なっていてもよい。該「置換基を有するベンゼン環」としては、ハロゲン原子（例、フッ素原子、塩素原子）、Ｃ1-6アルキル基（例、メチル）およびＣ1-6アルコキシ基から選択される1ないし3個（好ましくは2個）の置換基で置換されたベンゼン環が好ましく、ハロゲン原子（例、フッ素原子、塩素原子）およびＣ１－６アルキル基（例、メチル）から選択される１ないし３個（好ましくは２個）の置換基で置換されたベンゼン環がより好ましく、特に、１ないし３個（とりわけ2個）のハロゲン原子（例、フッ素原子、塩素原子）で置換されたベンゼン環が好ましい。 The “benzene ring having a substituent” represented by ring A has 1 to 5 substituents, and when a plurality of substituents are present, each substituent may be the same or different. The “substituent benzene ring” is 1 to 3 selected from a halogen atom (eg, fluorine atom, chlorine atom), a C 1-6 alkyl group (eg, methyl) and a C 1-6 alkoxy group. A benzene ring substituted with (preferably 2) substituents is preferred, and 1 to 3 (selected from a halogen atom (eg, fluorine atom, chlorine atom) and a C 1-6 alkyl group (eg, methyl) ( A benzene ring substituted with 2) substituents is more preferred, and a benzene ring substituted with 1 to 3 (especially 2) halogen atoms (eg, fluorine atom, chlorine atom) is particularly preferred.
　環Ａ上の置換基同士が結合して、環Ａと共に形成する「置換基を有していてもよい８～１０員芳香族縮合環」の「８～１０員芳香族縮合環」としては、ナフタレン、ベンゾフラン、インダゾール等が挙げられる。当該「８～１０員芳香族縮合環」が有していてもよい置換基としては、環Ａで表される５～６員芳香族複素環が有していてもよい置換基と同様のものが挙げられる。該置換基の数は1ないし5個、好ましくは1ないし3個、より好ましくは1または2個である。置換基が複数存在する場合、各置換基は同一であっても異なっていてもよい。 As the “8 to 10-membered aromatic condensed ring” of the “optionally substituted 8- to 10-membered aromatic condensed ring” formed by combining the substituents on the ring A together with the ring A, Naphthalene, benzofuran, indazole and the like can be mentioned. The substituent that the “8 to 10-membered aromatic condensed ring” may have is the same as the substituent that the 5 to 6-membered aromatic heterocyclic ring represented by ring A may have. Is mentioned. The number of the substituent is 1 to 5, preferably 1 to 3, and more preferably 1 or 2. When a plurality of substituents are present, each substituent may be the same or different.
　環Ａとしては、「置換基を有するベンゼン環」が好ましい。
　環Ａとしては、好ましくは、 As ring A, a “benzene ring having a substituent” is preferable.
As ring A, preferably,
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
等の、２個のハロゲン原子で置換されたベンゼン環が挙げられる。特に好ましくは、 And a benzene ring substituted with two halogen atoms. Particularly preferably,
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
である。 It is.
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
で表される基は、 The group represented by
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
で表される基を示す。
　環Ｂ1、環Ｂ2または環Ｂ３はさらに置換基を有していてもよい。ただし、環Ｂ1、環Ｂ2または環Ｂ３を構成する窒素原子に結合した水素原子は置換されないことが好ましい。環Ｂ、環Ｂ2または環Ｂ３がさらに有していてもよい置換基としては、
（１）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、
（２）シアノ基、
（３）ヒドロキシ基、
（４）1ないし3個のハロゲン原子で置換されていてもよいＣ1-6アルキル基、
（５）1ないし3個のハロゲン原子で置換されていてもよいＣ1-6アルコキシ基、および
（６）オキソ基
から選択される置換基が挙げられる。該置換基の数は1ないし5個、好ましくは1ないし3個、より好ましくは1または2個である。置換基が複数存在する場合、各置換基は同一であっても異なっていてもよい。 The group represented by these is shown.
Ring B 1 , ring B 2 or ring B 3 may further have a substituent. However, it is preferable that the hydrogen atom bonded to the nitrogen atom constituting Ring B 1 , Ring B 2 or Ring B 3 is not substituted. As the substituent that ring B, ring B 2 or ring B 3 may further have,
(1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom),
(2) a cyano group,
(3) a hydroxy group,
(4) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(5) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and (6) a substituent selected from an oxo group. The number of the substituent is 1 to 5, preferably 1 to 3, and more preferably 1 or 2. When a plurality of substituents are present, each substituent may be the same or different.
　環Ｂ1、環Ｂ2または環Ｂ３は、環ＡおよびＲ1以外の置換基を有していない態様が好ましい。 Ring B 1 , ring B 2 or ring B 3 preferably has no substituent other than ring A and R 1 .
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
は、単結合または二重結合を示す。 Represents a single bond or a double bond.
　Ｘ１、Ｘ２およびＸ３のいずれか１つは－ＮＨ－を示し、他の２つは各々独立して－ＣＲ２Ｒ３－（Ｒ２およびＲ３は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。）で表される基を示す。 Any one of X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or a C 1-6 alkyl group which may be substituted.).
　環Ｂが環Ｂ１または環Ｂ２である場合、Ｒ１は、ヒドロキシ基、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す。
　環Ｂが環Ｂ３である場合、Ｒ１は、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、（ａ）ハロゲン原子、（ｂ）Ｃ１－６アルコキシ基、（ｃ）－Ｓ－Ｒ１ａ、（ｄ）－ＳＯ２－Ｒ１ａ、（ｅ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｆ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｇ）－ＮＨ－ＣＯ－Ｒ１ａ、（ｈ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｉ）－ＮＨ－ＳＯ２－Ｒ１ａ、（ｊ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）および（ｋ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル（式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す。 When Ring B is Ring B 1 or Ring B 2 , R 1 is a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, a substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or an optionally substituted carbamoyl group,.
When ring B is ring B 3 , R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a C 1-6 alkoxy group (C) -S-R 1a , (d) -SO 2 -R 1a , (e) -SO 2 -N (R 1b ) (R 1c ), (f) -N (R 1b ) (R 1c ) (G) —NH—CO—R 1a , (h) —NH—CO—N (R 1b ) (R 1c ), (i) —NH—SO 2 —R 1a , (j) —NH—SO 2 —N (R 1b ) (R 1c ) and (k) 1H-pyrazol-1-yl optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group (wherein R 1a Is a C 1-6 alkyl group, R 1b and R 1c are each independently a hydrogen atom or C 1-6 A C 1-6 alkyl group substituted with 1 to 3 substituents selected from: a C 1-6 alkoxy group which may be substituted, or an carbamoyl group which may be substituted; Indicates.
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
で表される基としては、好ましくは、 As the group represented by
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
で表される基が挙げられ、より好ましくは、Ｘ１、Ｘ２およびＸ３の組み合わせ（Ｘ１、Ｘ２、Ｘ３）は（－ＮＨ－、－ＣＨ２－、－ＣＨ２－）または（－ＣＨ２－、－ＣＨ２－、－ＮＨ－）であり、環Ｂ２は環ＡおよびＲ1以外の置換基を有していない。 More preferably, the combination of X 1 , X 2 and X 3 (X 1 , X 2 , X 3 ) is (—NH—, —CH 2 —, —CH 2 —) or (-CH 2 -, - CH 2 -, - NH-) and is, ring B 2 does not have a ring a and R 1 substituent other than.
　本明細書中、「置換されていてもよいＣ1-6アルキル基」の「Ｃ1-6アルキル基」が有していてもよい置換基、および「置換されたＣ1-6アルキル基」の「Ｃ1-6アルキル基」が有する置換基としては、
（１）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、
（２）シアノ基、
（３）ヒドロキシ基、
（４）ニトロ基、
（５）ホルミル基、
（６）アミノ基、
（７）モノ-またはジ-Ｃ1-6アルキルアミノ基（例、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ）、
（８）Ｃ1-6アルキル-カルボニルアミノ基（例、アセチルアミノ、エチルカルボニルアミノ）、
（９）Ｃ1-6アルコキシ-カルボニルアミノ基（例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、tert-ブトキシカルボニルアミノ）、
（１０）1ないし3個のハロゲン原子で置換されていてもよいＣ1-6アルコキシ基（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ、トリフルオロメトキシ）、
（１１）Ｃ7-12アラルキルオキシ基（例、ベンジルオキシ）、
（１２）Ｃ6-10アリールオキシ基（例、フェノキシ）、
（１３）Ｃ1-6アルキル-カルボニルオキシ基（例、アセチルオキシ）、
（１４）カルボキシ基、
（１５）Ｃ1-6アルコキシ-カルボニル基（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、tert-ブトキシカルボニル）、
（１６）Ｃ7-12アラルキルオキシ-カルボニル基（例、ベンジルオキシカルボニル）、
（１７）Ｃ6-10アリールオキシ-カルボニル基（例、フェニルオキシカルボニル）、
（１８）Ｃ1-6アルキル-カルボニル基（例、アセチル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、2,2-ジメチルプロピルカルボニル）、
（１９）Ｃ3-6シクロアルキル-カルボニル基（例、シクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニル）、
（２０）Ｃ7-12アラルキル-カルボニル基（例、ベンジルカルボニル）、
（２１）Ｃ6-10アリール-カルボニル基（例、ベンゾイル）、
（２２）カルバモイル基、
（２３）チオカルバモイル基、
（２４）モノ-またはジ-（Ｃ1-6アルキル）カルバモイル基（例、メチルカルバモイル、エチルカルバモイル、プロピルカルバモイル、イソプロピルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイル、ジプロピルカルバモイル）、
（２５）モノ-またはジ-（Ｃ7-12アラルキル）カルバモイル基（例、ベンジルカルバモイル、ジベンジルカルバモイル）、
（２６）チオール基、
（２７）Ｃ1-6アルキルチオ基（例、メチルチオ、エチルチオ、プロピルチオ）、
（２８）Ｃ7-12アラルキルチオ基（例、ベンジルチオ）、
（２９）Ｃ1-6アルキルスルホニル基（例、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル）、
（３０）Ｃ3-6シクロアルキルスルホニル基（例、シクロプロピルスルホニル、シクロブチルスルホニル、シクロペンチルスルホニル）、
（３１）Ｃ6-10アリールスルホニル基（例、フェニルスルホニル、1-ナフチルスルホニル、2-ナフチルスルホニル）、
（３２）Ｃ7-12アラルキルスルホニル基（例、ベンジルスルホニル）、
（３３）ウレイド基、
（３４）モノ-またはジ-（Ｃ1-6アルキル）ウレイド基（例、メチルウレイド、エチルウレイド、プロピルウレイド）、
（３５）モノ-またはジ-（Ｃ6-10アリール）ウレイド基（例、フェニルウレイド、1-ナフチルウレイド、2-ナフチルウレイド）、
（３６）スルファモイル基、
（３７）モノ-またはジ-（Ｃ1-6アルキル）スルファモイル基（例、メチルスルファモイル）、
（３８）1ないし3個のハロゲン原子で置換されていてもよいＣ1-6アルキルスルホニルアミノ基（例、メチルスルホニルアミノ、エチルスルホニルアミノ）、
（３９）スルファモイルアミノ基、
（４０）モノ-またはジ-（Ｃ1-6アルキル）スルファモイルアミノ基（例、メチルスルファモイルアミノ、エチルスルファモイルアミノ、ジメチルスルファモイルアミノ）、および
（４１）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい５～６員芳香族複素環（例、ピラゾリル（例えば、１Ｈ－ピラゾール－１－イル））
から選択される置換基が挙げられる。該置換基の数は1ないし4個、好ましくは1ないし3個、より好ましくは1個である。置換基が複数存在する場合、各置換基は同一であっても異なっていてもよい。 In the present specification, the “C 1-6 alkyl group” of the “ optionally substituted C 1-6 alkyl group” may have a substituent, and the “substituted C 1-6 alkyl group” As the substituent of the “C 1-6 alkyl group” of
(1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom),
(2) a cyano group,
(3) a hydroxy group,
(4) Nitro group,
(5) formyl group,
(6) amino group,
(7) mono- or di-C 1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino),
(8) C 1-6 alkyl-carbonylamino group (eg, acetylamino, ethylcarbonylamino),
(9) C 1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino),
(10) C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy) ),
(11) C 7-12 aralkyloxy group (eg, benzyloxy),
(12) C 6-10 aryloxy group (eg, phenoxy),
(13) C 1-6 alkyl-carbonyloxy group (eg, acetyloxy),
(14) a carboxy group,
(15) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl),
(16) C 7-12 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl),
(17) C 6-10 aryloxy-carbonyl group (eg, phenyloxycarbonyl),
(18) C 1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, 2,2-dimethylpropylcarbonyl),
(19) C 3-6 cycloalkyl-carbonyl group (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl),
(20) C 7-12 aralkyl-carbonyl group (eg, benzylcarbonyl),
(21) C 6-10 aryl-carbonyl group (eg, benzoyl),
(22) a carbamoyl group,
(23) a thiocarbamoyl group,
(24) mono- or di- (C 1-6 alkyl) carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl),
(25) mono- or di- (C 7-12 aralkyl) carbamoyl group (eg, benzylcarbamoyl, dibenzylcarbamoyl),
(26) a thiol group,
(27) C 1-6 alkylthio group (eg, methylthio, ethylthio, propylthio),
(28) C 7-12 aralkylthio group (eg, benzylthio),
(29) C 1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl),
(30) C 3-6 cycloalkylsulfonyl group (eg, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl),
(31) C 6-10 arylsulfonyl group (eg, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl),
(32) C 7-12 aralkylsulfonyl group (eg, benzylsulfonyl),
(33) Ureido group,
(34) mono- or di- (C 1-6 alkyl) ureido groups (eg, methylureido, ethylureido, propylureido),
(35) mono- or di- (C 6-10 aryl) ureido group (eg, phenylureido, 1-naphthylureido, 2-naphthylureido),
(36) a sulfamoyl group,
(37) mono- or di- (C 1-6 alkyl) sulfamoyl group (eg, methylsulfamoyl),
(38) a C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino) optionally substituted with 1 to 3 halogen atoms,
(39) Sulfamoylamino group,
(40) mono- or di- (C 1-6 alkyl) sulfamoylamino groups (eg, methylsulfamoylamino, ethylsulfamoylamino, dimethylsulfamoylamino), and (41) carboxy group and methyl 5- to 6-membered aromatic heterocycle optionally substituted with 1 to 3 substituents selected from the group (eg, pyrazolyl (eg, 1H-pyrazol-1-yl))
The substituent selected from these is mentioned. The number of the substituent is 1 to 4, preferably 1 to 3, and more preferably 1. When a plurality of substituents are present, each substituent may be the same or different.
　本明細書中、「置換されていてもよいＣ1-6アルコキシ基」の「Ｃ1-6アルコキシ基」が有していてもよい置換基としては、前記の「置換されていてもよいＣ1-6アルキル基」が有していてもよい置換基と同様のものが挙げられる。該置換基の数は1ないし4個、好ましくは1ないし3個、より好ましくは1個である。置換基が複数存在する場合、各置換基は同一であっても異なっていてもよい。 In the present specification, the substituent that the “C 1-6 alkoxy group” of the “optionally substituted C 1-6 alkoxy group” may have is the above-mentioned “optionally substituted C 1 Examples thereof include the same substituents that the “ 1-6 alkyl group” may have. The number of the substituent is 1 to 4, preferably 1 to 3, and more preferably 1. When a plurality of substituents are present, each substituent may be the same or different.
　本明細書中、「置換されていてもよいカルボキシ基」としては、
（１）カルボキシ基、
（２）Ｃ1-6アルコキシ-カルボニル基（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ブトキシカルボニル、tert-ブトキシカルボニル）、
（３）Ｃ6-10アリールオキシ-カルボニル基（例、フェノキシカルボニル、ナフトキシカルボニル）、
（４）Ｃ7-12アラルキルオキシ-カルボニル基（例、ベンジルオキシカルボニル、2-フェニルエチルオキシカルボニル）
が挙げられる。 In the present specification, the “optionally substituted carboxy group”
(1) a carboxy group,
(2) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl),
(3) C 6-10 aryloxy-carbonyl group (eg, phenoxycarbonyl, naphthoxycarbonyl),
(4) C 7-12 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 2-phenylethyloxycarbonyl)
Is mentioned.
　本明細書中、「置換されていてもよいアミノ基」としては、
（１）アミノ基、
（２）モノ-またはジ-Ｃ1-6アルキルアミノ基（例、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ）、
（３）Ｃ3-6シクロアルキルアミノ基（例、シクロプロピルアミノ、シクロブチルアミノ、シクロペンチルアミノ、シクロヘキシルアミノ）、
（４）Ｃ6-10アリールアミノ基（例、フェニルアミノ、1-ナフチルアミノ、2-ナフチルアミノ）、
（５）Ｃ7-12アラルキルアミノ基（例、ベンジルアミノ、2-フェニルエチルアミノ、1-フェニルエチルアミノ）、
（６）ヒドラジノ基、
（７）モノ-またはジ-（Ｃ1-6アルキルスルホニル）アミノ基（例、メチルスルホニルアミノ）、
（８）モノ-またはジ-（Ｃ1-6アルキル-カルボニル）アミノ基（例、アセチルアミノ）、
（９）モノ-またはジ-（Ｃ1-6アルコキシ-カルボニル）アミノ基（例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、tert-ブトキシカルボニルアミノ）、
（１０）置換されていてもよい環状アミノ基、
（１１）スルファモイルアミノ基
が挙げられる。ジ置換アミノ基の場合、２個の置換基は同一であっても異なっていてもよい。 In the present specification, the “optionally substituted amino group”
(1) an amino group,
(2) mono- or di-C 1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino),
(3) C 3-6 cycloalkylamino group (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino),
(4) C 6-10 arylamino group (eg, phenylamino, 1-naphthylamino, 2-naphthylamino),
(5) C 7-12 aralkylamino group (eg, benzylamino, 2-phenylethylamino, 1-phenylethylamino),
(6) hydrazino group,
(7) mono- or di- (C 1-6 alkylsulfonyl) amino group (eg, methylsulfonylamino),
(8) mono- or di- (C 1-6 alkyl-carbonyl) amino group (eg, acetylamino),
(9) mono- or di- (C 1-6 alkoxy-carbonyl) amino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino),
(10) an optionally substituted cyclic amino group,
(11) A sulfamoylamino group can be mentioned. In the case of a disubstituted amino group, the two substituents may be the same or different.
　「置換されていてもよい環状アミノ基」の「環状アミノ基」が有していてもよい置換基としては、
（１）オキソ基、
（２）前記の「置換されていてもよいＣ1-6アルキル基」の「Ｃ1-6アルキル基」が有していてもよい置換基、
（３）ハロゲン原子、ヒドロキシ基およびＣ1-6アルコキシ基から選ばれる1ないし3個の置換基で置換されていてもよいＣ1-6アルキル基（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、1-メチルプロピル、ペンチル、イソペンチル、ネオペンチル、tert-ペンチル、1,2-ジメチルプロピル、ヘキシル、2-メチルペンチル、3-メチルペンチル、1,2-ジメチルブチル、1,2,2-トリメチルプロピル、トリフルオロメチル、ヒドロキシエチル）、
（４）Ｃ7-12アラルキル基（例、ベンジル、2-フェニルエチル、1-フェニルエチル、3-フェニルプロピル、4-フェニルブチル）、
（５）Ｃ3-6シクロアルキル基（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル）、および
（６）ハロゲン原子、ヒドロキシ、Ｃ1-6アルキル基およびＣ1-6アルコキシ基から選ばれる1ないし3個の置換基で置換されていてもよいＣ6-10アリール基（例、フェニル、1-ナフチル、2-ナフチル、2-クロロフェニル）
から選択される置換基が挙げられる。該置換基の数は1ないし4個、好ましくは1ないし3個である。置換基が複数存在する場合、各置換基は同一であっても異なっていてもよい。 As the substituent that the “cyclic amino group” of the “optionally substituted cyclic amino group” may have,
(1) an oxo group,
(2) the substituent which the “C 1-6 alkyl group” of the “ optionally substituted C 1-6 alkyl group” may have,
(3) C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl) optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group and a C 1-6 alkoxy group , Isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 1,2-dimethyl Butyl, 1,2,2-trimethylpropyl, trifluoromethyl, hydroxyethyl),
(4) C 7-12 aralkyl group (eg, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl),
(5) C 3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), and (6) 1 to 1 selected from halogen atom, hydroxy, C 1-6 alkyl group and C 1-6 alkoxy group C 6-10 aryl group optionally substituted by three substituents (eg, phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl)
The substituent selected from these is mentioned. The number of the substituent is 1 to 4, preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different.
　本明細書中、「置換されていてもよいカルバモイル基」としては、
（１）カルバモイル基、
（２）モノ-またはジ-（Ｃ1-6アルキル）カルバモイル基（例、メチルカルバモイル、エチルカルバモイル、プロピルカルバモイル、イソプロピルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイル、ジプロピルカルバモイル）、
（３）モノ-またはジ-（Ｃ6-10アリール）カルバモイル基（例、フェニルカルバモイル、ナフチルカルバモイル、ジフェニルカルバモイル、ジナフチルカルバモイル）、
（４）モノ-またはジ-（Ｃ7-12アラルキル）カルバモイル基（例、ベンジルカルバモイル、ジベンジルカルバモイル）
が挙げられる。ジ置換カルバモイル基の場合、２個の置換基は同一であっても異なっていてもよい。 In the present specification, the “optionally substituted carbamoyl group”
(1) a carbamoyl group,
(2) mono- or di- (C 1-6 alkyl) carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl),
(3) mono- or di- (C 6-10 aryl) carbamoyl group (eg, phenylcarbamoyl, naphthylcarbamoyl, diphenylcarbamoyl, dinaphthylcarbamoyl),
(4) Mono- or di- (C 7-12 aralkyl) carbamoyl group (eg, benzylcarbamoyl, dibenzylcarbamoyl)
Is mentioned. In the case of a disubstituted carbamoyl group, the two substituents may be the same or different.
　Ｒ１で表される「置換されたＣ1-6アルキル基」の好ましい例としては、
　　　（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ1-6アルコキシ基（例、メトキシ）、
　　　（ｄ）-Ｓ-Ｒ1a、
　　　（ｅ）-ＳＯ2-Ｒ1a（例、－ＳＯ２－メチル）、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＳＯ２－Ｎ（Ｈ）（メチル））、
　　　（ｇ）-Ｎ（Ｒ1b）（Ｒ1c）、
　　　（ｈ）-ＮＨ-ＣＯ-Ｒ1a、
　　　（ｉ）-ＮＨ-ＣＯ-Ｎ（Ｒ1b）（Ｒ1c）（例、－ＮＨ－ＣＯ－ＮＨ２、－ＮＨ－ＣＯ－Ｎ（Ｈ）（エチル））、
　　　（ｊ）-ＮＨ-ＳＯ2-Ｒ1a（例、－ＮＨ－ＳＯ２－メチル）あるいは１ないし３個のハロゲン原子で置換されたＣ1-6アルキルスルホニルアミノ基（例、トリフルオロメチルスルホニルアミノ）、
　　　（ｋ）-ＮＨ-ＳＯ2-Ｎ（Ｒ1b）（Ｒ1c）（例、－ＮＨ－ＳＯ２－Ｎ（Ｈ）（メチル））、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａ、Ｒ１ｂおよびＲ１ｃは上記で定義した通りである。）
から選択される1ないし4個（好ましくは1ないし3個、より好ましくは1個）の置換基で置換されたＣ1-6アルキル基（例、メチル、エチル）が挙げられ、より好ましくは、
　　　（ａ）ヒドロキシ基、
　　　（ｂ）－ＳＯ２－Ｒ１ａ（例、－ＳＯ２－メチル）、および
　　　（ｃ）－ＮＨ－ＳＯ２－Ｒ１ａ（例、－ＮＨ－ＳＯ２－メチル）
（式中、Ｒ１ａは上記で定義した通りである。）
から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基（例、メチル、エチル）が挙げられる。 Preferred examples of the “substituted C 1-6 alkyl group” represented by R 1 include
(A) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group (eg, methoxy),
(D) -S-R 1a ,
(E) —SO 2 —R 1a (eg, —SO 2 -methyl),
(F) —SO 2 —N (R 1b ) (R 1c ) (eg, —SO 2 —N (H) (methyl)),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ) (eg, —NH—CO—NH 2 , —NH—CO—N (H) (ethyl)),
(J) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl) or a C 1-6 alkylsulfonylamino group substituted with 1 to 3 halogen atoms (eg, trifluoromethylsulfonylamino) ),
(K) —NH—SO 2 —N (R 1b ) (R 1c ) (eg, —NH—SO 2 —N (H) (methyl)), and (1) 1 selected from a carboxy group and a methyl group Or 1H-pyrazol-1-yl optionally substituted with three substituents (wherein R 1a , R 1b and R 1c are as defined above).
And a C 1-6 alkyl group (eg, methyl, ethyl) substituted with 1 to 4 (preferably 1 to 3, more preferably 1) substituents selected from:
(A) a hydroxy group,
(B) —SO 2 —R 1a (eg, —SO 2 -methyl), and (c) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl)
(Wherein R 1a is as defined above.)
A C 1-6 alkyl group substituted with 1 to 3 substituents selected from (eg, methyl, ethyl).
　Ｒ1で表される「置換されていてもよいＣ1-6アルコキシ基」の好ましい例としては、
　　　（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）、
　　　（ｄ）－Ｓ－Ｒ１ａ、
　　　（ｅ）－ＳＯ２－Ｒ１ａ、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、
　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａ、Ｒ１ｂおよびＲ１ｃは上記で定義した通りである。）
から選択される１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ基（例、メトキシ、エトキシ）
が挙げられ、より好ましくは、Ｃ１－６アルコキシ基（例、メトキシ）で置換されていてもよいＣ１－６アルコキシ基（例、メトキシ、エトキシ）が挙げられ、さらに好ましくは、置換基を有していないＣ1-6アルコキシ基（例、メトキシ、エトキシ）が挙げられる。 As preferable examples of the “optionally substituted C 1-6 alkoxy group” represented by R 1 ,
(A) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group (eg, methoxy),
(D) -SR 1a ,
(E) —SO 2 —R 1a ,
(F) —SO 2 —N (R 1b ) (R 1c ),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ),
(J) —NH—SO 2 —R 1a ,
(K) —NH—SO 2 —N (R 1b ) (R 1c ), and (1) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group 1-yl (wherein R 1a , R 1b and R 1c are as defined above).
A C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with 1 to 3 substituents selected from
And more preferably, a C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with a C 1-6 alkoxy group (eg, methoxy), and more preferably a substituent group. Examples thereof include C 1-6 alkoxy groups which are not present (eg, methoxy, ethoxy).
　Ｒ1で表される「置換されていてもよいカルボキシ基」の好ましい例としては、
（１）カルボキシ基、
（２）Ｃ1-6アルコキシ-カルボニル基（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ブトキシカルボニル、tert-ブトキシカルボニル）
が挙げられ、より好ましくは、Ｃ1-6アルコキシ-カルボニル基（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ブトキシカルボニル、tert-ブトキシカルボニル）が挙げられ、さらに好ましくは、エトキシカルボニルが挙げられる。 As a preferable example of the “optionally substituted carboxy group” represented by R 1 ,
(1) a carboxy group,
(2) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl)
More preferred is a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl), and even more preferred is ethoxycarbonyl.
　Ｒ1で表される「置換されていてもよいアミノ基」の好ましい例としては、
（１）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、および
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）
から選択される１ないし３個の置換基で置換されてもよいモノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ基（例、メチルカルボニルアミノ）、
（２）Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ）、
（３）スルファモイルアミノ基
が挙げられ、より好ましくは、Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ）が挙げられる。 Preferred examples of the “optionally substituted amino group” represented by R 1 include
(1) (a) a halogen atom,
(B) a hydroxy group, and (c) a C 1-6 alkoxy group (eg, methoxy)
A mono- or di- (C 1-6 alkyl-carbonyl) amino group (eg, methylcarbonylamino) which may be substituted with 1 to 3 substituents selected from
(2) C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino),
(3) A sulfamoylamino group is exemplified, and a C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino) is more preferred.
　Ｒ1で表される「置換されていてもよいカルバモイル基」の好ましい例としては、モノ-またはジ-（Ｃ1-6アルキル）カルバモイル基（例、メチルカルバモイル）が挙げられ、より好ましくは、メチルカルバモイルが挙げられる。 Preferable examples of the “optionally substituted carbamoyl group” represented by R 1 include a mono- or di- (C 1-6 alkyl) carbamoyl group (eg, methylcarbamoyl), more preferably And methylcarbamoyl.
　Ｒ1の好ましい例としては、
（１）ヒドロキシ基、
（２）Ｃ1-6アルコキシ-カルボニル基、
（３）Ｃ1-6アルコキシ基、または
（４）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ1-6アルコキシ基、
　　　（ｄ）-Ｓ-Ｒ1a、
　　　（ｅ）-ＳＯ2-Ｒ1a、
　　　（ｆ）-Ｎ（Ｒ1b）（Ｒ1c）、
　　　（ｇ）-ＮＨ-ＣＯ-Ｒ1a、
　　　（ｈ）-ＮＨ-ＣＯ-Ｎ（Ｒ1b）（Ｒ1c）、
　　　（ｉ）-ＮＨ-ＳＯ2-Ｒ1a、および
　　　（ｊ）-ＮＨ-ＳＯ2-Ｎ（Ｒ1b）（Ｒ1c）
（式中、Ｒ1aは、Ｃ1-6アルキル基を、Ｒ1bおよびＲ1cは、それぞれ独立して水素原子またはＣ1-6アルキル基を表す。）から選択される1個の置換基で置換されたＣ1-6アルキル基
が挙げられる。 Preferred examples of R 1 include
(1) a hydroxy group,
(2) C 1-6 alkoxy-carbonyl group,
(3) a C 1-6 alkoxy group, or (4) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group,
(D) -S-R 1a ,
(E) -SO 2 -R 1a ,
(F) -N (R 1b ) (R 1c ),
(G) -NH-CO-R 1a ,
(H) -NH-CO-N (R 1b ) (R 1c ),
(I) —NH—SO 2 —R 1a , and (j) —NH—SO 2 —N (R 1b ) (R 1c )
(Wherein R 1a represents a C 1-6 alkyl group, and R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group) A substituted C 1-6 alkyl group can be mentioned.
　また、Ｒ1の別の好ましい例としては、
（１）ヒドロキシ基、
（２）Ｃ１－６アルコキシ－カルボニル基（例、エトキシカルボニル）、
（３）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）、
　　　（ｄ）－Ｓ－Ｒ１ａ、
　　　（ｅ）－ＳＯ２－Ｒ１ａ、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、
　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａ、Ｒ１ｂおよびＲ１ｃは上記で定義した通りである。）から選択される１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ基（例、メトキシ、エトキシ）、
（４）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、および
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）
から選択される１ないし３個の置換基で置換されてもよいモノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ基（例、メチルカルボニルアミノ）、
（５）Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ）、
（６）モノ-またはジ-（Ｃ1-6アルキル）カルバモイル基（例、メチルカルバモイル）、
（７）スルファモイルアミノ基、または
（８）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）、
　　　（ｄ）－Ｓ－Ｒ１ａ、
　　　（ｅ）－ＳＯ２－Ｒ１ａ（例、－ＳＯ２－メチル）、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＳＯ２－Ｎ（Ｈ）（メチル））、
　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＮＨ－ＣＯ－ＮＨ２、－ＮＨ－ＣＯ－Ｎ（Ｈ）（エチル））、
　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ（例、－ＮＨ－ＳＯ２－メチル）あるいは１ないし３個のハロゲン原子で置換されたＣ1-6アルキルスルホニルアミノ基（例、トリフルオロメチルスルホニルアミノ）、
　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＮＨ－ＳＯ２－Ｎ（Ｈ）（メチル））、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａ、Ｒ１ｂおよびＲ１ｃは上記で定義した通りである。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基（例、メチル、エチル）
が挙げられ、より好ましくは、
（１）ヒドロキシ基、
（２）Ｃ１－６アルコキシ－カルボニル基（例、エトキシカルボニル）、
（３）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）、
　　　（ｄ）－Ｓ－Ｒ１ａ、
　　　（ｅ）－ＳＯ２－Ｒ１ａ、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、
　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａ、Ｒ１ｂおよびＲ１ｃは上記で定義した通りである。）から選択される１ないし３個の置換基で置換されたＣ１－６アルコキシ基（例、エトキシ）、
（４）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、および
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）
から選択される１ないし３個の置換基で置換されてもよいモノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ基（例、メチルカルボニルアミノ）、
（５）Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ）、
（６）スルファモイルアミノ基、または
（７）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）、
　　　（ｄ）－Ｓ－Ｒ１ａ、
　　　（ｅ）－ＳＯ２－Ｒ１ａ（例、－ＳＯ２－メチル）、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＳＯ２－Ｎ（Ｈ）（メチル））、
　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＮＨ－ＣＯ－ＮＨ２、－ＮＨ－ＣＯ－Ｎ（Ｈ）（エチル））、
　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ（例、－ＮＨ－ＳＯ２－メチル）あるいは１ないし３個のハロゲン原子で置換されたＣ1-6アルキルスルホニルアミノ基（例、トリフルオロメチルスルホニルアミノ）、
　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＮＨ－ＳＯ２－Ｎ（Ｈ）（メチル））、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａ、Ｒ１ｂおよびＲ１ｃは上記で定義した通りである。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基（例、メチル、エチル）
が挙げられ、さらに好ましくは、
（１）（ａ）ヒドロキシ基、
　　　（ｂ）－ＳＯ２－Ｒ１ａ（例、－ＳＯ２－メチル）、および
　　　（ｃ）－ＮＨ－ＳＯ２－Ｒ１ａ（例、－ＮＨ－ＳＯ２－メチル）
（式中、Ｒ１ａは上記で定義した通りである。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基（例、メチル、エチル）、または
（２）Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ）
が挙げられる。 As another preferred example of R 1 ,
(1) a hydroxy group,
(2) C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl),
(3) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group (eg, methoxy),
(D) -SR 1a ,
(E) —SO 2 —R 1a ,
(F) —SO 2 —N (R 1b ) (R 1c ),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ),
(J) —NH—SO 2 —R 1a ,
(K) —NH—SO 2 —N (R 1b ) (R 1c ), and (l) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from 1-yl (wherein R 1a , R 1b and R 1c are as defined above) Eg, methoxy, ethoxy),
(4) (a) a halogen atom,
(B) a hydroxy group, and (c) a C 1-6 alkoxy group (eg, methoxy)
A mono- or di- (C 1-6 alkyl-carbonyl) amino group (eg, methylcarbonylamino) which may be substituted with 1 to 3 substituents selected from
(5) C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino),
(6) mono- or di- (C 1-6 alkyl) carbamoyl group (eg, methylcarbamoyl),
(7) a sulfamoylamino group, or (8) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group (eg, methoxy),
(D) -SR 1a ,
(E) —SO 2 —R 1a (eg, —SO 2 -methyl),
(F) —SO 2 —N (R 1b ) (R 1c ) (eg, —SO 2 —N (H) (methyl)),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ) (eg, —NH—CO—NH 2 , —NH—CO—N (H) (ethyl)),
(J) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl) or a C 1-6 alkylsulfonylamino group substituted with 1 to 3 halogen atoms (eg, trifluoromethylsulfonylamino) ),
(K) —NH—SO 2 —N (R 1b ) (R 1c ) (eg, —NH—SO 2 —N (H) (methyl)), and (l) 1 selected from a carboxy group and a methyl group 1 to 3 selected from 1H-pyrazol-1-yl optionally substituted with 3 substituents (wherein R 1a , R 1b and R 1c are as defined above) C 1-6 alkyl group substituted by a substituent of (eg, methyl, ethyl)
More preferably,
(1) a hydroxy group,
(2) C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl),
(3) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group (eg, methoxy),
(D) -SR 1a ,
(E) —SO 2 —R 1a ,
(F) —SO 2 —N (R 1b ) (R 1c ),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ),
(J) —NH—SO 2 —R 1a ,
(K) —NH—SO 2 —N (R 1b ) (R 1c ), and (1) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group A C 1-6 alkoxy group substituted with 1 to 3 substituents selected from 1-yl (wherein R 1a , R 1b and R 1c are as defined above) (eg, ethoxy ),
(4) (a) a halogen atom,
(B) a hydroxy group, and (c) a C 1-6 alkoxy group (eg, methoxy)
A mono- or di- (C 1-6 alkyl-carbonyl) amino group (eg, methylcarbonylamino) which may be substituted with 1 to 3 substituents selected from
(5) C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino),
(6) a sulfamoylamino group, or (7) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group (eg, methoxy),
(D) -SR 1a ,
(E) —SO 2 —R 1a (eg, —SO 2 -methyl),
(F) —SO 2 —N (R 1b ) (R 1c ) (eg, —SO 2 —N (H) (methyl)),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ) (eg, —NH—CO—NH 2 , —NH—CO—N (H) (ethyl)),
(J) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl) or a C 1-6 alkylsulfonylamino group substituted with 1 to 3 halogen atoms (eg, trifluoromethylsulfonylamino) ),
(K) —NH—SO 2 —N (R 1b ) (R 1c ) (eg, —NH—SO 2 —N (H) (methyl)), and (l) 1 selected from a carboxy group and a methyl group 1 to 3 selected from 1H-pyrazol-1-yl optionally substituted with 3 substituents (wherein R 1a , R 1b and R 1c are as defined above) C 1-6 alkyl group substituted by a substituent of (eg, methyl, ethyl)
More preferably,
(1) (a) a hydroxy group,
(B) —SO 2 —R 1a (eg, —SO 2 -methyl), and (c) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl)
(Wherein R 1a is as defined above) a C 1-6 alkyl group (eg, methyl, ethyl) substituted with 1 to 3 substituents selected from (2) C 1-6 alkylsulfonylamino groups (eg, methylsulfonylamino)
Is mentioned.
　Ｒ2とＲ3の好ましい例としては、ともに水素原子である。すなわち、Ｘ１、Ｘ２およびＸ３の好ましい組み合わせ（Ｘ１、Ｘ２、Ｘ３）は、（－ＮＨ－、－ＣＨ２－、－ＣＨ２－）、（－ＣＨ２－、－ＮＨ－、－ＣＨ２－）または（－ＣＨ２－、－ＣＨ２－、－ＮＨ－）である。 Preferable examples of R 2 and R 3 are both hydrogen atoms. That, X 1, preferred combinations of X 2 and X 3 (X 1, X 2 , X 3) is, (- NH -, - CH 2 -, - CH 2 -), (- CH 2 -, - NH- , -CH 2 -) or (-CH 2 -, - CH 2 -, - is NH-).
　式(I)で表される化合物またはその塩（以下、化合物(I)又は本願発明化合物と称する）の好適な例としては、以下の化合物が挙げられる。
［化合物(I)］
　環Ａが、2個のハロゲン原子で置換されたベンゼン環であり、
Ｒ1が、
（１）ヒドロキシ基、
（２）Ｃ1-6アルコキシ-カルボニル基、
（３）Ｃ1-6アルコキシ基、または
（４）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ1-6アルコキシ基、
　　　（ｄ）-Ｓ-Ｒ1a、
　　　（ｅ）-ＳＯ2-Ｒ1a、
　　　（ｆ）-Ｎ（Ｒ1b）（Ｒ1c）、
　　　（ｇ）-ＮＨ-ＣＯ-Ｒ1a、
　　　（ｈ）-ＮＨ-ＣＯ-Ｎ（Ｒ1b）（Ｒ1c）、
　　　（ｉ）-ＮＨ-ＳＯ2-Ｒ1a、および
　　　（ｊ）-ＮＨ-ＳＯ2-Ｎ（Ｒ1b）（Ｒ1c）
（式中、Ｒ1aは、Ｃ1-6アルキル基を、Ｒ1bおよびＲ1cは、それぞれ独立して水素原子またはＣ1-6アルキル基を表す。）から選択される1個の置換基で置換されたＣ1-6アルキル基であり、
環Ｂ1及びＢ2が、環ＡおよびＲ1以外の置換基を有していない、化合物(I)。 Preferable examples of the compound represented by formula (I) or a salt thereof (hereinafter referred to as compound (I) or the present invention compound) include the following compounds.
[Compound (I)]
Ring A is a benzene ring substituted with two halogen atoms,
R 1 is
(1) a hydroxy group,
(2) C 1-6 alkoxy-carbonyl group,
(3) a C 1-6 alkoxy group, or (4) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group,
(D) -S-R 1a ,
(E) -SO 2 -R 1a ,
(F) -N (R 1b ) (R 1c ),
(G) -NH-CO-R 1a ,
(H) -NH-CO-N (R 1b ) (R 1c ),
(I) —NH—SO 2 —R 1a , and (j) —NH—SO 2 —N (R 1b ) (R 1c )
(Wherein R 1a represents a C 1-6 alkyl group, and R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group) A substituted C 1-6 alkyl group,
Compound (I) in which rings B 1 and B 2 have no substituents other than rings A and R 1 .
　また、化合物（Ｉ）の別の好適な例としては、以下の化合物が挙げられる。
［化合物（Ｉ－１）］
　環Ａが、ハロゲン原子（例、フッ素原子、塩素原子）およびＣ１－６アルキル基（例、メチル）から選択される１ないし３個の置換基で置換されたベンゼン環であり、
Ｒ１が、
（１）ヒドロキシ基、
（２）Ｃ１－６アルコキシ－カルボニル基（例、エトキシカルボニル）、
（３）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）、
　　　（ｄ）－Ｓ－Ｒ１ａ、
　　　（ｅ）－ＳＯ２－Ｒ１ａ、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、
　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａ、Ｒ１ｂおよびＲ１ｃは上記で定義した通りである。）から選択される１ないし３個の置換基で置換されたＣ１－６アルコキシ基（例、エトキシ）、
（４）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、および
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）
から選択される１ないし３個の置換基で置換されてもよいモノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ基（例、メチルカルボニルアミノ）、
（５）Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ）、
（６）スルファモイルアミノ基、または
（７）（ａ）ハロゲン原子、
　　　（ｂ）ヒドロキシ基、
　　　（ｃ）Ｃ１－６アルコキシ基（例、メトキシ）、
　　　（ｄ）－Ｓ－Ｒ１ａ、
　　　（ｅ）－ＳＯ２－Ｒ１ａ（例、－ＳＯ２－メチル）、
　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＳＯ２－Ｎ（Ｈ）（メチル））、
　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＮＨ－ＣＯ－ＮＨ２、－ＮＨ－ＣＯ－Ｎ（Ｈ）（エチル））、
　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ（例、－ＮＨ－ＳＯ２－メチル）あるいは１ないし３個のハロゲン原子で置換されたＣ1-6アルキルスルホニルアミノ基（例、トリフルオロメチルスルホニルアミノ）、
　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）（例、－ＮＨ－ＳＯ２－Ｎ（Ｈ）（メチル））、および
　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
（式中、Ｒ１ａ、Ｒ１ｂおよびＲ１ｃは上記で定義した通りである。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基（例、メチル、エチル）であり、
環Ｂ１または環Ｂ３は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない、化合物（Ｉ）。 Moreover, the following compounds are mentioned as another suitable example of compound (I).
[Compound (I-1)]
Ring A is a benzene ring substituted with 1 to 3 substituents selected from a halogen atom (eg, fluorine atom, chlorine atom) and a C 1-6 alkyl group (eg, methyl);
R 1 is
(1) a hydroxy group,
(2) C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl),
(3) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group (eg, methoxy),
(D) -SR 1a ,
(E) —SO 2 —R 1a ,
(F) —SO 2 —N (R 1b ) (R 1c ),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ),
(J) —NH—SO 2 —R 1a ,
(K) —NH—SO 2 —N (R 1b ) (R 1c ), and (1) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group A C 1-6 alkoxy group substituted with 1 to 3 substituents selected from 1-yl (wherein R 1a , R 1b and R 1c are as defined above) (eg, ethoxy ),
(4) (a) a halogen atom,
(B) a hydroxy group, and (c) a C 1-6 alkoxy group (eg, methoxy)
A mono- or di- (C 1-6 alkyl-carbonyl) amino group (eg, methylcarbonylamino) which may be substituted with 1 to 3 substituents selected from
(5) C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino),
(6) a sulfamoylamino group, or (7) (a) a halogen atom,
(B) a hydroxy group,
(C) a C 1-6 alkoxy group (eg, methoxy),
(D) -SR 1a ,
(E) —SO 2 —R 1a (eg, —SO 2 -methyl),
(F) —SO 2 —N (R 1b ) (R 1c ) (eg, —SO 2 —N (H) (methyl)),
(G) -N (R 1b ) (R 1c ),
(H) -NH-CO-R 1a ,
(I) —NH—CO—N (R 1b ) (R 1c ) (eg, —NH—CO—NH 2 , —NH—CO—N (H) (ethyl)),
(J) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl) or a C 1-6 alkylsulfonylamino group substituted with 1 to 3 halogen atoms (eg, trifluoromethylsulfonylamino) ),
(K) —NH—SO 2 —N (R 1b ) (R 1c ) (eg, —NH—SO 2 —N (H) (methyl)), and (l) 1 selected from a carboxy group and a methyl group 1 to 3 selected from 1H-pyrazol-1-yl optionally substituted with 3 substituents (wherein R 1a , R 1b and R 1c are as defined above) A C 1-6 alkyl group substituted with a substituent of (for example, methyl, ethyl),
Ring B 1 or Ring B 3 has no substituents other than Ring A and R 1 , and Ring B 2 is a ring A, R 1 , and any one of X 1 , X 2 and X 3 is a substituent Compound (I) having no substituent other than that substituent.
［化合物（Ｉ－２）］
　環Ａが、１ないし３個のハロゲン原子（例、フッ素原子、塩素原子）で置換されたベンゼン環であり、
Ｒ１が、
（１）（ａ）ヒドロキシ基、
　　　（ｂ）－ＳＯ２－Ｒ１ａ（例、－ＳＯ２－メチル）、および
　　　（ｃ）－ＮＨ－ＳＯ２－Ｒ１ａ（例、－ＮＨ－ＳＯ２－メチル）
（式中、Ｒ１ａは上記で定義した通りである。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基（例、メチル、エチル）、または
（２）Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ）
　　であり、
環Ｂ１または環Ｂ３は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない、化合物（Ｉ）。 [Compound (I-2)]
Ring A is a benzene ring substituted with 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom),
R 1 is
(1) (a) a hydroxy group,
(B) —SO 2 —R 1a (eg, —SO 2 -methyl), and (c) —NH—SO 2 —R 1a (eg, —NH—SO 2 -methyl)
(Wherein R 1a is as defined above) a C 1-6 alkyl group (eg, methyl, ethyl) substituted with 1 to 3 substituents selected from (2) C 1-6 alkylsulfonylamino groups (eg, methylsulfonylamino)
And
Ring B 1 or Ring B 3 has no substituents other than Ring A and R 1 , and Ring B 2 is a ring A, R 1 , and any one of X 1 , X 2 and X 3 is a substituent Compound (I) having no substituent other than that substituent.
　化合物（Ｉ）として、具体的には、実施例１～４３の化合物が挙げられ、中でも、
（３Ｒ，４Ｒ）－３－（３－クロロ－４－フルオロフェニル）－４－［（メチルスルホニル）メチル］アゼパンまたはその塩（実施例２５）、
（３ＲＳ，４ＲＳ）－３－（３，４－ジクロロフェニル）－４－［（メチルスルホニル）メチル］アゼパンの光学活性体またはその塩（実施例２９（(3R*,4R*)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン　塩酸塩（保持時間が小さい方のBoc体から誘導）、又は、実施例３０（(3R*,4R*)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン　塩酸塩（保持時間が大きい方のBoc体から誘導）：但し、塩に関しては塩酸塩に限定されない）、
Ｎ－［（３Ｒ，４Ｒ）－３－（３，４－ジクロロフェニル）アゼパン－４－イル］メタンスルホンアミドまたはその塩（実施例３１）、
（１ＲＳ）－１－［（３ＲＳ，４ＲＳ）－３－（３，４－ジクロロフェニル）アゼパン－４－イル］エタン－１，２－ジオールまたはその塩（実施例３７）、
（１ＲＳ）－１－［（３ＳＲ，４ＲＲ）－３－（３，４－ジクロロフェニル）アゼパン－４－イル］エタン－１，２－ジオールまたはその塩（実施例３８）、
５－（３，４－ジクロロフェニル）－６－［（メチルスルホニル）メチル］－２，３，４，７－テトラヒドロ－１Ｈ－アゼピンまたはその塩（実施例３９）、および
Ｎ－｛［４－（３，４－ジクロロフェニル）－２，５，６，７－テトラヒドロ－１Ｈ－アゼピン－３－イル］メチル｝メタンスルホンアミドまたははその塩（実施例４０）
が好ましく、
（３Ｒ，４Ｒ）－３－（３－クロロ－４－フルオロフェニル）－４－［（メチルスルホニル）メチル］アゼパンまたはその塩（実施例２５）、
（３ＲＳ，４ＲＳ）－３－（３，４－ジクロロフェニル）－４－［（メチルスルホニル）メチル］アゼパンの光学活性体またはその塩（実施例２９（(3R*,4R*)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン　塩酸塩（保持時間が小さい方のBoc体から誘導）、又は、実施例３０（(3R*,4R*)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン　塩酸塩（保持時間が大きい方のBoc体から誘導）：但し、塩に関しては塩酸塩に限定されない）、
Ｎ－［（３Ｒ，４Ｒ）－３－（３，４－ジクロロフェニル）アゼパン－４－イル］メタンスルホンアミドまたはその塩（実施例３１）、
（１ＲＳ）－１－［（３ＳＲ，４ＲＲ）－３－（３，４－ジクロロフェニル）アゼパン－４－イル］エタン－１，２－ジオールまたはその塩（実施例３８）、および
５－（３，４－ジクロロフェニル）－６－［（メチルスルホニル）メチル］－２，３，４，７－テトラヒドロ－１Ｈ－アゼピンまたはその塩（実施例３９）
がより好ましい。 Specific examples of compound (I) include the compounds of Examples 1 to 43. Among them,
(3R, 4R) -3- (3-chloro-4-fluorophenyl) -4-[(methylsulfonyl) methyl] azepane or a salt thereof (Example 25),
(3RS, 4RS) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane optically active substance or salt thereof (Example 29 ((3R * , 4R * )-3- (3 , 4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane hydrochloride (derived from the Boc form with a smaller retention time) or Example 30 ((3R * , 4R * )-3- (3, 4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride (derived from the Boc form having a larger retention time): provided that the salt is not limited to hydrochloride)
N-[(3R, 4R) -3- (3,4-dichlorophenyl) azepan-4-yl] methanesulfonamide or a salt thereof (Example 31),
(1RS) -1-[(3RS, 4RS) -3- (3,4-dichlorophenyl) azepan-4-yl] ethane-1,2-diol or a salt thereof (Example 37),
(1RS) -1-[(3SR, 4RR) -3- (3,4-dichlorophenyl) azepan-4-yl] ethane-1,2-diol or a salt thereof (Example 38),
5- (3,4-dichlorophenyl) -6-[(methylsulfonyl) methyl] -2,3,4,7-tetrahydro-1H-azepine or a salt thereof (Example 39), and N-{[4- ( 3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methyl} methanesulfonamide or a salt thereof (Example 40)
Is preferred,
(3R, 4R) -3- (3-chloro-4-fluorophenyl) -4-[(methylsulfonyl) methyl] azepane or a salt thereof (Example 25),
(3RS, 4RS) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane optically active substance or salt thereof (Example 29 ((3R * , 4R * )-3- (3 , 4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane hydrochloride (derived from the Boc form with a smaller retention time) or Example 30 ((3R * , 4R * )-3- (3, 4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride (derived from the Boc form having a larger retention time): provided that the salt is not limited to hydrochloride)
N-[(3R, 4R) -3- (3,4-dichlorophenyl) azepan-4-yl] methanesulfonamide or a salt thereof (Example 31),
(1RS) -1-[(3SR, 4RR) -3- (3,4-dichlorophenyl) azepan-4-yl] ethane-1,2-diol or a salt thereof (Example 38), and 5- (3 4-Dichlorophenyl) -6-[(methylsulfonyl) methyl] -2,3,4,7-tetrahydro-1H-azepine or a salt thereof (Example 39)
Is more preferable.
　化合物(I)が塩を形成する場合、このような塩としては、例えば、無機塩基との塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩が挙げられる。 When the compound (I) forms a salt, 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 Examples include salts with acidic amino acids.
　無機塩基との塩の好適な例としては、ナトリウム塩、カリウム塩などのアルカリ金属塩；カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩；アルミニウム塩などが挙げられる。 Preferable examples of 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.
　有機塩基との塩の好適な例としては、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ジシクロヘキシルアミン、N,N’-ジベンジルエチレンジアミンなどとの塩が挙げられる。 Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like.
　無機酸との塩の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩が挙げられる。 Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
　有機酸との塩の好適な例としては、ギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸などとの塩が挙げられる。 Preferable examples of salts with organic acids 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.
　塩基性アミノ酸との塩の好適な例としては、アルギニン、リジン、オルニチンなどとの塩が挙げられる。 Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
　酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸などとの塩が挙げられる。 Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
　これらの塩のなかでも、薬学的に許容し得る塩が好ましい。薬学的に許容しうる好ましい塩としては、化合物内に塩基性官能基を有する場合には、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸等の無機酸との塩、または酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、p-トルエンスルホン酸等の有機酸との塩が挙げられる。また、化合物内に酸性官能基を有する場合には、アルカリ金属塩（例、ナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩、バリウム塩等）等の無機塩、アンモニウム塩等が挙げられる。 Among these salts, pharmaceutically acceptable salts are preferable. Preferred 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. And 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. In addition, when the compound has an acidic functional group, 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.
　化合物(I)は、水和物又は/及び溶媒和物を形成する場合があるが、いずれの場合も本願発明に含まれ、水和物又は/及び溶媒和物とは、水和物又は溶媒和物及びそれらの混合の何れであってもよい。 Compound (I) may form a hydrate or / and a solvate, and any case is included in the present invention, and the hydrate or / and solvate is a hydrate or a solvent. Any of a Japanese product and a mixture thereof may be used.
　次に化合物(I)の製造法について述べる。
　なお、反応式中の各化合物は、記載を省略しているが、それぞれ記載された構造式の化合物のエナンチオマーも包含する。反応式中の各化合物は、塩を形成していてもよい。このような塩としては、金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩等が挙げられる。金属塩としては、ナトリウム塩、カリウム塩などのアルカリ金属塩；カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩；アルミニウム塩等が挙げられる。有機塩基との塩としては、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、2,6-ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、N,N’-ジベンジルエチレンジアミン等との塩が挙げられる。無機酸との塩としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩としては、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸等との塩が挙げられる。塩基性アミノ酸との塩としては、アルギニン、リジン、オルニチン等との塩が挙げられ、酸性アミノ酸との塩としては、アスパラギン酸、グルタミン酸等との塩が挙げられる。このうち、薬学的に許容し得る塩が好ましい。 Next, a method for producing compound (I) will be described.
In addition, although description is abbreviate | omitted for each compound in reaction formula, the enantiomer of the compound of the structural formula each described is also included. Each compound in the reaction formula may form a salt. Examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Examples of the metal salt 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. Salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. Can be mentioned. Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene And salts with sulfonic acid and the like. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like. Of these, pharmaceutically acceptable salts are preferred.
　また、反応式中の各化合物は水和物又は/及び溶媒和物の何れであってもよい。該水和物等としては、0.23水和物、0.5水和物、1水和物、1水和物1溶媒和物、2溶媒和物等が挙げられる。 In addition, each compound in the reaction formula may be either a hydrate or / and a solvate. Examples of the hydrate include 0.23 hydrate, 0.5 hydrate, monohydrate, monohydrate 1 solvate, 2 solvate and the like.
　各工程で得られた化合物は、その反応液を粗製物として直接次の反応に用いることもできるが、常法に従って反応混合物から単離することもでき、それ自体が公知の手段、たとえば、抽出、濃縮、中和、濾過、蒸留、再結晶、クロマトグラフィーなどの分離手段により容易に精製することができる。あるいは、反応式中の化合物が市販されている場合には市販品をそのまま用いることもできる。 The compound obtained in each step can be used as a crude product directly in the next reaction as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be isolated by a means known per se, for example, extraction. It can be easily purified by separation means such as concentration, neutralization, filtration, distillation, recrystallization and chromatography. Or when the compound in reaction formula is marketed, a commercial item can also be used as it is.
　化合物(I)は、環Ａと置換基Ｒ１の位置および二重結合の有無により、以下の化合物(Ia)－(Ig)を含んでいる。以下、化合物(Ia)－(Ig)の製造法について説明する。 Compound (I) contains the following compounds (Ia)-(Ig) depending on the position of ring A and substituent R 1 and the presence or absence of a double bond. Hereinafter, a method for producing compounds (Ia)-(Ig) will be described.
　なお、環Ａが置換されていてもよい５～６員芳香族複素環である場合も、以下に示された製造法に準じて、相当する化合物を用い、対応する化合物を合成することができる。 Even when ring A is an optionally substituted 5- to 6-membered aromatic heterocyclic ring, the corresponding compound can be synthesized using the corresponding compound according to the production method shown below. .
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
[式中、 [Where
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
は化合物（I）の環Ａがベンゼン環であることを示し、各記号は前記と同意義を示す。]
[化合物(Ia)の製造法] Indicates that ring A of compound (I) is a benzene ring, and each symbol has the same meaning as described above. ]
[Production Method of Compound (Ia)]
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
[式中、PRG1は保護基を、その他の各記号は前記と同意義を示す。]
　化合物(Ia)は、例えば工程1において、化合物(IIa)の脱保護によって製造することができる。PRG1で示される「保護基」としては、例えばGreene's protective groups in organic synthesis 4thedition (Wiley-International Publication)に記載のものが用いられるが、好ましくはtert-ブトキシカルボニル(Boc)基、ベンジルオキシカルボニル(Cbz)基、9-フルオレニルメチルオキシカルボニル(Fmoc)基等のカルバメート系保護基、アセチル(Ac)基、トリフルオロアセチル基等のアミド系保護基、またはベンジル(Bzl)基、メチル基等のアルキル系保護基が挙げられる。工程1における脱保護の方法は、例えば上記Greene's protective groups in organic synthesis 4theditionに記載の方法が用いられるが、例えば、保護基がtert-ブトキシカルボニル基であれば、塩酸、トリフルオロ酢酸などの酸処理等による方法、ベンジル基であれば、パラジウムなどの金属触媒を用いた接触還元やクロロギ酸アルキル等による方法が好ましい。保護基がtert-ブトキシカルボニル基の場合、酸処理に用いる「酸」は、塩化水素の有機溶媒溶液、塩酸あるいはトリフルオロ酢酸が好ましく用いられる。該「有機溶媒」は、例えばエタノールやメタノール等のアルコール系溶媒、酢酸エチル等のエステル系溶媒が好ましい。用いる「酸」の当量は、通常、化合物(IIa)に対して1当量から溶媒量、好ましくは1当量から100当量である。反応溶媒は、例えばエタノールやメタノール等のアルコール系溶媒、酢酸エチル等のエステル系溶媒が好ましく用いられる。反応温度は、通常、-78℃から200℃、好ましくは0℃から50℃である。反応時間は、通常、1分間から48時間、好ましくは5分間から24時間である。 [Wherein PRG 1 represents a protecting group, and other symbols are as defined above. ]
Compound (Ia) can be produced, for example, by deprotecting compound (IIa) in Step 1. The "protecting group" represented by PRG 1, for example, Greene's protective groups in organic synthesis 4 th edition , but are used those described in (Wiley-International Publication), preferably tert- butoxycarbonyl (Boc) group, a benzyloxy Carbamate protecting groups such as carbonyl (Cbz) group, 9-fluorenylmethyloxycarbonyl (Fmoc) group, amide protecting groups such as acetyl (Ac) group, trifluoroacetyl group, or benzyl (Bzl) group, methyl And alkyl-based protecting groups such as a group. As the deprotection method in Step 1, for example, the method described in Greene's protective groups in organic synthesis 4 th edition is used. For example, if the protective group is a tert-butoxycarbonyl group, hydrochloric acid, trifluoroacetic acid, etc. In the case of a benzyl group, a method using acid treatment or the like, a catalytic reduction using a metal catalyst such as palladium, an alkyl chloroformate or the like is preferable. When the protecting group is a tert-butoxycarbonyl group, the “acid” used in the acid treatment is preferably an organic solvent solution of hydrogen chloride, hydrochloric acid or trifluoroacetic acid. The “organic solvent” is preferably an alcohol solvent such as ethanol or methanol, or an ester solvent such as ethyl acetate. The equivalent amount of the “acid” to be used is generally 1 equivalent to a solvent amount, preferably 1 equivalent to 100 equivalents, relative to compound (IIa). As the reaction solvent, for example, alcohol solvents such as ethanol and methanol, and ester solvents such as ethyl acetate are preferably used. The reaction temperature is usually -78 ° C to 200 ° C, preferably 0 ° C to 50 ° C. The reaction time is usually 1 minute to 48 hours, preferably 5 minutes to 24 hours.
　なお、化合物(I)の製造に関する全ての中間体の保護基による保護及び脱保護は適宜前記したGreene's protective groups in organic synthesis 4thedition (Wiley-International Publication)等に記載の方法に準じて行うことができる。 The compound protection and deprotection by protecting groups of all the intermediates for the preparation of (I) be carried out according to a method described appropriately aforementioned Greene's protective groups in organic synthesis 4 th edition (Wiley-International Publication) , etc. Can do.
　化合物(IIa)に含まれる化合物(IIa1) (Ｒ１は、-ＯＨを示す。)および化合物(IIa2) (化合物(IIa1)のＲ1が-Ｏ-Alkyl1である化合物。)は、例えば以下の方法により製造することができる。 Compound (IIa 1 ) (R 1 represents —OH) and Compound (IIa 2 ) (compound in which R 1 of compound (IIa 1 ) is —O—Alkyl 1 ) included in Compound (IIa) are: For example, it can be produced by the following method.
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
[式中、Ｍ1は金属またはその塩を、Alkyl1は置換されていてもよいＣ1-6アルキル基を、その他の各記号は前記と同意義を示す。ここで、Alkyl1が示す「置換されていてもよいＣ1-6アルキル基」の「Ｃ1-6アルキル基」および該「Ｃ1-6アルキル基」が有していてもよい置換基は前記と同意義を示す。] [Wherein, M 1 is a metal or a salt thereof, Alkyl 1 is an optionally substituted C 1-6 alkyl group, and other symbols are as defined above. Here, shown is and Alkyl 1 "C 1-6 alkyl group" and the "C 1-6 alkyl group" substituent optionally possessed by the "optionally substituted C 1-6 alkyl group" The meaning is the same as above. ]
　化合物(IIa1) (Ｒ1は、-ＯＨを示す。)は、例えば工程2において、化合物(III)と国際公開第2009/012125号パンフレットに記載の化合物(IV) (PRG1は、-Bocを示す。)の付加反応によって製造することができる。化合物(III)の「Ｍ1」は、アルカリ金属、アルカリ土類金属またはその塩が好ましく、中でもリチウムやハロゲン化マグネシウムが好ましい。 Compound (IIa 1 ) (R 1 represents —OH), for example, in Step 2, compound (III) and compound (IV) (PRG 1 described in International Publication No. 2009/012125 pamphlet) It can be produced by the addition reaction of “M 1 ” of the compound (III) is preferably an alkali metal, an alkaline earth metal or a salt thereof, and lithium or magnesium halide is particularly preferable.
　このようにして得られた化合物(IIa1)は、さらに工程3においてアルキル基を導入し、化合物(IIa2) (Ｒ1は、-Ｏ-Alkyl1を示す。)とすることができる。「Ｏ-アルキル化」は、例えばTetrahedron Lett., 30, 641 (1989)に記載の方法に準じて行うことができる。
[化合物(Ib)の製造法] The compound (IIa 1 ) thus obtained can be further converted into a compound (IIa 2 ) (R 1 represents —O-Alkyl 1 ) by introducing an alkyl group in Step 3. “O-alkylation” can be performed according to the method described in Tetrahedron Lett., 30, 641 (1989), for example.
[Production Method of Compound (Ib)]
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
[式中、各記号は前記と同意義を示す。]
　化合物(Ib)は、例えば工程4において、化合物(IIb)の脱保護によって製造することができる。PRG1で示される「保護基」としては、例えば工程1と同様のものが用いられるが、中でもtert-ブトキシカルボニル(Boc)基等が好ましい。工程4は、工程１と同様の反応条件、またはこれに準じる条件で行うことができる。 [Wherein each symbol is as defined above. ]
Compound (Ib) can be produced, for example, by deprotecting compound (IIb) in Step 4. As the “protecting group” represented by PRG 1 , for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group and the like are preferable. Step 4 can be performed under the same reaction conditions as in step 1 or conditions similar thereto.
　化合物(IIb)に含まれる化合物(IIb1) (化合物(IIb)のＲ1が-ＣＯ2Alkyl2である化合物。)は、例えば以下の方法により製造することができる。 Compound (IIb 1 ) (compound in which R 1 of compound (IIb) is —CO 2 Alkyl 2 ) contained in compound (IIb) can be produced, for example, by the following method.
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
[式中、Alkyl2はＣ1-6アルキル基を、Ｘ1はハロゲン原子を、Tfはトリフルオロメタンスルホニル基を、Ｍ2は金属またはその誘導体を、その他の各記号は前記と同意義を示す。ここで、Alkyl2が示す「Ｃ1-6アルキル基」とは前記と同意義を示す。] [Wherein Alkyl 2 represents a C 1-6 alkyl group, X 1 represents a halogen atom, Tf represents a trifluoromethanesulfonyl group, M 2 represents a metal or a derivative thereof, and other symbols are as defined above. . Here, the “C 1-6 alkyl group” represented by Alkyl 2 has the same meaning as described above. ]
　化合物(VI)、(VII)は、工程5において、化合物(V)の環拡大化によって製造することができる。化合物(VI)と(VII)は、互いに位置異性体の関係にあり、双方の混合物、あるいはどちらかに偏った形で存在する。該「環拡大化」は、例えばBioorganic and Medicinal Chemistry Letters, 18, 2103 -2108(2008)に記載の方法に準じて行うことができる。これらはシリカゲルカラムクロマトグラフィーや再結晶等の精製法によって分離することができる。 Compounds (VI) and (VII) can be produced by ring expansion of compound (V) in step 5. Compounds (VI) and (VII) are in a positional isomer relationship with each other and exist in a mixture of both or in a biased form. The “ring expansion” can be performed according to the method described in, for example, Bioorganic “and Medicinal” Chemistry “Letters”, “18”, “2103” -2108 (2008). These can be separated by a purification method such as silica gel column chromatography or recrystallization.
　化合物(VIII)は、工程6において、化合物(VI)のトリフラート化あるいはハロゲン化によって製造することができる。該「トリフラート化」は、例えばComprehensive Organic Functional Group Transformations II (Elsevier Pergamon), vol.2, 633-634に記載の方法に準じて行うことができる。また、該「ハロゲン化」は、例えばJournal of the American Chemical Society, 65, 2208 (1943)に記載の方法に準じて行うことができる。該「ハロゲン化」の「ハロゲン」は、好ましくは塩素、臭素またはヨウ素である。 Compound (VIII) can be produced by triflating or halogenating compound (VI) in Step 6. The “triflating” can be carried out according to the method described in, for example, Comprehensive Organic Functional Group Transformations II (Elsevier Pergamon), vol.2, 633-634. In addition, the “halogenation” can be performed according to the method described in, for example, Journal of American Chemical Society, 65, 2208 (1943). The “halogen” in the “halogenated” is preferably chlorine, bromine or iodine.
　化合物(IIe1)は、工程7において、化合物(VIII)あるいは(IX)と化合物(X)とのクロスカップリングによって製造することができる。本工程は、例えばTetrahedron, 58, 9633-9695 (2002)に記載の鈴木－宮浦カップリング反応、あるいは例えばOrganic Reactions, 50, 1-652 (1997)に記載のStilleカップリング反応等に準じて行うことができる。化合物(X)は、鈴木－宮浦カップリング反応であれば有機ボロン酸化合物(Ｍ2はボロン酸あるいはボロン酸エステルを示す。)、Stilleカップリング反応であれば有機スズ化合物(Ｍ2はトリアルキルスズを示す。)である。本工程は、好ましくは鈴木－宮浦カップリング反応を用いる。 Compound (IIe 1 ) can be produced by cross-coupling of compound (VIII) or (IX) and compound (X) in Step 7. This step is performed according to the Suzuki-Miyaura coupling reaction described in, for example, Tetrahedron, 58, 9633-9695 (2002), or the Stille coupling reaction described in, for example, Organic Reactions, 50, 1-652 (1997). be able to. Compound (X) is an organic boronic acid compound (M 2 represents a boronic acid or a boronic acid ester) for the Suzuki-Miyaura coupling reaction, and an organic tin compound (M 2 is a trialkyl) for the Stille coupling reaction. Tin is shown.) This step preferably uses the Suzuki-Miyaura coupling reaction.
　化合物(XI)は、工程8において、化合物(IIe1)の還元によって製造することができる。該「還元」は、当業者に公知の方法を用いることができ、例えば水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化ホウ素亜鉛、シアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、シアノ水素化ホウ素リチウム、水素化ジブチルアルミニウム、水素化アルミニウム、水素化アルミニウムリチウム、ボラン錯体(ボラン－THF錯体等）、カテコールボランの金属水素化物などを用いた方法、パラジウム、白金、ロジウム、ラネーニッケルなどの遷移金属触媒を用いた接触還元反応による方法、あるいはマグネシウム、サマリウムなどの金属を用いる方法によって行うことができる。中でも、白金による接触還元反応、例えば国際公開第2004/005255号パンフレット記載による方法が好ましい。本工程で得られる化合物は、立体異性に基づくジアステレオマー混合物を与えることがあるが、これらは必要に応じてシリカゲルカラムクロマトグラフィーや再結晶等の方法で分離精製することができる。 Compound (XI) can be produced by reducing compound (IIe 1 ) in Step 8. The “reduction” can be performed by a method known to those skilled in the art, such as sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, cyanohydrogenation. Methods using lithium borohydride, dibutylaluminum hydride, aluminum hydride, lithium aluminum hydride, borane complexes (borane-THF complex, etc.), metal hydrides of catecholborane, transition metals such as palladium, platinum, rhodium, Raney nickel It can be performed by a catalytic reduction reaction using a catalyst or a method using a metal such as magnesium or samarium. Among them, a catalytic reduction reaction with platinum, for example, a method described in WO 2004/005255 pamphlet is preferable. The compound obtained in this step may give a diastereomeric mixture based on stereoisomerism, and these can be separated and purified by a method such as silica gel column chromatography or recrystallization, if necessary.
　化合物(IIb1)は、工程9において、化合物(XI)の異性化によって製造することができる。該「異性化」は「塩基」の存在下で行い、「塩基」としては、例えば、
　1)アルカリ金属またはアルカリ土類金属の水素化物(例、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウム)、アルカリ金属またはアルカリ土類金属のアミド類(例、リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムジシクロヘキシルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド)、アルカリ金属またはアルカリ土類金属のＣ１－６アルコキシド(例、ナトリウムメトキシド、ナトリウムエトキシド、カリウム tert-ブトキシド、ナトリウム tert-ブトキシド)などの強塩基；
　2)アルカリ金属またはアルカリ土類金属の水酸化物(例、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウム)、アルカリ金属またはアルカリ土類金属の炭酸塩(例、炭酸ナトリウム、炭酸カリウム、炭酸セシウム)、アルカリ金属またはアルカリ土類金属の炭酸水素塩(例、炭酸水素ナトリウム、炭酸水素カリウム)などの無機塩基；および
　3)トリエチルアミン、ジイソプロピルエチルアミン、N-メチルモルホリンなどのアミン類；例えばDBU(1,8-ジアザビシクロ〔5.4.0〕ウンデカ-7-エン)、DBN(1,5-ジアザビシクロ〔4.3.0〕ノナ-5-エン)のアミジン類；例えばピリジン、ジメチルアミノピリジン、イミダゾール、2,6-ルチジンなどの塩基性複素環化合物などの有機塩基などが挙げられるが、中でも、例えばナトリウムエトキシドのアルカリ金属またはアルカリ土類金属のＣ１－６アルコキシドを用いることが好ましい。本工程は、例えばWO2008/141462に記載の方法に準じて行うことができる。 Compound (IIb 1 ) can be produced by isomerization of compound (XI) in Step 9. The “isomerization” is carried out in the presence of a “base”, and as the “base”, for example,
1) Alkali metal or alkaline earth metal hydrides (e.g. lithium hydride, sodium hydride, potassium hydride, calcium hydride), alkali metal or alkaline earth metal amides (e.g. lithium amide, sodium amide) , Lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide), alkali metal or alkaline earth metal C 1-6 alkoxide (eg, sodium methoxide) Strong base such as sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide);
2) Alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, carbonate) Potassium, cesium carbonate), inorganic bases such as alkali metal or alkaline earth metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate); and 3) amines such as triethylamine, diisopropylethylamine, N-methylmorpholine; For example, amidines of DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene); for example, pyridine, dimethylaminopyridine, imidazole Organic bases such as basic heterocyclic compounds such as 2,6-lutidine, etc. It is preferred to use a C 1-6 alkoxide of the genus or alkaline earth metals. This step can be performed, for example, according to the method described in WO2008 / 141462.
　化合物(IIb)に含まれる化合物(IIb2) (化合物(IIb)のＲ1が-ＣＨ2ＯＨである化合物。)、(IIb3) (化合物(IIb)のＲ1が-ＣＨ2Ｌ1である化合物。)、(IIb4) (化合物(IIb)のＲ1が-ＣＨ2Ｓ-Alkyl3である化合物。)、(IIb5) (化合物(IIb)のＲ1が-ＣＨ2ＳＯ2-Alkyl3である化合物。)、(IIb6) (化合物(IIb)のＲ1が-ＣＨ2Ｓ-ＣＯ-Alkyl4である化合物。)、(IIb7) (化合物(IIb)のＲ1が-ＣＨ2ＳＯ2-Ｃｌである化合物。)および(IIb8) (化合物(IIb)のＲ1が-ＣＨ2ＳＯ2-Ｎ-(Alkyl5)(Alkyl6)である化合物。)は、例えば以下の方法により化合物(IIb1)から誘導することができる。 Compound (IIb 2 ) (compound in which R 1 of compound (IIb) is —CH 2 OH), (IIb 3 ) (R 1 of compound (IIb) is —CH 2 L 1 ) A compound.), (IIb 4 ) (a compound in which R 1 of compound (IIb) is —CH 2 S-Alkyl 3 ), (IIb 5 ) (R 1 of a compound (IIb) is —CH 2 SO 2 — A compound in which Alkyl 3 is present.), (IIb 6 ) (a compound in which R 1 of compound (IIb) is —CH 2 S—CO—Alkyl 4 ), (IIb 7 ) (in which R 1 of compound (IIb) is − Compounds that are CH 2 SO 2 —Cl.) And (IIb 8 ) (compounds in which R 1 of compound (IIb) is —CH 2 SO 2 —N— (Alkyl 5 ) (Alkyl 6 )) are for example: It can be derived from compound (IIb 1 ) by the method of
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
[式中、Ｌ1は脱離基を、Alkyl3及びAlkyl4は各々置換されていてもよいＣ1-6アルキル基を、Alkyl5およびAlkyl6はそれぞれ水素原子または置換されていてもよいＣ1-6アルキル基を、その他の各記号は前記と同意義を示す。ここで、Alkyl3、Alkyl4、Alkyl5及びAlkyl6が示す「置換されていてもよいＣ1-6アルキル基」の「Ｃ1-6アルキル基」および該「Ｃ1-6アルキル基」が有していてもよい置換基は前記と同意義を示す。] [Wherein L 1 is a leaving group, Alkyl 3 and Alkyl 4 are each an optionally substituted C 1-6 alkyl group, and Alkyl 5 and Alkyl 6 are each a hydrogen atom or an optionally substituted C The 1-6 alkyl group and other symbols are as defined above. Here, “C 1-6 alkyl group” and “C 1-6 alkyl group” of “optionally substituted C 1-6 alkyl group” represented by Alkyl 3 , Alkyl 4 , Alkyl 5 and Alkyl 6 are The substituents that may be present have the same meaning as described above. ]
　化合物(IIb2)は、工程10において、化合物(IIb1)の還元によって製造することができる。該「還元」は、工程8における「還元」に準じた方法で実施できるが、中でも水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化アルミニウムリチウム等の金属水素化物を用いた方法が好ましい。 Compound (IIb 2 ) can be produced by reducing compound (IIb 1 ) in Step 10. The “reduction” can be performed by a method according to “reduction” in step 8, but among them, a method using a metal hydride such as sodium borohydride, lithium borohydride, lithium aluminum hydride or the like is preferable.
　化合物(IIb3)は、工程11において、化合物(IIb2)の水酸基を脱離基Ｌ1に変換することによって製造することができる。脱離基L1としては、例えばハロゲン原子(例えば、塩素原子、臭素原子、ヨウ素原子)、ハロゲン原子で置換されていてもよいＣ1-6アルキルスルホニルオキシ(例えば、メタンスルホニルオキシ、エタンスルホニルオキシ、トリフルオロメタンスルホニルオキシ)、Ｃ1-6アルキルで置換されていてもよいＣ6-10アリールスルホニルオキシ(例えばベンゼンスルホニルオキシ、p-トルエンスルホニルオキシ)が用いられる。中でもハロゲン原子、メタンスルホニルオキシが好ましい。脱離基Ｌ1がハロゲン原子の場合は、例えばJournal of the American Chemical Society, 107, 3950-3955 (1985)に記載の方法、脱離基L1がメタンスルホニルオキシの場合は、例えばSynthesis, 6, 627-629 (1995)に記載の方法に準じて実施することができる。 Compound (IIb 3 ) can be produced by converting the hydroxyl group of compound (IIb 2 ) to leaving group L 1 in step 11. Examples of the leaving group L 1 include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), C 1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy) optionally substituted with a halogen atom. , Trifluoromethanesulfonyloxy), C 6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy) optionally substituted with C 1-6 alkyl is used. Of these, a halogen atom and methanesulfonyloxy are preferred. When the leaving group L 1 is a halogen atom, for example, the method described in Journal of the American Chemical Society, 107, 3950-3955 (1985), and when the leaving group L 1 is methanesulfonyloxy, for example, Synthesis, 6 , 627-629 (1995).
　化合物(IIb4)は、工程12において、化合物(IIb3)の脱離基L1を対応するチオールで置換することによって製造することができる。本工程では、適宜塩基を用いてもよい。該「塩基」は、例えば工程9で用いた「塩基」が用いられるが、中でも水素化ナトリウムなどのアルカリ金属水素化物が好ましい。また、チオールの代わりに、チオールのアルカリ金属塩を用いてもよい。本工程は、例えばJournal of Medicinal Chemistry, (48), 4679-4689 (2005)に記載の方法に準じて実施することができる。 Compound (IIb 4 ) can be produced by replacing the leaving group L 1 of compound (IIb 3 ) with the corresponding thiol in Step 12. In this step, a base may be used as appropriate. As the “base”, for example, the “base” used in Step 9 is used, and among them, an alkali metal hydride such as sodium hydride is preferable. Moreover, you may use the alkali metal salt of thiol instead of thiol. This step can be performed, for example, according to the method described in Journal of Medicinal Chemistry, (48), 4679-4689 (2005).
　化合物(IIb5)は、工程13において、化合物(IIb4)の酸化によって製造することができる。該「酸化」は、3-クロロフェニル過安息香酸、過ヨウ素酸ナトリウム、過酸化水素水、過酢酸、Oxone(登録商標)などの酸化剤を用いて行なうことができるが、中でも3-クロロフェニル過安息香酸等が好ましい。本工程は、例えばJournal of Organic Chemistry, 68, 5075-5083 (2003)に記載の方法に準じて行うことができる。 Compound (IIb 5 ) can be produced by oxidation of compound (IIb 4 ) in Step 13. The “oxidation” can be performed using an oxidizing agent such as 3-chlorophenyl perbenzoic acid, sodium periodate, hydrogen peroxide solution, peracetic acid, Oxone (registered trademark), among others 3-chlorophenyl perbenzoic acid. An acid or the like is preferable. This step can be performed according to the method described in, for example, Journal of Organic Chemistry, 68, 5075-5083 (2003).
　化合物(IIb6)は、工程14において、化合物(IIb3)の脱離基L1を対応するアルキルチオカルボン酸で置換することによって製造することができる。本工程では、適宜塩基を用いてもよい。該「塩基」は、例えば工程9で用いた「塩基」が用いられるが、中でも有機塩基、水素化ナトリウム、水素化カリウムなどのアルカリ金属水素化物、あるいは炭酸セシウム等のアルカリ金属炭酸塩が好ましい。また、アルキルチオカルボン酸の代わりに、アルキルチオカルボン酸のアルカリ金属塩を用いてもよい。本工程は、例えば国際公開第2005/013975号パンフレットに記載の方法に準じて実施することができる。 Compound (IIb 6 ) can be produced by replacing the leaving group L 1 of compound (IIb 3 ) with the corresponding alkylthiocarboxylic acid in Step 14. In this step, a base may be used as appropriate. As the “base”, for example, the “base” used in Step 9 is used, and among them, an organic base, an alkali metal hydride such as sodium hydride or potassium hydride, or an alkali metal carbonate such as cesium carbonate is preferable. Moreover, you may use the alkali metal salt of alkylthiocarboxylic acid instead of alkylthiocarboxylic acid. This step can be performed, for example, according to the method described in International Publication No. 2005/013975 pamphlet.
　化合物(IIb7)は、工程15において、化合物(IIb6)のクロロスルホニル化（スルホニルクロリドへの変換）によって製造することができる。該「クロロスルホニル化」は、例えば、水中あるいは水－酢酸エチル、アセトニトリル等のエステルとの混合溶媒中、あるいはエタノールやメタノール等のアルコール系溶媒中、塩素ガス、塩化スルフリルあるいはN-クロロスクシンイミドなどのクロル化剤を用いる方法、あるいは過酸化水素で酸化した後に塩化チオニルで処理する方法によって行なうことができるが、中でもN-クロロスクシンイミドが好ましい。本工程は、例えばSynthesis, 24, 4131-4134 (2006) に記載の方法に準じて行うことができる。 Compound (IIb 7 ) can be produced by chlorosulfonylation (conversion to sulfonyl chloride) of compound (IIb 6 ) in Step 15. The “chlorosulfonylation” is exemplified by chlorine gas, sulfuryl chloride, N-chlorosuccinimide, etc. Although it can be carried out by a method using a chlorinating agent or a method of treating with thionyl chloride after oxidation with hydrogen peroxide, N-chlorosuccinimide is particularly preferred. This step can be performed, for example, according to the method described in Synthesis, 24, 4131-4134 (2006).
　化合物(IIb8)は、工程16において、化合物(IIb7)のスルホンアミド化によって製造することができる。該「スルホンアミド化」は、自体公知の方法、例えば塩基の存在下、スルホニルクロリドとの反応によって行うことができる。該「塩基」は、例えば工程9における塩基を利用できるが、中でも、トリエチルアミンなどの三級アミンが好ましい。
[化合物(Ic)の製造法] Compound (IIb 8 ) can be produced by sulfonamidation of compound (IIb 7 ) in Step 16. The “sulfonamidation” can be carried out by a method known per se, for example, by reaction with sulfonyl chloride in the presence of a base. As the “base”, for example, the base in Step 9 can be used, among which a tertiary amine such as triethylamine is preferable.
[Production Method of Compound (Ic)]
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
[式中、各記号は前記と同意義を示す。]
　化合物(Ic)は、例えば工程17において、化合物(IIc)の脱保護によって製造することができる。PRG1で示される「保護基」としては、例えば工程1と同様のものが用いられるが、中でもtert-ブトキシカルボニル(Boc)基が好ましい。工程17は、工程１と同様の反応条件、またはこれに準じる条件で行うことができる。 [Wherein each symbol is as defined above. ]
Compound (Ic) can be produced, for example, by deprotecting compound (IIc) in Step 17. As the “protecting group” represented by PRG 1 , for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group is preferable. Step 17 can be carried out under the same reaction conditions as in Step 1 or conditions analogous thereto.
　化合物(IIc)に含まれる化合物(IIc1) (化合物(IIc)のＲ1が-ＣＯ2Alkyl7である化合物。)は、例えば以下の方法により製造することができる。 Compound (IIc 1 ) (compound in which R 1 of compound (IIc) is —CO 2 Alkyl 7 ) contained in compound (IIc) can be produced, for example, by the following method.
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
[式中、Alkyl7は置換されていてもよいＣ1-6アルキル基を、その他の各記号は前記と同意義を示す。ここで、Alkyl7が示す「置換されていてもよいＣ1-6アルキル基」の「Ｃ1-6アルキル基」および該「Ｃ1-6アルキル基」が有していてもよい置換基は前記と同意義を示す。] [In the formula, Alkyl 7 represents an optionally substituted C 1-6 alkyl group, and other symbols are as defined above. Here, shown is and Alkyl 7 "C 1-6 alkyl group" and the "C 1-6 alkyl group" substituent optionally possessed by the "optionally substituted C 1-6 alkyl group" The meaning is the same as above. ]
　化合物(XIII)は、工程18において、化合物(XII)の環拡大化により製造することができる。本工程は、工程5と同様の反応条件、またはこれに準じる条件で行うことができる。 Compound (XIII) can be produced by ring expansion of compound (XII) in Step 18. This step can be carried out under the same reaction conditions as in step 5 or conditions analogous thereto.
　化合物(IIc1)は、例えば工程19、20、21および22を順次行うことにより、化合物(XIII)から化合物(XIV)あるいは(XV)、(IIf1)および(XVII)を経て製造することができる。該「工程19、20、21および22」は、それぞれ前記工程6、7、8および9に準じて行うことができる。
[化合物(Id)の製造法] Compound (IIc 1 ) can be produced from compound (XIII) through compound (XIV) or (XV), (IIf 1 ) and (XVII), for example, by sequentially performing steps 19, 20, 21 and 22. it can. The “steps 19, 20, 21 and 22” can be carried out according to the aforementioned steps 6, 7, 8 and 9, respectively.
[Production Method of Compound (Id)]
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
[式中、各記号は前記と同意義を示す。]
　化合物(Id)は、例えば工程23において、化合物(IId)の脱保護によって製造することができる。PRG1で示される「保護基」としては、例えば工程1と同様のものが用いられるが、中でもtert-ブトキシカルボニル(Boc)基が好ましい。工程23は、工程１と同様の反応条件、またはこれに準じる条件で行うことができる。 [Wherein each symbol is as defined above. ]
Compound (Id) can be produced, for example, by deprotecting compound (IId) in Step 23. As the “protecting group” represented by PRG 1 , for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group is preferable. Step 23 can be carried out under the same reaction conditions as in Step 1 or conditions analogous thereto.
　化合物(IId)に含まれる化合物(IId1) (化合物(IId)のＲ1が-ＣＯ2Alkyl2である化合物。)は、例えば以下の方法により製造することができる。 Compound (IId 1 ) (compound in which R 1 of compound (IId) is —CO 2 Alkyl 2 ) contained in compound (IId) can be produced, for example, by the following method.
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
[式中、各記号は前記と同意義を示す。]
　化合物(VII)は、前記工程5において化合物(VI)と共に生じた位置異性体をシリカゲルカラムクロマトグラフィーにより精製することにより得ることができる。また、ここに示した工程24、25、26および27は、それぞれ前記工程6、7、8および9に準じて行うことができる。 [Wherein each symbol is as defined above. ]
Compound (VII) can be obtained by purifying the regioisomer generated together with compound (VI) in Step 5 by silica gel column chromatography. Further, the steps 24, 25, 26 and 27 shown here can be carried out according to the steps 6, 7, 8 and 9, respectively.
　化合物(IId)に含まれる化合物(IId2) (化合物(IId)のＲ1が-ＣＨ2ＯＨである化合物。)、(IId3) (化合物(IId)のＲ１が-ＣＨ2ＳＯ2-Alkyl8である化合物。)、(IId4) (化合物(IId)のＲ1が-ＣＨ2Ｌ2である化合物。)、(IId5) (化合物(IId)のＲ1が-ＣＨ2Ｎ3である化合物。)、(IId6) (化合物(IId)のＲ1が-ＣＨ2ＮＨ2である化合物。)、(IId7) (化合物(IId)のＲ1が-ＣＨ2ＮＨＣＯＮ(Alkyl9)(Alkyl10)である化合物。)、(IId8) (化合物(IId)のＲ1が-ＣＨ2ＮＨＳＯ2Alkyl11である化合物。)および(IId9) (化合物(IId)のＲ1が-ＣＨ2ＮＨＳＯ2Ｎ(Alkyl12)(Alkyl13)である化合物。)は、例えば以下の方法により化合物(IId1)から誘導することができる。 Compound (IId 2 ) (compound in which R 1 of compound (IId) is —CH 2 OH), (IId 3 ) (R 1 of compound (IId) is —CH 2 SO 2 — Compound in which Alkyl 8 is present.), (IId 4 ) (compound in which R 1 of compound (IId) is —CH 2 L 2 ), (IId 5 ) (R 1 in compound (IId) is —CH 2 N 3 (IId 6 ) (compound in which R 1 of compound (IId) is —CH 2 NH 2 ), (IId 7 ) (R 1 in compound (IId) is —CH 2 NHCON (Alkyl 9 ) (Alkyl 10 ).), (IId 8 ) (Compound (IId) where R 1 is —CH 2 NHSO 2 Alkyl 11 ) and (IId 9 ) (Compound (IId) where R 1 is -CH 2 NHSO 2 N (Alkyl 12 ) (Alkyl 13 ).) Can be derived from compound (IId 1 ) by the following method, for example.
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
[式中、Ｌ2は脱離基を、Alkyl8およびAlkyl11は各々置換されていてもよいＣ1-6アルキル基を、Alkyl9、Alkyl10、Alkyl12およびAlkyl13はそれぞれ水素原子または置換されていてもよいＣ1-6アルキル基を、その他の各記号は前記と同意義を示す。ここで、Alkyl8、Alkyl9、Alkyl10、Alkyl11、Alkyl12およびAlkyl13が示す「置換されていてもよいＣ1-6アルキル基」の「Ｃ1-6アルキル基」および該「Ｃ1-6アルキル基」が有していてもよい置換基とは前記と同意義を示す。] [Wherein L 2 is a leaving group, Alkyl 8 and Alkyl 11 are each an optionally substituted C 1-6 alkyl group, and Alkyl 9 , Alkyl 10 , Alkyl 12 and Alkyl 13 are hydrogen atoms or substituted, respectively. In the C 1-6 alkyl group which may be substituted , other symbols are as defined above. Here, Alkyl 8, Alkyl 9, Alkyl 10, Alkyl 11, Alkyl 12 and and Alkyl 13 are "C 1-6 alkyl group" of the "optionally substituted C 1-6 alkyl group" shown and the "C 1 The substituent which the “ -6 alkyl group” may have has the same meaning as described above. ]
　化合物(IId2)は、工程28において、化合物(IId1)の還元によって製造することができる。該「還元」は、例えば前記工程10の方法に準じて実施することができる。 Compound (IId 2 ) can be produced by reducing compound (IId 1 ) in step 28. The “reduction” can be performed, for example, according to the method of Step 10 described above.
　化合物(IId3)は、工程29において、化合物(IId2)の側鎖水酸基をスルホン基に変換すること（側鎖スルホン体への変換）によって製造することができる。該「スルホン基への変換」は、例えば前記工程11-13の方法に準じて実施することができる。 Compound (IId 3 ) can be produced by converting the side chain hydroxyl group of compound (IId 2 ) to a sulfone group (conversion to a side chain sulfone) in Step 29. The “conversion to a sulfone group” can be carried out, for example, according to the method of Step 11-13.
　化合物(IId5)は、工程30において化合物(IId2)の側鎖水酸基を脱離基Ｌ2とした後、工程31においてアジド化することによって製造することができる。脱離基L2は、前記Ｌ1と同様のものが用いられるが、例えばメタンスルホニルオキシ基、塩素原子等が好ましい。該「アジド化」においては、自体公知の方法を用いることができ、アジ化ナトリウム、トリメチルシリルアジド等のアジド化剤が用いられる。 Compound (IId 5 ) can be produced by converting the side chain hydroxyl group of compound (IId 2 ) into a leaving group L 2 in Step 30 and then azidating in Step 31. As the leaving group L 2 , those similar to the above L 1 can be used, and for example, a methanesulfonyloxy group, a chlorine atom and the like are preferable. In the “azidation”, a method known per se can be used, and an azidating agent such as sodium azide or trimethylsilyl azide is used.
　化合物(IId6)は、工程32において、アジド誘導体(IId5)のアジド基を還元することによって製造することができる。該「アジド基の還元」は、工程8で用いた還元条件のほか、例えばTetrahedron, 48, 1353-1406 (1992)に記載のStaudinger反応によっても実施することができる。 Compound (IId 6 ) can be produced by reducing the azide group of the azide derivative (IId 5 ) in step 32. The “reduction of the azide group” can be carried out by the Staudinger reaction described in, for example, Tetrahedron, 48, 1353-1406 (1992) in addition to the reduction conditions used in Step 8.
　化合物(IId7)は、工程33において、化合物(IId6)のウレア化によって製造することができる。該「ウレア化」は、自体公知の方法に準じて実施することができ、例えばアルキルイソシアネート類との反応、Journal of Medicinal Chemistry, 36, 2984-2997 (1993)に記載のフェニルカルバメートを経る方法で製造することができる。中でも末端無置換のウレアの製造には、イソシアン酸トリメチルシリルの使用が好ましい。 Compound (IId 7 ) can be produced by urea formation of compound (IId 6 ) in Step 33. The “urea” can be carried out according to a method known per se, for example, a reaction with an alkyl isocyanate, a method via a phenyl carbamate described in Journal of Medicinal Chemistry, 36, 2984-2997 (1993). Can be manufactured. Among these, the use of trimethylsilyl isocyanate is preferred for the production of terminal-unsubstituted urea.
　化合物(IId8)は、工程34において、化合物(IId6)のスルホンアミド化によって製造することができる。該「スルホンアミド化」は、自体公知の方法に準じて実施することができ、例えば塩基の存在下、スルホニルクロリドとの反応によって行うことができる。該「塩基」は、例えば工程9における塩基を利用できるが、トリエチルアミンなどの三級アミンが好ましい。 Compound (IId 8 ) can be produced by sulfonamidation of compound (IId 6 ) in Step 34. The “sulfonamidation” can be carried out according to a method known per se, for example, by reaction with sulfonyl chloride in the presence of a base. As the “base”, for example, the base in Step 9 can be used, but a tertiary amine such as triethylamine is preferable.
　化合物(IId9)は、工程35において、化合物(IId6)のスルファミド化によって製造することができる。該「スルファミド化」は、例えば国際公開第2007/049041号パンフレットに記載のスルファモイルクロリドとの縮合による方法、Organic Letters, 3 (14), 2241-2243 (2001)に記載のN-(tert-ブトキシカルボニル)-N-[4-(ジメチルアザニウミリデン)-1,4-ジヒドロピリジン-1-イルスルホニル]アザニドを用いる方法によって行うことができる。
[化合物(Ie)の製造法] Compound (IId 9 ) can be produced by sulfamidation of compound (IId 6 ) in Step 35. The “sulfamidation” is, for example, a method by condensation with sulfamoyl chloride described in International Publication No. 2007/049041, Pamphlet N- (tert) described in Organic Letters, 3 (14), 2241-2243 (2001). It can be carried out by a method using -butoxycarbonyl) -N- [4- (dimethylazanimilidene) -1,4-dihydropyridin-1-ylsulfonyl] azanide.
[Production Method of Compound (Ie)]
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
[式中、各記号は前記と同意義を示す。]
　化合物(Ie)は、例えば工程36において、化合物(IIe)の脱保護によって製造することができる。PRG1で示される「保護基」としては、例えば工程1と同様のものが用いられるが、中でもtert-ブトキシカルボニル(Boc)基が好ましい。工程36は、工程１と同様の反応条件、またはこれに準じる条件で行うことができる。 [Wherein each symbol is as defined above. ]
Compound (Ie) can be produced, for example, by deprotecting compound (IIe) in Step 36. As the “protecting group” represented by PRG 1 , for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group is preferable. Step 36 can be performed under the same reaction conditions as in step 1 or conditions similar thereto.
　化合物(IIe)に含まれる化合物(IIe1) (化合物(IIe)のＲ1が-ＣＯ2Alkyl2である化合物。)は、前記工程7から得られ、化合物(IIe2) (化合物(IIe)のＲ1が-ＣＨ2ＯＨである化合物。)及び化合物(IIe3) (化合物(IIe)のＲ1が-ＣＨ2Ｏ-Alkyl14である化合物。)は、例えば以下の方法により化合物(IIe1)から誘導することができる。 Compound (IIe 1 ) (compound in which R 1 of compound (IIe) is —CO 2 Alkyl 2 ) contained in compound (IIe) is obtained from Step 7 above, and compound (IIe 2 ) (compound (IIe) A compound in which R 1 is —CH 2 OH.) And a compound (IIe 3 ) (a compound in which R 1 of compound (IIe) is —CH 2 O—Alkyl 14 ) are obtained by, for example, 1 ) can be derived from.
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
[式中、Alkyl14は置換されていてもよいＣ1-6アルキル基を、その他の各記号は前記と同意義を示す。ここで、Alkyl14が示す「置換されていてもよいＣ1-6アルキル基」の「Ｃ1-6アルキル基」および該「Ｃ1-6アルキル基」が有していてもよい置換基は前記と同意義を示す。] [Wherein, Alkyl 14 represents an optionally substituted C 1-6 alkyl group, and other symbols are as defined above. Here, shown is and Alkyl 14 "C 1-6 alkyl group" and the "C 1-6 alkyl group" substituent optionally possessed by the "optionally substituted C 1-6 alkyl group" The meaning is the same as above. ]
　化合物(IIe2)は、工程37において、化合物(IIe1)の還元によって製造することができる。該「還元」は、例えば前記工程10の方法に準じて実施することができる。 Compound (IIe 2 ) can be produced by reduction of compound (IIe 1 ) in Step 37. The “reduction” can be performed, for example, according to the method of Step 10 described above.
　化合物(IIe3)は、工程38において、化合物(IIe2)の「Ｏ-アルキル化」によって製造することができる。該「Ｏ-アルキル化」は、例えば前記工程3の方法に準じて実施することができる。
[化合物(If)の製造法] Compound (IIe 3 ) can be produced in step 38 by “O-alkylation” of compound (IIe 2 ). The “O-alkylation” can be carried out, for example, according to the method of Step 3.
[Production Method of Compound (If)]
Figure JPOXMLDOC01-appb-C000078
 
Figure JPOXMLDOC01-appb-C000078
 
[式中、各記号は前記と同意義を示す。]
　化合物(If)は、例えば工程39において、化合物(IIf)の脱保護によって製造することができる。PRG1で示される「保護基」としては、例えば工程1と同様のものが用いられるが、中でもtert-ブトキシカルボニル(Boc)基が好ましい。工程39は、工程１と同様の反応条件、またはこれに準じる条件で行うことができる。 [Wherein each symbol is as defined above. ]
Compound (If) can be produced, for example, by deprotecting compound (IIf) in Step 39. As the “protecting group” represented by PRG 1 , for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group is preferable. Step 39 can be performed under the same reaction conditions as in step 1 or conditions similar thereto.
　化合物(IIf)に含まれる化合物(IIf1) (Ｒ1は、-ＣＯ2Alkyl7を示す。)は、前記工程20より得られるものである。
[化合物(Ig)の製造法] The compound (IIf 1 ) (R 1 represents —CO 2 Alkyl 7 ) contained in the compound (IIf) is obtained from the step 20.
[Production Method of Compound (Ig)]
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
[式中、各記号は前記と同意義を示す。]
　化合物(Ig)は、例えば工程40において、化合物(IIg)の脱保護によって製造することができる。PRG1で示される「保護基」としては、例えば工程1と同様のものが用いられるが、中でもtert-ブトキシカルボニル(Boc)基等が好ましい。工程40は、工程１と同様の反応条件、またはこれに準じる条件で行うことができる。 [Wherein each symbol is as defined above. ]
Compound (Ig) can be produced, for example, by deprotecting compound (IIg) in Step 40. As the “protecting group” represented by PRG 1 , for example, those similar to those in Step 1 are used, and among them, a tert-butoxycarbonyl (Boc) group and the like are preferable. Step 40 can be performed under the same reaction conditions as in step 1 or conditions similar thereto.
　化合物(IIg)に含まれる化合物(IIg1) (化合物(IIg)のＲ1が-ＣＯ2Alkyl2である化合物。)は、前記工程25から得られ、化合物(IIg2) (化合物(IIg)のＲ1が-ＣＨ2ＯＨである化合物。)は、例えば以下の方法により化合物(IIe1)から誘導することができる。 The compound (IIg 1 ) (compound in which R 1 of the compound (IIg) is —CO 2 Alkyl 2 ) contained in the compound (IIg) is obtained from the step 25, and the compound (IIg 2 ) (compound (IIg) In which R 1 is —CH 2 OH.) Can be derived from compound (IIe 1 ) by the following method, for example.
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
[式中、各記号は前記と同意義を示す。]
　化合物(IIg2)は、工程41において、化合物(IIg1)の還元によって製造することができる。該「還元」は、例えば前記工程10の方法に準じて実施することができる。 [Wherein each symbol is as defined above. ]
Compound (IIg 2 ) can be produced by reducing compound (IIg 1 ) in Step 41. The “reduction” can be performed, for example, according to the method of Step 10 described above.
　化合物(I)が遊離化合物として得られた場合には、自体公知の方法あるいはそれに準ずる方法によって、目的とする塩に変換することができ、逆に塩で得られた場合には、自体公知の方法あるいはそれに準ずる方法により、遊離体または目的とする他の塩に変換することができる。 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.
　このような方法により生成した化合物(I)は、例えば、再結晶、蒸留、クロマトグラフィー等の通常の分離手段により単離、精製することができる。 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.
　化合物(I)が、光学異性体、立体異性体、位置異性体、回転異性体を含有する場合には、これらも化合物(I)として含有されるとともに、それらの混合物も化合物(I)に含まれ、自体公知の合成手法、分離手法（例えば、濃縮、溶媒抽出、カラムクロマトグラフィー、再結晶等）によりそれぞれを単品として得ることができる。例えば光学異性体は自体公知の方法により製造することができる。具体的には、光学活性な合成中間体を用いる、または、最終物のラセミ体を常法に従って光学分割することにより光学異性体を得る。 When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and mixtures thereof are also included in compound (I). Each can be obtained as a single product by a synthesis method and a separation method known per se (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.). For example, optical isomers 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.
　光学分割法としては、自体公知の方法である、例えば、分別再結晶法、キラルカラム法、ジアステレオマー法が用いられる。
　１）分別再結晶法
　ラセミ体と光学活性な化合物（(+)-マンデル酸、(-)-マンデル酸、(+)-酒石酸、(-)-酒石酸、(+)-1-フェネチルアミン、(-)-1-フェネチルアミン、シンコニン、(-)-シンコニジン、ブルシン等）と塩を形成させ、これを分別再結晶法によって分離し、所望により、中和工程を経てフリーの光学異性体を得る方法。
　２）キラルカラム法
　ラセミ体またはその塩を光学異性体分離用カラム（キラルカラム）にかけて分離する方法。例えば液体クロマトグラフィーの場合、ENANTIO-OVM（東ソー社製）あるいは、CHIRALシリーズ（ダイセル化学工業社製）等のキラルカラムに光学異性体の混合物を添加し、水、種々の緩衝液（リン酸緩衝液等）、有機溶媒（エタノール、メタノール、イソプロパノール、アセトニトリル、トリフルオロ酢酸、ジエチルアミン等）を単独あるいは混合した溶液として展開させることにより、光学異性体を分離する。また、例えばガスクロマトグラフィーの場合、CP-Chirasil-DeX CB（ジーエルサイエンス社製）等のキラルカラムを使用して分離する。
　３）ジアステレオマー法
　ラセミ体の混合物を光学活性な試薬との化学反応によってジアステレオマーの混合物とし、これを通常の分離手段（分別再結晶、クロマトグラフィー法等）等を経て単一物質とした後、加水分解反応等の化学的な処理により光学活性な試薬部位を切り離すことにより光学異性体を得る方法。例えば、化合物(I)が分子内にヒドロキシまたは1，2級アミノを有する場合、該化合物と光学活性な有機酸（MTPA〔α-メトキシ-α-（トリフルオロメチル）フェニル酢酸〕、(-)-メントキシ酢酸等）とを縮合反応に付すことにより、それぞれエステル体またはアミド体のジアステレオマーが得られる。一方、化合物(I)がカルボン酸基を有する場合、該化合物と光学活性アミンまたはアルコール試薬とを縮合反応に付すことにより、それぞれアミド体またはエステル体のジアステレオマーが得られる。分離されたジアステレオマーは、酸加水分解あるいは塩基性加水分解反応に付すことにより、元の化合物の光学異性体に変換される。 As the optical resolution method, methods known per se, for example, fractional recrystallization method, chiral column method, diastereomer method are used.
1) Fractional recrystallization method Racemate and optically active compounds ((+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (- ) -1-phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.) to form a salt, which is separated by fractional recrystallization, and if desired, a free optical isomer is obtained through a neutralization step.
2) Chiral column method A method in which a racemate or a salt thereof is separated by applying to an optical isomer separation column (chiral column). For example, in the case of liquid chromatography, 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 buffer solutions (phosphate buffer solutions) Etc.) and an organic solvent (ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) are developed as a single or mixed solution to separate optical isomers. For example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
3) Diastereomer method A racemic mixture is converted into a diastereomer mixture by a chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (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. For example, when the compound (I) has hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (−) -Mentoxyacetic acid or the like) is subjected to a condensation reaction to obtain an ester or amide diastereomer, respectively. On the other hand, when the compound (I) has a carboxylic acid group, an amide or ester diastereomer can be 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.
　化合物(I)は、結晶であってもよい。化合物(I)は単一の結晶形を有していてもよく、また複数の結晶形の混合物であってもよい。 Compound (I) may be a crystal. Compound (I) may have a single crystal form or a mixture of a plurality of crystal forms.
　化合物(I)は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性（構造、融点、融解熱、吸湿性、溶解性および安定性等）を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。 Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a co-crystal or co-crystal salt is two or more unique solids each having different physical properties (structure, melting point, heat of fusion, hygroscopicity, solubility and stability, etc.) at room temperature. Means a crystalline substance composed of The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
　化合物(I)の結晶は、化合物(I)に自体公知の結晶化法を適用して、結晶化することによって製造することができる。 The crystal of compound (I) can be produced by crystallization by applying a crystallization method known per se to compound (I).
　ここで、結晶化法としては、例えば、溶液からの結晶化法、蒸気からの結晶化法、溶融体からの結晶化法等が挙げられる。 Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.
　該「溶液からの結晶化法」としては、化合物の溶解度に関係する因子（溶媒組成、ｐＨ、温度、イオン強度、酸化還元状態等）または溶媒の量を変化させることによって、飽和していない状態から過飽和状態に移行させる方法が一般的であり、具体的には、例えば濃縮法、徐冷法、反応法（拡散法、電解法）、水熱育成法、融剤法等が挙げられる。用いられる溶媒としては、例えば、芳香族炭化水素類（ベンゼン、トルエン、キシレン等）、ハロゲン化炭化水素類（ジクロロメタン、クロロホルム等）、飽和炭化水素類（ヘキサン、ヘプタン、シクロヘキサン等）、エーテル類（ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン等）、ニトリル類（アセトニトリル等）、ケトン類（アセトン等）、スルホキシド類（ジメチルスルホキシド等）、酸アミド類（N,N-ジメチルホルムアミド等）、エステル類（酢酸エチル等）、アルコール類（メタノール、エタノール、イソプロピルアルコール等）、水が挙げられる。これらの溶媒は単独あるいは二種以上を適当な割合（例、1:1ないし1:100（容積比））で混合して用いられる。必要に応じて種晶を使用することもできる。 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. In general, 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. Examples of the solvent used include aromatic hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), saturated hydrocarbons (hexane, heptane, cyclohexane, etc.), ethers ( Diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (acetonitrile, etc.), ketones (acetone, etc.), sulfoxides (dimethyl sulfoxide, etc.), acid amides (N, N-dimethylformamide, etc.), esters ( Ethyl acetate), alcohols (methanol, ethanol, isopropyl alcohol, etc.), and water. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)). A seed crystal can also be used as needed.
　該「蒸気からの結晶化法」としては、例えば気化法（封管法、気流法）、気相反応法、化学輸送法が挙げられる。 Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, and a chemical transport method.
　該「溶融体からの結晶化法」としては、例えばノルマルフリージング法（引上げ法、温度傾斜法、ブリッジマン法）、帯溶融法（ゾーンレベリング法、フロートゾーン法）、特殊成長法（VLS法、液相エピタキシー法）が挙げられる。 Examples of the “crystallization from melt” 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).
　結晶化法の好適な例としては、化合物(I)を20～120℃の温度下に、適当な溶媒（メタノール、エタノール等のアルコール類等）に溶解し、得られる溶液を溶解時の温度以下（例えば0～50℃、好ましくは0～20℃）に冷却する方法等が挙げられる。 As a preferred example of the crystallization method, compound (I) is dissolved in an appropriate solvent (alcohol such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is below the temperature at the time of dissolution. Examples thereof include a method of cooling to 0 to 50 ° C. (preferably 0 to 20 ° C.).
　このようにして得られる化合物(I)の結晶は、例えばろ過等によって単離することができる。 The crystals of compound (I) thus obtained can be isolated by, for example, filtration.
　得られた結晶の解析方法としては、粉末Ｘ線回折による結晶解析の方法が一般的である。さらに、結晶の方位を決定する方法としては、機械的な方法または光学的な方法等も挙げられる。 As an analysis method of the obtained crystal, a crystal analysis method by powder X-ray diffraction is common. Further, examples of the method for determining the crystal orientation include a mechanical method and an optical method.
　上記の製造法で得られる化合物(I)の結晶は、高純度、高品質であり、吸湿性が低く、通常条件下で長期間保存しても変質せず、安定性に極めて優れている。また、生物学的性質（体内動態（吸収性、分布、代謝、***）、薬効発現等）にも優れ、医薬として極めて有用である。 The crystals of compound (I) obtained by the above production method have high purity and high quality, low hygroscopicity, do not change even when stored for a long time under normal conditions, and are extremely excellent in stability. In addition, it has excellent biological properties (pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of medicinal effects, etc.) and is extremely useful as a medicine.
　同位元素（例、3Ｈ，14Ｃ，35Ｓ，125Ｉなど）などで標識された化合物(I)および化合物(I)の重水素変換体も、本願発明に含まれる。 Compound (I) labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.) and a deuterium converter of compound (I) are also included in the present invention.
　化合物(I)はプロドラッグであってもよく、化合物(I)のプロドラッグとは、生体内における生理条件下で酵素や胃酸等による反応により化合物(I)に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物(I)に変化する化合物、胃酸等により加水分解などを起こして化合物(I)に変化する化合物を示し、これらも本願発明に含まれる。化合物(I)のプロドラッグとしては、化合物(I)のアミノ基がアシル化、アルキル化、りん酸化された化合物［例、化合物(I)のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（5-メチル-2-オキソ-1,3-ジオキソレン-4-イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、tert-ブチル化された化合物］；化合物(I)の水酸基がアシル化、アルキル化、りん酸化、ほう酸化された化合物（例、化合物(I)の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物）；化合物(I)のカルボキシ基がエステル化、アミド化された化合物［例、化合物(I)のカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（5-メチル-2-オキソ-1,3-ジオキソレン-4-イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物］などが挙げられる。これらの化合物は自体公知の方法によって化合物(I)から製造することができる。 Compound (I) may be a prodrug, and 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, enzymatically. Compounds that undergo oxidation, reduction, hydrolysis, etc. to change to compound (I), and compounds that undergo hydrolysis, etc. by gastric acid, etc. to change to compound (I) are shown, and these are also included in the present invention. 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. , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound]; compound Compounds in which the hydroxyl group of (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated Dimethylaminomethylcarbonylated compound); a compound in which the carboxy group of compound (I) is esterified or amidated [eg, the carboxy group of compound (I) is ethyl Esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3 -Dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound] and the like. These compounds can be produced from compound (I) by a method known per se.
　また、化合物(I)のプロドラッグは、広川書店1990年刊「医薬品の開発」第７巻分子設計163頁から198頁に記載されているような、生理的条件で化合物(I)に変化するものであってもよい。 In addition, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990 “Pharmaceutical Development”, Volume 7, pages 163 to 198 of molecular design. It may be.
　「化合物(I)またはそのプロドラッグ」（以下化合物(I’)と略記する）は、優れたモノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有する。 “Compound (I) or a prodrug thereof” (hereinafter abbreviated as compound (I ′)) has an excellent monoamine (such as serotonin, norepinephrine, dopamine) reuptake inhibitory activity.
　また、化合物(I’)は、毒性が低く、安全である。特に、光毒性を示さない点で有用である。 In addition, compound (I ′) has low toxicity and is safe. In particular, it is useful in that it does not exhibit phototoxicity.
　化合物(I’)は、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト）に対して、脳内モノアミン類（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有する物質として、脳内モノアミン類が再取り込みされるのを阻害し、うつ病・不安症等の精神神経疾患の症状を改善する。 Compound (I ′) is reuptaked into mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human) by brain monoamines (serotonin, norepinephrine, dopamine, etc.) As a substance having an inhibitory activity, it inhibits reuptake of monoamines in the brain and improves symptoms of neuropsychiatric diseases such as depression and anxiety.
　また、化合物(I’)は、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト）に対して、モノアミン類（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有する物質として、モノアミン類が再取り込みされるのを阻害し、腹圧性尿失禁等の下部尿路症状を改善する。 Compound (I ′) is reuptaked by monoamines (serotonin, norepinephrine, dopamine, etc.) to mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human). As a substance having inhibitory activity, it inhibits reuptake of monoamines and improves lower urinary tract symptoms such as stress urinary incontinence.
　本願発明の態様としては、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト）に対して、化合物(I’)を有効量投与することを特徴とする、うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮および腹圧性尿失禁の予防または治療方法が挙げられる。 An embodiment of the present invention is characterized in that an effective amount of Compound (I ′) is administered to a mammal (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human). To prevent or treat depression, anxiety, attention deficit / hyperactivity disorder, menopause, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia and stress urinary incontinence Can be mentioned.
　また、本願発明の態様としては、うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮および腹圧性尿失禁の予防または治療薬を製造するための、化合物(I’)の使用が挙げられる。 The embodiments of the present invention include depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia and stress urine The use of compound (I ′) for producing a prophylactic or therapeutic drug for incontinence is mentioned.
　化合物(I’)は毒性が低く、かつ副作用も少ない等の医薬品として優れた性質も有するので、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト）に対して、例えば、以下の疾患の予防・治療のために有用である。
（１）中枢神経疾患
（ａ）精神神経疾患〔例、うつ病（例、大うつ病、脳血管障害性うつ、季節性うつ、薬剤起因うつ、HIV性うつ）、不安症（例、全般性不安障害、社会不安障害、強迫性障害、パニック障害、外傷後ストレス障害）、注意欠陥・多動性障害（ADHD）、更年期障害、双極性障害、躁病、反復性うつ病、持続性気分感情障害（例、気分循環症、気分変調症）、抑うつ神経症、睡眠障害、日周リズム障害、摂食障害、薬剤依存症、月経前緊張症、自閉症、更年期による気分障害、老人性認知症、軽度認知機能障害、過眠症、心身症、躁うつ病、心的外傷後ストレス障害（Posttraumatic stress disorder: PTSD）、統合失調症、不安神経症、強迫性神経症、脳卒中や脳血管障害に伴う気分障害や運動障害〕
（ｂ）神経変性疾患（例、筋線維症、アルツハイマー病、パーキンソン病、神経変性疾患に伴う気分障害）
（２）各種疼痛（例、神経因性疼痛、炎症性疼痛、繊維筋痛症）
（３）下部尿路症状（例、過活動膀胱、腹圧性尿失禁、混合型尿失禁、骨盤内臓痛、間質性膀胱炎に伴う下部尿路症状等の排尿異常、男性下部尿路症状）
（４）骨盤臓器脱（例、膣前壁脱、膣後壁脱、子宮脱、膣尖端の脱、直腸脱（直腸瘤）、小腸瘤、膀胱瘤、尿道瘤）
（５）筋萎縮関連疾患〔例、廃用性筋萎縮、カヘキシアに伴う筋萎縮（ＣＯＰＤ、癌などの疾患で誘導される）〕
（６）その他の疾患〔例、糖尿病、肥満、過敏性腸症候群（IBS）、ムズムズ脚症候群（RLS）、慢性疲労症候群、月経前症候群（PMS）、機能性胃腸症（FD）、過敏性腸症候群、便失禁、消化器系疾患、禁煙、各種依存症、加齢性筋肉減弱症（サルコペニア）〕 Since compound (I ′) has excellent properties as a pharmaceutical product with low toxicity and few side effects, mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans) For example, it is useful for the prevention and treatment of the following diseases.
(1) Central nervous system disease (a) Psychiatric and neurological diseases [eg, depression (eg, major depression, cerebrovascular disorder depression, seasonal depression, drug-induced depression, HIV depression), anxiety (eg, generality) Anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder), attention deficit / hyperactivity disorder (ADHD), menopause, bipolar disorder, mania, recurrent depression, persistent mood emotion disorder (Eg, mood circulatory disorder, dysthymia), depressive neurosis, sleep disorders, diurnal rhythm disorders, eating disorders, drug addiction, premenstrual tension, autism, mood disorders due to menopause, senile dementia , Mild cognitive impairment, hypersomnia, psychosomatic disorder, manic depression, posttraumatic stress disorder (PTSD), schizophrenia, anxiety, obsessive compulsive disorder, stroke and cerebrovascular disorder Accompanying mood disorders and movement disorders)
(B) Neurodegenerative diseases (eg, myofibrosis, Alzheimer's disease, Parkinson's disease, mood disorders associated with neurodegenerative diseases)
(2) Various pains (eg, neuropathic pain, inflammatory pain, fibromyalgia)
(3) Lower urinary tract symptoms (eg, overactive bladder, stress urinary incontinence, mixed urinary incontinence, pelvic visceral pain, lower urinary tract symptoms associated with interstitial cystitis, male lower urinary tract symptoms)
(4) Pelvic organ prolapse (eg, vaginal prolapse, retrovaginal prolapse, uterine prolapse, vaginal prolapse, rectal prolapse (rectal aneurysm), small intestinal aneurysm, cystocele, urethral aneurysm)
(5) Muscle atrophy-related diseases [eg, disuse muscle atrophy, muscle atrophy associated with cachexia (induced by diseases such as COPD and cancer)]
(6) Other diseases [eg, diabetes, obesity, irritable bowel syndrome (IBS), Musm's leg syndrome (RLS), chronic fatigue syndrome, premenstrual syndrome (PMS), functional gastroenteropathy (FD), irritable bowel Syndrome, fecal incontinence, digestive system disease, smoking cessation, various addictions, age-related muscle weakness (sarcopenia))
　化合物(I’)は、モノアミン再取り込み阻害薬として有用であり、特に、うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の予防・治療薬として有用である。また、化合物(I’)は、セロトニン、ノルエピネフリンおよびドーパミンの再取り込み阻害活性を有することから、Triple Reuptake Inhibitorとして有用である。中でも、化合物(I’)は、ノルエピネフリンの再取り込み阻害活性を有することから、ノルエピネフリン再取り込み阻害薬として有用である。
　化合物（I’）は、ポジトロン断層法(Positron emission tomography； PET)において、炭素１１(11C)、フッ素１８(18F)、酸素１５(15O)、窒素１３(13N)等の陽電子放出核種で標識することにより、トレーサーとしても使用が可能である。 Compound (I ′) is useful as a monoamine reuptake inhibitor, and is particularly useful as a prophylactic / therapeutic agent for depression, anxiety, attention deficit / hyperactivity disorder or stress urinary incontinence. In addition, compound (I ′) is useful as a triple reuptake inhibitor because it has serotonin, norepinephrine and dopamine reuptake inhibitory activity. Among them, compound (I ′) has a norepinephrine reuptake inhibitory activity, and is therefore useful as a norepinephrine reuptake inhibitor.
Compound (I ′) is a positron emission tomography (PET) that emits positrons such as carbon 11 ( 11 C), fluorine 18 ( 18 F), oxygen 15 ( 15 O), nitrogen 13 ( 13 N), etc. It can be used as a tracer by labeling with nuclides.
　本願発明において、「モノアミン再取り込み阻害薬」とは、神経伝達物質であるセロトニン、ノルエピネフリンおよびドーパミンから選ばれる少なくとも１つのモノアミンの再取り込み阻害薬を意味する。「モノアミン再取り込み阻害薬」としては、セロトニン再取り込み阻害薬、ノルエピネフリン再取り込み阻害薬、ドーパミン再取り込み阻害薬、セロトニン－ノルエピネフリン再取り込み阻害薬、ノルエピネフリン－ドーパミン再取り込み阻害薬、セロトニン－ドーパミン再取り込み阻害薬、セロトニン－ノルエピネフリン－ドーパミン再取り込み阻害薬が挙げられる。 In the present invention, “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.
　化合物(I’)を含有する医薬は、医薬製剤の製造法として自体公知の方法（例、日本薬局方記載の方法等）に従って、化合物(I’)を単独で、または薬理学的に許容される担体と混合して、例えば錠剤（糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む）、丸剤、散剤、顆粒剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤（例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤）、エアゾール剤、フィルム剤（例、口腔内崩壊フィルム、口腔粘膜貼付フィルム）、注射剤（例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤）、点滴剤、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、坐剤（例、肛門坐剤、膣坐剤）、ペレット、経鼻剤、経肺剤（吸入剤）、点眼剤等として、経口的または非経口的（例、静脈内、筋肉内、皮下、臓器内、鼻腔内、皮内、点眼、脳内、直腸内、膣内、腹腔内、腫瘍内部、腫瘍の近位等への投与および直接的な病巣への投与）に安全に投与することができる。徐放性製剤の調製は、特開平9-263545号公報に記載の方法に準ずることができる。 A pharmaceutical containing compound (I ′) is compound (I ′) alone or pharmacologically acceptable according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia, etc.). For example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules) ), Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, oral cavity) Internal disintegration film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), instillation, transdermal preparation, ointment, lotion, Patches, suppositories (eg, anal suppositories, vagina Agents), pellets, nasal agents, pulmonary agents (inhalants), eye drops, etc., orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, Administration into the brain, rectum, intravaginal, intraperitoneal, intratumoral, proximal to the tumor, etc. and direct administration to the lesion). Preparation of sustained-release preparations can be performed according to the method described in JP-A-9-263545.
　本願発明の製剤において、化合物(I’)の含有量は、製剤の形態によって相違するが、通常、製剤全体に対する化合物(I)の量として0.01～100重量％、好ましくは0.1～50重量％、さらに好ましくは0.5～20重量％程度である。 In the preparation of the present invention, the content of the compound (I ′) varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight as the amount of the compound (I) relative to the whole preparation, More preferably, it is about 0.5 to 20% by weight.
　投与量は化合物(I’)の種類、投与ルート、症状、患者の年令などによっても異なるが、例えば、うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛または腹圧性尿失禁の成人患者に経口的に投与する場合、1日当たり体重1kgあたり化合物(I)として約0.005～50mg、好ましくは約0.05～10mg、さらに好ましくは約0.2～4mgを1～3回程度に分割投与できる。 The dose varies depending on the type of compound (I '), administration route, symptoms, patient age, etc., but for example, depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain or stress urine When orally administered to adult patients with 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 doses. it can.
　本願発明の医薬組成物が徐放性製剤である場合の投与量は、化合物(I’)の種類と含量、剤形、薬物放出の持続時間、投与対象動物（例、ヒト、ラット、マウス、ネコ、イヌ、ウサギ、ウシ、ブタ等の哺乳動物）、投与目的により種々異なるが、例えば非経口投与により適用する場合には、１週間に約0.1～約100mgの化合物(I’)が投与製剤から放出されるようにすればよい。 When the pharmaceutical composition of the present invention is a sustained-release preparation, 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, and pigs), 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. May be released from the.
　前記の薬理学的に許容され得る担体としては、例えば、賦形剤（例えば、デンプン、乳糖、白糖、炭酸カルシウム、リン酸カルシウム）、結合剤（例えば、デンプン、アラビアゴム、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、結晶セルロース、アルギン酸、ゼラチン、ポリビニルピロリドン）、滑沢剤（例えば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク）、崩壊剤（例えば、カルボキシメチルセルロースカルシウム、タルク）、希釈剤（例えば、注射用水、生理食塩水）、添加剤（例えば、安定剤、保存剤、着色剤、香料、溶解助剤、乳化剤、緩衝剤、等張化剤）が挙げられる。 Examples of the pharmacologically acceptable carrier include excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, Crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone), lubricant (eg, stearic acid, magnesium stearate, calcium stearate, talc), disintegrant (eg, carboxymethylcellulose calcium, talc), diluent (eg, water for injection, Physiological saline) and additives (for example, stabilizers, preservatives, colorants, fragrances, solubilizers, emulsifiers, buffers, isotonic agents).
　例えば、注射剤とするには、化合物(I’)を分散剤（例、Tween 80、HCO-60等の界面活性剤、カルボキシメチルセルロース、アルギン酸ナトリウム、ヒアルロン酸等の多糖類、ポリソルベート）、保存剤（例、メチルパラベン、プロピルパラベン）、等張化剤（例、塩化ナトリウム、マンニトール、ソルビトール、ブドウ糖）、緩衝剤（例、炭酸カルシウム）、pH調整剤（例、リン酸ナトリウム、リン酸カリウム）等と共に水性懸濁剤とすることにより実用的な注射用製剤が得られる。また、ゴマ油、コーン油などの植物油あるいはこれにレシチンなどのリン脂質を混合したもの、あるいは中鎖脂肪酸トリグリセリド（例、ミグリオール812）と共に分散して油性懸濁剤として実際に使用できる注射剤とする。 For example, for injection, compound (I ′) is used as a dispersant (eg, surfactants such as Tween 80, HCO-60, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, polysorbate), preservatives (Eg, methylparaben, propylparaben), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose), buffers (eg, calcium carbonate), pH adjusters (eg, sodium phosphate, potassium phosphate), etc. A practical injectable preparation can be obtained by preparing an aqueous suspension together. In addition, vegetable oils such as sesame oil and corn oil or those mixed with phospholipids such as lecithin or dispersed with medium-chain fatty acid triglycerides (eg, Miglyol 812) to make an injection that can actually be used as an oily suspension. .
　本願発明の予防・治療薬においては、他の薬剤と共に用いることもできる。 The preventive / therapeutic agent of the present invention can be used together with other drugs.
　化合物(I’)と配合又は併用し得る薬物（以下、併用薬物と略記する）としては、例えば、以下のようなものが用いられる。 Examples of the drug that can be blended or used in combination with the compound (I ′) (hereinafter abbreviated as a concomitant drug) include the following.
（１）他の中枢神経疾患の予防・治療薬
　うつ病治療薬、不安症治療薬（例、クロルジアゼポキシド、ジアゼパム、クロラゼプ酸カリウム、ロラゼパム、クロナゼパム、アルプラゾラム等のベンゾジアゼパン）、気分安定薬（例、炭酸リチウム）、5-HT2拮抗薬（例、ネファゾドン）、5-HT1A作動薬（例、タンドスピロン、ブスピロン、Gepiron）、CRF拮抗薬（例、Pexacerfont）、β3作動薬（例、Amibegron）、メラトニン作動薬（例、ラメルテオン、agomelatine）、α2拮抗薬（例、ミルタザピン、セチプチリン）、NK2拮抗薬（例、Saredutant）、GR拮抗薬（例、Mifepristone）、NK-1拮抗薬（例、Casopitant、Orvepitant）、統合失調症治療薬（例、クロルプロマジン、ハロペリドール、スルピリド、クロザピン、アリピプラゾール、クエチアピン、オランザピン、リスペリドン）、アセチルコリンエステラーゼ阻害剤（例、ドネペジル、リバスチグミン、ガランタミン、ザナペジル）、NMDA拮抗薬（例、メマンチン）、βアミロイド蛋白産生、分泌、蓄積、凝集および/または沈着抑制剤[βセクレターゼ阻害剤、γセクレターゼ阻害作用剤、βアミロイド蛋白凝集阻害作用剤（例、βアミロイド蛋白凝集阻害作用剤（例、PTI-00703、ALZHEMED（NC-531）、 (3α,5β,7α,12α)-トリヒドロキシコラン-24-オイル-L-ロイシル-L-バリル-L-フェニルアラニル-L-フェニルアラニル-L-アラニン（特表平11－514333）、PPI-558（特表2001－500852）、2-(4-メトキシフェニル）-3-［4-［3-（ジエチルアミノ）プロポキシ］ベンゾイル］-5-クロロベンゾフラン（Biochem.J.（1999），340（1），283－289））、βアミロイドワクチン、βアミロイド分解酵素等]、脳機能賦活薬（例、アニラセタム、ニセルゴリン）、パーキンソン病治療薬[例、ドーパミン受容体作動薬（例、L-ドーパ、ブロモクリプテン、パーゴライド、タリペキソール、プラシペキソール、カベルゴリン、アダマンタジン）、COMT阻害剤（例、エンタカポン）]、注意欠陥・多動性障害治療薬（例、モダフィニル）、筋萎縮性側索硬化症治療薬（例、リルゾール、神経栄養因子）、不眠症治療薬（例、エチゾラム、ゾピクロン、トリアゾラム、ゾルピデム、インディプロン）、過眠症治療薬（例、モダフィニル）、抗サイトカイン薬（TNF阻害薬、MAPキナーゼ阻害薬）、ステロイド薬（例、デキサメサゾン、ヘキセストロール、酢酸コルチゾン）等が挙げられる。 (1) Other central nervous disease prophylactic / therapeutic drugs Depressant drugs, anxiety drugs (eg, chlordiazepoxide, diazepam, potassium chlorazepate, lorazepam, clonazepam, benzodiazepane such as alprazolam), mood stabilizers (eg, carbonic acid carbonate) Lithium), 5-HT2 antagonists (eg, nefazodone), 5-HT1A agonists (eg, tandospirone, buspirone, Gepiron), CRF antagonists (eg, Pexacerfont), β3 agonists (eg, Amibegron), melatonin agonists (Eg, ramelteon, agomelatine), α2 antagonist (eg, mirtazapine, cetipitrine), NK2 antagonist (eg, Saredutant), GR antagonist (eg, Mifepristone), NK-1 antagonist (eg, Casopitant, Orvepitant), Drugs for treating schizophrenia (eg, chlorpromazine, haloperidol, sulpiride, clozapine, aripiprazole, quetiapine, olanzapine, risperide ), Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine, galantamine, zanapezil), NMDA antagonists (eg, memantine), β-amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitors [β-secretase inhibitors, γ Secretase inhibitor, β amyloid protein aggregation inhibitor (eg, β amyloid protein aggregation inhibitor (eg, PTI-00703, ALZHEMED (NC-531), (3α, 5β, 7α, 12α) -trihydroxychorane- 24-Oil-L-Leucyl-L-Valyl-L-Phenylalanyl-L-Phenylalanyl-L-Alanine (Special Table H11-514333), PPI-558 (Special Table 2001-500852) 4-methoxyphenyl) -3- [4- [3- (diethylamino) propoxy] benzoyl] -5-chlorobenzofuran (Biochem. J. (1999), 340 (1), 283-289)), β-amyloid vaccine, β-amyloid-degrading enzyme etc.], brain function activator ( Eg, aniracetam, nicergoline), Parkinson's disease drug [eg, dopamine receptor agonist (eg, L-dopa, bromocriptene, pergolide, talipexol, prasipexol, cabergoline, adamantazine), COMT inhibitor (eg, entacapone) ], Attention deficit / hyperactivity disorder (eg, modafinil), amyotrophic lateral sclerosis (eg, riluzole, neurotrophic factor), insomnia (eg, etizolam, zopiclone, triazolam, zolpidem , Indiplon), hypersomnia drug (eg, modafinil), anti-cytokine drug (TNF inhibitor, MAP kinase inhibitor), steroid drug (eg, dexamethasone, hexestrol, cortisone acetate) and the like.
（２）他の腹圧性尿失禁の予防・治療薬
　アドレナリンα１受容体アゴニスト（例、塩酸エフェドリン、塩酸ミトドリン）、アドレナリンβ2受容体アゴニスト（例、クレンブテロール（Clenbuterol））、ノルエピネフリン取り込み阻害物質、ノルエピネフリンおよびセロトニン取り込み阻害物質（例、デュロキセチン）、３環性抗うつ薬（例、塩酸イミプラミン）、抗コリン薬又は平滑筋刺激薬（例、塩酸オキシブチニン、塩酸プロピベリン、塩酸セリメベリン）、女性ホルモン薬（例、結合型エストロゲン（プレマリン）、エストリオール）等が挙げられる。 (2) Other prophylactic / therapeutic agents for stress urinary incontinence Adrenaline α1 receptor agonist (eg, ephedrine hydrochloride, mitodrine hydrochloride), Adrenaline β2 receptor agonist (eg, Clenbuterol), Norepinephrine uptake inhibitor, Norepinephrine and Serotonin uptake inhibitors (eg, duloxetine), tricyclic antidepressants (eg, imipramine hydrochloride), anticholinergic drugs or smooth muscle stimulants (eg, oxybutynin hydrochloride, propiverine hydrochloride, serimevelin hydrochloride), female hormone drugs (eg, Conjugated estrogens (premarin), estriol) and the like.
（３）糖尿病治療剤
　インスリン製剤〔例、ウシ、ブタの膵臓から抽出された動物インスリン製剤；大腸菌、イーストを用い、遺伝子工学的に合成したヒトインスリン製剤；インスリン亜鉛；プロタミンインスリン亜鉛；インスリンのフラグメント又は誘導体（例、D-カイロイノシトール）〕、インスリン感受性増強剤（例、塩酸ピオグリタゾン、トログリタゾン、ロシグリタゾン又はそのマレイン酸塩、レグリタザル、イサグリタゾン、2,2'-[2(Z)-ブテン-1,4-ジイル]ジオキシビス(1,4-フェニレン)ビス(メチレン)ビス[1,2,4-オキサジアゾール-3,5(2H,4H)-ジオン]、ファルグリタザル、5-(2,4-ジオキソチアゾリジン-5-イルメチル)-2-メトキシ-N-[4-(トリフルオロメチル)ベンジル]ベンズアミド、1-(2,4-ジクロロベンジル)-2-メチル-N-(ペンチルスルホニル)-1H-ベンゾイミダゾール-6-カルボキサミド、リボグリタゾン 塩酸塩）、α-グルコシダーゼ阻害剤（例、ボグリボース、アカルボース、ミグリトール、エミグリテート）、ビグアナイド剤（例、フェンホルミン、メトホルミン、ブホルミン）、スルホニルウレア剤（例、トルブタミド、グリベンクラミド、グリクラジド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリメピリド）やその他のインスリン分泌促進剤（例、レパグリニド、セナグリニド、ミチグリニド又はそのカルシウム塩水和物、インスリノトロピン、ナテグリニド）、ジペプチジルペプチダーゼＩＶ阻害剤（例、ビルダグリプチン、シタグリプチン、サクサグリプチン、アログリプチン、1-[2-[2-(5-シアノピリジン-2-イルアミノ)エチルアミノ]アセチル]ピロリジン-2(S)-カルボニトリル、タラボスタット、2(S)-アミノ-3(S)-メチル-1-(3-チアゾリジニル)ペンタン-1-オン フマラート）、β3アゴニスト（例、 (R,R)-5-[2-[2-(3-クロロフェニル)-2-ヒドロキシエチルアミノ]プロピル]-1,3-ベンゾジオキソール-2,2-ジカルボン酸 二ナトリウム塩、アミベグロン 塩酸塩、4-（2-（（2-ヒドロキシ-2-（2-（トリフルオロメチル）-4-チアゾリル）エチル）-アミノ）プロピル）フェノキシ酢酸、ラファベグロン、AZ40140）、アミリンアゴニスト（例、プラムリンチド）、ホスホチロシンホスファターゼ阻害剤（例、バナジン酸）、糖新生阻害剤（例、グリコーゲンホスホリラーゼ阻害剤、グルコース-6-ホスファターゼ阻害剤、グルカゴン拮抗剤）、SGLT（sodium-glucose cotransporter）阻害剤（例、3-(5-ベンゾフラニル)-1-[2-ヒドロキシ-6-[6-O-(メトキシカルボニル)-beta-D-グルコピラノシルオキシ]-4-メチルフェニル]-1-プロパノン）等が挙げられる。 (3) 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, D-caylinositol)], insulin sensitivity enhancers (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, leglitazar, isaglitazone, 2,2 '-[2 (Z) -butene-1 , 4-Diyl] dioxybis (1,4-phenylene) bis (methylene) bis [1,2,4-oxadiazole-3,5 (2H, 4H) -dione], farglitazar, 5- (2,4- Dioxothiazolidine-5-ylmethyl) -2-methoxy-N- [4- (trifluoromethyl) benzyl] benzamide, 1- (2,4-dichlorobenzyl) -2-methyl-N- (pentylsulfonyl) -1H -Benzo Imidazole-6-carboxamide, riboglitazone hydrochloride), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate), biguanides (eg, phenformin, metformin, buformin), sulfonylureas (eg, tolbutamide, glibenclamide) , Gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride) and other insulin secretagogues (eg, repaglinide, senaglinide, mitiglinide or its calcium salt hydrate, insulinotropin, nateglinide), dipeptidyl Peptidase IV inhibitors (eg, vildagliptin, sitagliptin, saxagliptin, alogliptin, 1- [2- [2- (5-cyanopyridin-2-ylamino) ethylamino] acetyl] pyrrole -2 (S) -carbonitrile, tarabostat, 2 (S) -amino-3 (S) -methyl-1- (3-thiazolidinyl) pentan-1-one fumarate), β3 agonist (eg, (R, R ) -5- [2- [2- (3-Chlorophenyl) -2-hydroxyethylamino] propyl] -1,3-benzodioxole-2,2-dicarboxylic acid disodium salt, amibegron hydrochloride, 4- (2-((2-hydroxy-2- (2- (trifluoromethyl) -4-thiazolyl) ethyl) -amino) propyl) phenoxyacetic acid, raphabegron, AZ40140), amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibition Agents (eg, vanadic acid), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists), SGLT (sodium-glucose cotransporter) inhibitors (eg, 3- (5- Benzofuranyl) -1- [2-hydroxy-6- [6-O- (me Alkoxycarbonyl) -beta-D-glucopyranosyloxy] -4-methylphenyl] -1-propanone) and the like.
（４）糖尿病性合併症治療剤
　アルドース還元酵素阻害剤（例、トルレスタット、エパルレスタット、ゼナレスタット、ゾポルレスタット、フィダレスタット（SNK-860）、ミナルレスタット（ARI-509）、リサレスタット）、神経栄養因子（例、NGF、NT-3）、AGE阻害剤（例、ALT-945、ピマゲジン、ピラトキサチン、N-フェナシルチアゾリウムブロミド（N-フェナシルチアゾリウム ブロマイド）、EXO-226）、活性酸素消去薬（例、チオクト酸）、脳血管拡張剤（例、チアプリド）等が挙げられる。 (4) Antidiabetic complications aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minalrestat (ARI-509), lisarestat), neurotrophic factor ( Eg, NGF, NT-3), AGE inhibitor (eg, ALT-945, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (N-phenacylthiazolium bromide), EXO-226), active oxygen scavenging Examples thereof include drugs (eg, thioctic acid), cerebral vasodilators (eg, thioprid) and the like.
（５）抗高脂血症剤
　コレステロール合成阻害剤であるスタチン系化合物（例、プラバスタチン、シンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、セリバスタチン又はそれらの塩（例、ナトリウム塩等））、スクアレン合成酵素阻害剤あるいはトリグリセリド低下作用を有するフィブラート系化合物（例、ベザフィブラート、クロフィブラート、シムフィブラート、クリノフィブラート）等が挙げられる。 (5) Antihyperlipidemic agents Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt)), squalene synthase inhibition Or a fibrate compound having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate) and the like.
（６）降圧剤
　アンジオテンシン変換酵素阻害剤（例、カプトプリル、エナラプリル、デラプリル）、アンジオテンシンＩＩ拮抗剤（例、ロサルタン、カンデサルタン　シレキセチル）、カルシウム拮抗剤（例、マニジピン、ニフェジピン、アムロジピン、エホニジピン、ニカルジピン）、クロニジン等が挙げられる。 (6) Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril), angiotensin II antagonist (eg, losartan, candesartan cilexetil), calcium antagonist (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine), And clonidine.
（７）抗肥満剤
　中枢性抗肥満薬（例、デキスフェンフルラミン、フェンフルラミン、フェンテルミン、シブトラミン、アンフェプラモン、デキサンフェタミン、マジンドール、フェニルプロパノールアミン、クロベンゾレックス）、膵リパーゼ阻害薬（例、オルリスタット）、β3アゴニスト（例、(R,R)-5-[2-[2-(3-クロロフェニル)-2-ヒドロキシエチルアミノ]プロピル]-1,3-ベンゾジオキソール-2,2-ジカルボン酸 二ナトリウム塩、アミベグロン 塩酸塩、UL-TG-307、ラファベグロン、AZ40140）、ペプチド性食欲抑制薬（例、レプチン、CNTF（毛様体神経栄養因子））、コレシストキニンアゴニスト（例、リンチトリプト、FPL-15849）、5-HT2C受容体アゴニスト（例、ロルカセリン）等が挙げられる。 (7) Anti-obesity drugs Central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex), pancreatic lipase inhibitor ( Eg, orlistat), β3 agonist (eg, (R, R) -5- [2- [2- (3-chlorophenyl) -2-hydroxyethylamino] propyl] -1,3-benzodioxole-2, 2-dicarboxylic acid disodium salt, amibegron hydrochloride, UL-TG-307, rafabegron, AZ40140), peptidic appetite suppressant (eg, leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonist (eg , Lynchtripto, FPL-15849), 5-HT2C receptor agonist (eg, lorcaserine) and the like.
（８）利尿剤
　キサンチン誘導体（例、サリチル酸ナトリウムテオブロミン、サリチル酸カルシウムテオブロミン）、チアジド系製剤（例、エチアジド、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンジルヒドロクロロチアジド、ペンフルチジド、ポリチアジド、メチクロチアジド）、抗アルドステロン製剤（例、スピロノラクトン、トリアムテレン）、炭酸脱水酵素阻害剤（例、アセタゾラミド）、クロルベンゼンスルホンアミド系製剤（例、クロルタリドン、メフルシド、インダパミド）、アゾセミド、イソソルビド、エタクリン酸、ピレタニド、ブメタニド、フロセミド等が挙げられる。 (8) Diuretics Xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclothiad ), Anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide), azosemides, isosorbide, ethacrynic acid, piretanide, bumetanide And furosemide.
（９）化学療法剤
　アルキル化剤（例、サイクロフォスファミド、イフォスファミド）、代謝拮抗剤（例、メソトレキセート、5-フルオロウラシル）、抗癌性抗生物質（例、マイトマイシン、アドリアマイシン）、植物由来抗癌剤（例、ビンクリスチン、ビンデシン、タキソール）、シスプラチン、カルボプラチン、エトポシド等、なかでも5-フルオロウラシル誘導体であるフルツロンあるいはネオフルツロンが挙げられる。 (9) Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil), anticancer antibiotics (eg, mitomycin, adriamycin), plant-derived anticancer agents ( For example, vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide and the like, among others, 5-fluorouracil derivative flurtulon or neoflutulon can be mentioned.
（１０）免疫療法剤
　微生物又は細菌成分（例、ムラミルジペプチド誘導体、ピシバニール）、免疫増強活性のある多糖類（例、レンチナン、シゾフィラン、クレスチン）、遺伝子工学的手法で得られるサイトカイン（例、インターフェロン、インターロイキン（IL））、コロニー刺激因子（例、顆粒球コロニー刺激因子、エリスロポエチン）等、なかでもIL-1、IL-2、IL-12が挙げられる。 (10) Immunotherapeutic agents Microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil), immunopotentiating polysaccharides (eg, lentinan, schizophyllan, krestin), cytokines obtained by genetic engineering techniques (eg, interferon) , Interleukin (IL)), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin), among others, IL-1, IL-2 and IL-12.
（１１）動物モデルや臨床で悪液質改善作用が認められている薬剤
　プロゲステロン誘導体（例、メゲステロールアセテート）〔ジャーナル・オブ・クリニカル・オンコロジー（Journal of Clinical Oncology）、第12巻、213-225頁、1994年〕、メトクロプラミド系薬剤、テトラヒドロカンナビノール系薬剤（いずれも上記文献を参照）、脂肪代謝改善剤（例、エイコサペンタエン酸）〔ブリティシュ・ジャーナル・オブ・キャンサー（British Journal of Cancer）、第68巻、314～318頁、1993年〕、成長ホルモン、IGF-1、あるいは悪液質を誘導する因子であるTNF-α、LIF、IL-6、オンコスタチンMに対する抗体等が挙げられる。 (11) Drugs that have been shown to improve cachexia in animal models and clinical settings Progesterone derivatives (eg, megesterol acetate) [Journal of Clinical Oncology, Vol. 12, 213-225 Page, 1994], metoclopramide drugs, tetrahydrocannabinol drugs (see the above references), fat metabolism improvers (eg, eicosapentaenoic acid) [British Journal of Cancer, 68, 314-318, 1993], antibodies against growth hormone, IGF-1, or cachexia-inducing factors TNF-α, LIF, IL-6, oncostatin M, and the like.
（１２）消炎剤
　ステロイド剤（例、デキサメサゾン）、ヒアルロン酸ナトリウム、シクロオキシゲナーゼ阻害剤（例、インドメタシン、ケトプロフェン、ロキソプロフェン、メロキシカム、アムピロキシカム、セレコキシブ、ロフェコキシブ）等が挙げられる。 (12) Anti-inflammatory agents Steroid agents (eg, dexamethasone), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib) and the like.
（１３）その他
　糖化阻害剤（例、塩化アラゲブリウム）、神経再生促進薬（例、Y-128、チムコダル ジメシラート、prosaptide）、中枢神経系作用薬（例、デシプラミン、アミトリプチリン、イミプラミン、フロキセチン、パロキセチン、ドキセピンなどの抗うつ薬）、抗てんかん薬（例、ラモトリジン、カルバマゼピン）、抗不整脈薬（例、メキシレチン）、アセチルコリン受容体リガンド（例、エバニクリン）、エンドセリン受容体拮抗薬（例、アトラセンタン）、モノアミン取り込み阻害薬（例、トラマドル）、インドールアミン取り込み阻害薬（例、フロキセチン、パロキセチン）、麻薬性鎮痛薬（例、モルヒネ）、GABA受容体作動薬（例、ギャバペンチン）、GABA取り込み阻害薬（例、チアガビン）、α２受容体作動薬（例、クロニジン）、局所鎮痛薬（例、カプサイシン）、プロテインキナーゼC阻害剤（例、ルボキシスタウリン メシレート）、抗不安薬（例、ベンゾジアゼパン類）、ホスホジエステラーゼ阻害薬（例、シルデナフィル）、ドーパミン受容体作動薬（例、アポモルフィン）、ドーパミン受容体拮抗薬（例、ハロペリドール）、ノルアドレナリンおよびドパミン再取り込み阻害剤（例、ブプロピオン）、セロトニン受容体作動薬（例、クエン酸タンドスピロン、スマトリプタン）、セロトニン受容体拮抗薬（例、塩酸シプロヘプタジン、オンダンセトロン）、セロトニン取り込み阻害薬（例、マレイン酸フルボキサミン、フロキセチン、パロキセチン）、睡眠導入剤（例、トリアゾラム、ゾルピデム）、抗コリン剤、α１受容体遮断薬（例、タムスロシン、シロドシン、ナフトピジル）、筋弛緩薬（例、バクロフェン）、カリウムチャンネル開口薬（例、ニコランジル）、カルシウムチャンネル遮断薬（例、ニフェジピン）、アルツハイマー病予防・治療薬（例、ドネペジル、リバスチグミン、ガランタミン）、パーキンソン病治療薬（例、L-ドーパ）、多発性硬化症予防・治療薬（例、インターフェロンβ-1ａ）、ヒスタミンＨ１受容体阻害薬（例、塩酸プロメタジン）、プロトンポンプ阻害薬（例、ランソプラゾール、オメプラゾール）、抗血栓薬（例、アスピリン、シロスタゾール）、NK-2受容体アンタゴニスト、HIV感染症治療薬（サキナビル、ジドブジン、ラミブジン、ネビラピン）、慢性閉塞性肺疾患治療薬（サルメテロール、チオトロピウムブロミド、シロミラスト）等が挙げられる。 (13) Others Glycation inhibitors (eg, allagebrium chloride), nerve regeneration promoters (eg, Y-128, thymcodar dimesylate, prosaptide), central nervous system drugs (eg, desipramine, amitriptyline, imipramine, floxetine, paroxetine, doxepin) Antidepressants), antiepileptic drugs (eg, lamotrigine, carbamazepine), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, evaniculin), endothelin receptor antagonists (eg, atrasentan), monoamines Uptake inhibitors (eg, tramadol), indoleamine uptake inhibitors (eg, floxetine, paroxetine), narcotic analgesics (eg, morphine), GABA receptor agonists (eg, gabapentin), GABA uptake inhibitors (eg, Tiagabine), alpha 2 receptor agonist (eg clonidine) , Topical analgesics (eg, capsaicin), protein kinase C inhibitors (eg, ruboxistaurin mesylate), anxiolytics (eg, benzodiazepanes), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg Eg, apomorphine), dopamine receptor antagonist (eg, haloperidol), noradrenaline and dopamine reuptake inhibitor (eg, bupropion), serotonin receptor agonist (eg, tandospirone citrate, sumatriptan), serotonin receptor antagonist (Eg, cyproheptadine hydrochloride, ondansetron), serotonin uptake inhibitors (eg, fluvoxamine maleate, floxetine, paroxetine), sleep inducers (eg, triazolam, zolpidem), anticholinergic agents, α 1 receptor blockers (eg, , Tamsulosin, white Syn, naphthopidyl), muscle relaxants (eg, baclofen), potassium channel openers (eg, nicorandil), calcium channel blockers (eg, nifedipine), Alzheimer's disease prevention and treatment (eg, donepezil, rivastigmine, galantamine), Parkinson's disease treatment (eg, L-dopa), multiple sclerosis prevention / treatment (eg, interferon β-1a), histamine H 1 receptor inhibitor (eg, promethazine hydrochloride), proton pump inhibitor (eg, Lansoprazole, omeprazole), antithrombotic drugs (eg, aspirin, cilostazol), NK-2 receptor antagonists, HIV infection drugs (saquinavir, zidovudine, lamivudine, nevirapine), chronic obstructive pulmonary disease drugs (salmeterol, tiotropium bromide) , Silomilast) and the like.
　抗コリン剤としては、例えば、アトロピン、スコポラミン、ホマトロピン、トロピカミド、シクロペントラート、臭化ブチルスコポラミン、臭化プロパンテリン、臭化メチルベナクチジウム、臭化メペンゾラート、フラボキサート、ピレンゼピン、臭化イプラトピウム、トリヘキシフェニジル、オキシブチニン、プロピベリン、ダリフェナシン、トルテロジン、テミベリン、塩化トロスピウム又はその塩（例、硫酸アトロピン、臭化水素酸スコポラミン、臭化水素酸ホマトロピン、塩酸シクロペントラート、塩酸フラボキサート、塩酸ピレンゼピン、塩酸トリヘキシフェニジル、塩酸オキシブチニン、酒石酸トルテロジン）が用いられ、なかでも、オキシブチニン、プロピベリン、ダリフェナシン、トルテロジン、テミベリン、塩化トロスピウム又はその塩（例、塩酸オキシブチニン、酒石酸トルテロジン）が好適である。また、アセチルコリンエステラーゼ阻害薬（例、ジスチグミン）なども使用することができる。 Examples of the anticholinergic agent 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) are used, among which oxybutynin, propiverine, darifenacin, tolterodine, temiverine, toss chloride Um or a salt thereof (e.g., oxybutynin hydrochloride, tolterodine tartrate) are suitable. An acetylcholinesterase inhibitor (eg, distigmine) can also be used.
　NK-2受容体アンタゴニストとしては、例えば、(S)-5-フルオロ-3-[2-[4-メトキシ-4-(フェニルスルフィニルメチル)ピペリジン-1-イル]エチル]-1H-インドール、GR149861、SR48968（saredutant）、(+)-(R)-N-[1-[2-[4-ベンゾイル-2-(3,4-ジフルオロフェニル)モルホリン-2-イル]エチル]-4-フェニルピペリジン-4-イル]-N',N'-ジメチル尿素、N-[2-(3,4-ジクロロフェニル)-4-[スピロ[イソベンゾフラン-1(3H),4'-ピペリジン]-1'-イル]ブチル]-N-メチルベンズアミド、N-[2-(3,4-ジクロロフェニル)-4-[スピロ[ベンゾ[b]チオフェン-1(3H),4'-ピペリジン]-1'-イル]ブチル]-N-メチルベンズアミド S-オキシド、3(R)-[1(S)-(3,4-ジクロロフェニル)-3-[4-[[S(S)]-2-(メチルスルフィニル)フェニル]ピペリジン-1-イル]プロピル]-2-エチル-2,3-ジヒドロ-1H-イソインドール-1-オン、N-[2(S)-(3,4-ジクロロフェニル)-4-(スピロ[インデン-1,4'-ピペリジン]-1'-イル)ブチル]-N-メチル-3,5-ビス(トリフルオロメチル)ベンズアミド、1-[2-[3-(3,4-ジクロロフェニル)-1-(3,4,5-トリメトキシベンゾイル)ピロリジン-3(R)-イル]エチル]-4-フェニルピペリジン-4-カルボキサミド 塩酸塩、3-シアノ-N-[2(S)-(3,4-ジクロロフェニル)-4-[4-[2-[(S)-メチルスルフィニル]フェニル]ピペリジン-1-イル]ブチル]-N-メチルナフタレン-1-カルボキサミド フマラート、(R)-3-(3,4-ジクロロフェニル)-3-[2-[4-(モルホリン-4-イルカルボニル)-4-フェニルピペリジン-1-イル]エチル]-1-(3,4,5-トリメトキシベンゾイル)ピロリジン 塩酸塩、N-[3(R)-(3,4-ジクロロフェニル)-5-[4-(2-オキソピペリジン-1-イル)ピペリジン-1-イル]-2(Z)-(メトキシイミノ)ペンチル]-N-メチル-3,5-ジクロロベンズアミド、1-ベンジル-N-[2-[2-(3,4-ジクロロフェニル)-4-(3,5-ジメチルベンゾイル)ピペラジン-1-イル]-2-オキソエチル]ピペリジン-4-アミン、1'-[2-[2(R)-(3,4-ジクロロフェニル)-4-(3,4,5-トリメトキシベンゾイル)モルホリン-2-イル]エチル]スピロ[ベンゾ[c]チオフェン-1(3H)-4'-ピペリジン] 2(S)-酸化物 塩酸塩などのピペリジン誘導体、(3R,4R,5R,7R)-2-[2-(インドール-3-イル)アセチル]-4-(2-メトキシフェニル)-7,7-ジフェニルペルヒドロイソインドール-4,5-ジオールなどのペルヒドロイソインドール誘導体、2-フェニル-3-[4-(1-ピペリジニル)ピペリジン-1-イルメチル]-N-[1(S),2,2-トリメチルプロピル]キノリン-4-カルボキサミドなどのキノリン誘導体、4-(4-クロロフェニルアミノ)-2-[4-[2-(ヒドロキシイミノ)プロパノイル]ピペラジン-1-イル]-6-イソプロピル-6,7-ジヒドロ-5H-ピロロ[3,4-d]ピリミジン-7-オンなどのピロロピリミジン誘導体、MEN11420（nepadutant）、(6R,12S,15S,27S,30S,35aS)-6-ベンジル-27-(2-カルバモイルエチル)-12-(2-カルボキシエチル)-15,30-ジイソプロピル-13,28,31-トリメチル-9,24-ビス(1-メチルプロピル)ペルヒドロピリド[1,2-v]ピロロ[1,2-g]-10-オキサ-4,7,13,16,22,25,28,31,34-ノナアザシクロトリアコンチン-5,8,11,14,17,23,26,29,32,35-デカノン、シクロ(グルタミニル-トリプトフィル-フェニルアラニル-グリシル-ロイシル-メチオニル)、PD-147714（CAM-2291）、MEN10376、2-[(3S,9aS)-6,9-エタノ-1,4-ジオキソペルヒドロピリド[1,2-a]ピラジン-3-イル]アセチル-D-(1-ヒドロキシスクシニル)トリプトフィル-L-フェニルアラニン N-ベンジル-N-メチルアミド ナトリウム塩などのプソイドペプチド誘導体、シクロヘキシルカルボニル-グリシル-アラニル-D-トリプトフィル-フェニルアラニン ジメチルアミド、5-(3,4-ジクロロフェニル)-4(R)-[N-メチル-3,5-ビス(トリフルオロメチル)ベンズアミド]-N-[2-オキソペルヒドロアゼパン-3(R)-イル]-2(E)-ペンテンアミド、ベンゾイル-アラニル-アラニル-D-トリプトフィル-フェニルアラニル-D-プロリル-プロリル-ノルロイシルアミド、4-[1-[2-[1-(シクロプロピルメチル)-3(S)-(3,4-ジクロロフェニル)-6-オキソピペリジン-3-イル]エチル]アゼチジン-3-イル]ピペラジン-1-スルホンアミド、ＭＥＮ１０３７６、シクロ[L-メチオニル-L-アスパルチル-L-トリプトフィル-L-フェニルアラニル-[2(S),3-ジアミノプロピオニル]-ロイシン] C-4.2-N-3.5-ラクタム、又はそれらの塩が挙げられる。 Examples of the NK-2 receptor antagonist include (S) -5-fluoro-3- [2- [4-methoxy-4- (phenylsulfinylmethyl) piperidin-1-yl] ethyl] -1H-indole, GR149861. , SR48968 (saredutant), (+)-(R) -N- [1- [2- [4-benzoyl-2- (3,4-difluorophenyl) morpholin-2-yl] ethyl] -4-phenylpiperidine -4-yl] -N ', N'-dimethylurea, N- [2- (3,4-dichlorophenyl) -4- [spiro [isobenzofuran-1 (3H), 4'-piperidine] -1'- Yl] butyl] -N-methylbenzamide, N- [2- (3,4-dichlorophenyl) -4- [spiro [benzo [b] thiophene-1 (3H), 4'-piperidin] -1'-yl] Butyl] -N-methylbenzamide S-oxide, 3 (R)-[1 (S)-(3,4-dichlorophenyl) -3- [4-[[S (S)]-2- (methylsulfinyl) phenyl ] Piperidin-1-yl] propyl] -2-ethyl-2,3-dihydro-1H-isoindol-1-one, N- [2 (S)-(3,4-dichlorophenyl) -4- (spiro [ Inn Den-1,4'-piperidine] -1'-yl) butyl] -N-methyl-3,5-bis (trifluoromethyl) benzamide, 1- [2- [3- (3,4-dichlorophenyl)- 1- (3,4,5-trimethoxybenzoyl) pyrrolidin-3 (R) -yl] ethyl] -4-phenylpiperidine-4-carboxamide succinate, 3-cyano-N- [2 (S)-(3 , 4-Dichlorophenyl) -4- [4- [2-[(S) -methylsulfinyl] phenyl] piperidin-1-yl] butyl] -N-methylnaphthalene-1-carboxamide fumarate, (R) -3- ( 3,4-dichlorophenyl) -3- [2- [4- (morpholin-4-ylcarbonyl) -4-phenylpiperidin-1-yl] ethyl] -1- (3,4,5-trimethoxybenzoyl) pyrrolidine Hydrochloride, N- [3 (R)-(3,4-dichlorophenyl) -5- [4- (2-oxopiperidin-1-yl) piperidin-1-yl] -2 (Z)-(methoxyimino) Pentyl] -N-methyl-3,5-dichlorobenzamide, 1-benzyl-N- [2- [2- (3,4-dichlorophenyl) -4- (3,5-dimethyl) Benzoyl) piperazin-1-yl] -2-oxoethyl] piperidin-4-amine, 1 '-[2- [2 (R)-(3,4-dichlorophenyl) -4- (3,4,5-trimethoxy Piperidine derivatives such as (benzoyl) morpholin-2-yl] ethyl] spiro [benzo [c] thiophene-1 (3H) -4'-piperidine] 2 (S) -oxide'hydrochloride, (3R, 4R, 5R, 7R ) -2- [2- (Indol-3-yl) acetyl] -4- (2-methoxyphenyl) -7,7-diphenylperhydroisoindole-4,5-diol and other perhydroisoindole derivatives, 2 Quinoline derivatives such as 4-phenyl-3- [4- (1-piperidinyl) piperidin-1-ylmethyl] -N- [1 (S), 2,2-trimethylpropyl] quinoline-4-carboxamide, 4- (4- Chlorophenylamino) -2- [4- [2- (hydroxyimino) propanoyl] piperazin-1-yl] -6-isopropyl-6,7-dihydro-5H-pyrrolo [3,4-d] pyrimidin-7-one Pyrrolopyrimidine derivatives such as MEN11420 (n epadutant), (6R, 12S, 15S, 27S, 30S, 35aS) -6-benzyl-27- (2-carbamoylethyl) -12- (2-carboxyethyl) -15,30-diisopropyl-13,28,31 -Trimethyl-9,24-bis (1-methylpropyl) perhydropyrido [1,2-v] pyrrolo [1,2-g] -10-oxa-4,7,13,16,22,25,28,31 , 34-Nonaazacyclotriacontin-5,8,11,14,17,23,26,29,32,35-decanone, cyclo (glutaminyl-tryptophyll-phenylalanyl-glycyl-leucyl-methionyl), PD- 147714 (CAM-2291), MEN10376, 2-[(3S, 9aS) -6,9-ethano-1,4-dioxoperhydropyrido [1,2-a] pyrazin-3-yl] acetyl-D Pseudopeptide derivatives such as-(1-hydroxysuccinyl) tryptophyll-L-phenylalanine N-benzyl-N-methylamide sodium salt, cyclohexylcarbonyl-glycyl-alanyl-D-tryptophyll-phenylalanine dimethylamide, 5- (3,4- Dichlorofe ) -4 (R)-[N-methyl-3,5-bis (trifluoromethyl) benzamide] -N- [2-oxoperhydroazepan-3 (R) -yl] -2 (E)- Pentenamide, benzoyl-alanyl-alanyl-D-tryptophyll-phenylalanyl-D-prolyl-prolyl-norleucylamide, 4- [1- [2- [1- (cyclopropylmethyl) -3 (S)- (3,4-Dichlorophenyl) -6-oxopiperidin-3-yl] ethyl] azetidin-3-yl] piperazine-1-sulfonamide, MEN10376, cyclo [L-methionyl-L-aspartyl-L-tryptophyll-L- Phenylalanyl- [2 (S), 3-diaminopropionyl] -leucine] C-4.2-N-3.5-lactam, or a salt thereof.
　併用に際しては、化合物(I’)と併用薬物の投与時期は限定されず、化合物(I’)またはその医薬組成物と併用薬物またはその医薬組成物とを、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。併用薬物の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、投与ルート、疾患、組み合わせ等により適宜選択することができる。 In the combined use, the administration time of the compound (I ′) and the concomitant drug is not limited, and the compound (I ′) or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are administered simultaneously to the administration subject. Alternatively, 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.
　併用の投与形態は、特に限定されず、投与時に、化合物(I’)と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、
（１）化合物(I’)またはその医薬組成物と併用薬物とを同時に製剤化して得られる単一の製剤の投与、
（２）化合物(I’)またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、
（３）化合物(I’)またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、
（４）化合物(I’)またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、
（５）化合物(I’)またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与（例えば、化合物(I’)またはその医薬組成物；併用薬物またはその医薬組成物の順序での投与、あるいは逆の順序での投与）などが挙げられる。 The administration form of the combination is not particularly limited, and it is sufficient that the compound (I ′) and the concomitant drug are combined at the time of administration. Examples of such 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 thereof and a concomitant drug or a pharmaceutical composition thereof at different time intervals in different administration routes (for example, compound (I ′) or a pharmaceutical composition thereof; administration of a concomitant drug or a pharmaceutical composition thereof in the order, or administration in the reverse order).
　更に具体的には、本願発明の併用剤を投与するに際しては、同時期に投与してもよいが、併用薬物を先に投与した後、化合物(I’)を投与してもよいし、化合物(I’)を先に投与し、その後で併用薬物を投与してもよい。時間差をおいて投与する場合、時間差は投与する有効成分、剤形、投与方法により異なるが、例えば、併用薬物を先に投与する場合、併用薬物を投与した後1分～3日以内、好ましくは10分～1日以内、より好ましくは15分～1時間以内に化合物(I’)を投与する方法が挙げられる。化合物(I’)を先に投与する場合、化合物(I’)を投与した後、1分～1日以内、好ましくは10分～6時間以内、より好ましくは15分から1時間以内に併用薬物を投与する方法が挙げられる。 More specifically, when administering the concomitant drug of the present invention, it may be administered at the same time, but after the concomitant drug is administered first, compound (I ′) may be administered, (I ′) may be administered first, followed by administration of the concomitant drug. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when administering a concomitant drug first, within 1 minute to 3 days after administration of the concomitant drug, preferably The method includes administering Compound (I ′) within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound (I ′) is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound (I ′). The method of administration is mentioned.
　本願発明の併用剤における化合物(I’)と併用薬物との配合比は、投与対象、投与ルート、疾患等により適宜選択することができる。 The compounding ratio of the compound (I ′) and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
　例えば、本願発明の併用剤における化合物(I’)の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01ないし100重量％、好ましくは約0.1ないし50重量％、さらに好ましくは約0.5ないし20重量％程度である。 For example, the content of compound (I ′) 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 based on the whole preparation. Is about 0.5 to 20% by weight.
　本願発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01ないし100重量％、好ましくは約0.1ないし50重量％、さらに好ましくは約0.5ないし20重量％程度である。 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 0.5 to 20%, based on the whole preparation. It is about wt%.
　本願発明の併用剤における担体等の添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約１ないし99.99重量％、好ましくは約10ないし90重量％程度である。 The content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
　また、化合物(I’)および併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。 In addition, when the compound (I ′) and the concomitant drug are formulated separately, the same content may be used.
　化合物(I’)および併用薬物をそれぞれ別々に製剤化する場合の投与量は化合物(I’)の種類、投与ルート、症状、患者の年齢などによっても異なるが、例えば、うつ病、不安症、注意欠陥・多動性障害または腹圧性尿失禁の成人患者に経口的に投与する場合、1日当たり体重1kgあたり化合物(I)として約0.005～50mg、好ましくは約0.05～10mg、さらに好ましくは約0.2～4mgを1～3回程度に分割投与できる。 The dose when compound (I ′) and a concomitant drug are separately formulated varies depending on the type of compound (I ′), administration route, symptoms, patient age, etc., for example, depression, anxiety, When administered orally to adult patients with 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, as compound (I) per kg body weight per day Up to 4 mg can be divided into 1 to 3 doses.
　化合物(I’)および併用薬物をそれぞれ別々に製剤化する場合で、本願発明の医薬組成物が徐放性製剤である場合の投与量は、化合物(I’)の種類と含量、剤形、薬物放出の持続時間、投与対象動物（例、ヒト、ラット、マウス、ネコ、イヌ、ウサギ、ウシ、ブタ等の哺乳動物）、投与目的により種々異なるが、例えば非経口投与により適用する場合には、1週間に約0.1～約100mgの化合物(I’)が投与製剤から放出されるようにすればよい。 When the compound (I ′) and the concomitant drug are formulated separately, and the pharmaceutical composition of the present invention is a sustained-release preparation, the dosage is the type and content of the compound (I ′), the dosage form, It varies depending on the duration of drug release, the animal to be administered (eg, mammals such as humans, rats, mice, cats, dogs, rabbits, cows, pigs, etc.) and the purpose of administration. For example, when applied by parenteral administration About 0.1 to about 100 mg of compound (I ′) may be released from the administered preparation per week.
　併用薬物は、副作用が問題とならない範囲でどのような量を設定することも可能である。併用薬物としての一日投与量は、症状の程度、投与対象の年齢、性別、体重、感受性差、投与の時期、間隔、医薬製剤の性質、調剤、種類、有効成分の種類などによって異なり、特に限定されないが、薬物の量として通常、たとえば経口投与で哺乳動物1kg体重あたり約0.001～2000mg、好ましくは約0.01～500mg、さらに好ましくは、約0.1～100mg程度であり、これを通常1日1～4回に分けて投与する。 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, weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although not limited, 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 a mammal, for example, by oral administration. Divide into 4 doses.
　本願発明の医薬組成物は低毒性で安全に使用することができる。特に以下に示す実施例化合物は、経口投与されたときの吸収性において優れており、経口用製剤のために有利に使用できる。また光毒性を示さない点においても優れている。 The pharmaceutical composition of the present invention has low toxicity and can be used safely. In particular, 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.
　本願発明は、更に以下の実施例、試験例および製剤例によって詳しく説明されるが、これらは本願発明を限定するものではなく、また本願発明の範囲を逸脱しない範囲で変化させてもよい。 The present invention is further described in detail by the following examples, test examples and formulation examples, but these are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
　以下の実施例中の「室温」は通常約10℃ないし約35℃を示す。混合溶媒において示した比は、特に断らない限り容量比を示す。「%」は、特に断らない限り重量%を示す。 “Room temperature” in the following examples usually indicates about 10 ° C. to about 35 ° C. The ratio shown in the mixed solvent is a volume ratio unless otherwise specified. “%” Indicates wt% unless otherwise specified.
　シリカゲルカラムクロマトグラフィーにおいて、NHと記載した場合は、アミノプロピルシラン結合シリカゲルを用いた。溶出溶媒の比は、特に断らない限り容量比を示す。 In the silica gel column chromatography, when described as NH, aminopropylsilane-bonded silica gel was used. The ratio of elution solvent indicates a volume ratio unless otherwise specified.
　以下の実施例においては下記の略号を使用する。
　THF:テトラヒドロフラン、DMF:ジメチルホルムアミド、CDCl3:重クロロホルム、DMSO:ジメチルスルホキシド The following abbreviations are used in the following examples.
THF: Tetrahydrofuran, DMF: dimethylformamide, CDCl 3: deuterated chloroform, DMSO: dimethyl sulfoxide
　1H NMR(プロトン核磁気共鳴スペクトル)はフーリエ変換型NMRで測定した。解析にはACD/SpecManager(商品名)などを用いた。水酸基やアミノ基などのプロトンが非常に緩やかなピークについては記載していない。 1 H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier transform NMR. For the analysis, ACD / SpecManager (trade name) was used. Peaks with very gentle protons such as hydroxyl groups and amino groups are not described.
　MS(マススペクトル)は、LC/MS(液体クロマトグラフ質量分析計)により測定した。イオン化法としては、ESI(Electrospray Ionization、エレクトロスプレーイオン化)法、または、APCI(Atomospheric Pressure Cheimcal Ionization、大気圧化学イオン化)法を用いた。データは実測値(Found)を記載した。通常、分子イオンピークが観測されるが、tert-ブトキシカルボニル基(-Boc)を有する化合物の場合、フラグメントイオンとして、tert-ブトキシカルボニル基あるいはtert-ブチル基が脱離したピークが観測されることもある。また、水酸基(-OH)を有する化合物の場合、フラグメントイオンとして、H2Oが脱離したピークが観測されることもある。塩の場合は、通常、フリー体の分子イオンピークもしくはフラグメントイオンピークが観測される。 MS (mass spectrum) was measured by LC / MS (liquid chromatograph mass spectrometer). As the ionization method, an ESI (Electrospray Ionization) method or an APCI (Atomospheric Pressure Cheimcal Ionization) method was used. The data described the actual measurement (Found). Usually, a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (-Boc), a peak from which the tert-butoxycarbonyl group or tert-butyl group is eliminated should be observed as a fragment ion. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
　融点は、例えば微量融点測定器（ヤナコ、MP-500D型）またはDSC（示差走査熱量分析）装置（SEIKO，EXSTAR6000）等を用いて測定される融点を意味する。
　なお、合成した各化合物は下記表１－１から表１－９に記載した。 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) device (SEIKO, EXSTAR6000).
The synthesized compounds are shown in Table 1-1 to Table 1-9 below.
実施例1
4-(3,4-ジクロロフェニル)アゼパン-4-オール 塩酸塩
A) tert-ブチル 4-(3,4-ジクロロフェニル)-4-ヒドロキシアゼパン-1-カルボキシラート
　WO2003-103669記載の方法に準じて調製したtert-ブチル 4-オキソアゼパン-1-カルボキシラート(5.0 g)のジエチルエーテル(10 mL)溶液に、別途調製した3,4-ジクロロフェニルマグネシウムブロミド-ジエチルエーテル溶液(約25.7 mmol)を氷冷下加えた。反応混合物を氷冷下で30分撹拌後、水を加え、酢酸エチルで抽出した。抽出液を5% クエン酸水溶液、水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(4.60 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.47 (9H, s), 1.60-2.25 (7H, m), 3.20-3.85 (4H, m), 7.20-7.25 (1H, m), 7.38 (1H, d, J = 8.7 Hz), 7.56 (1H, d, J = 2.4 Hz). Example 1
4- (3,4-Dichlorophenyl) azepan-4-ol hydrochloride
A) tert-butyl 4- (3,4-dichlorophenyl) -4-hydroxyazepane-1-carboxylate tert-butyl 4-oxoazepane-1-carboxylate (5.0 g) prepared according to the method described in WO2003-103669 ) In diethyl ether (10 mL) was added separately prepared 3,4-dichlorophenylmagnesium bromide-diethyl ether solution (about 25.7 mmol) under ice cooling. The reaction mixture was stirred for 30 minutes under ice-cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with 5% aqueous citric acid solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.60 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.47 (9H, s), 1.60-2.25 (7H, m), 3.20-3.85 (4H, m), 7.20-7.25 (1H, m), 7.38 (1H, d , J = 8.7 Hz), 7.56 (1H, d, J = 2.4 Hz).
B) 4-(3,4-ジクロロフェニル)アゼパン-4-オール 塩酸塩
　tert-ブチル 4-(3,4-ジクロロフェニル)-4-ヒドロキシアゼパン-1-カルボキシラート(330 mg)のエタノール(5 mL)溶液に12 mol/kg, w/w 塩化水素-エタノール溶液(5 mL)を加え、室温で15分間撹拌した。溶媒を減圧下留去し、残渣をエタノール－酢酸エチルから結晶化することにより、標題化合物(247 mg)を無色結晶として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.60-1.80 (3H, m), 2.04 (1H, br. s.), 2.20-2.60 (3H, m), 3.00-3.30 (3H, m), 5.53 (1H, s), 7.50 (1H, dd, J = 8.4, 2.1 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 2.1 Hz), 8.80-9.35 (2H, m).
MS (ESI+): [M+H]+ 260.2. B) 4- (3,4-Dichlorophenyl) azepan-4-ol hydrochloride tert-butyl 4- (3,4-dichlorophenyl) -4-hydroxyazepane-1-carboxylate (330 mg) in ethanol (5 mL ) 12 mol / kg, w / w hydrogen chloride-ethanol solution (5 mL) was added to the solution, and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (247 mg) as colorless crystals.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.60-1.80 (3H, m), 2.04 (1H, br.s.), 2.20-2.60 (3H, m), 3.00-3.30 (3H, m), 5.53 (1H, s), 7.50 (1H, dd, J = 8.4, 2.1 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 2.1 Hz), 8.80-9.35 (2H , m).
MS (ESI +): [M + H] + 260.2.
実施例2
4-(3,4-ジクロロフェニル)-4-メトキシアゼパン 塩酸塩
A) tert-ブチル 4-(3,4-ジクロロフェニル)-4-メトキシアゼパン-1-カルボキシラート
　tert-ブチル 4-(3,4-ジクロロフェニル)-4-ヒドロキシアゼパン-1-カルボキシラート(850 mg)のDMF(10 mL)溶液に室温中60 %水素化ナトリウム(142 mg)、ヨウ化メチル(0.22 mL)を加え、30分間撹拌した。反応混合物に水を加え、溶媒を減圧下留去した。残渣を酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(806 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.47 (9H, s), 1.60-2.25 (6H, m), 3.00 (3H, s), 3.15-3.40 (2H, m), 3.45-3.85 (2H, m), 7.15-7.20 (1H, m), 7.35-7.45 (2H, m). Example 2
4- (3,4-Dichlorophenyl) -4-methoxyazepane hydrochloride
A) tert-butyl 4- (3,4-dichlorophenyl) -4-methoxyazepane-1-carboxylate tert-butyl 4- (3,4-dichlorophenyl) -4-hydroxyazepane-1-carboxylate (850 mg) in DMF (10 mL) at room temperature was added 60% sodium hydride (142 mg) and methyl iodide (0.22 mL), and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (806 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.47 (9H, s), 1.60-2.25 (6H, m), 3.00 (3H, s), 3.15-3.40 (2H, m), 3.45-3.85 (2H, m ), 7.15-7.20 (1H, m), 7.35-7.45 (2H, m).
B) 4-(3,4-ジクロロフェニル)-4-メトキシアゼパン 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.70-1.80 (1H, m), 1.85-2.20 (4H, m), 2.25-2.40 (1H, m), 2.94 (3H, s), 3.00-3.30 (4H, m), 7.35 (1H, dd, J = 8.4, 2.1 Hz), 7.56 (1H, d, J = 2.1 Hz), 7.66 (1H, d, J = 8.4 Hz), 9.20-9.45 (2H, br).
MS (ESI+): [M+H]+ 274.1.  B) 4- (3,4-Dichlorophenyl) -4-methoxyazepane hydrochloride The title compound was obtained in the same manner as in Step B of Example 1.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.70-1.80 (1H, m), 1.85-2.20 (4H, m), 2.25-2.40 (1H, m), 2.94 (3H, s), 3.00-3.30 (4H, m), 7.35 (1H, dd, J = 8.4, 2.1 Hz), 7.56 (1H, d, J = 2.1 Hz), 7.66 (1H, d, J = 8.4 Hz), 9.20-9.45 (2H, br).
MS (ESI +): [M + H] + 274.1.
実施例3
4-(3,4-ジクロロフェニル)-4-エトキシアゼパン 塩酸塩
A) tert-ブチル 4-(3,4-ジクロロフェニル)-4-エトキシアゼパン-1-カルボキシラート
　実施例2の工程Aと同様の方法により、tert-ブチル 4-(3,4-ジクロロフェニル)-4-ヒドロキシアゼパン-1-カルボキシラート(510 mg)およびヨウ化エチル(0.17 mL)から標題化合物(480 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.17 (3H, t, J = 7.0 Hz), 1.45 (9H, s), 1.60-2.25 (6H, m), 2.95-3.85 (6H, m), 7.15-7.20 (1H, m), 7.35-7.45 (2H, m). Example 3
4- (3,4-Dichlorophenyl) -4-ethoxyazepane hydrochloride
A) tert-butyl 4- (3,4-dichlorophenyl) -4-ethoxyazepane-1-carboxylate In the same manner as in Step A of Example 2, tert-butyl 4- (3,4-dichlorophenyl)- The title compound (480 mg) was obtained from 4-hydroxyazepane-1-carboxylate (510 mg) and ethyl iodide (0.17 mL).
1 H NMR (300 MHz, CDCl 3 ) δ 1.17 (3H, t, J = 7.0 Hz), 1.45 (9H, s), 1.60-2.25 (6H, m), 2.95-3.85 (6H, m), 7.15- 7.20 (1H, m), 7.35-7.45 (2H, m).
B) 4-(3,4-ジクロロフェニル)-4-エトキシアゼパン 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.12 (3H, t, J = 6.9 Hz), 1.70-1.80 (1H, m), 1.85-2.20 (4H, m), 2.25-2.40 (1H, m), 3.00-3.30 (6H, m), 7.36 (1H, dd, J = 8.4, 2.1 Hz), 7.55 (1H, d, J = 2.1 Hz), 7.65 (1H, d, J = 8.4 Hz), 9.00-9.40 (2H, br).
MS (ESI+): [M+1]+ 288.1. B) 4- (3,4-Dichlorophenyl) -4-ethoxyazepane hydrochloride The title compound was obtained in the same manner as in Step B of Example 1.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.12 (3H, t, J = 6.9 Hz), 1.70-1.80 (1H, m), 1.85-2.20 (4H, m), 2.25-2.40 (1H, m ), 3.00-3.30 (6H, m), 7.36 (1H, dd, J = 8.4, 2.1 Hz), 7.55 (1H, d, J = 2.1 Hz), 7.65 (1H, d, J = 8.4 Hz), 9.00 -9.40 (2H, br).
MS (ESI +): [M + 1] + 288.1.
実施例4
4-(3,4-ジクロロフェニル)-4-(2-メトキシエトキシ)アゼパン 塩酸塩
A) tert-ブチル 4-(3,4-ジクロロフェニル)-4-(2-メトキシエトキシ)アゼパン-1-カルボキシラート
　実施例2の工程Aと同様の方法により、tert-ブチル 4-(3,4-ジクロロフェニル)-4-ヒドロキシアゼパン-1-カルボキシラート(700 mg)およびメタンスルホン酸2-メトキシエチル(378 mg)から標題化合物(725 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.44 (9H, s), 1.60-2.25 (6H, m), 3.10-3.40 (4H, m), 3.37 (3H, s),  3.45-3.90 (4H, m), 7.20-7.30 (1H, m), 7.35-7.45 (1H, m), 7.50-7.55 (1H, m). Example 4
4- (3,4-Dichlorophenyl) -4- (2-methoxyethoxy) azepane hydrochloride
A) tert-butyl 4- (3,4-dichlorophenyl) -4- (2-methoxyethoxy) azepane-1-carboxylate In the same manner as in step A of Example 2, tert-butyl 4- (3,4 The title compound (725 mg) was obtained from -dichlorophenyl) -4-hydroxyazepane-1-carboxylate (700 mg) and 2-methoxyethyl methanesulfonate (378 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.44 (9H, s), 1.60-2.25 (6H, m), 3.10-3.40 (4H, m), 3.37 (3H, s), 3.45-3.90 (4H, m ), 7.20-7.30 (1H, m), 7.35-7.45 (1H, m), 7.50-7.55 (1H, m).
B) 4-(3,4-ジクロロフェニル)-4-(2-メトキシエトキシ)アゼパン 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.70-1.80 (1H, m), 1.90-2.20 (4H, m), 2.25-2.40 (1H, m), 3.00-3.30 (6H, m), 3.34 (3H, s), 3.40-3.50 (2H, m), 7.39 (1H, dd, J = 8.4, 1.8 Hz), 7.63 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 7.8 Hz), 8.90-9.40 (2H, br).
MS (ESI+): [M+1]+ 318.1. B) 4- (3,4-Dichlorophenyl) -4- (2-methoxyethoxy) azepane hydrochloride The title compound was obtained in the same manner as in Step B of Example 1.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.70-1.80 (1H, m), 1.90-2.20 (4H, m), 2.25-2.40 (1H, m), 3.00-3.30 (6H, m), 3.34 (3H, s), 3.40-3.50 (2H, m), 7.39 (1H, dd, J = 8.4, 1.8 Hz), 7.63 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 7.8 Hz), 8.90-9.40 (2H, br).
MS (ESI +): [M + 1] + 318.1.
実施例5
4-(2-メチルフェニル)アゼパン-4-オール　塩酸塩
A) tert-ブチル 4-ヒドロキシ-4-(2-メチルフェニル)アゼパン-1-カルボキシラート
　実施例1の工程Aと同様の方法により、tert-ブチル 4-オキソアゼパン-1-カルボキシラート(1.0 g)および1.0M 2-メチルフェニルマグネシウムブロミド/THF(6.6 mL)溶液から標題化合物(661 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41-1.64 (1H, m), 1.47 (9H, s), 1.70-1.98 (3H, m), 2.10-2.34 (3H, m), 2.52 (3H, s), 3.28-3.36 (2H, m), 3.55-3.82 (2H, m), 7.15 (3H, br s), 7.52 (1H, br s). Example 5
4- (2-Methylphenyl) azepan-4-ol hydrochloride
A) tert-butyl 4-hydroxy-4- (2-methylphenyl) azepan-1-carboxylate In the same manner as in Step A of Example 1, tert-butyl 4-oxoazepane-1-carboxylate (1.0 g) The title compound (661 mg) was obtained from a 1.0 M 2-methylphenylmagnesium bromide / THF (6.6 mL) solution.
1 H NMR (300 MHz, CDCl 3 ) δ 1.41-1.64 (1H, m), 1.47 (9H, s), 1.70-1.98 (3H, m), 2.10-2.34 (3H, m), 2.52 (3H, s ), 3.28-3.36 (2H, m), 3.55-3.82 (2H, m), 7.15 (3H, br s), 7.52 (1H, br s).
B) 4-(2-メチルフェニル)アゼパン-4-オール　塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 206.3. B) 4- (2-Methylphenyl) azepan-4-ol hydrochloride In the same manner as in Step B of Example 1, the title compound was obtained.
MS (ESI +): [M + H] + 206.3.
実施例6
4-メトキシ-4-(2-メチルフェニル)アゼパン　塩酸塩
A) tert-ブチル 4-メトキシ-4-(2-メチルフェニル)アゼパン-1-カルボキシラート
　実施例2の工程Aと同様の方法により、tert-ブチル 4-ヒドロキシ-4-(2-メチルフェニル)アゼパン-1-カルボキシラート(230 mg)、60%水素化ナトリウム(45 mg)およびヨウ化メチル(0.07 mL)から標題化合物(232 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.43-1.46 (9H, m), 1.70-2.36 (6H, m), 2.53 (3H, d, J = 3.3 Hz), 2.97 (3H, s), 3.26-3.39 (2H, m), 3.51-3.88 (2H, m), 7.13-7.15 (3H, m), 7.22-7.25 (1H, m). Example 6
4-Methoxy-4- (2-methylphenyl) azepan hydrochloride
A) tert-butyl 4-methoxy-4- (2-methylphenyl) azepan-1-carboxylate In the same manner as in Step A of Example 2, tert-butyl 4-hydroxy-4- (2-methylphenyl) The title compound (232 mg) was obtained from azepane-1-carboxylate (230 mg), 60% sodium hydride (45 mg) and methyl iodide (0.07 mL).
1 H NMR (300 MHz, CDCl 3 ) δ 1.43-1.46 (9H, m), 1.70-2.36 (6H, m), 2.53 (3H, d, J = 3.3 Hz), 2.97 (3H, s), 3.26- 3.39 (2H, m), 3.51-3.88 (2H, m), 7.13-7.15 (3H, m), 7.22-7.25 (1H, m).
B) 4-メトキシ-4-(2-メチルフェニル)アゼパン　塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 220.3. B) 4-Methoxy-4- (2-methylphenyl) azepane hydrochloride The title compound was obtained in the same manner as in Step B of Example 1.
MS (ESI +): [M + H] + 220.3.
実施例7
4-エトキシ-4-(2-メチルフェニル)アゼパン 塩酸塩
A) tert-ブチル 4-エトキシ-4-(2-メチルフェニル)アゼパン-1-カルボキシラート
　実施例2の工程Aと同様の方法により、tert-ブチル 4-ヒドロキシ-4-(2-メチルフェニル)アゼパン-1-カルボキシラート(190 mg)、60%水素化ナトリウム(136 mg)およびヨウ化エチル(0.28 mL)から標題化合物(178 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.36-1.82 (3H, m), 1.43-1.46 (9H, m), 1.68-2.15 (6H, m), 2.55 (3H, d, J = 3.0 Hz), 2.94-3.13 (2H, m), 3.24-3.38 (2H, m), 3.50-3.86 (2H, m), 7.13-7.14 (3H, m), 7.22-7.25 (1H, m). Example 7
4-Ethoxy-4- (2-methylphenyl) azepane hydrochloride
A) tert-butyl 4-ethoxy-4- (2-methylphenyl) azepan-1-carboxylate In the same manner as in Step A of Example 2, tert-butyl 4-hydroxy-4- (2-methylphenyl) The title compound (178 mg) was obtained from azepan-1-carboxylate (190 mg), 60% sodium hydride (136 mg) and ethyl iodide (0.28 mL).
1 H NMR (300 MHz, CDCl 3 ) δ 1.36-1.82 (3H, m), 1.43-1.46 (9H, m), 1.68-2.15 (6H, m), 2.55 (3H, d, J = 3.0 Hz), 2.94-3.13 (2H, m), 3.24-3.38 (2H, m), 3.50-3.86 (2H, m), 7.13-7.14 (3H, m), 7.22-7.25 (1H, m).
B)4-エトキシ-4-(2-メチルフェニル)アゼパン 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 234.4. B) 4-Ethoxy-4- (2-methylphenyl) azepane hydrochloride The title compound was obtained in the same manner as in Step B of Example 1.
MS (ESI +): [M + H] + 234.4.
実施例8
エチル 3-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-4-カルボキシラート フマル酸塩
A) 1-tert-ブチル 4-エチル 3-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-1,4-ジカルボキシラート
　60%水素化ナトリウム(350 mg)と脱水ジエチルエーテル(15 mL)の混合液に、J. Med. Chem. 29, 224-229 (1986)記載の方法に準じて調製した1-tert-ブチル4-エチル 3-オキソアゼパン-1,4-ジカルボキシラート(1.0 g)のジエチルエーテル(10 mL)溶液を氷冷下加えて90分間撹拌後、更にトリフルオロメタンスルホン酸無水物(0.9 mL)のジエチルエーテル(10 mL)溶液を滴下した。室温で40分間撹拌後、飽和塩化アンモニウム水を加え、分液した。水層を酢酸エチルで2度抽出し、抽出液を無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣はこれ以上精製することなく、次の反応に用いた。
　上記生成物およびテトラキストリフェニルホスフィンパラジウム(202 mg)のトルエン (20 mL)-エタノール(4.0 mL)の混合液に2.5M二炭酸ナトリウム水溶液(2.1 mL)を加え、反応系内をアルゴンで置換した。反応混合液に3,4-ジクロロフェニルボロン酸(803 mg)を加え、80℃で2時間加熱した。反応混合液を室温に冷却、酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(1.3 g)を得た。
1H NMR (300 MHz, CDCl3) δ 0.85-0.94 (3H, m), 1.44-1.49 (9H, m), 1.92-2.03 (2H, m), 2.62-2.66 (2H, m), 3.55-3.68 (2H, m), 3.84-3.95 (2H, m), 4.17 (2H, d, J = 8 Hz), 7.20-7.38 (3H, m). Example 8
Ethyl 3- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-4-carboxylate fumarate
A) 1-tert-butyl 4-ethyl 3- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate 60% sodium hydride (350 mg) And 1-tert-butyl 4-ethyl 3-oxoazepane-1,4 prepared according to the method described in J. Med. Chem. 29, 224-229 (1986). -A solution of -dicarboxylate (1.0 g) in diethyl ether (10 mL) was added with ice cooling and stirred for 90 minutes, and then a solution of trifluoromethanesulfonic anhydride (0.9 mL) in diethyl ether (10 mL) was added dropwise. After stirring at room temperature for 40 minutes, saturated aqueous ammonium chloride was added to separate the layers. The aqueous layer was extracted twice with ethyl acetate, the extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was used in the next reaction without further purification.
To the mixture of the above product and tetrakistriphenylphosphine palladium (202 mg) in toluene (20 mL) -ethanol (4.0 mL) was added 2.5M aqueous sodium bicarbonate (2.1 mL), and the reaction system was replaced with argon. . To the reaction mixture, 3,4-dichlorophenylboronic acid (803 mg) was added and heated at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.3 g).
1 H NMR (300 MHz, CDCl 3 ) δ 0.85-0.94 (3H, m), 1.44-1.49 (9H, m), 1.92-2.03 (2H, m), 2.62-2.66 (2H, m), 3.55-3.68 (2H, m), 3.84-3.95 (2H, m), 4.17 (2H, d, J = 8 Hz), 7.20-7.38 (3H, m).
B) エチル 3-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-4-カルボキシラート フマル酸塩
　実施例8の工程Aで得た1-tert-ブチル 4-エチル 3-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-1,4-ジカルボキシラート(98 mg)と2N 塩酸/エタノール溶液(1.4 mL)の混合液を室温で4時間撹拌した。反応混合液を減圧下溶媒を留去し、残渣を酢酸エチル-エタノール混液で希釈し、飽和重曹水で中和した。有機層を水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣を酢酸エチル(2.0 mL)に溶解し、無水フマル酸(27.5 mg)/エタノール(0.5 mL)溶液を加え、室温で30分撹拌した。反応混合液を減圧下溶媒を留去し、表題化合物(78 mg)を白色固体として得た。
MS (ESI+): [M+H]+ 314.0. B) Ethyl 3- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-4-carboxylate fumarate 1-tert-butyl 4-hydroxylate obtained in Step A of Example 8 Mix a mixture of ethyl 3- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (98 mg) and 2N hydrochloric acid / ethanol solution (1.4 mL). Stir at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure, the residue was diluted with an ethyl acetate-ethanol mixture, and neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (2.0 mL), a solution of fumaric anhydride (27.5 mg) / ethanol (0.5 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to give the title compound (78 mg) as a white solid.
MS (ESI +): [M + H] + 314.0.
実施例9
6-(3,4-ジクロロフェニル)-5-(メトキシメチル)-2,3,4,7-テトラヒドロ-1H-アゼピン 塩酸塩
A) tert-ブチル 6-(3,4-ジクロロフェニル)-5-(ヒドロキシメチル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート
　水素化ホウ素ナトリウム(54 mg)のTHF(1.2 mL)-エタノール(0.8 mL)溶液に塩化カルシウム(80 mg)を加え、室温で20分間撹拌した。この反応混合液に実施例8の工程Aで得られた1-tert-ブチル 4-エチル 3-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-1,4-ジカルボキシラート(100 mg)のTHF(0.8 mL)溶液を加え、室温で16時間撹拌した。水に反応混合液を注ぎ、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(72 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.30 (1H, br s), 1.41-1.49 (9H, m), 1.86-1.94 (2H, m), 2,46-2.55 (2H, m), 3.56-3.66 (2H, m), 3.90 (2H, br s), 4.10 (2H, br s), 7.02-7.41 (3H, m). Example 9
6- (3,4-Dichlorophenyl) -5- (methoxymethyl) -2,3,4,7-tetrahydro-1H-azepine hydrochloride
A) tert-butyl 6- (3,4-dichlorophenyl) -5- (hydroxymethyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate sodium borohydride (54 mg) in THF Calcium chloride (80 mg) was added to a (1.2 mL) -ethanol (0.8 mL) solution, and the mixture was stirred at room temperature for 20 minutes. To this reaction mixture, 1-tert-butyl 4-ethyl 3- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,4 obtained in Step A of Example 8 was added. -A solution of dicarboxylate (100 mg) in THF (0.8 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (72 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.30 (1H, br s), 1.41-1.49 (9H, m), 1.86-1.94 (2H, m), 2,46-2.55 (2H, m), 3.56- 3.66 (2H, m), 3.90 (2H, br s), 4.10 (2H, br s), 7.02-7.41 (3H, m).
B) tert-ブチル 6-(3,4-ジクロロフェニル)-5-(メトキシメチル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート
　tert-ブチル 6-(3,4-ジクロロフェニル)-5-(ヒドロキシメチル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(69 mg)のTHF(2.0 mL)溶液に室温中60 %水素化ナトリウム(11 mg)を加え、10分撹拌した。反応混合液にヨウ化メチル(0.02 mL)を加え、16時間撹拌した。反応混合液に水を加え、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(65 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.41-1.48 (9H, m), 1.87-1.94 (2H, m), 2.41-2.49 (2H, m), 3.18 (3H, d, J = 6.3 Hz), 3.55-3.65 (4H, m), 4.09 (2H, s), 7.02-7.05 (0.5H, m), 7.28-7.31 (0.5H, m), 7.37-7.42 (2H, m). B) tert-butyl 6- (3,4-dichlorophenyl) -5- (methoxymethyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate tert-butyl 6- (3,4- Dichlorophenyl) -5- (hydroxymethyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (69 mg) in THF (2.0 mL) at room temperature with 60% sodium hydride (11 mg ) Was added and stirred for 10 minutes. Methyl iodide (0.02 mL) was added to the reaction mixture and stirred for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (65 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.41-1.48 (9H, m), 1.87-1.94 (2H, m), 2.41-2.49 (2H, m), 3.18 (3H, d, J = 6.3 Hz), 3.55-3.65 (4H, m), 4.09 (2H, s), 7.02-7.05 (0.5H, m), 7.28-7.31 (0.5H, m), 7.37-7.42 (2H, m).
C) 6-(3,4-ジクロロフェニル)-5-(メトキシメチル)-2,3,4,7-テトラヒドロ-1H-アゼピン 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 286.3. C) 6- (3,4-Dichlorophenyl) -5- (methoxymethyl) -2,3,4,7-tetrahydro-1H-azepine hydrochloride The title compound was obtained in the same manner as in Step B of Example 1. It was.
MS (ESI +): [M + H] + 286.3.
実施例10
エチル (3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-4-カルボキシラート フマル酸塩
A) 1-tert-ブチル 4-エチル(3RS,4SR)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート
　実施例8の工程Aで得た1-tert-ブチル 4-エチル3-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-1,4-ジカルボキシラート(1.34 g)のメタノール(30 mL)溶液に3% プラチナ-サルファイデッドカーボン(300 mg)を加え、水素雰囲気下室温で24時間撹拌した。反応混合液をセライト濾過し、濾液を減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(0.53 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.05 (3H, dt, J = 7.2, 2.7 Hz), 1.46-1.48 (9H, m), 1.65-1.92 (2H, m), 2.04-2.10 (2H, m), 2.85-3.12 (2H, m), 3.35-3.60 (2H, m), 3.80-4.03 (4H, m), 7.04-7.10 (1H, m), 7.25-7.34 (2H, m). Example 10
Ethyl (3RS, 4RS) -3- (3,4-dichlorophenyl) azepan-4-carboxylate fumarate
A) 1-tert-butyl 4-ethyl (3RS, 4SR) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate 1-tert-butyl 4-ethyl obtained in Step A of Example 8 Ethyl 3- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (1.34 g) in methanol (30 mL) in 3% platinum-sulfite Dead carbon (300 mg) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.53 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.05 (3H, dt, J = 7.2, 2.7 Hz), 1.46-1.48 (9H, m), 1.65-1.92 (2H, m), 2.04-2.10 (2H, m ), 2.85-3.12 (2H, m), 3.35-3.60 (2H, m), 3.80-4.03 (4H, m), 7.04-7.10 (1H, m), 7.25-7.34 (2H, m).
B) 1-tert-ブチル 4-エチル (3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート
　1-tert-ブチル 4-エチル (3RS,4SR)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート(530 mg)のエタノール(11 mL)溶液にナトリウムエトキシド(96 mg)を加え、室温で96時間撹拌した。反応混合液を減圧下濃縮後、残渣を酢酸エチルで希釈し、水および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物 (399 mg) を得た。
1H NMR (300 MHz, CDCl3) δ 0.96 (3H, t, J = 7.2 Hz), 1.49 (9H, s), 1.80-2.15 (4H, m), 2.60-2.71 (1H, m), 2.88 (1H, dt, J = 10.8, 3.3 Hz), 3.20-3.70 (4H, m), 3.83 (2H, q, J = 7.2 Hz), 7.00 (1H, dd, J = 8.1, 2.1 Hz), 7.25 (1H, d, J = 2.1 Hz), 7.31-7.33 (1H, m). B) 1-tert-butyl 4-ethyl (3RS, 4RS) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate 1-tert-butyl 4-ethyl (3RS, 4SR) -3- Sodium ethoxide (96 mg) was added to a solution of (3,4-dichlorophenyl) azepane-1,4-dicarboxylate (530 mg) in ethanol (11 mL), and the mixture was stirred at room temperature for 96 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (399 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.96 (3H, t, J = 7.2 Hz), 1.49 (9H, s), 1.80-2.15 (4H, m), 2.60-2.71 (1H, m), 2.88 ( 1H, dt, J = 10.8, 3.3 Hz), 3.20-3.70 (4H, m), 3.83 (2H, q, J = 7.2 Hz), 7.00 (1H, dd, J = 8.1, 2.1 Hz), 7.25 (1H , d, J = 2.1 Hz), 7.31-7.33 (1H, m).
C) エチル (3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-4-カルボキシラート フマル酸塩
　実施例8の工程Bと同様の方法により標題化合物を得た。
MS (ESI+): [M+H]+ 316.3. C) Ethyl (3RS, 4RS) -3- (3,4-dichlorophenyl) azepan-4-carboxylate fumarate The title compound was obtained in the same manner as in Step B of Example 8.
MS (ESI +): [M + H] + 316.3.
実施例11
[(3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]メタノール 塩酸塩
A) tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラート
　水素化ホウ素ナトリウム(214 mg)のTHF(4.8 mL)-エタノール(3.2 mL)溶液に塩化カルシウム(314 mg)を加え、室温で20分間撹拌した。この反応混合液に実施例10の工程Bで得られた1-tert-ブチル 4-エチル (3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート(392 mg)のTHF(4.8 mL)溶液を加え、室温で16時間撹拌した。10%クエン酸水溶液に反応混合液を注ぎ、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(325 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.24 (1H, br s), 1.47 (9H, s), 1.70-1.80 (2H, m), 2.04-2.15 (2H, m), 2.63-3.23 (4H, m), 3.39-3.90 (4H, m), 7.00-7.09 (1H, m), 7.25-7.39 (2H, m). Example 11
[(3RS, 4RS) -3- (3,4-dichlorophenyl) azepan-4-yl] methanol hydrochloride
A) tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4- (hydroxymethyl) azepan-1-carboxylate sodium borohydride (214 mg) in THF (4.8 mL) -ethanol ( 3.2 mL) solution was added with calcium chloride (314 mg) and stirred at room temperature for 20 minutes. To this reaction mixture, 1-tert-butyl 4-ethyl (3RS, 4RS) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate (392 mg) obtained in Step B of Example 10 was added. ) In THF (4.8 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was poured into 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (325 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.24 (1H, br s), 1.47 (9H, s), 1.70-1.80 (2H, m), 2.04-2.15 (2H, m), 2.63-3.23 (4H, m), 3.39-3.90 (4H, m), 7.00-7.09 (1H, m), 7.25-7.39 (2H, m).
B) [(3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]メタノール 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 274.1. B) [(3RS, 4RS) -3- (3,4-Dichlorophenyl) azepan-4-yl] methanol hydrochloride In the same manner as in Step B of Example 1, the title compound was obtained.
MS (ESI +): [M + H] + 274.1.
実施例12
(3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン 塩酸塩
A) tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(メチルスルファニル)メチル]アゼパン-1-カルボキシラート
　実施例11の工程Aで得られたtert-ブチル(3RS,4RS)-3-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラート(252 mg)のTHF(5.0 mL)溶液に氷冷下トリエチルアミン(0.14 mL)およびメタンスルホニルクロリド(0.06 mL)を加え、室温で4時間撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をDMF(2.7 mL)溶液に溶解し、この混合液にナトリウムチオメトキシド(75 mg)を加え、室温で18時間撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(229 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.28-1.42 (1H, m), 1.48 (9H, s), 1.59-1.86 (2H, m), 1.93 (3H, s), 2.04-2.40 (4H, m), 2.64-2.74 (1H, m), 2.84-3.15 (2H, m), 3.59-3.89 (2H, m), 6.99-7.08 (1H, m), 7.25-7.40 (2H, m). Example 12
(3RS, 4RS) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride
A) tert-Butyl (3RS, 4RS) -3- (3,4-Dichlorophenyl) -4-[(methylsulfanyl) methyl] azepan-1-carboxylate tert-Butyl obtained in Step A of Example 11 ( 3RS, 4RS) -3- (3,4-dichlorophenyl) -4- (hydroxymethyl) azepane-1-carboxylate (252 mg) in THF (5.0 mL) was added to triethylamine (0.14 mL) and methanesulfonyl under ice-cooling. Chloride (0.06 mL) was added and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (2.7 mL) solution, sodium thiomethoxide (75 mg) was added to the mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (229 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.28-1.42 (1H, m), 1.48 (9H, s), 1.59-1.86 (2H, m), 1.93 (3H, s), 2.04-2.40 (4H, m ), 2.64-2.74 (1H, m), 2.84-3.15 (2H, m), 3.59-3.89 (2H, m), 6.99-7.08 (1H, m), 7.25-7.40 (2H, m).
B) tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン-1-カルボキシラート
　実施例12の工程Aで得られたtert-ブチル(3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(メチルスルファニル)メチル]アゼパン-1-カルボキシラート(62 mg)のトルエン(1.5 mL)溶液に、氷冷下m-クロロ過安息香酸(81 mg)を加え、室温で4時間撹拌した。反応混合液を酢酸エチルで希釈し、飽和重曹水、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(65 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.48 (9H, s), 1.70-1.85 (1H, m), 2.04-2.18 (1H, m), 2.38-3.16 (8H, m), 2.72 (3H, d, J = 4.8 Hz), 3.65-3.86 (2H, m), 7.05-7.13 (1H, m), 7.30-7.45 (2H, m). B) tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane-1-carboxylate tert-butyl obtained in Step A of Example 12 ( 3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfanyl) methyl] azepane-1-carboxylate (62 mg) in toluene (1.5 mL) was added to m-chloroperoxide under ice-cooling. Benzoic acid (81 mg) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (65 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.48 (9H, s), 1.70-1.85 (1H, m), 2.04-2.18 (1H, m), 2.38-3.16 (8H, m), 2.72 (3H, d , J = 4.8 Hz), 3.65-3.86 (2H, m), 7.05-7.13 (1H, m), 7.30-7.45 (2H, m).
C) (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 336.1. C) (3RS, 4RS) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride In the same manner as in Step B of Example 1, the title compound was obtained.
MS (ESI +): [M + H] + 336.1.
実施例13
1-[(3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]-N-メチルメタンスルホンアミド 塩酸塩
A) tert-ブチル (3RS,4RS)-4-[(アセチルスルファニル)メチル]-3-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート
　実施例11の工程Aで得られたtert-ブチル(3RS,4RS)-3-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラート(1.0 g)のTHF(20 mL)溶液に、氷冷下トリエチルアミン(1.12 mL)およびメタンスルホニルクロリド(0.41 mL)を加え、室温で2.5時間撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をアセトニトリル(20 mL)溶液に溶解し、炭酸セシウム(870 mg)、チオ酢酸(0.19 mL)を加え、60℃に加温して2時間撹拌した。反応混合液を室温に冷却後、酢酸エチルで希釈し、水および飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(948 mg)を得た。
1H NMR (300 MHz, CDCl3) δ1.26-1.39 (1H, m), 1.48 (9H, s), 1.62-1.76 (1H, m), 1.81-2.16 (3H, m), 2.29 (3H, s), 2.38-2.76 (2H, m), 2.76-3.03 (2H, m), 3.04-3.20 (1H, m), 3.56-3.89 (2H, m), 6.97-7.15 (1H, m), 7.27-7.48 (2H, m). Example 13
1-[(3RS, 4RS) -3- (3,4-Dichlorophenyl) azepan-4-yl] -N-methylmethanesulfonamide hydrochloride
A) tert-Butyl (3RS, 4RS) -4-[(acetylsulfanyl) methyl] -3- (3,4-dichlorophenyl) azepan-1-carboxylate tert-Butyl obtained in Step A of Example 11 ( 3RS, 4RS) -3- (3,4-dichlorophenyl) -4- (hydroxymethyl) azepane-1-carboxylate (1.0 g) in THF (20 mL) was added to triethylamine (1.12 mL) and methane under ice-cooling. Sulfonyl chloride (0.41 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (20 mL) solution, cesium carbonate (870 mg) and thioacetic acid (0.19 mL) were added, and the mixture was heated to 60 ° C. and stirred for 2 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (948 mg).
1 H NMR (300 MHz, CDCl 3 ) δ1.26-1.39 (1H, m), 1.48 (9H, s), 1.62-1.76 (1H, m), 1.81-2.16 (3H, m), 2.29 (3H, s), 2.38-2.76 (2H, m), 2.76-3.03 (2H, m), 3.04-3.20 (1H, m), 3.56-3.89 (2H, m), 6.97-7.15 (1H, m), 7.27- 7.48 (2H, m).
B) tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(メチルスルファモイル)メチル]アゼパン-1-カルボキシラート
　実施例13の工程Aで得られたtert-ブチル (3RS,4RS)-4-[(アセチルスルファニル)メチル]-3-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート(868 mg)のアセトニトリル(8 mL)溶液に、氷冷下1N塩酸(1.0 mL)およびN-クロロスクシンイミド(1.07 g)を加え、室温で30分間撹拌した。反応混合液に飽和食塩水(5.0 mL)を加え、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣1.0g中120 mgをTHF(3.5 mL)溶液に溶解し、氷冷下トリエチルアミン(0.07 mL)およびジメチルアミン(31 mg)を加え、室温で16時間撹拌した。反応混合液を酢酸エチルで抽出し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(42 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.32-1.45 (1H, m), 1.48 (9H, s), 1.65-1.89 (1H, m), 2.06-2.35 (2H, m), 2.42-2.58 (4H, m), 2.58-3.22 (5H, m), 3.61-4.03 (3H, m), 7.01-7.20 (1H, m), 7.28-7.53 (2H, m). B) tert-Butyl (3RS, 4RS) -3- (3,4-Dichlorophenyl) -4-[(methylsulfamoyl) methyl] azepan-1-carboxylate tert--obtained in Step 13 of Example 13 To a solution of butyl (3RS, 4RS) -4-[(acetylsulfanyl) methyl] -3- (3,4-dichlorophenyl) azepan-1-carboxylate (868 mg) in acetonitrile (8 mL) was added 1N hydrochloric acid under ice-cooling. (1.0 mL) and N-chlorosuccinimide (1.07 g) were added and stirred at room temperature for 30 minutes. To the reaction mixture was added saturated brine (5.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 120 mg in 1.0 g of the obtained residue was dissolved in a THF (3.5 mL) solution, triethylamine (0.07 mL) and dimethylamine (31 mg) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (42 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.32-1.45 (1H, m), 1.48 (9H, s), 1.65-1.89 (1H, m), 2.06-2.35 (2H, m), 2.42-2.58 (4H , m), 2.58-3.22 (5H, m), 3.61-4.03 (3H, m), 7.01-7.20 (1H, m), 7.28-7.53 (2H, m).
C) 1-[(3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]-N-メチルメタンスルホンアミド 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 351.2. C) 1-[(3RS, 4RS) -3- (3,4-dichlorophenyl) azepan-4-yl] -N-methylmethanesulfonamide hydrochloride The title compound was prepared in the same manner as in Step B of Example 1. Obtained.
MS (ESI +): [M + H] + 351.2.
実施例14
エチル 4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-3-カルボキシラート 塩酸塩
A)1-tert-ブチル 3-エチル 4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-1,3-ジカルボキシラート
　実施例8の工程Aと同様の方法により、1-tert-ブチル 3-エチル 4-オキソアゼパン-1,3-ジカルボキシラート(143 mg)から標題化合物(44 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.92 (3H, t, J = 7.2 Hz), 1.32-1.50 (9H, m), 1.85-2.00 (2H, m), 2.50-2.70 (2H, m), 3.54-3.70 (2H, m), 3.90 (2H, t, J = 7.5 Hz), 4.18-4.38 (2H, m), 6.93 (1H, d, J = 7.8 Hz), 7.13-7.24 (1H, m), 7.36 (1H, d, J = 8.4 Hz). Example 14
Ethyl 4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-3-carboxylate hydrochloride
A) 1-tert-butyl 3-ethyl 4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,3-dicarboxylate Similar to step A of Example 8. By the method, the title compound (44 mg) was obtained from 1-tert-butyl 3-ethyl 4-oxoazepane-1,3-dicarboxylate (143 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.92 (3H, t, J = 7.2 Hz), 1.32-1.50 (9H, m), 1.85-2.00 (2H, m), 2.50-2.70 (2H, m), 3.54-3.70 (2H, m), 3.90 (2H, t, J = 7.5 Hz), 4.18-4.38 (2H, m), 6.93 (1H, d, J = 7.8 Hz), 7.13-7.24 (1H, m) , 7.36 (1H, d, J = 8.4 Hz).
B) エチル 4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-3-カルボキシラート 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 314.3. B) Ethyl 4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-3-carboxylate hydrochloride The title compound was obtained in the same manner as in Step B of Example 1. .
MS (ESI +): [M + H] + 314.3.
実施例15
[4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-3-イル]メタノール 塩酸塩
A) tert-ブチル 5-(3,4-ジクロロフェニル)-6-(ヒドロキシメチル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート
　実施例9の工程Aと同様の方法により、1-tert-ブチル 3-エチル 4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-1,3-ジカルボキシラート(2.50 g)から標題化合物(1.75 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.48 (9H, s), 1.68-1.74 (2H, m), 2.64-2.68 (2H, m), 3.67 (2H, t, J = 5.7 Hz), 3.82 (2H, d, J = 5.7 Hz), 4.00 (2H, s), 4.63 (1H, t, J = 5.4 Hz), 7.06 (1H, dd, J = 8.4, 1.8 Hz), 7.27 (1H, d, J = 1.8 Hz), 7.37 (1H, d, J = 8.4 Hz). Example 15
[4- (3,4-Dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methanol hydrochloride
A) tert-butyl 5- (3,4-dichlorophenyl) -6- (hydroxymethyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate The same method as in step A of Example 9 1-tert-butyl 3-ethyl 4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,3-dicarboxylate (2.50 g) to give the title compound (1.75 g) was obtained.
1 H NMR (300 MHz, CDCl 3 ) δ 1.48 (9H, s), 1.68-1.74 (2H, m), 2.64-2.68 (2H, m), 3.67 (2H, t, J = 5.7 Hz), 3.82 ( 2H, d, J = 5.7 Hz), 4.00 (2H, s), 4.63 (1H, t, J = 5.4 Hz), 7.06 (1H, dd, J = 8.4, 1.8 Hz), 7.27 (1H, d, J = 1.8 Hz), 7.37 (1H, d, J = 8.4 Hz).
B) [4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-3-イル]メタノール 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 272.3. B) [4- (3,4-Dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methanol hydrochloride The title compound was obtained in the same manner as in Step B of Example 1. It was.
MS (ESI +): [M + H] + 272.3.
実施例16
エチル (3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-カルボキシラート 塩酸塩
A) 1-tert-ブチル 3-エチル(3RS,4RS)-4-(3,4-ジクロロフェニル)アゼパン-1,3-ジカルボキシラート
　実施例14の工程Aで得られた1-tert-ブチル 3-エチル 4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-1,3-ジカルボキシラート(350 mg)のメタノール(8.0 mL)溶液に酸化白金(39 mg)を加え、水素雰囲気下室温で5時間撹拌した。反応混合液をセライト濾過し、濾液を減圧下溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(95 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 0.95 (3H, t, J = 7.2 Hz), 1.42-1.54 (9H, m), 1.66-1.78 (1H, m), 1.82-1.98 (2H, m), 2.38-2.56 (1H, m), 2.80-3.30 (3H, m), 3.36-3.56 (1H, m), 3.70-4.14 (4H, m), 6.90-7.04 (1H, m), 7.16-7.26 (1H, m), 7.28-7.37 (1H, m). Example 16
Ethyl (3RS, 4SR) -4- (3,4-dichlorophenyl) azepane-3-carboxylate hydrochloride
A) 1-tert-butyl 3-ethyl (3RS, 4RS) -4- (3,4-dichlorophenyl) azepane-1,3-dicarboxylate 1-tert-butyl 3 obtained in Step A of Example 14 -Platinum 4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepine-1,3-dicarboxylate (350 mg) in methanol (8.0 mL) in platinum oxide (39 mg ) Was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (95 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 0.95 (3H, t, J = 7.2 Hz), 1.42-1.54 (9H, m), 1.66-1.78 (1H, m), 1.82-1.98 (2H, m), 2.38-2.56 (1H, m), 2.80-3.30 (3H, m), 3.36-3.56 (1H, m), 3.70-4.14 (4H, m), 6.90-7.04 (1H, m), 7.16-7.26 (1H , m), 7.28-7.37 (1H, m).
B) 1-tert-ブチル 3-エチル (3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-1,3-ジカルボキシラート
　実施例10の工程Bと同様の方法により、1-tert-ブチル 3-エチル (3RS,4RS)-4-(3,4-ジクロロフェニル)アゼパン-1,3-ジカルボキシラート(13 g)から標題化合物(5.1 g)を得た。
1H NMR (300 MHz, CDCl3) δ0.92-1.08 (3H, m), 1.44-1.55 (9H, m), 1.62-1.90 (3H, m), 1.98-2.12 (1H, m), 2.67-2.96 (2H, m), 3.08-3.30 (2H, m), 3.62-4.10 (4H, m), 6.94-7.02 (1H, m), 7.20-7.26 (1H, m), 7.30-7.36 (1H, m). B) 1-tert-butyl 3-ethyl (3RS, 4SR) -4- (3,4-dichlorophenyl) azepane-1,3-dicarboxylate In the same manner as in Step B of Example 10, The title compound (5.1 g) was obtained from butyl 3-ethyl (3RS, 4RS) -4- (3,4-dichlorophenyl) azepane-1,3-dicarboxylate (13 g).
1 H NMR (300 MHz, CDCl 3 ) δ0.92-1.08 (3H, m), 1.44-1.55 (9H, m), 1.62-1.90 (3H, m), 1.98-2.12 (1H, m), 2.67- 2.96 (2H, m), 3.08-3.30 (2H, m), 3.62-4.10 (4H, m), 6.94-7.02 (1H, m), 7.20-7.26 (1H, m), 7.30-7.36 (1H, m ).
C) エチル (3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-カルボキシラート 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 316.1. C) Ethyl (3RS, 4SR) -4- (3,4-dichlorophenyl) azepane-3-carboxylate hydrochloride In the same manner as in Step B of Example 1, the title compound was obtained.
MS (ESI +): [M + H] + 316.1.
実施例17
(3RS,4SR)-4-(3,4-ジクロロフェニル)-3-[(メチルスルホニル)メチル]アゼパン 塩酸塩
A) tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-(ヒドロキシメチル)アゼパン-1-カルボキシラート
　実施例9の工程Aと同様の方法により、1-tert-ブチル 3-エチル(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-1,3-ジカルボキシラート(1.6 g)から標題化合物 (1.3 g) を得た。
H NMR (400 MHz, CDCl3) δ1.44-1.53 (9H, m), 1.58-1.96 (4H, m), 2.40-2.60 (1H, m), 2.82-2.98 (1H, m), 3.10-4.04 (6H, m), 6.95-7.08 (1H, m), 7.24-7.30 (1H, m), 7.30-7.40 (1H, m). 1Hは観測されなかった. Example 17
(3RS, 4SR) -4- (3,4-Dichlorophenyl) -3-[(methylsulfonyl) methyl] azepan hydrochloride
A) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3- (hydroxymethyl) azepane-1-carboxylate In the same manner as in Step 9 of Example 9, 1-tert-butyl The title compound (1.3 g) was obtained from 3-ethyl (3RS, 4SR) -4- (3,4-dichlorophenyl) azepane-1,3-dicarboxylate (1.6 g).
H NMR (400 MHz, CDCl 3 ) δ1.44-1.53 (9H, m), 1.58-1.96 (4H, m), 2.40-2.60 (1H, m), 2.82-2.98 (1H, m), 3.10-4.04 (6H, m), 6.95-7.08 (1H, m), 7.24-7.30 (1H, m), 7.30-7.40 (1H, m). 1H was not observed.
B)tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-[(メチルスルホニル)メチル]アゼパン-1-カルボキシラート
　tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-(ヒドロキシメチル)アゼパン-1-カルボキシラートから、実施例12の工程A、Bと同様の方法により標題化合物を得た。
1H NMR (300 MHz, CDCl3) δ1.45-1.56 (9H, m), 1.63-1.78 (2H, m), 1.80-2.14 (2H, m), 2.38-2.68 (2H, m), 2.62-2.94 (4H, m), 2.96-3.20 (1H, m), 3.32-3.60 (3H, m), 3.78-4.12 (1H, m), 7.04 (1H, dd, J = 8.0, 1.6 Hz), 7.26 (1H, s), 7.35-7.48 (1H, m). B) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-[(methylsulfonyl) methyl] azepan-1-carboxylate tert-butyl (3RS, 4SR) -4- (3, The title compound was obtained from 4-dichlorophenyl) -3- (hydroxymethyl) azepan-1-carboxylate in the same manner as in Steps A and B of Example 12.
1 H NMR (300 MHz, CDCl 3 ) δ1.45-1.56 (9H, m), 1.63-1.78 (2H, m), 1.80-2.14 (2H, m), 2.38-2.68 (2H, m), 2.62- 2.94 (4H, m), 2.96-3.20 (1H, m), 3.32-3.60 (3H, m), 3.78-4.12 (1H, m), 7.04 (1H, dd, J = 8.0, 1.6 Hz), 7.26 ( 1H, s), 7.35-7.48 (1H, m).
C) (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-[(メチルスルホニル)メチル]アゼパン 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 336.1. C) (3RS, 4SR) -4- (3,4-Dichlorophenyl) -3-[(methylsulfonyl) methyl] azepan hydrochloride In the same manner as in Step B of Example 1, the title compound was obtained.
MS (ESI +): [M + H] + 336.1.
実施例18
1-{[(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-イル]メチル}-3-エチル尿素 塩酸塩
A)tert-ブチル (3RS,4SR)-3-(アジドメチル)-4-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート
　実施例17の工程Aで得られたtert-ブチル(3RS,4SR)-4-(3,4-ジクロロフェニル)-3-[(メチルスルホニル)メチル]アゼパン-1-カルボキシラート(1.28 g)のジクロロメタン(25 mL)溶液に、トリエチルアミン(1.05 g)、メタンスルホニルクロリド(0.7 g)のジクロロメタン(2.0 mL)溶液を加え、室温で一晩撹拌した。反応混合液を酢酸エチルおよび水で希釈後分離し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、淡黄色油状物(1.54 g)を得た。生成物はこれ以上精製することなく、次の反応に使用した。
　上記で得られた油状物(1.54 g)のDMF(15 mL)溶液にアジ化ナトリウム(0.68 g)を加え、60℃で一晩撹拌した。反応混合液を室温に冷却後、酢酸エチルおよび水で希釈し、分離した。有機層を水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、標題化合物(1.35 g)を得た。
1H NMR (300 MHz, CDCl3) δ1.45-1.54 (9H, m), 1.64-1.74 (2H, m), 1.78-2.10 (3H, m), 2.28-2.54 (1H, m), 2.96-3.08 (2H, m), 3.10-3.32 (2H, m), 3.52-3.94 (2H, m), 6.94-7.04 (1H, m), 7.18-7.24 (1H, m), 7.32-7.44 (1H, m). Example 18
1-{[(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl} -3-ethylurea hydrochloride
A) tert-butyl (3RS, 4SR) -3- (azidomethyl) -4- (3,4-dichlorophenyl) azepan-1-carboxylate tert-butyl (3RS, 4SR) obtained in Step 17 of Example 17 To a solution of -4- (3,4-dichlorophenyl) -3-[(methylsulfonyl) methyl] azepane-1-carboxylate (1.28 g) in dichloromethane (25 mL), triethylamine (1.05 g), methanesulfonyl chloride (0.7 g) in dichloromethane (2.0 mL) was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and water and separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale-yellow oil (1.54 g). . The product was used in the next reaction without further purification.
To a solution of the oil (1.54 g) obtained above in DMF (15 mL) was added sodium azide (0.68 g), and the mixture was stirred at 60 ° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and separated. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.35 g).
1 H NMR (300 MHz, CDCl 3 ) δ1.45-1.54 (9H, m), 1.64-1.74 (2H, m), 1.78-2.10 (3H, m), 2.28-2.54 (1H, m), 2.96- 3.08 (2H, m), 3.10-3.32 (2H, m), 3.52-3.94 (2H, m), 6.94-7.04 (1H, m), 7.18-7.24 (1H, m), 7.32-7.44 (1H, m ).
B) tert-ブチル (3RS,4RS)-3-(アミノメチル)-4-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート
　tert-ブチル (3RS,4SR)-3-(アジドメチル)-4-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート(1.35 g)のTHF(30 mL)溶液にトリフェニルホスフィン (1.00 g)と水(3.0 mL)を加え、50℃で24時間撹拌した。室温に冷却後反応混合液を濃縮後、残留溶媒を凍結乾燥により留去し、標題化合物(2.45 g)をトリフェニルフォスフィンオキサイドとの混合物として得た。
MS (ESI+), found:372.8. B) tert-butyl (3RS, 4RS) -3- (aminomethyl) -4- (3,4-dichlorophenyl) azepan-1-carboxylate tert-butyl (3RS, 4SR) -3- (azidomethyl) -4- Triphenylphosphine (1.00 g) and water (3.0 mL) were added to a solution of (3,4-dichlorophenyl) azepan-1-carboxylate (1.35 g) in THF (30 mL), and the mixture was stirred at 50 ° C. for 24 hours. After cooling to room temperature, the reaction mixture was concentrated, and the residual solvent was evaporated by lyophilization to give the title compound (2.45 g) as a mixture with triphenylphosphine oxide.
MS (ESI +), found: 372.8.
C) tert-ブチル (3RS,4RS)-4-(3,4-ジクロロフェニル)-3-{[(エチルカルバモイル)アミノ]メチル}アゼパン-1-カルボキシラート
　tert-ブチル (3RS,4RS)-3-(アミノメチル)-4-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート(546 mg)のジクロロメタン(6.0 mL)溶液に、エチルイソシアネート(68 mg)のジクロロメタン(6.0 mL)溶液を加え、室温で一晩撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣を分取HPLC (0.1% TFA添加)で精製して標題化合物(270 mg)を得た。
1H NMR (400 MHz, CDCl3) δ 0.98-1.12 (3H, m), 1.42-1.54 (9H, m), 1.68-1.98 (5H, m), 2.18-2.34 (1H, m), 2.72-3.24 (5H, m), 3.25-3.84 (3H, m), 4.15-4.38 (1H, m), 5.25 (1H, brs), 7.01 (1H, d, J = 8.0 Hz), 7.23 (1H, s), 7.32-7.40 (1H, m). C) tert-butyl (3RS, 4RS) -4- (3,4-dichlorophenyl) -3-{[(ethylcarbamoyl) amino] methyl} azepan-1-carboxylate tert-butyl (3RS, 4RS) -3- To a solution of (aminomethyl) -4- (3,4-dichlorophenyl) azepane-1-carboxylate (546 mg) in dichloromethane (6.0 mL) was added a solution of ethyl isocyanate (68 mg) in dichloromethane (6.0 mL) at room temperature. And stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (0.1% TFA added) to give the title compound (270 mg).
1 H NMR (400 MHz, CDCl 3 ) δ 0.98-1.12 (3H, m), 1.42-1.54 (9H, m), 1.68-1.98 (5H, m), 2.18-2.34 (1H, m), 2.72-3.24 (5H, m), 3.25-3.84 (3H, m), 4.15-4.38 (1H, m), 5.25 (1H, brs), 7.01 (1H, d, J = 8.0 Hz), 7.23 (1H, s), 7.32-7.40 (1H, m).
D)1-{[(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-イル]メチル}-3-エチル尿素 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 344.2. D) 1-{[(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl} -3-ethylurea hydrochloride The title compound was prepared in the same manner as in Step B of Example 1. Got.
MS (ESI +): [M + H] + 344.2.
実施例19
N-{[(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-イル]メチル}-1,1,1-トリフルオロメタンスルホンアミド 塩酸塩
A) tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-({[(トリフルオロメチル)スルホニル]アミノ}メチル)アゼパン-1-カルボキシラート
　実施例18の工程Bで得られたtert-ブチル(3RS,4RS)-3-(アミノメチル)-4-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート(546 mg)のジクロロメタン(6.0 mL)溶液にN-フェニルトリフルオロメタンスルホンイミド(574 mg)およびトリエチルアミン(178 mg)を加え、18時間加熱還流した。反応混合液を冷却後酢酸エチルで希釈し、水および飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣を分取HPLC (0.1% TFA添加)で精製して標題化合物(200 mg)を得た。
1H NMR (400 MHz, CDCl3) δ 1.50 (9H, s), 1.60-1.70 (1H, m), 1.82-1.98 (3H, m), 2.08-2.18 (1H, m), 2.46-2.58 (1H, m), 2.70-2.82 (1H, m), 2.86-2.96 (1H, m), 3.08-3.18 (1H, m), 3.26-3.38 (1H, m), 3.96-4.06 (1H, m), 4.12-4.18 (1H, m), 7.04 (1H, d, J = 8.4 Hz), 7.29 (1H, s), 7.37 (1H, d, J = 8.0 Hz), 7.98 (1H, brs). Example 19
N-{[(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl} -1,1,1-trifluoromethanesulfonamide hydrochloride
A) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-({[(trifluoromethyl) sulfonyl] amino} methyl) azepan-1-carboxylate In step B of Example 18 The obtained tert-butyl (3RS, 4RS) -3- (aminomethyl) -4- (3,4-dichlorophenyl) azepan-1-carboxylate (546 mg) in dichloromethane (6.0 mL) was added to N-phenyl trifluoro L-methanesulfonimide (574 mg) and triethylamine (178 mg) were added, and the mixture was heated to reflux for 18 hours. The reaction mixture was cooled, diluted with ethyl acetate, and washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC (0.1% TFA added) to give the title compound (200 mg).
1 H NMR (400 MHz, CDCl 3 ) δ 1.50 (9H, s), 1.60-1.70 (1H, m), 1.82-1.98 (3H, m), 2.08-2.18 (1H, m), 2.46-2.58 (1H , m), 2.70-2.82 (1H, m), 2.86-2.96 (1H, m), 3.08-3.18 (1H, m), 3.26-3.38 (1H, m), 3.96-4.06 (1H, m), 4.12 -4.18 (1H, m), 7.04 (1H, d, J = 8.4 Hz), 7.29 (1H, s), 7.37 (1H, d, J = 8.0 Hz), 7.98 (1H, brs).
B) N-{[(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-イル]メチル}-1,1,1-トリフルオロメタンスルホンアミド 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 405.1. B) N-{[(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl} -1,1,1-trifluoromethanesulfonamide hydrochloride As in Step B of Example 1 The title compound was obtained by this method.
MS (ESI +): [M + H] + 405.1.
実施例20
N-{[(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-イル]メチル}-N'-メチル硫酸 ジアミド 塩酸塩
A) tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-{[(メチルスルファモイル)アミノ]メチル}アゼパン-1-カルボキシラート
　実施例18の工程Bで得られたtert-ブチル(3RS,4RS)-3-(アミノメチル)-4-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート(546 mg)のジクロロメタン(6.0 mL)溶液に、トリエチルアミン(163 mg)およびメチルスルファモイルクロリド(124 mg)のジクロロメタン(1.0 mL)溶液を加え、室温で24時間撹拌した。反応混合液を酢酸エチルで希釈後、水および飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去し、残渣を分取HPLC (0.1% TFA添加)で精製して標題化合物(220 mg)を得た。
1H NMR (400 MHz, CDCl3) δ1.40-1.58 (9H, m), 1.60-1.76 (1H, m), 1.78-1.96 (3H, m), 2.04-2.12 (1H, m), 2.22-2.50 (1H, m), 2.57-2.74 (4H, m), 2.78-3.16 (2H, m), 3.32-3.46 (1H, m), 3.70-3.98 (2H, m), 4.12-4.26 (1H, m), 5.81 (1H, t, J = 6.0 Hz), 6.95-7.08 (1H, m), 7.20-7.28 (1H, m), 7.32-7.42 (1H, m). Example 20
N-{[(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl} -N'-methylsulfuric acid diamide hydrochloride
A) tert-Butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-{[(methylsulfamoyl) amino] methyl} azepan-1-carboxylate obtained in Step B of Example 18 To a solution of tert-butyl (3RS, 4RS) -3- (aminomethyl) -4- (3,4-dichlorophenyl) azepane-1-carboxylate (546 mg) in dichloromethane (6.0 mL) was added triethylamine (163 mg). Then, a solution of methylsulfamoyl chloride (124 mg) in dichloromethane (1.0 mL) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC (0.1% TFA added) to give the title compound (220 mg).
1 H NMR (400 MHz, CDCl 3 ) δ1.40-1.58 (9H, m), 1.60-1.76 (1H, m), 1.78-1.96 (3H, m), 2.04-2.12 (1H, m), 2.22- 2.50 (1H, m), 2.57-2.74 (4H, m), 2.78-3.16 (2H, m), 3.32-3.46 (1H, m), 3.70-3.98 (2H, m), 4.12-4.26 (1H, m ), 5.81 (1H, t, J = 6.0 Hz), 6.95-7.08 (1H, m), 7.20-7.28 (1H, m), 7.32-7.42 (1H, m).
B) N-{[(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-イル]メチル}-N'-メチル硫酸 ジアミド 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 366.1. B) N-{[(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl} -N′-methylsulfuric acid diamide hydrochloride In the same manner as in Step B of Example 1, The title compound was obtained.
MS (ESI +): [M + H] + 366.1.
実施例21
エチル 5-(3,4-ジクロロフェニル)-2,3,6,7-テトラヒドロ-1H-アゼピン-4-カルボキシラート 塩酸塩
A)1-tert-ブチル 4-エチル 5-(3,4-ジクロロフェニル)-2,3,6,7-テトラヒドロ-1H-アゼピン-1,4-ジカルボキシラート
　実施例8の工程Aと同様の方法により、Synthetic Communications, 1992, 22, 1249-1258記載の方法で調製した1-tert-ブチル 4-エチル 5-オキソアゼパン-1,4-ジカルボキシラート(465 mg)から標題化合物(482 mg)を得た。
MS (ESI+): [M+H(-Boc)]+ 314.3. Example 21
Ethyl 5- (3,4-dichlorophenyl) -2,3,6,7-tetrahydro-1H-azepine-4-carboxylate hydrochloride
A) 1-tert-butyl 4-ethyl 5- (3,4-dichlorophenyl) -2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate Similar to step A of Example 8. The title compound (482 mg) was obtained from 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (465 mg) prepared by the method described in Synthetic Communications, 1992, 22, 1249-1258. Obtained.
MS (ESI +): [M + H (-Boc)] + 314.3.
B) エチル 5-(3,4-ジクロロフェニル)-2,3,6,7-テトラヒドロ-1H-アゼピン-4-カルボキシラート 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 314.3. B) Ethyl 5- (3,4-dichlorophenyl) -2,3,6,7-tetrahydro-1H-azepine-4-carboxylate hydrochloride The title compound was obtained in the same manner as in Step B of Example 1. .
MS (ESI +): [M + H] + 314.3.
実施例22
エチル (4RS,5RS)-5-(3,4-ジクロロフェニル)アゼパン-4-カルボキシラート 塩酸塩
A) 1-tert-ブチル 4-エチル(4RS,5RS)-5-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート
　実施例10の工程A及およびBと同様の工程により、実施例21の工程Aで得られた1-tert-ブチル 4-エチル5-(3,4-ジクロロフェニル)-2,3,6,7-テトラヒドロ-1H-アゼピン-1,4-ジカルボキシラート(470 mg)から標題化合物(65 mg)を得た。
1H NMR (400 MHz, CDCl3) δ0.96 (3H, t, J = 7.2 Hz), 1.49 (9H, s), 1.80-2.15 (4H, m), 2.60-2.71 (1H, m), 2.88 (1H, dt, J = 10.8, 3.3 Hz), 3.20-3.70 (4H, m), 3.83 (2H, q. J = 7.2 Hz), 7.00 (1H, dd, J = 8.1, 2.1 Hz), 7.25 (1H, d, J = 2.1 Hz), 7.31-7.33 (1H, m). Example 22
Ethyl (4RS, 5RS) -5- (3,4-dichlorophenyl) azepane-4-carboxylate hydrochloride
A) 1-tert-butyl 4-ethyl (4RS, 5RS) -5- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate Carried out by the same steps as steps A and B of Example 10. 1-tert-Butyl 4-ethyl 5- (3,4-dichlorophenyl) -2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (470) obtained in Step A of Example 21 mg) gave the title compound (65 mg).
1 H NMR (400 MHz, CDCl 3 ) δ0.96 (3H, t, J = 7.2 Hz), 1.49 (9H, s), 1.80-2.15 (4H, m), 2.60-2.71 (1H, m), 2.88 (1H, dt, J = 10.8, 3.3 Hz), 3.20-3.70 (4H, m), 3.83 (2H, q. J = 7.2 Hz), 7.00 (1H, dd, J = 8.1, 2.1 Hz), 7.25 ( 1H, d, J = 2.1 Hz), 7.31-7.33 (1H, m).
B) エチル (4RS,5RS)-5-(3,4-ジクロロフェニル)アゼパン-4-カルボキシラート 塩酸塩
　実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 316.1. B) Ethyl (4RS, 5RS) -5- (3,4-dichlorophenyl) azepan-4-carboxylate hydrochloride In the same manner as in Step B of Example 1, the title compound was obtained.
MS (ESI +): [M + H] + 316.1.
実施例23
(4RS)-4-(4-クロロ-3-メチルフェニル)-4-メトキシアゼパン 塩酸塩
　実施例1の工程A及び実施例2と同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 254.2.  Example 23
(4RS) -4- (4-Chloro-3-methylphenyl) -4-methoxyazepane hydrochloride The title compound was obtained in the same manner as in Step A of Example 1 and Example 2.
MS (ESI +): [M + H] + 254.2.
実施例24
(4RS)-4-(4-クロロフェニル)-4-メトキシアゼパン 塩酸塩
　実施例1の工程A及び実施例2と同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 240.2.  Example 24
(4RS) -4- (4-Chlorophenyl) -4-methoxyazepane hydrochloride The title compound was obtained in the same manner as in Step A of Example 1 and Example 2.
MS (ESI +): [M + H] + 240.2.
実施例25
(3R,4R)-3-(3-クロロ-4-フルオロフェニル)-4-[(メチルスルホニル)メチル]アゼパン　フマル酸塩
A) tert-ブチル (3R,4R)-3-(3-クロロ-4-フルオロフェニル)-4-[(ヒドロキシメチル)メチル]アゼパン-1-カルボキシラート
　実施例8及び10と同様の方法により得られた1-tert-ブチル 4-エチル (3RS,4RS)-3-(3-クロロ-4-フルオロフェニル)アゼパン-1,4-ジカルボキシラートを光学分割した。保持時間の大きい方は、X線結晶解析より、(3S,4S)-3-(3-クロロ-4-フルオロフェニル)アゼパン-1,4-ジカルボキシラートであることを確認した。分割により誘導された保持時間が小さい方の(3R,4R)-3-(3-クロロ-4-フルオロフェニル)アゼパン-1,4-ジカルボキシラートから実施例11の工程Aと同様の方法により標題化合物を得た。
MS (ESI+): [M+H-(tBu)]+ 302.2. [α]D = +10.09°±0.08° Example 25
(3R, 4R) -3- (3-Chloro-4-fluorophenyl) -4-[(methylsulfonyl) methyl] azepane fumarate
A) tert-butyl (3R, 4R) -3- (3-chloro-4-fluorophenyl) -4-[(hydroxymethyl) methyl] azepan-1-carboxylate obtained by a method similar to that in Examples 8 and 10. The resulting 1-tert-butyl 4-ethyl (3RS, 4RS) -3- (3-chloro-4-fluorophenyl) azepane-1,4-dicarboxylate was optically resolved. The longer retention time was confirmed to be (3S, 4S) -3- (3-chloro-4-fluorophenyl) azepane-1,4-dicarboxylate by X-ray crystallography. In the same manner as in Step A of Example 11 from (3R, 4R) -3- (3-chloro-4-fluorophenyl) azepane-1,4-dicarboxylate having a smaller retention time induced by resolution. The title compound was obtained.
MS (ESI +): [M + H- (tBu)] + 302.2. [Α] D = + 10.09 ° ± 0.08 °
B) tert-ブチル (3R,4R)-3-(3-クロロ-4-フルオロフェニル)-4-[(メチルスルファニル)メチル]アゼパン-1-カルボキシラート
　工程Aで得られたtert-ブチル (3R,4R)-3-(3-クロロ-4-フルオロフェニル)-4-[(ヒドロキシメチル)メチル]アゼパン-1-カルボキシラートから、実施例12の工程A、Bと同様の方法により標題化合物を得た。
1H NMR (300 MHz, CDCl3) δ 1.28-1.45 (1H, m), 1.46-1.55 (9H, m), 1.67-1.88 (1H, m), 2.01-2.21 (1H, m), 2.30-2.60 (2H, m), 2.61-2.68 (1H, m), 2.71 (3H, d, J = 5.3 Hz), 2.75-2.84 (2H, m), 2.84-3.23 (2H, m), 3.63-3.92 (2H, m), 7.06-7.20 (2H, m), 7.23-7.35 (1H, m). B) tert-butyl (3R, 4R) -3- (3-chloro-4-fluorophenyl) -4-[(methylsulfanyl) methyl] azepan-1-carboxylate tert-butyl (3R) obtained in step A , 4R) -3- (3-Chloro-4-fluorophenyl) -4-[(hydroxymethyl) methyl] azepane-1-carboxylate from the title compound in a manner similar to Example 12, Steps A and B. Obtained.
1 H NMR (300 MHz, CDCl 3 ) δ 1.28-1.45 (1H, m), 1.46-1.55 (9H, m), 1.67-1.88 (1H, m), 2.01-2.21 (1H, m), 2.30-2.60 (2H, m), 2.61-2.68 (1H, m), 2.71 (3H, d, J = 5.3 Hz), 2.75-2.84 (2H, m), 2.84-3.23 (2H, m), 3.63-3.92 (2H , m), 7.06-7.20 (2H, m), 7.23-7.35 (1H, m).
C) (3R,4R)-3-(3-クロロ-4-フルオロフェニル)-4-[(メチルスルホニル)メチル]アゼパン　フマル酸塩
　実施例8の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 320.3. C) (3R, 4R) -3- (3-Chloro-4-fluorophenyl) -4-[(methylsulfonyl) methyl] azepan fumarate The title compound was obtained in the same manner as in Step B of Example 8. It was.
MS (ESI +): [M + H] + 320.3.
実施例26
1-{[(3R,4R)-3-(3-クロロ-4-フルオロフェニル)アゼパン-4-イル]メチル}尿素　塩酸塩
A) tert-ブチル (3R,4R)-3-(アミノメチル)-4-(3-クロロ-4-フルオロフェニル)アゼパン-1-カルボキシラート
　実施例25の工程Aで得られたtert-ブチル(3R,4R)-3-(3-クロロ-4-フルオロフェニル)-4-[(ヒドロキシメチル)メチル]アゼパン-1-カルボキシラートから、実施例18の工程A及びBと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H-(tBu)]+ 301.2. [α]D = +8.44°±0.08° Example 26
1-{[(3R, 4R) -3- (3-Chloro-4-fluorophenyl) azepan-4-yl] methyl} urea hydrochloride
A) tert-butyl (3R, 4R) -3- (aminomethyl) -4- (3-chloro-4-fluorophenyl) azepan-1-carboxylate tert-butyl obtained in Step A of Example 25 ( 3R, 4R) -3- (3-Chloro-4-fluorophenyl) -4-[(hydroxymethyl) methyl] azepane-1-carboxylate from the title compound in a manner similar to Example 18, Steps A and B. A compound was obtained.
MS (ESI +): [M + H- (tBu)] + 301.2. [Α] D = + 8.44 ° ± 0.08 °
B) tert-ブチル (3R,4R)-4-[(カルバモイルアミノ)メチル]-3-(3-クロロ-4-フルオロフェニル)アゼパン-1-カルボキシラート
　tert-ブチル (3R,4R)-3-(アミノメチル)-4-(3-クロロ-4-フルオロフェニル)アゼパン-1-カルボキシラート(200 mg)のTHF(3.5 mL)溶液にトリメチルシリルイソシアネート(0.11 mL)を加え、室温で3日間撹拌した。反応混合液を酢酸エチルで希釈後、水および飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(174 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.22-1.37 (1H, m), 1.47 (9H, m), 1.60-1.90 (3H, m), 1.90-2.18 (2H, m), 2.45-3.21 (4H, m), 3.51-3.89 (2H, m), 4.34 (2H, d, J = 4.5 Hz), 4.53-4.82 (1H, m), 6.99-7.14 (2H, m), 7.21-7.34 (1H, m). B) tert-butyl (3R, 4R) -4-[(carbamoylamino) methyl] -3- (3-chloro-4-fluorophenyl) azepan-1-carboxylate tert-butyl (3R, 4R) -3- Trimethylsilyl isocyanate (0.11 mL) was added to a solution of (aminomethyl) -4- (3-chloro-4-fluorophenyl) azepan-1-carboxylate (200 mg) in THF (3.5 mL), and the mixture was stirred at room temperature for 3 days. . The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (174 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.22-1.37 (1H, m), 1.47 (9H, m), 1.60-1.90 (3H, m), 1.90-2.18 (2H, m), 2.45-3.21 (4H , m), 3.51-3.89 (2H, m), 4.34 (2H, d, J = 4.5 Hz), 4.53-4.82 (1H, m), 6.99-7.14 (2H, m), 7.21-7.34 (1H, m ).
C) 1-{[(3R,4R)-3-(3-クロロ-4-フルオロフェニル)アゼパン-4-イル]メチル}尿素　塩酸塩
　tert-ブチル (3R,4R)-4-[(カルバモイルアミノ)メチル]-3-(3-クロロ-4-フルオロフェニル)アゼパン-1-カルボキシラートから、実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 300.4. C) 1-{[(3R, 4R) -3- (3-Chloro-4-fluorophenyl) azepan-4-yl] methyl} urea hydrochloride tert-butyl (3R, 4R) -4-[(carbamoylamino ) Methyl] -3- (3-chloro-4-fluorophenyl) azepane-1-carboxylate, and the title compound was obtained in the same manner as in Step B of Example 1.
MS (ESI +): [M + H] + 300.4.
実施例27
[(3S,4S)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]メタノール　塩酸塩
A) 1-tert-ブチル 4-エチル (3S,4S)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート
　実施例10の工程Bで得られた1-tert-ブチル 4-エチル (3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート(20 g)を光学分割に付し(CHIRALPAK AD、溶出液：ヘキサン/2-プロパノール = 95:5 (v/v))、1-tert-ブチル 4-エチル (3S,4S)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート(保持時間小: 10 g)と1-tert-ブチル4-エチル (3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート(保持時間大: 9.8 g)をそれぞれ得た。
　保持時間大の絶対配置はX線構造解析より(3R, 4R)-体と決定した。
保持時間小: MS (ESI+): [M+H(-tBu)]+ 360.1., >99.9% ee
保持時間大: MS (ESI+): [M+H(-tBu)]+ 360.1., 99.9% ee Example 27
[(3S, 4S) -3- (3,4-Dichlorophenyl) azepan-4-yl] methanol hydrochloride
A) 1-tert-butyl 4-ethyl (3S, 4S) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate 1-tert-butyl 4 obtained in Step B of Example 10 -Ethyl (3RS, 4RS) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate (20 g) was subjected to optical resolution (CHIRALPAK AD, eluent: hexane / 2-propanol = 95 : 5 (v / v)), 1-tert-butyl 4-ethyl (3S, 4S) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate (low retention time: 10 g) 1-tert-butyl 4-ethyl (3R, 4R) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate (large retention time: 9.8 g) was obtained.
The absolute configuration with a long retention time was determined to be (3R, 4R) -body by X-ray structural analysis.
Low retention time: MS (ESI +): [M + H (-tBu)] + 360.1.,> 99.9% ee
Long retention time: MS (ESI +): [M + H (-tBu)] + 360.1., 99.9% ee
B) tert-ブチル (3S,4S)-3-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラート
 
　1-tert-ブチル 4-エチル (3S,4S)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート(保持時間小)から実施例11の工程Aと同様の方法で表題化合物を得た。
MS (ESI+): [M+H]+ 274.3. B) tert-butyl (3S, 4S) -3- (3,4-dichlorophenyl) -4- (hydroxymethyl) azepan-1-carboxylate
1-tert-Butyl 4-ethyl (3S, 4S) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate (with a short retention time) was used in the same manner as in Step A of Example 11. A compound was obtained.
MS (ESI +): [M + H] + 274.3.
C) [(3S,4S)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]メタノール　塩酸塩
　tert-ブチル (3S,4S)-3-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラートから、実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 274.3. C) [(3S, 4S) -3- (3,4-Dichlorophenyl) azepan-4-yl] methanol hydrochloride tert-butyl (3S, 4S) -3- (3,4-dichlorophenyl) -4- (hydroxy The title compound was obtained from methyl) azepan-1-carboxylate in the same manner as in Step B of Example 1.
MS (ESI +): [M + H] + 274.3.
実施例28
[(3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]メタノール　塩酸塩
A) tert-ブチル (3R,4R)-3-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラート
　実施例27の工程Aで得られた1-tert-ブチル 4-エチル (3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラートから、実施例11の工程Aと同様の方法により、標題化合物を得た。
1H NMR (300 MHz, CDCl3) δ 1.14-1.27 (1H, m), 1.34-1.43 (1H, m), 1.46 (9H, m), 1,62-1.86 (2H, m), 2.01-2.21 (2H, m), 2.54-2.79 (1H, m), 2.84-3.29 (3H, m), 3.42 (1H, d, J = 10.2 Hz), 3.55-3.93 (2H, m), 6.97-7.14 (1H, m), 7.27-7.45 (2H, m). Example 28
[(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] methanol hydrochloride
A) tert-Butyl (3R, 4R) -3- (3,4-Dichlorophenyl) -4- (hydroxymethyl) azepan-1-carboxylate 1-tert-butyl 4-obtained in Step 27 of Example 27 The title compound was obtained from ethyl (3R, 4R) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate in the same manner as in Step A of Example 11.
1 H NMR (300 MHz, CDCl 3 ) δ 1.14-1.27 (1H, m), 1.34-1.43 (1H, m), 1.46 (9H, m), 1,62-1.86 (2H, m), 2.01-2.21 (2H, m), 2.54-2.79 (1H, m), 2.84-3.29 (3H, m), 3.42 (1H, d, J = 10.2 Hz), 3.55-3.93 (2H, m), 6.97-7.14 (1H , m), 7.27-7.45 (2H, m).
B) [(3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]メタノール　塩酸塩
　tert-ブチル (3R,4R)-3-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラートから、実施例1の工程Bと同様の方法により、標題化合物を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.55-2.08 (5H, m), 2.78-3.27 (6H, m), 3.36-3.52 (1H, m), 4.54 (1H, br s), 7.22-7.34 (1H, m), 7.54-7.68 (2H, m), 9.27 (2H, br s). B) [(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] methanol hydrochloride tert-butyl (3R, 4R) -3- (3,4-dichlorophenyl) -4- (hydroxy The title compound was obtained from methyl) azepan-1-carboxylate in the same manner as in Step B of Example 1.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.55-2.08 (5H, m), 2.78-3.27 (6H, m), 3.36-3.52 (1H, m), 4.54 (1H, br s), 7.22- 7.34 (1H, m), 7.54-7.68 (2H, m), 9.27 (2H, br s).
実施例29
（３ＲＳ，４ＲＳ）－３－（３，４－ジクロロフェニル）－４－［（メチルスルホニル）メチル］アゼパンの光学活性体の塩酸塩：
(3R*,4R*)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン　塩酸塩（保持時間が小さい方のBoc体から誘導）
A) tert-ブチル (3R*,4R*)-4-(3,4-ジクロロフェニル)-3-[(メチルスルホニル)メチル]アゼパン-1-カルボキシラート（保持時間小）
　実施例12の工程A、Bで得られたtert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン-1-カルボキシラート(397 mg)を光学分割に付し(CHIRALPAK AD、溶出液：ヘキサン/エタノール = 9:1 (v/v))、tert-ブチル (3R*,4R*)-4-(3,4-ジクロロフェニル)-3-[(メチルスルホニル)メチル]アゼパン-1-カルボキシラート(保持時間小: 187 mg)とtert-ブチル (3R*,4R*)-4-(3,4-ジクロロフェニル)-3-[(メチルスルホニル)メチル]アゼパン-1-カルボキシラート(保持時間大: 193 mg)をそれぞれ得た。
保持時間小: MS (ESI+): [M+H(-tBu)]+ 380.3., >99.9% ee.
保持時間大: MS (ESI+): [M+H(-tBu)]+ 380.3., >99.9% ee. Example 29
Hydrochloride of optically active form of (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane:
(3R * , 4R * ) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride (derived from the Boc form with the smaller retention time)
A) tert-butyl (3R * , 4R * )-4- (3,4-dichlorophenyl) -3-[(methylsulfonyl) methyl] azepan-1-carboxylate (low retention time)
Tert-Butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan-1-carboxylate (397 mg) obtained in steps A and B of Example 12 Was subjected to optical resolution (CHIRALPAK AD, eluent: hexane / ethanol = 9: 1 (v / v)), tert-butyl (3R * , 4R * )-4- (3,4-dichlorophenyl) -3- [(Methylsulfonyl) methyl] azepane-1-carboxylate (low retention time: 187 mg) and tert-butyl (3R * , 4R * )-4- (3,4-dichlorophenyl) -3-[(methylsulfonyl) Methyl] azepan-1-carboxylate (large retention time: 193 mg) was obtained.
Low retention time: MS (ESI +): [M + H (-tBu)] + 380.3.,> 99.9% ee.
Long retention time: MS (ESI +): [M + H (-tBu)] + 380.3.,> 99.9% ee.
B) (3R*,4R*)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン　塩酸塩（保持時間が小さい方のBoc体から誘導）
　tert-ブチル (3R*,4R*)-4-(3,4-ジクロロフェニル)-3-[(メチルスルホニル)メチル]アゼパン-1-カルボキシラート (保持時間小)(171 mg)に 2 N 塩化水素-エタノール溶液(4.7 mL)を加え、室温で6時間撹拌した。溶媒を減圧下留去し、残渣をエタノール－イソプロピルエーテルから結晶化することにより、標題化合物(121 mg)を無色結晶として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.76-1.98 (3H, m), 2.26-2.69 (2H, m), 2.84 (3H, s), 3.01-3.18 (5H, m), 3.34-3.47 (2H, m), 7.33 (1H, dd, J = 8.4, 1.8 Hz), 7.62-7.66 (2H, m), 9.30 (2H, br s). MS (ESI+): [M+H]+ 336.2. B) (3R * , 4R * ) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride (derived from Boc form with smaller retention time)
tert-butyl (3R * , 4R * ) -4- (3,4-dichlorophenyl) -3-[(methylsulfonyl) methyl] azepane-1-carboxylate (short retention time) (171 mg) with 2 N hydrogen chloride -An ethanol solution (4.7 mL) was added, and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-isopropyl ether to give the title compound (121 mg) as colorless crystals.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.76-1.98 (3H, m), 2.26-2.69 (2H, m), 2.84 (3H, s), 3.01-3.18 (5H, m), 3.34-3.47 (2H, m), 7.33 (1H, dd, J = 8.4, 1.8 Hz), 7.62-7.66 (2H, m), 9.30 (2H, br s). MS (ESI +): [M + H] + 336.2.
実施例30
（３ＲＳ，４ＲＳ）－３－（３，４－ジクロロフェニル）－４－［（メチルスルホニル）メチル］アゼパンの光学活性体の塩酸塩：
(3R*,4R*)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)メチル]アゼパン　塩酸塩（保持時間が大きい方のBoc体から誘導）
　実施例29、工程Aで得たtert-ブチル (3R*,4R*)-4-(3,4-ジクロロフェニル)-3-[(メチルスルホニル)メチル]アゼパン-1-カルボキシラート (保持時間大)(175 mg)に 2 N 塩化水素-エタノール溶液(4.7 mL)を加え、室温で6時間撹拌した。溶媒を減圧下留去し、残渣をエタノール－イソプロピルエーテルから結晶化することにより、標題化合物(120 mg)を無色結晶として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.76-1.98 (3H, m), 2.27-2.69 (2H, m), 2.83 (3H, s), 3.08-3.15 (5H, m), 3.39-3.48 (2H, m), 7.33 (1H, dd, J = 8.4, 1.8 Hz), 7.62-7.66 (2H, m), 9.32 (2H, br s). MS (ESI+): [M+H]+ 336.2. Example 30
Hydrochloride of optically active form of (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane:
(3R * , 4R * ) -3- (3,4-Dichlorophenyl) -4-[(methylsulfonyl) methyl] azepan hydrochloride (derived from the Boc body with the longer retention time)
Tert-butyl (3R * , 4R * )-4- (3,4-dichlorophenyl) -3-[(methylsulfonyl) methyl] azepan-1-carboxylate obtained in Example 29, Step A (large retention time) 2N Hydrogen chloride-ethanol solution (4.7 mL) was added to (175 mg), and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-isopropyl ether to give the title compound (120 mg) as colorless crystals.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.76-1.98 (3H, m), 2.27-2.69 (2H, m), 2.83 (3H, s), 3.08-3.15 (5H, m), 3.39-3.48 (2H, m), 7.33 (1H, dd, J = 8.4, 1.8 Hz), 7.62-7.66 (2H, m), 9.32 (2H, br s). MS (ESI +): [M + H] + 336.2.
実施例31
N-[(3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]メタンスルホンアミド　塩酸塩
A) (3R,4R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)アゼパン-4-カルボン酸
　実施例27の工程Aで得られた1-tert-ブチル 4-エチル (3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-1,4-ジカルボキシラート(2.0 g)のエタノール(50 mL)溶液に水酸化ナトリウム水溶液(15 mL)を加え、50℃で1晩撹拌した。反応混合液を2N塩酸で中和し、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄して無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣をイソプロピルエーテルで結晶化し標題化合物(1.36 g)を得た。
MS (ESI+): [M-H]+ 386.0. Example 31
N-[(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] methanesulfonamide hydrochloride
A) (3R, 4R) -1- (tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) azepane-4-carboxylic acid 1-tert-butyl 4-ethyl obtained in Step A of Example 27 To a solution of (3R, 4R) -3- (3,4-dichlorophenyl) azepane-1,4-dicarboxylate (2.0 g) in ethanol (50 mL) was added aqueous sodium hydroxide (15 mL) at 50 ° C. Stir overnight. The reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl ether to give the title compound (1.36 g).
MS (ESI +): [MH] + 386.0.
B) tert-ブチル (3R,4R)-4-アミノ-3-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート
　(3R,4R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)アゼパン-4-カルボン酸のトルエン(10 mL)溶液にトリエチルアミン(0.18 mL)及びジフェニルホスホリルアジド(0.42 mL)を加え、90℃で30分間撹拌した。反応溶液を室温に冷却後、8N水酸化ナトリウム水溶液(10 mL)に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄して無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、標題化合物(1.36 g)を得た。得られた粗生成物は精製することなく次の反応に使用した。
MS (ESI+): [M+H(-tBu)]+ 303.1. B) tert-butyl (3R, 4R) -4-amino-3- (3,4-dichlorophenyl) azepan-1-carboxylate (3R, 4R) -1- (tert-butoxycarbonyl) -3- (3, Triethylamine (0.18 mL) and diphenylphosphoryl azide (0.42 mL) were added to a solution of 4-dichlorophenyl) azepane-4-carboxylic acid in toluene (10 mL), and the mixture was stirred at 90 ° C. for 30 minutes. The reaction solution was cooled to room temperature, poured into 8N aqueous sodium hydroxide solution (10 mL), and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.36 g). The obtained crude product was used for the next reaction without purification.
MS (ESI +): [M + H (-tBu)] + 303.1.
C) tert-ブチル (3R,4R)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)アミノ]アゼパン-1-カルボキシラート
　tert-ブチル (3R,4R)-4-アミノ-3-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート(148 mg)のTHF(4 mL)溶液に、氷冷下トリエチルアミン(0.17 mL)およびメタンスルホニルクロリド(0.06 mL)を加え、室温で2時間撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(108 mg)を得た。
1H NMR (300 MHz, CDCl3) δ1.48 (9H, s), 1.63 (1H, br s), 1.64-1.88 (1H, m), 1.93-2.14 (1H, m), 2.21-2.32 (1H, m), 2.36 (3H, d, J = 13.9 Hz), 2.56-2.83 (1H, m), 2.88-3.21 (2H, m), 3.42-3.59 (1H, m), 3.60-3.94 (2H, m), 4.06-4.19 (1H, m), 7.10 (1H, dd, J = 15.3, 8.5 Hz), 7.29-7.50 (2H, m). C) tert-butyl (3R, 4R) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) amino] azepan-1-carboxylate tert-butyl (3R, 4R) -4-amino-3 To a solution of-(3,4-dichlorophenyl) azepane-1-carboxylate (148 mg) in THF (4 mL) was added triethylamine (0.17 mL) and methanesulfonyl chloride (0.06 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Stir. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and 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 (108 mg).
1 H NMR (300 MHz, CDCl 3 ) δ1.48 (9H, s), 1.63 (1H, br s), 1.64-1.88 (1H, m), 1.93-2.14 (1H, m), 2.21-2.32 (1H , m), 2.36 (3H, d, J = 13.9 Hz), 2.56-2.83 (1H, m), 2.88-3.21 (2H, m), 3.42-3.59 (1H, m), 3.60-3.94 (2H, m ), 4.06-4.19 (1H, m), 7.10 (1H, dd, J = 15.3, 8.5 Hz), 7.29-7.50 (2H, m).
D) N-[(3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]メタンスルホンアミド　塩酸塩
　tert-ブチル (3R,4R)-3-(3,4-ジクロロフェニル)-4-[(メチルスルホニル)アミノ]アゼパン-1-カルボキシラートから実施例1の工程Bと同様の方法により、標題化合物を得た。
1H NMR (300 MHz, CDCl3) δ1.74-2.01 (3H, m), 2.08-2.20 (1H, m), 2.26 (3H, s), 2.93-3.23 (4H, m), 3.41-3.67 (2H, m), 7.36 (1H, dd, J = 8.3, 1.9 Hz), 7.43 (1H, d, J = 9.0 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.68 (1H, d, J = 1.9 Hz), 9.34 (2H, be s). MS (ESI+): [M+H]+ 338.9. D) N-[(3R, 4R) -3- (3,4-dichlorophenyl) azepan-4-yl] methanesulfonamide hydrochloride tert-butyl (3R, 4R) -3- (3,4-dichlorophenyl)- The title compound was obtained from 4-[(methylsulfonyl) amino] azepane-1-carboxylate in the same manner as in Step B of Example 1.
1 H NMR (300 MHz, CDCl 3 ) δ1.74-2.01 (3H, m), 2.08-2.20 (1H, m), 2.26 (3H, s), 2.93-3.23 (4H, m), 3.41-3.67 ( 2H, m), 7.36 (1H, dd, J = 8.3, 1.9 Hz), 7.43 (1H, d, J = 9.0 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.68 (1H, d, J = 1.9 Hz), 9.34 (2H, be s). MS (ESI +): [M + H] + 338.9.
実施例32
N-[(3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]-2-メトキシアセトアミド　塩酸塩
A) tert-ブチル (3R,4R)-3-(3,4-ジクロロフェニル)-4-[(メトキシアセチル)アミノ]アゼパン-1-カルボキシラート
　実施例31の工程Bで得られたtert-ブチル(3R,4R)-4-アミノ-3-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート(132 mg)のTHF(3 mL)溶液に、トリエチルアミン(0.15 mL)およびメトキシアセチルクロリド(0.07 mL)を加え、1晩撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(92 mg)を得た。
1H NMR (300 MHz, CDCl3) δ1.43-1.58 (10H, m), 1.72-1.96 (1H, m), 1.96-2.17 (2H, m), 2.67-3.17 (3H, m), 3.20 (3H, d, J = 7.9 Hz), 3.46-3.95 (4H, m), 4.15-4.28 (1H, m), 6.29 (1H, d, J = 8.7 Hz), 7.09 (1H, ddd, J = 17.7, 8.3, 1.9 Hz), 7.29-7.43 (2H, m). Example 32
N-[(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] -2-methoxyacetamide hydrochloride
A) tert-butyl (3R, 4R) -3- (3,4-dichlorophenyl) -4-[(methoxyacetyl) amino] azepan-1-carboxylate tert-butyl obtained in Step B of Example 31 ( 3R, 4R) -4-amino-3- (3,4-dichlorophenyl) azepane-1-carboxylate (132 mg) in THF (3 mL) was added to triethylamine (0.15 mL) and methoxyacetyl chloride (0.07 mL). And stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and 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 (92 mg).
1 H NMR (300 MHz, CDCl 3 ) δ1.43-1.58 (10H, m), 1.72-1.96 (1H, m), 1.96-2.17 (2H, m), 2.67-3.17 (3H, m), 3.20 ( 3H, d, J = 7.9 Hz), 3.46-3.95 (4H, m), 4.15-4.28 (1H, m), 6.29 (1H, d, J = 8.7 Hz), 7.09 (1H, ddd, J = 17.7, 8.3, 1.9 Hz), 7.29-7.43 (2H, m).
B) N-[(3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]-2-メトキシアセトアミド　塩酸塩
　tert-ブチル (3R,4R)-3-(3,4-ジクロロフェニル)-4-[(メトキシアセチル)アミノ]アゼパン-1-カルボキシラートから実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 331.1. B) N-[(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] -2-methoxyacetamide hydrochloride tert-butyl (3R, 4R) -3- (3,4-dichlorophenyl ) -4-[(Methoxyacetyl) amino] azepane-1-carboxylate gave the title compound in the same manner as in Step B of Example 1.
MS (ESI +): [M + H] + 331.1.
実施例33
N-[(3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]アセトアミド　塩酸塩
A) tert-ブチル (3R,4R)-4-(アセチルアミノ)-3-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート
　実施例31の工程Bで得られたtert-ブチル(3R,4R)-4-アミノ-3-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラート(150 mg)のTHF(4 mL)溶液に、トリエチルアミン(0.18 mL)およびアセチルクロリド(0.06 mL)を加え、室温で1時間撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(96 mg)を得た。
1H NMR (300 MHz, CDCl3) δ1.37-1.56 (9H, m), 1.70-1.89 (2H, m), 1.94-2.19 (4H, m), 2.62-3.01 (2H, m), 3.05-3.22 (1H, m), 3.60-3.93 (2H, m), 4.05-4.25 (2H, m), 5.20 (1H, d, J = 8.7 Hz), 7.01-7.17 (1H, m), 7.29-7.43 (2H, m). Example 33
N-[(3R, 4R) -3- (3,4-Dichlorophenyl) azepan-4-yl] acetamide hydrochloride
A) tert-butyl (3R, 4R) -4- (acetylamino) -3- (3,4-dichlorophenyl) azepan-1-carboxylate tert-butyl (3R, 4R) obtained in Step B of Example 31 ) -4-Amino-3- (3,4-dichlorophenyl) azepane-1-carboxylate (150 mg) in THF (4 mL) was added triethylamine (0.18 mL) and acetyl chloride (0.06 mL) at room temperature. For 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and 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 (96 mg).
1 H NMR (300 MHz, CDCl 3 ) δ1.37-1.56 (9H, m), 1.70-1.89 (2H, m), 1.94-2.19 (4H, m), 2.62-3.01 (2H, m), 3.05- 3.22 (1H, m), 3.60-3.93 (2H, m), 4.05-4.25 (2H, m), 5.20 (1H, d, J = 8.7 Hz), 7.01-7.17 (1H, m), 7.29-7.43 ( 2H, m).
B) N-[(3R,4R)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]アセトアミド　塩酸塩
　tert-ブチル (3R,4R)-4-(アセチルアミノ)-3-(3,4-ジクロロフェニル)アゼパン-1-カルボキシラートから実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 301.1. B) N-[(3R, 4R) -3- (3,4-dichlorophenyl) azepan-4-yl] acetamide hydrochloride tert-butyl (3R, 4R) -4- (acetylamino) -3- (3, The title compound was obtained from 4-dichlorophenyl) azepan-1-carboxylate in the same manner as in Step B of Example 1.
MS (ESI +): [M + H] + 301.1.
実施例34
(3R,4R)-3-(3,4-ジクロロフェニル)-N-メチルアゼパン-4-カルボキサミド　塩酸塩
A) tert-ブチル (3R,4R)-3-(3,4-ジクロロフェニル)-4-(メチルカルバモイル)アゼパン-1-カルボキシラート
　実施例31の工程Aで得られた(3R,4R)-1-(tert-ブトキシカルボニル)-3-(3,4-ジクロロフェニル)アゼパン-4-カルボン酸(200 mg)と40%メチルアミン-メタノール溶液(40 mg)のDMF(5 mL)溶液に、1-ヒドロキシベンゾトリアゾール(77 mg)および1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド　塩酸塩(109 mg)を加え、室温で1晩撹拌した。反応混合液を酢酸エチルで希釈し、飽和重曹水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(179 mg)を得た。
1H NMR (300 MHz, CDCl3) δ1.47 (9H, s), 1.64-2.31 (5H, m), 2.57 (3H, d, J = 4.5 Hz), 2.91-3.28 (3H, m), 3.61-4.00 (2H, m), 5.09 (1H, br s), 6.97-7.11 (1H, m), 7.22-7.43 (2H, m). Example 34
(3R, 4R) -3- (3,4-Dichlorophenyl) -N-methylazepan-4-carboxamide hydrochloride
A) tert-butyl (3R, 4R) -3- (3,4-dichlorophenyl) -4- (methylcarbamoyl) azepan-1-carboxylate (3R, 4R) -1 obtained in Step A of Example 31 In a DMF (5 mL) solution of-(tert-butoxycarbonyl) -3- (3,4-dichlorophenyl) azepane-4-carboxylic acid (200 mg) and 40% methylamine-methanol solution (40 mg), 1- Hydroxybenzotriazole (77 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (109 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and 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 (179 mg).
1 H NMR (300 MHz, CDCl 3 ) δ1.47 (9H, s), 1.64-2.31 (5H, m), 2.57 (3H, d, J = 4.5 Hz), 2.91-3.28 (3H, m), 3.61 -4.00 (2H, m), 5.09 (1H, br s), 6.97-7.11 (1H, m), 7.22-7.43 (2H, m).
B) (3R,4R)-3-(3,4-ジクロロフェニル)-N-メチルアゼパン-4-カルボキサミド　塩酸塩
　tert-ブチル (3R,4R)-3-(3,4-ジクロロフェニル)-4-(メチルカルバモイル)アゼパン-1-カルボキシラートから実施例1の工程Bと同様の方法により、標題化合物を得た。
MS (ESI+): [M+H]+ 301.0. B) (3R, 4R) -3- (3,4-Dichlorophenyl) -N-methylazepan-4-carboxamide hydrochloride tert-butyl (3R, 4R) -3- (3,4-dichlorophenyl) -4- (methyl The title compound was obtained from carbamoyl) azepan-1-carboxylate in the same manner as in Step B of Example 1.
MS (ESI +): [M + H] + 301.0.
実施例35
1-{[(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-イル]メチル}-3-メチル-1H-ピラゾール-5-カルボン酸　塩酸塩
A) tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-{[(メチルスルホニル)オキシ]メチル}アゼパン-1-カルボキシラート
　メタンスルホニルクロリド(0.132 mL, 1.71 mmol) を tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-(ヒドロキシメチル)アゼパン-1-カルボキシラート(427 mg, 1.14 mmol) とトリエチルアミン(0.318 mL, 2.28 mmol) のTHF (8 mL) 溶液に室温で加え、終夜撹拌した。反応液を減圧下濃縮した後、希炭酸水素ナトリウム水溶液を加え、エチルアセタートで抽出した。抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、減圧下で濃縮し、標題化合物(550 mg)を得た。本化合物は精製することなく、次の反応に用いた。
1H NMR (300 MHz, CDCl3) δ 1.46-1.55 (9H, m), 1.62-1.78 (2H, m), 1.80-1.91 (1H, m), 1.91-2.30 (2H, m), 2.40-2.64 (1H, m), 2.87-2.99 (3H, m), 3.03-3.42 (2H, m), 3.46-4.08 (4H, m), 7.00 (1H, dt, J = 5.6, 2.7 Hz), 7.20-7.26 (1H, m), 7.39 (1H, dd, J = 7.9, 5.7 Hz). MS (ESI+): [M+H(-tBu)]+ 395.9.  Example 35
1-{[(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl} -3-methyl-1H-pyrazole-5-carboxylic acid hydrochloride
A) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-{[(methylsulfonyl) oxy] methyl} azepan-1-carboxylate methanesulfonyl chloride (0.132 mL, 1.71 mmol) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3- (hydroxymethyl) azepane-1-carboxylate (427 mg, 1.14 mmol) and triethylamine (0.318 mL, 2.28 mmol) in THF ( 8 mL) was added to the solution at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (550 mg). This compound was used in the next reaction without purification.
1 H NMR (300 MHz, CDCl 3 ) δ 1.46-1.55 (9H, m), 1.62-1.78 (2H, m), 1.80-1.91 (1H, m), 1.91-2.30 (2H, m), 2.40-2.64 (1H, m), 2.87-2.99 (3H, m), 3.03-3.42 (2H, m), 3.46-4.08 (4H, m), 7.00 (1H, dt, J = 5.6, 2.7 Hz), 7.20-7.26 (1H, m), 7.39 (1H, dd, J = 7.9, 5.7 Hz). MS (ESI +): [M + H (-tBu)] + 395.9.
B) tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-{[5-(エトキシカルボニル)-3-メチル-1H-ピラゾール-1-イル]メチル}アゼパン-1-カルボキシラート
tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-{[3-(エトキシカルボニル)-5-メチル-1H-ピラゾール-1-イル]メチル}アゼパン-1-カルボキシラート
　実施例35の工程Aで得られたtert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-{[(メチルスルホニル)オキシ]メチル}アゼパン-1-カルボキシラート(516 mg, 1.14 mmol)のDMF(10 mL)溶液に炭酸カリウム(236 mg, 1.71 mmol)とエチル 3-メチル-1H-ピラゾール-5-カルボキシラート(193 mg, 1.25 mmol) を加え、70℃で 4.5 時間撹拌した。反応液を水で希釈した後、エチルアセタートで抽出し、抽出液を0.1M 塩酸と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、減圧下で濃縮した。残渣をカラムクロマトグラフィーで精製し、tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-{[5-(エトキシカルボニル)-3-メチル-1H-ピラゾール-1-イル]メチル}アゼパン-1-カルボキシラート(292 mg, 0.572 mmol, 50.2 %) を無色油状物として、tert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-{[3-(エトキシカルボニル)-5-メチル-1H-ピラゾール-1-イル]メチル}アゼパン-1-カルボキシラート(125 mg, 0.245 mmol, 21.48 %) をアモルファスの泡状化合物として得た。
3-メチル-5-エトキシカルボニル異性体: MS (ESI+): [M+H]+ 510.1
5-メチル-3-エトキシカルボニル異性体: MS (ESI+): [M+H]+ 510.1 B) tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-{[5- (ethoxycarbonyl) -3-methyl-1H-pyrazol-1-yl] methyl} azepan-1- Carboxylate
tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-{[3- (ethoxycarbonyl) -5-methyl-1H-pyrazol-1-yl] methyl} azepan-1-carboxylate Tert-Butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-{[(methylsulfonyl) oxy] methyl} azepane-1-carboxylate obtained in Step A of Example 35 (516 mg , 1.14 mmol) in DMF (10 mL) was added potassium carbonate (236 mg, 1.71 mmol) and ethyl 3-methyl-1H-pyrazole-5-carboxylate (193 mg, 1.25 mmol), and the mixture was 4.5 hours at 70 ° C. Stir. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with 0.1 M hydrochloric acid and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography and tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-{[5- (ethoxycarbonyl) -3-methyl-1H-pyrazol-1-yl ] Methyl} azepane-1-carboxylate (292 mg, 0.572 mmol, 50.2%) as a colorless oil, tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-{[3- (Ethoxycarbonyl) -5-methyl-1H-pyrazol-1-yl] methyl} azepan-1-carboxylate (125 mg, 0.245 mmol, 21.48%) was obtained as an amorphous foamy compound.
3-Methyl-5-ethoxycarbonyl isomer: MS (ESI +): [M + H] + 510.1
5-Methyl-3-ethoxycarbonyl isomer: MS (ESI +): [M + H] + 510.1
C) 1-{[(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-イル]メチル}-3-メチル-1H-ピラゾール-5-カルボン酸 塩酸塩
　実施例35の工程Bで得られたtert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-{[5-(エトキシカルボニル)-3-メチル-1H-ピラゾール-1-イル]メチル}アゼパン-1-カルボキシラート(292 mg, 0.57 mmol)のエタノール(4 mL)溶液に2M 水酸化ナトリウム水溶液(0.858 mL, 1.72 mmol) を加え、50℃で終夜撹拌した。反応液を1M 塩酸で中和した後、エチルアセタートで抽出し、抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、減圧下濃縮した。残渣に4M 塩化水素エチルアセタート溶液(4 mL, 16.00 mmol)を加え、1時間撹拌した。反応液を減圧下濃縮した後、残渣にジエチルエーテルを加え、固体をろ取して、標題化合物(218 mg, 0.521 mmol, 91 %) を白色の固体として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.71-2.03 (4H, m), 2.14 (3H, s), 2.60-2.76 (1H, m), 2.78-3.18 (5H, m), 4.13 (1H, dd, J = 13.8, 4.7 Hz), 4.29 (1H, dd, J = 13.6, 9.4 Hz), 6.53 (1H, s), 7.28 (1H, dd, J = 8.3, 1.9 Hz), 7.49-7.60 (2H, m), 9.13 (1H, brs), 9.34 (1H, brs), 13.21 (1H, brs). MS (ESI+): [M+H]+ 382.0. C) 1-{[(3RS, 4SR) -4- (3,4-Dichlorophenyl) azepan-3-yl] methyl} -3-methyl-1H-pyrazole-5-carboxylic acid hydrochloride Step B of Example 35 Tert-butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-{[5- (ethoxycarbonyl) -3-methyl-1H-pyrazol-1-yl] methyl} azepane- To a solution of 1-carboxylate (292 mg, 0.57 mmol) in ethanol (4 mL) was added 2M aqueous sodium hydroxide solution (0.858 mL, 1.72 mmol), and the mixture was stirred at 50 ° C. overnight. The reaction mixture was neutralized with 1M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To the residue was added 4M hydrogen chloride ethyl acetate solution (4 mL, 16.00 mmol), and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the solid was collected by filtration to give the title compound (218 mg, 0.521 mmol, 91%) as a white solid.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.71-2.03 (4H, m), 2.14 (3H, s), 2.60-2.76 (1H, m), 2.78-3.18 (5H, m), 4.13 (1H , dd, J = 13.8, 4.7 Hz), 4.29 (1H, dd, J = 13.6, 9.4 Hz), 6.53 (1H, s), 7.28 (1H, dd, J = 8.3, 1.9 Hz), 7.49-7.60 ( 2H, m), 9.13 (1H, brs), 9.34 (1H, brs), 13.21 (1H, brs). MS (ESI +): [M + H] + 382.0.
実施例36
1-{[(3RS,4SR)-4-(3,4-ジクロロフェニル)アゼパン-3-イル]メチル}-5-メチル-1H-ピラゾール-3-カルボン酸　塩酸塩
　実施例35の工程Cと同様の工程により、実施例35の工程Bで得られたtert-ブチル (3RS,4SR)-4-(3,4-ジクロロフェニル)-3-{[3-(エトキシカルボニル)-5-メチル-1H-ピラゾール-1-イル]メチル}アゼパン-1-カルボキシラートから標題化合物(98 mg) を白色固体として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.74-1.99 (4H, m), 2.01 (3H, s), 2.65-2.79 (1H, m), 2.79-2.92 (1H, m), 2.97-3.23 (4H, m), 3.73 (1H, dd, J = 14.4, 3.8 Hz), 3.99 (1H, dd, J = 14.2, 9.6 Hz), 6.41 (1H, s), 7.35 (1H, dd, J = 8.3, 1.9 Hz), 7.59-7.66 (2H, m), 9.19 (2H, brs), 12.55 (1H, brs). MS (ESI+): [M+H]+ 382.1.  Example 36
1-{[(3RS, 4SR) -4- (3,4-dichlorophenyl) azepan-3-yl] methyl} -5-methyl-1H-pyrazole-3-carboxylic acid hydrochloride As in Step C of Example 35 Tert-Butyl (3RS, 4SR) -4- (3,4-dichlorophenyl) -3-{[3- (ethoxycarbonyl) -5-methyl-1H-- obtained in Step B of Example 35 The title compound (98 mg) was obtained as a white solid from pyrazol-1-yl] methyl} azepan-1-carboxylate.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.74-1.99 (4H, m), 2.01 (3H, s), 2.65-2.79 (1H, m), 2.79-2.92 (1H, m), 2.97-3.23 (4H, m), 3.73 (1H, dd, J = 14.4, 3.8 Hz), 3.99 (1H, dd, J = 14.2, 9.6 Hz), 6.41 (1H, s), 7.35 (1H, dd, J = 8.3 , 1.9 Hz), 7.59-7.66 (2H, m), 9.19 (2H, brs), 12.55 (1H, brs). MS (ESI +): [M + H] + 382.1.
実施例37
(1RS)-1-[(3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]エタン-1,2-ジオール　塩酸塩
A) tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-ホルミルアゼパン-1-カルボキシラート
　tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラートのアセトニトリル(20 mL)溶液へデス-マーチン試薬(5.4 g)を加え、0℃にて2時間撹拌した。反応混合物へ飽和重曹水を加えた後、酢酸エチルにて抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー (展開溶媒；ヘキサン：酢酸エチル)にて精製し、標題化合物(2.73 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.48 (9H, s), 1.56-1.66 (1H, m), 1.69-1.91 (1H, m), 2.06-2.30 (2H, m), 2.69 (1H, t, J = 10.0 Hz), 2.86-3.37 (3H, m), 3.58-4.02 (2H, m), 6.97-7.17 (1H, m), 7.28-7.45 (2H, m), 9.15-9.72 (1H, m). Example 37
(1RS) -1-[(3RS, 4RS) -3- (3,4-Dichlorophenyl) azepan-4-yl] ethane-1,2-diol hydrochloride
A) tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-formylazepane-1-carboxylate tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl)- Dess-Martin reagent (5.4 g) was added to a solution of 4- (hydroxymethyl) azepan-1-carboxylate in acetonitrile (20 mL), and the mixture was stirred at 0 ° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate) to obtain the title compound (2.73 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.48 (9H, s), 1.56-1.66 (1H, m), 1.69-1.91 (1H, m), 2.06-2.30 (2H, m), 2.69 (1H, t , J = 10.0 Hz), 2.86-3.37 (3H, m), 3.58-4.02 (2H, m), 6.97-7.17 (1H, m), 7.28-7.45 (2H, m), 9.15-9.72 (1H, m ).
B) tert-ブチル (3RS,4SR)-3-(3,4-ジクロロフェニル)-4-ビニルアゼパン-1-カルボキシラート
　窒素雰囲気下-78℃にて、メチルトリフェニルホスホニウム ブロミド(3.4 g)のテトラヒドロフラン(10 mL)溶液へn-ブチルリチウム(1.6 Mのヘキサン溶液、6.4 mL)を加え、0℃にて30分撹拌した。同温にて反応混合物へ(3RS,4RS)-tert-ブチル 3-(3,4-ジクロロフェニル)-4-ホルミルアゼパン-1-カルボキシラート(2.7 g)のテトラヒドロフラン(10 mL)溶液を滴下した。反応混合物を0℃にて20分撹拌後、室温にて終夜撹拌した。反応混合物へ水を加えた後、酢酸エチルにて抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー (展開溶媒；ヘキサン：酢酸エチル)にて精製し、標題化合物(1.98 g) を得た。
1H NMR (300 MHz, CDCl3) δ 1.38-1.59 (10H, m), 1.63-1.98 (2H, m), 2.29 (2H, brs), 2.48-2.79 (1H, m), 2.85-3.30 (2H, m), 3.49-3.99 (2H, m), 4.64-4.90 (2H, m), 5.32-5.67 (1H, m), 6.87-7.09 (1H, m), 7.17-7.26 (1H, m), 7.34 (1H, t, J = 8.3 Hz). MS (ESI+): [M+H-(tBu)]+ 314.1. B) tert-Butyl (3RS, 4SR) -3- (3,4-dichlorophenyl) -4-vinylazepane-1-carboxylate Methyltriphenylphosphonium bromide (3.4 g) in tetrahydrofuran (3.4 g) at -78 ° C under nitrogen atmosphere 10 mL) solution was added n-butyllithium (1.6 M hexane solution, 6.4 mL), and the mixture was stirred at 0 ° C. for 30 minutes. A solution of (3RS, 4RS) -tert-butyl 3- (3,4-dichlorophenyl) -4-formylazepan-1-carboxylate (2.7 g) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture at the same temperature. . The reaction mixture was stirred at 0 ° C. for 20 minutes and then at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate) to obtain the title compound (1.98 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.38-1.59 (10H, m), 1.63-1.98 (2H, m), 2.29 (2H, brs), 2.48-2.79 (1H, m), 2.85-3.30 (2H , m), 3.49-3.99 (2H, m), 4.64-4.90 (2H, m), 5.32-5.67 (1H, m), 6.87-7.09 (1H, m), 7.17-7.26 (1H, m), 7.34 (1H, t, J = 8.3 Hz). MS (ESI +): [M + H- (tBu)] + 314.1.
C) tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(1RS)-1,2-ジヒドロキシエチル]アゼパン-1-カルボキシラートおよびtert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(1SR)-1,2-ジヒドロキシエチル]アゼパン-1-カルボキシラートの混合物（ジアステレオマー混合物）
　tert-ブチル(3RS,4SR)-3-(3,4-ジクロロフェニル)-4-ビニルアゼパン-1-カルボキシラート(2.0 g)と4-メチルモルホリン-N-オキシド(1.5 g)のアセトニトリル/アセトン/水(v/v/v = 1/1/1, 15 mL)混合溶液へ酸化オスミウム(VIII)固定化触媒I(和光純薬cat.153-02581、1.5 g) を加え、室温にて2時間撹拌した。触媒をセライトにて除去した後、残渣へ飽和塩化アンモニウム水溶液を加えた。反応混合物を酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(展開溶媒；ヘキサン：酢酸エチル)にて精製し、標題化合物(1.74 g) を得た。
MS (ESI+): [M+H-(tBu)]+ 348.0. C) tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(1RS) -1,2-dihydroxyethyl] azepane-1-carboxylate and tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(1SR) -1,2-dihydroxyethyl] azepan-1-carboxylate mixture (diastereomeric mixture)
tert-Butyl (3RS, 4SR) -3- (3,4-dichlorophenyl) -4-vinylazepane-1-carboxylate (2.0 g) and 4-methylmorpholine-N-oxide (1.5 g) in acetonitrile / acetone / water (v / v / v = 1/1/1, 15 mL) Add osmium oxide (VIII) immobilized catalyst I (Wako Pure Chemicals cat.153-02581, 1.5 g) to the mixed solution, and stir at room temperature for 2 hours did. After removing the catalyst with celite, a saturated aqueous ammonium chloride solution was added to the residue. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate) to obtain the title compound (1.74 g).
MS (ESI +): [M + H- (tBu)] + 348.0.
D) tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(1RS)-1,2-ジヒドロキシエチル]アゼパン-1-カルボキシラート
　工程Cにて得られたジアステレオマー混合物(56 mg)をHPLC(C18、移動相：水/アセトニトリル(0.1% 酢酸アンモニウム含有系))にて分取し、得られた画分(ジアステレオマーのうち低極性分画)に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、減圧下濃縮し、標題化合物 (50 mg) を得た。
MS (ESI+): [M+H-(tBu)]+ 348.0. D) tert-Butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(1RS) -1,2-dihydroxyethyl] azepane-1-carboxylate Diastereoisomer obtained in Step C The mer mixture (56 mg) was separated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% ammonium acetate)), and the obtained fraction (low polarity fraction of diastereomers) was saturated. Aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (50 mg).
MS (ESI +): [M + H- (tBu)] + 348.0.
E) (1RS)-1-[(3RS,4RS)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]エタン-1,2-ジオール　塩酸塩
　tert-ブチル(3RS,4RS)-3-(3,4-ジクロロフェニル)-4-((RS)-1,2-ジヒドロキシエチル)アゼパン-1-カルボキシラート (50 mg)のエタノール(4 mL)溶液へ12.8規定の塩化水素のエタノール(2 mL)溶液を加え、室温にて30分撹拌した。溶媒を減圧留去した後、残渣を再結晶(エタノール：ジエチルエーテル)し、標題化合物(40 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.46-2.13 (5H, m), 2.83-3.22 (6H, m), 3.35-3.54 (2H, m), 4.45 (1H, t, J = 4.5 Hz), 4.65 (1H, brs), 7.30 (1H, dd, J = 8.3, 1.9 Hz), 7.44 (2H, brs), 7.61 (1H, d, J = 1.9 Hz), 7.62 (1H, d, J = 4.2 Hz). MS (ESI+): [M+H]+ 304.0. E) (1RS) -1-[(3RS, 4RS) -3- (3,4-Dichlorophenyl) azepan-4-yl] ethane-1,2-diol hydrochloride tert-butyl (3RS, 4RS) -3- To a solution of (3,4-dichlorophenyl) -4-((RS) -1,2-dihydroxyethyl) azepane-1-carboxylate (50 mg) in ethanol (4 mL), 12.8 N hydrogen chloride in ethanol (2 mL) ) Solution was added and stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, the residue was recrystallized (ethanol: diethyl ether) to obtain the title compound (40 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.46-2.13 (5H, m), 2.83-3.22 (6H, m), 3.35-3.54 (2H, m), 4.45 (1H, t, J = 4.5 Hz ), 4.65 (1H, brs), 7.30 (1H, dd, J = 8.3, 1.9 Hz), 7.44 (2H, brs), 7.61 (1H, d, J = 1.9 Hz), 7.62 (1H, d, J = 4.2 Hz). MS (ESI +): [M + H] + 304.0.
実施例38
(1RS)-1-[(3SR,4SR)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]エタン-1,2-ジオール　塩酸塩
A) tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(1SR)-1,2-ジヒドロキシエチル]アゼパン-1-カルボキシラート
　実施例36の工程Cにて得られたジアステレオマー混合物(56 mg)をHPLC (C18、移動相：水/アセトニトリル (0.1% 酢酸アンモニウム含有系)) にて分取し、得られた画分(ジアステレオマーのうち高極性分画)に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、減圧下濃縮し、標題化合物 (15 mg) を得た。
MS (ESI+): [M+H-(tBu)]+ 348.0. Example 38
(1RS) -1-[(3SR, 4SR) -3- (3,4-Dichlorophenyl) azepan-4-yl] ethane-1,2-diol hydrochloride
A) tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(1SR) -1,2-dihydroxyethyl] azepane-1-carboxylate obtained in Example 36, step C The obtained diastereomeric mixture (56 mg) was fractionated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% ammonium acetate)), and the obtained fraction (highly polar fraction of diastereomers). Saturated aqueous sodium hydrogen carbonate solution was added to the aqueous solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (15 mg).
MS (ESI +): [M + H- (tBu)] + 348.0.
B) (1RS)-1-[(3SR,4SR)-3-(3,4-ジクロロフェニル)アゼパン-4-イル]エタン-1,2-ジオール　塩酸塩
　tert-ブチル (3RS,4RS)-3-(3,4-ジクロロフェニル)-4-[(1SR)-1,2-ジヒドロキシエチル]アゼパン-1-カルボキシラート(15 mg)のエタノール(4 mL)溶液へ12.8規定の塩化水素のエタノール(2 mL)溶液を加え、室温にて30分撹拌した。溶媒を減圧留去した後、残渣を再結晶(エタノール：ジエチルエーテル)し、標題化合物(9 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.49-2.12 (5H, m), 2.94-3.29 (6H, m), 3.35-3.49 (2H, m), 4.45 (1H, t, J = 5.5 Hz), 4.59 (1H, brs), 7.29 (1H, dd, J = 8.3, 1.9 Hz), 7.57 (1H, d, J = 1.9 Hz), 7.61 (1H, d, J = 8.3 Hz), 9.21 (2H, brs). MS (ESI+): [M+H]+ 304.0. B) (1RS) -1-[(3SR, 4SR) -3- (3,4-Dichlorophenyl) azepan-4-yl] ethane-1,2-diol hydrochloride tert-butyl (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(1SR) -1,2-dihydroxyethyl] azepane-1-carboxylate (15 mg) in ethanol (4 mL) solution to 12.8 N hydrogen chloride in ethanol (2 mL) ) Solution was added and stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, the residue was recrystallized (ethanol: diethyl ether) to obtain the title compound (9 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.49-2.12 (5H, m), 2.94-3.29 (6H, m), 3.35-3.49 (2H, m), 4.45 (1H, t, J = 5.5 Hz ), 4.59 (1H, brs), 7.29 (1H, dd, J = 8.3, 1.9 Hz), 7.57 (1H, d, J = 1.9 Hz), 7.61 (1H, d, J = 8.3 Hz), 9.21 (2H , brs). MS (ESI +): [M + H] + 304.0.
実施例39
5-(3,4-ジクロロフェニル)-6-((メチルスルホニル)メチル)-2,3,4,7-テトラヒドロ-1H-アゼピン　塩酸塩
A) tert-ブチル5-(3,4-ジクロロフェニル)-6-[(メチルスルファニル)メチル]-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート
　実施例15の工程Aで得られたtert-ブチル5-(3,4-ジクロロフェニル)-6-(ヒドロキシメチル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(220 mg)のTHF(4.5 mL)溶液に、氷冷下トリエチルアミン(0.25 mL)およびメタンスルホニルクロリド(0.1 mL)を加え、室温で2.5時間撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をDMF(2.5 mL)溶液に溶解し、この混合液にナトリウムチオメトキシド(61 mg)を加え、室温で18時間撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(177 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 1.75-1.91 (2H, m), 1.92 (3H, s), 2.51-2.53 (2H, m), 3.12 (1H, s), 3.18 (1H, s), 3.56-3.66 (2H, m), 4.08-4.13 (2H, m), 6.90-6.96 (1H, m), 7.18-7.20 (1H, m), 7.39 (1H, d, J = 8.4Hz). Example 39
5- (3,4-Dichlorophenyl) -6-((methylsulfonyl) methyl) -2,3,4,7-tetrahydro-1H-azepine hydrochloride
A) tert-butyl 5- (3,4-dichlorophenyl) -6-[(methylsulfanyl) methyl] -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate In step A of Example 15 The resulting tert-butyl 5- (3,4-dichlorophenyl) -6- (hydroxymethyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (220 mg) in THF (4.5 mL ) To the solution were added triethylamine (0.25 mL) and methanesulfonyl chloride (0.1 mL) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (2.5 mL) solution, sodium thiomethoxide (61 mg) was added to the mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (177 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, s), 1.75-1.91 (2H, m), 1.92 (3H, s), 2.51-2.53 (2H, m), 3.12 (1H, s), 3.18 (1H, s), 3.56-3.66 (2H, m), 4.08-4.13 (2H, m), 6.90-6.96 (1H, m), 7.18-7.20 (1H, m), 7.39 (1H, d, J = 8.4Hz).
B) tert-ブチル5-(3,4-ジクロロフェニル)-6-[(メチルスルホニル)メチル]-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート
　工程Aで得られたtert-ブチル 5-(3,4-ジクロロフェニル)-6-[(メチルスルファニル)メチル]-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(170 mg)のトルエン(5.0 mL)溶液に、氷冷下m-クロロ過安息香酸(223 mg)を加え、室温で2時間撹拌した。反応混合液を酢酸エチルで希釈し、飽和重曹水、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(167 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, d, J = 6.9 Hz), 1.80-1.95 (2H, m), 2.60-2.64 (2H, m), 2.75 (3H, d, J = 11 Hz), 3.61-3.70 (2H, m), 3.80 (1H, s), 3.93 (1H, s), 4.18 (2H, s), 6.99-7.06 (1H, m), 7.23-7.26 (1H, m), 7.43 (1H, t, J = 7.2 Hz). B) tert-butyl 5- (3,4-dichlorophenyl) -6-[(methylsulfonyl) methyl] -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate tert obtained in step A -Butyl 5- (3,4-dichlorophenyl) -6-[(methylsulfanyl) methyl] -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (170 mg) in toluene (5.0 mL) To the solution, m-chloroperbenzoic acid (223 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (167 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, d, J = 6.9 Hz), 1.80-1.95 (2H, m), 2.60-2.64 (2H, m), 2.75 (3H, d, J = 11 Hz), 3.61-3.70 (2H, m), 3.80 (1H, s), 3.93 (1H, s), 4.18 (2H, s), 6.99-7.06 (1H, m), 7.23-7.26 (1H, m) , 7.43 (1H, t, J = 7.2 Hz).
C) 5-(3,4-ジクロロフェニル)-6-[(メチルスルホニル)メチル]-2,3,4,7-テトラヒドロ-1H-アゼピン　塩酸塩
　工程Bで得られたtert-ブチル 5-(3,4-ジクロロフェニル)-6-[(メチルスルホニル)メチル]-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(157 mg)のエタノール(1 mL)溶液に14.7 mol/kg, w/w 塩化水素-エタノール溶液(0.4 mL)を加え、室温で90分間撹拌した。溶媒を減圧下留去し、残渣をエタノール－酢酸エチルから結晶化することにより、標題化合物(117 mg)を無色結晶として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.89 (2H, br s), 2.68-2.72 (2H, m), 2.91 (3H, s), 3.30-3.35 (2H, m), 3.94 (2H, s), 4.01 (2H, s), 7.23-7.28 (1H, m), 7.54-7.57 (1H, m), 7.67 (1H, d, J = 8.4 Hz), 9.30 (2H, br s). MS (ESI+): [M+H]+ 334.3. C) 5- (3,4-Dichlorophenyl) -6-[(methylsulfonyl) methyl] -2,3,4,7-tetrahydro-1H-azepine hydrochloride tert-butyl 5- (3 , 4-Dichlorophenyl) -6-[(methylsulfonyl) methyl] -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (157 mg) in ethanol (1 mL) solution at 14.7 mol / kg , w / w Hydrogen chloride-ethanol solution (0.4 mL) was added, and the mixture was stirred at room temperature for 90 minutes. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (117 mg) as colorless crystals.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.89 (2H, br s), 2.68-2.72 (2H, m), 2.91 (3H, s), 3.30-3.35 (2H, m), 3.94 (2H, s), 4.01 (2H, s), 7.23-7.28 (1H, m), 7.54-7.57 (1H, m), 7.67 (1H, d, J = 8.4 Hz), 9.30 (2H, br s) .MS ( ESI +): [M + H] + 334.3.
実施例40
N-{[4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-3-イル]メチル}メタンスルホンアミド　塩酸塩
A) tert-ブチル 6-(アジドメチル)-5-(3,4-ジクロロフェニル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート
　実施例15の工程Aで得られたtert-ブチル5-(3,4-ジクロロフェニル)-6-(ヒドロキシメチル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(1.0 g)のTHF(20 mL)溶液に、氷冷下トリエチルアミン(1.12 mL)およびメタンスルホニルクロリド(0.42 mL)を加え、室温で2.5時間撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をDMF(20 mL)溶液に溶解し、この混合液にアジ化ナトリウム(262 mg)を加え、室温で18時間撹拌した。反応混合液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(744 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 1.91 (2H, br s), 2.33-2.57(2H, m), 3.60-3.78 (4H, m), 4.06-4.10 (2H, m), 6.85-6.95 (1H, m), 7.15 (1H, s), 7.41 (1H, d, J = 8.7 Hz). Example 40
N-{[4- (3,4-Dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methyl} methanesulfonamide hydrochloride
A) tert-Butyl 6- (azidomethyl) -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate tert obtained in Step A of Example 15 To a solution of -butyl 5- (3,4-dichlorophenyl) -6- (hydroxymethyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (1.0 g) in THF (20 mL), Triethylamine (1.12 mL) and methanesulfonyl chloride (0.42 mL) were added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (20 mL) solution, sodium azide (262 mg) was added to the mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (744 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, s), 1.91 (2H, br s), 2.33-2.57 (2H, m), 3.60-3.78 (4H, m), 4.06-4.10 (2H, m), 6.85-6.95 (1H, m), 7.15 (1H, s), 7.41 (1H, d, J = 8.7 Hz).
B) tert-ブチル 6-(アミノメチル)-5-(3,4-ジクロロフェニル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート
　工程Aで得られたtert-ブチル 6-(アジドメチル)-5-(3,4-ジクロロフェニル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(733 mg)のMeOH(18 mL)溶液にジメチルスルフィド (2滴)と10% パラジウム－カーボン粉末(140 mg)を加え、水素気流下室温で４時間撹拌した。反応混合液を窒素置換後セライトろ過し、濾液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(744 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.36 (2H, br s), 1.49 (9H, s), 1.80-1.90 (2H, m), 2.50 (2H, m), 3.11 (2H, d, J = 12 Hz), 3.59-3.66 (2H, m), 6.88-6.96 (1H, m), 7.18 (1H, d, J = 11 Hz), 7.37 (1H, d, J = 7.8 Hz). B) tert-butyl 6- (aminomethyl) -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate tert-butyl 6 obtained in step A Dimethyl sulfide (2 drops) in a solution of-(azidomethyl) -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (733 mg) in MeOH (18 mL) ) And 10% palladium-carbon powder (140 mg) were added, and the mixture was stirred at room temperature for 4 hours under a hydrogen stream. The reaction mixture was purged with nitrogen and filtered through celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (744 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.36 (2H, br s), 1.49 (9H, s), 1.80-1.90 (2H, m), 2.50 (2H, m), 3.11 (2H, d, J = 12 Hz), 3.59-3.66 (2H, m), 6.88-6.96 (1H, m), 7.18 (1H, d, J = 11 Hz), 7.37 (1H, d, J = 7.8 Hz).
C) tert-ブチル 5-(3,4-ジクロロフェニル)-6-{[(メチルスルホニル)アミノ]メチル}-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート
　工程Bで得られたtert-ブチル 6-(アミノメチル)-5-(3,4-ジクロロフェニル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(120 mg)のTHF(3.0 mL)溶液に、氷冷下トリエチルアミン(0.14 mL)およびメタンスルホニルクロリド(0.05 mL)を加え、室温で3時間撹拌した。反応混合液を酢酸エチルで希釈後、水および飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(140 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.28 (9H, s), 1.72-1.80 (2H, m), 2.60-2.64 (2H, m), 2.86 (3H, s), 3.48 (2H, d, J = 5.1 Hz), 3.66 (2H, t, J = 5.7 Hz), 3.96 (2H, s), 6.82-6.86 (1H, m), 7.00 (1H, dd, J = 8.1, 2.1 Hz), 7.23 (1H, d, J = 2.1 Hz), 7.40 (1H, d, J = 8.1 Hz). C) tert-butyl 5- (3,4-dichlorophenyl) -6-{[(methylsulfonyl) amino] methyl} -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate obtained in step B Tert-butyl 6- (aminomethyl) -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (120 mg) in THF (3.0 mL) To the solution were added triethylamine (0.14 mL) and methanesulfonyl chloride (0.05 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (140 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.28 (9H, s), 1.72-1.80 (2H, m), 2.60-2.64 (2H, m), 2.86 (3H, s), 3.48 (2H, d, J = 5.1 Hz), 3.66 (2H, t, J = 5.7 Hz), 3.96 (2H, s), 6.82-6.86 (1H, m), 7.00 (1H, dd, J = 8.1, 2.1 Hz), 7.23 (1H , d, J = 2.1 Hz), 7.40 (1H, d, J = 8.1 Hz).
D) N-{[4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-3-イル]メチル}メタンスルホンアミド　塩酸塩
　工程Cで得られたtert-ブチル 5-(3,4-ジクロロフェニル)-6-{[(メチルスルホニル)アミノ]メチル}-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(135 mg)のエタノール(1 mL)溶液に14.7 mol/kg, w/w 塩化水素-エタノール溶液(0.6 mL)を加え、室温で90分間撹拌した。溶媒を減圧下留去し、残渣をエタノール－酢酸エチルから結晶化することにより、標題化合物(86 mg)を無色結晶として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.88 (2H, br s), 2.62-2.65 (2H, m), 2.85 (3H, s), 3.34 (2H, s), 3.47 (2H, d, J = 6.0 Hz), 3.87 (2H, s), 7.22-7.26 (1H, m), 7.36 (1H, t, J = 6.0 Hz), 7.53 (1H, br s), 7.66 (1H, d, J = 8.1 Hz), 9.24 (2H, br s). MS (ESI+): [M+H]+349.3. D) N-{[4- (3,4-dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methyl} methanesulfonamide hydrochloride tert-butyl obtained in Step C 5- (3,4-dichlorophenyl) -6-{[(methylsulfonyl) amino] methyl} -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (135 mg) in ethanol (1 mL 14.7 mol / kg, w / w hydrogen chloride-ethanol solution (0.6 mL) was added to the solution, and the mixture was stirred at room temperature for 90 minutes. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (86 mg) as colorless crystals.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.88 (2H, br s), 2.62-2.65 (2H, m), 2.85 (3H, s), 3.34 (2H, s), 3.47 (2H, d, J = 6.0 Hz), 3.87 (2H, s), 7.22-7.26 (1H, m), 7.36 (1H, t, J = 6.0 Hz), 7.53 (1H, br s), 7.66 (1H, d, J = 8.1 Hz), 9.24 (2H, br s). MS (ESI +): [M + H] + 349.3.
実施例41
1-{[4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-3-イル]メチル}尿素　塩酸塩
A) tert-ブチル 6-[(カルバモイルアミノ)メチル]-5-(3,4-ジクロロフェニル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート
　実施例40の工程Bで得られたtert-ブチル 6-(アミノメチル)-5-(3,4-ジクロロフェニル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(105 mg)のTHF(1.5 mL)溶液にトリメチルシリルイソシアネート(0.06 mL)を加え、室温で3日間撹拌した。反応混合液を酢酸エチルで希釈後、水および飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製して標題化合物(107 mg)を得た。
1H NMR (300 MHz, CDCl3) δ 1.49 (9H, s), 1.75-1.82 (2H, m), 2.55-2.59 (2H, m), 3.59 (2H, d, J = 4.2 Hz), 3.64 (2H, t, J = 5.7 Hz), 3.93 (2H, s), 4.36 (2H, br s), 6.68 (1H, br s), 6.89 (1H, dd, J = 8.1, 2.1 Hz), 7.15 (1H, d, J = 2.1 Hz), 7.36 (1H, d, J = 8.1 Hz). Example 41
1-{[4- (3,4-Dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methyl} urea hydrochloride
A) tert-butyl 6-[(carbamoylamino) methyl] -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate In step B of Example 40 Obtained tert-butyl 6- (aminomethyl) -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (105 mg) in THF (1.5 mL) ) Trimethylsilyl isocyanate (0.06 mL) was added to the solution, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (107 mg).
1 H NMR (300 MHz, CDCl 3 ) δ 1.49 (9H, s), 1.75-1.82 (2H, m), 2.55-2.59 (2H, m), 3.59 (2H, d, J = 4.2 Hz), 3.64 ( 2H, t, J = 5.7 Hz), 3.93 (2H, s), 4.36 (2H, br s), 6.68 (1H, br s), 6.89 (1H, dd, J = 8.1, 2.1 Hz), 7.15 (1H , d, J = 2.1 Hz), 7.36 (1H, d, J = 8.1 Hz).
B) 1-{[4-(3,4-ジクロロフェニル)-2,5,6,7-テトラヒドロ-1H-アゼピン-3-イル]メチル}尿素　塩酸塩
　工程Aで得られたtert-ブチル 6-[(カルバモイルアミノ)メチル]-5-(3,4-ジクロロフェニル)-2,3,4,7-テトラヒドロ-1H-アゼピン-1-カルボキシラート(100 mg)のエタノール(0.75 mL)溶液に14.7 mol/kg, w/w 塩化水素-エタノール溶液(0.6 mL)を加え、室温で90分間撹拌した。溶媒を減圧下留去し、残渣をエタノール－酢酸エチルから結晶化することにより、標題化合物(66 mg)を無色結晶として得た。
1H NMR (300 MHz, DMSO-d6) δ 1.87 (2H, br s), 2.60-2.63 (2H, m),3.32 (2H, br s), 3.50 (2H, s), 3.77 (2H, s), 5.85 (2H, br s), 6.54 (1H, br s), 7.20-7.23 (1H, m), 7.49-7.50 (1H, m), 7.64 (1H, d, J = 8.1 Hz), 9.25 (2H, br s). MS (ESI+): [M+H]+ 314.3. B) 1-{[4- (3,4-Dichlorophenyl) -2,5,6,7-tetrahydro-1H-azepin-3-yl] methyl} urea hydrochloride tert-butyl 6- obtained from step A 14.7 mol of [(carbamoylamino) methyl] -5- (3,4-dichlorophenyl) -2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (100 mg) in ethanol (0.75 mL) / kg, w / w Hydrogen chloride-ethanol solution (0.6 mL) was added, and the mixture was stirred at room temperature for 90 minutes. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (66 mg) as colorless crystals.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.87 (2H, br s), 2.60-2.63 (2H, m), 3.32 (2H, br s), 3.50 (2H, s), 3.77 (2H, s ), 5.85 (2H, br s), 6.54 (1H, br s), 7.20-7.23 (1H, m), 7.49-7.50 (1H, m), 7.64 (1H, d, J = 8.1 Hz), 9.25 ( 2H, br s). MS (ESI +): [M + H] + 314.3.
実施例42
[(4RS)-4-(3,4-ジクロロフェニル)アゼパン-4-イル]メタノール　塩酸塩
A) 3-(3,4-ジクロロフェニル)シクロヘキサ-2-エン-1-オン
　マグネシウム(1.04 g)のTHF溶液(10 mL)に4-ブロモ-1,2-ジクロロベンゼン(9.67 g)のTHF溶液(20 mL)とヨウ素(3 mg)を室温で加え、窒素気流下、40℃で1時間攪拌した。反応混合物に3-エトキシシクロヘキサ-2-エノン(4.76 mL)のTHF溶液(10 mL)を0℃で滴下した。反応混合物を窒素気流下、室温で1時間攪拌した。反応混合物に1N塩酸水を室温で加えた。反応混合物を酢酸エチルで抽出した。抽出液を蒸留水と飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、標題化合物(5.51 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.16 (2H, quin, J = 6.3 Hz), 2.43-2.54 (2H, m), 2.72 (2H, td, J = 6.0, 1.5 Hz), 6.37 (1H, t, J = 1.5 Hz), 7.33-7.41 (1H, m), 7.45-7.51 (1H, m), 7.61 (1H, d, J = 2.3 Hz). Example 42
[(4RS) -4- (3,4-Dichlorophenyl) azepan-4-yl] methanol hydrochloride
A) 3- (3,4-Dichlorophenyl) cyclohex-2-en-1-one Magnesium (1.04 g) in THF (10 mL) in 4-bromo-1,2-dichlorobenzene (9.67 g) in THF (20 mL) and iodine (3 mg) were added at room temperature, and the mixture was stirred at 40 ° C. for 1 hour under a nitrogen stream. To the reaction mixture, a THF solution (10 mL) of 3-ethoxycyclohex-2-enone (4.76 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour under a nitrogen stream. 1N aqueous hydrochloric acid was added to the reaction mixture at room temperature. The reaction mixture was extracted with ethyl acetate. The extract was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (5.51 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.16 (2H, quin, J = 6.3 Hz), 2.43-2.54 (2H, m), 2.72 (2H, td, J = 6.0, 1.5 Hz), 6.37 (1H, t, J = 1.5 Hz), 7.33-7.41 (1H, m), 7.45-7.51 (1H, m), 7.61 (1H, d, J = 2.3 Hz).
B) (1RS)-1-(3,4-ジクロロフェニル)-3-オキソシクロヘキサンカルボニトリル
　3-(3,4-ジクロロフェニル)シクロヘキサ-2-エン-1-オン(5g)のDMF(60mL)と水(15mL)の溶液に、シアン化カリウム(2.7g)とトリエチルアミンヒドロクロリド(4.28g)を室温で加え、90℃で3時間攪拌した。反応混合物に飽和重曹水及び飽和チオ硫酸ナトリウム水溶液を室温で加え、室温で1時間攪拌した。反応混合物を酢酸エチルで抽出した。抽出液を蒸留水と飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、標題化合物(1.5 g)を得た。
1H NMR (300 MHz, CDCl3) δ 2.10-2.27 (3H, m), 2.33-2.48 (2H, m), 2.55-2.65 (1H, m), 2.75-2.83 (1H, m), 2.86-2.94 (1H, m), 7.33 (1H, dd, J = 8.5, 2.5 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.57 (1H, d, J = 2.3 Hz). B) (1RS) -1- (3,4-Dichlorophenyl) -3-oxocyclohexanecarbonitrile 3- (3,4-Dichlorophenyl) cyclohex-2-en-1-one (5 g) in DMF (60 mL) and water To a solution of (15 mL), potassium cyanide (2.7 g) and triethylamine hydrochloride (4.28 g) were added at room temperature, and the mixture was stirred at 90 ° C. for 3 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (1.5 g).
1 H NMR (300 MHz, CDCl 3 ) δ 2.10-2.27 (3H, m), 2.33-2.48 (2H, m), 2.55-2.65 (1H, m), 2.75-2.83 (1H, m), 2.86-2.94 (1H, m), 7.33 (1H, dd, J = 8.5, 2.5 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.57 (1H, d, J = 2.3 Hz).
C) (7RS)-7-(3,4-ジクロロフェニル)-1,4-ジオキサスピロ[4.5]デカン-7-カルボニトリル
　(1RS)-1-(3,4-ジクロロフェニル)-3-オキソシクロヘキサンカルボニトリル(1.5 g)のトルエン溶液(15 mL)にエチレングリコール(0.62 mL)とピリジニウム p-トルエンスルホナート(0.07 g)を加え、125℃で3時間攪拌した。反応混合物を酢酸エチルで希釈した。希釈液を蒸留水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、標題化合物(1.3 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.48-1.64 (1H, m), 1.65-1.78 (1H, m), 1.82-1.98 (3H, m), 2.08-2.39 (3H, m), 3.88-4.01 (2H, m), 4.05-4.17 (2H, m), 7.32-7.39 (1H, m), 7.42-7.51 (1H, m), 7.60 (1H, d, J = 2.3 Hz). C) (7RS) -7- (3,4-Dichlorophenyl) -1,4-dioxaspiro [4.5] decane-7-carbonitrile (1RS) -1- (3,4-Dichlorophenyl) -3-oxocyclohexanecarbonitrile Ethylene glycol (0.62 mL) and pyridinium p-toluenesulfonate (0.07 g) were added to a toluene solution (15 mL) of (1.5 g), and the mixture was stirred at 125 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (1.3 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.48-1.64 (1H, m), 1.65-1.78 (1H, m), 1.82-1.98 (3H, m), 2.08-2.39 (3H, m), 3.88-4.01 (2H, m), 4.05-4.17 (2H, m), 7.32-7.39 (1H, m), 7.42-7.51 (1H, m), 7.60 (1H, d, J = 2.3 Hz).
D) (7RS)-7-(3,4-ジクロロフェニル)-1,4-ジオキサスピロ[4.5]デカン-7-カルバルデヒド
　(7RS)-7-(3,4-ジクロロフェニル)-1,4-ジオキサスピロ[4.5]デカン-7-カルボニトリル(1.3 g)のトルエン溶液(15 mL)にジイソブチルアルミニウム ヒドリド(3.61 mL)を-78℃で滴下した。反応混合物を室温で1時間攪拌した。反応混合物に1N塩酸水を室温で加えた。反応混合物を酢酸エチルで抽出した。抽出液を蒸留水と飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、標題化合物(0.92 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.50 (2H, d, J = 5.3 Hz), 1.70-1.88 (3H, m), 2.00 (1H, s), 2.50-2.65 (2H, m), 3.90-4.08 (4H, m), 7.11 (1H, dd, J = 8.7, 2.3 Hz), 7.33-7.46 (2H, m), 9.35 (1H, d, J = 1.9 Hz). D) (7RS) -7- (3,4-Dichlorophenyl) -1,4-dioxaspiro [4.5] decane-7-carbaldehyde (7RS) -7- (3,4-dichlorophenyl) -1,4-dioxaspiro [ 4.5] Diisobutylaluminum hydride (3.61 mL) was added dropwise to a toluene solution (15 mL) of decane-7-carbonitrile (1.3 g) at -78 ° C. The reaction mixture was stirred at room temperature for 1 hour. 1N aqueous hydrochloric acid was added to the reaction mixture at room temperature. The reaction mixture was extracted with ethyl acetate. The extract was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (0.92 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.50 (2H, d, J = 5.3 Hz), 1.70-1.88 (3H, m), 2.00 (1H, s), 2.50-2.65 (2H, m), 3.90- 4.08 (4H, m), 7.11 (1H, dd, J = 8.7, 2.3 Hz), 7.33-7.46 (2H, m), 9.35 (1H, d, J = 1.9 Hz).
E) [(7RS)-(7-(3,4-ジクロロフェニル)-1,4-ジオキサスピロ[4.5]デカ-7-イル]メタノール
　(7RS)-7-(3,4-ジクロロフェニル)-1,4-ジオキサスピロ[4.5]デカン-7-カルバルデヒド(0.92 g)のメタノール溶液(10 mL)に水素化ホウ素ナトリウム(120 mg)を0℃で加え、室温で終夜攪拌した。反応混合物に0.1N塩酸水を室温で加えた。反応混合物を酢酸エチルで抽出した。抽出液を蒸留水と飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、標題化合物(0.91 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.45-1.56 (1H, m), 1.59-1.99 (7H, m), 2.16 (1H, d, J = 14.0 Hz), 3.60-3.71 (1H, m), 3.75-3.85 (1H, m), 3.86-4.07 (4H, m), 7.22 (1H, dd, J = 8.3, 2.3 Hz), 7.39 (1H, d, J = 8.7 Hz), 7.46 (1H, d, J = 2.3 Hz). E) [(7RS)-(7- (3,4-Dichlorophenyl) -1,4-dioxaspiro [4.5] dec-7-yl] methanol (7RS) -7- (3,4-dichlorophenyl) -1,4 -Dioxaspiro [4.5] decane-7-carbaldehyde (0.92 g) in methanol (10 mL) was added sodium borohydride (120 mg) at 0 ° C. and stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate, the extract was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure, and the residue was chromatographed on silica gel (hexane). / Ethyl acetate) to give the title compound (0.91 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.45-1.56 (1H, m), 1.59-1.99 (7H, m), 2.16 (1H, d, J = 14.0 Hz), 3.60-3.71 (1H, m), 3.75-3.85 (1H, m), 3.86-4.07 (4H, m), 7.22 (1H, dd, J = 8.3, 2.3 Hz), 7.39 (1H, d, J = 8.7 Hz), 7.46 (1H, d, J = 2.3 Hz).
F) (3RS)-3-(3,4-ジクロロフェニル)-3-(ヒドロキシメチル)シクロヘキサノン
　[(7RS)-(7-(3,4-ジクロロフェニル)-1,4-ジオキサスピロ[4.5]デカ-7-イル]メタノール(0.91 g)のアセトン溶液(5 mL)に1N塩酸水(5 mL)を加え、65℃で3時間攪拌した。反応混合物を酢酸エチルで希釈した。希釈液を蒸留水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、標題化合物(0.744 g)を得た。
1H NMR (300 MHz, CDCl3) δ1.47-2.40 (7H, m), 2.66 (1H, d, J = 14.7 Hz), 2.75-2.94 (1H, m), 3.53-3.74 (2H, m), 7.18 (1H, d, J = 8.3 Hz), 7.41 (2H, d, J = 8.3 Hz). F) (3RS) -3- (3,4-Dichlorophenyl) -3- (hydroxymethyl) cyclohexanone [(7RS)-(7- (3,4-dichlorophenyl) -1,4-dioxaspiro [4.5] dec-7 -Yl] Methanol (0.91 g) in acetone (5 mL) was added 1N aqueous hydrochloric acid (5 mL) and stirred for 3 hours at 65 ° C. The reaction mixture was diluted with ethyl acetate. After washing with brine and drying over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (0.744 g).
1 H NMR (300 MHz, CDCl 3 ) δ1.47-2.40 (7H, m), 2.66 (1H, d, J = 14.7 Hz), 2.75-2.94 (1H, m), 3.53-3.74 (2H, m) , 7.18 (1H, d, J = 8.3 Hz), 7.41 (2H, d, J = 8.3 Hz).
G) (3RS)-3-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-3-(3,4-ジクロロフェニル)シクロヘキサノン
　(3RS)-3-(3,4-ジクロロフェニル)-3-(ヒドロキシメチル)シクロヘキサノン(0.744 g)のTHF溶液(5 mL)にtert-ブチルジメチルクロロシラン(0.452 mg)とトリエチルアミン(0.569 mL)とN,N-ジメチル-4-アミノピリジン(10 mg)を加え、65℃で終夜攪拌した。反応混合物を酢酸エチルで希釈した。希釈液を蒸留水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチルで精製し、標題化合物を得た。
1H NMR (300 MHz, CDCl3) δ -0.01-0.04 (6H, m), 0.80-0.95 (9H, m), 1.52-1.64 (1H, m), 1.87-2.04 (1H, m), 2.13-2.45 (4H, m), 2.71-2.90 (2H, m), 3.37-3.50 (1H, m), 3.54-3.67 (1H, m), 7.21 (1H, dd, J = 8.7, 2.3 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.47 (1H, d, J = 2.3 Hz). G) (3RS) -3-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (3,4-dichlorophenyl) cyclohexanone (3RS) -3- (3,4-dichlorophenyl) -3- To a THF solution (5 mL) of (hydroxymethyl) cyclohexanone (0.744 g), tert-butyldimethylchlorosilane (0.452 mg), triethylamine (0.569 mL) and N, N-dimethyl-4-aminopyridine (10 mg) were added. Stir at 65 ° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound.
1 H NMR (300 MHz, CDCl 3 ) δ -0.01-0.04 (6H, m), 0.80-0.95 (9H, m), 1.52-1.64 (1H, m), 1.87-2.04 (1H, m), 2.13- 2.45 (4H, m), 2.71-2.90 (2H, m), 3.37-3.50 (1H, m), 3.54-3.67 (1H, m), 7.21 (1H, dd, J = 8.7, 2.3 Hz), 7.44 ( 1H, d, J = 8.3 Hz), 7.47 (1H, d, J = 2.3 Hz).
H) (5RS)-5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-5-(3,4-ジクロロフェニル)アゼパン-2-オン
　(3RS)-3-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-3-(3,4-ジクロロフェニル)シクロヘキサノン(0.88 g)のメタノール溶液(2 mL)にヒドロキシルアミンヒドロクロリド(0.316 mg)を加え、65℃で1時間攪拌した。反応混合物を酢酸エチルで希釈した。希釈液を蒸留水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した。残渣のピリジン溶液(4 mL)に、p-トルエンスルホニル クロリド(0.866 g)とN,N-ジメチル-4-アミノピリジン(0.01 g)を室温で加え、80℃で終夜攪拌した。反応混合物を酢酸エチルで希釈した。希釈液を蒸留水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、標題化合物(0.066 g)を得た。
1H NMR (300 MHz, CDCl3) δ-0.05-0.05 (6H, m), 0.89-0.98 (9H, m), 1.65-1.80 (1H, m), 1.87-2.09 (2H, m), 2.48-2.62 (1H, m), 2.88-2.98 (1H, m), 3.03-3.12
(1H, m), 3.17-3.43 (2H, m), 3.48 (2H, s), 6.01 (1H, brs), 7.41-7.46 (1H, m), 7.48-7.53 (1H, m), 7.61 (1H, d, J = 2.3 Hz). H) (5RS) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5- (3,4-dichlorophenyl) azepan-2-one (3RS) -3-({[tert-butyl Hydroxylamine hydrochloride (0.316 mg) was added to a methanol solution (2 mL) of (dimethyl) silyl] oxy} methyl) -3- (3,4-dichlorophenyl) cyclohexanone (0.88 g) and stirred at 65 ° C. for 1 hour. . The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. To the pyridine solution (4 mL) of the residue, p-toluenesulfonyl chloride (0.866 g) and N, N-dimethyl-4-aminopyridine (0.01 g) were added at room temperature, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (0.066 g).
1 H NMR (300 MHz, CDCl 3 ) δ-0.05-0.05 (6H, m), 0.89-0.98 (9H, m), 1.65-1.80 (1H, m), 1.87-2.09 (2H, m), 2.48- 2.62 (1H, m), 2.88-2.98 (1H, m), 3.03-3.12
(1H, m), 3.17-3.43 (2H, m), 3.48 (2H, s), 6.01 (1H, brs), 7.41-7.46 (1H, m), 7.48-7.53 (1H, m), 7.61 (1H , d, J = 2.3 Hz).
I) tert-ブチル (4RS)-4-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラート
　(5RS)-5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-5-(3,4-ジクロロフェニル)アゼパン-2-オン (0.066 g)のTHF溶液(2 mL)に1Mのテトラヒドロフラン-ボラン溶液(2 mL)を加え、65℃で2時間攪拌した。反応混合物に1Nの塩酸水(1 mL)を65℃で加え、60℃で1時間攪拌した。反応混合物に、トリエチルアミン(0.1 mL)と二炭酸ジ-tert-ブチル(0.057 mL)を室温で加え、室温で3時間攪拌した。反応混合物を酢酸エチルで希釈した。希釈液を蒸留水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、標題化合物(0.053 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.27 (1H, brs), 1.33-1.44 (9H, m), 1.57-1.69 (2H, m), 1.73-1.93 (2H, m), 2.18-2.42 (2H, m), 3.02-3.39 (3H, m), 3.46 (2H, s), 3.51-3.79 (1H, m), 7.15 (1H, dd, J = 8.5, 1.7 Hz), 7.38 (1H, d, J = 1.9 Hz), 7.44 (1H, d, J = 8.7 Hz). I) tert-butyl (4RS) -4- (3,4-dichlorophenyl) -4- (hydroxymethyl) azepan-1-carboxylate (5RS) -5-({[tert-butyl (dimethyl) silyl] oxy} To a THF solution (2 mL) of methyl) -5- (3,4-dichlorophenyl) azepan-2-one (0.066 g) was added 1M tetrahydrofuran-borane solution (2 mL), and the mixture was stirred at 65 ° C. for 2 hours. To the reaction mixture was added 1N aqueous hydrochloric acid (1 mL) at 65 ° C., and the mixture was stirred at 60 ° C. for 1 hr. To the reaction mixture, triethylamine (0.1 mL) and di-tert-butyl dicarbonate (0.057 mL) were added at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (0.053 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.27 (1H, brs), 1.33-1.44 (9H, m), 1.57-1.69 (2H, m), 1.73-1.93 (2H, m), 2.18-2.42 (2H , m), 3.02-3.39 (3H, m), 3.46 (2H, s), 3.51-3.79 (1H, m), 7.15 (1H, dd, J = 8.5, 1.7 Hz), 7.38 (1H, d, J = 1.9 Hz), 7.44 (1H, d, J = 8.7 Hz).
J) [(4RS)-4-(3,4-ジクロロフェニル)アゼパン-4-イル]メタノール　塩酸塩
　tert-ブチル (4RS)-4-(3,4-ジクロロフェニル)-4-(ヒドロキシメチル)アゼパン-1-カルボキシラートを用い、実施例1の工程Bと同様にして標題化合物を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.45-1.66 (1H, m), 1.86 (2H, dd, J = 14.6, 10.0 Hz), 2.01-2.22 (2H, m), 2.33 (1H, dd, J = 15.9, 8.0 Hz), 2.88 (1H, dd, J = 13.6, 9.5 Hz), 3.01 (2H, t, J = 5.1 Hz), 3.16-3.28 (1H, m), 3.35 (2H, d, J = 5.3 Hz), 4.89 (1H, t, J = 5.3 Hz), 7.32-7.41 (1H, m), 7.54-7.66 (2H, m), 8.95 (2H, brs). MS (ESI+): [M+]+ 274.1 J) [(4RS) -4- (3,4-Dichlorophenyl) azepan-4-yl] methanol hydrochloride tert-butyl (4RS) -4- (3,4-dichlorophenyl) -4- (hydroxymethyl) azepan- The title compound was obtained in the same manner as in Step B of Example 1 using 1-carboxylate.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.45-1.66 (1H, m), 1.86 (2H, dd, J = 14.6, 10.0 Hz), 2.01-2.22 (2H, m), 2.33 (1H, dd , J = 15.9, 8.0 Hz), 2.88 (1H, dd, J = 13.6, 9.5 Hz), 3.01 (2H, t, J = 5.1 Hz), 3.16-3.28 (1H, m), 3.35 (2H, d, J = 5.3 Hz), 4.89 (1H, t, J = 5.3 Hz), 7.32-7.41 (1H, m), 7.54-7.66 (2H, m), 8.95 (2H, brs). MS (ESI +): (M + ] + 274.1
実施例43
[(3RS)-3-(3,4-ジクロロフェニル)アゼパン-3-イル]メタノール　塩酸塩
A) (6RS)-6-(3,4-ジクロロフェニル)-6-(ヒドロキシメチル)アゼパン-2-オン
　実施例42の工程Gで得られた(3RS)-3-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-3-(3,4-ジクロロフェニル)シクロヘキサノン(0.459 g)のアセトニトリル溶液(10 mL)に塩化チタン(IV)(0.259 mL)とアジ化ナトリウム(154 mg)を加え、100℃で4時間攪拌した。反応混合物に飽和重曹水を室温で加え、酢酸エチルで抽出した。抽出液を蒸留水と飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下濃縮した後、残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製し、標題化合物(0.1 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.66-1.91 (4H, m), 2.13-2.33 (1H, m), 2.52 (2H, t, J = 5.9 Hz), 3.46-3.61 (2H, m), 3.64-3.75 (2H, m), 6.00 (1H, brs), 7.16 (1H, dd, J = 8.7, 2.3 Hz), 7.40 (1H, d, J = 2.3 Hz), 7.42-7.47 (1H, m). Example 43
[(3RS) -3- (3,4-Dichlorophenyl) azepan-3-yl] methanol hydrochloride
A) (6RS) -6- (3,4-Dichlorophenyl) -6- (hydroxymethyl) azepan-2-one (3RS) -3-({[tert-butyl ( Titanium (IV) chloride (0.259 mL) and sodium azide (154 mg) were added to a solution of (dimethyl) silyl] oxy} methyl) -3- (3,4-dichlorophenyl) cyclohexanone (0.459 g) in acetonitrile (10 mL) (10 mL). And stirred at 100 ° C. for 4 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (0.1 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.66-1.91 (4H, m), 2.13-2.33 (1H, m), 2.52 (2H, t, J = 5.9 Hz), 3.46-3.61 (2H, m), 3.64-3.75 (2H, m), 6.00 (1H, brs), 7.16 (1H, dd, J = 8.7, 2.3 Hz), 7.40 (1H, d, J = 2.3 Hz), 7.42-7.47 (1H, m) .
B) tert-ブチル (3RS)-3-(3,4-ジクロロフェニル)-3-(ヒドロキシメチル)アゼパン-1-カルボキシラート
　(6RS)-6-(3,4-ジクロロフェニル)-6-(ヒドロキシメチル)アゼパン-2-オンを用い、実施例42の工程Iと同様にして、標題化合物(0.1 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.40-1.99 (14H, m), 2.22-2.36 (1H, m), 2.81-3.19 (3H, m), 3.34 (1H, brs), 3.44 (2H, s), 3.64-3.84 (1H, m), 7.32 (1H, dd, J = 8.5, 2.5 Hz), 7.49-7.58 (2H, m). B) tert-butyl (3RS) -3- (3,4-dichlorophenyl) -3- (hydroxymethyl) azepan-1-carboxylate (6RS) -6- (3,4-dichlorophenyl) -6- (hydroxymethyl) ) Using azepan-2-one, the title compound (0.1 g) was obtained in the same manner as in Step 42 of Example 42.
1 H NMR (300 MHz, CDCl 3 ) δ 1.40-1.99 (14H, m), 2.22-2.36 (1H, m), 2.81-3.19 (3H, m), 3.34 (1H, brs), 3.44 (2H, s ), 3.64-3.84 (1H, m), 7.32 (1H, dd, J = 8.5, 2.5 Hz), 7.49-7.58 (2H, m).
C) [(3RS)-3-(3,4-ジクロロフェニル)アゼパン-3-イル]メタノール　塩酸塩
　tert-ブチル (3RS)-3-(3,4-ジクロロフェニル)-3-(ヒドロキシメチル)アゼパン-1-カルボキシラートを用い、実施例1の工程Bと同様にして標題化合物を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.42-1.57 (1H, m), 1.73 (3H, d, J = 4.9 Hz), 1.92 (1H, dd, J = 14.7, 9.8 Hz), 2.04-2.18 (1H, m), 2.87-2.99 (1H, m), 3.05-3.19 (1H, m), 3.37-3.51 (3H, m), 3.63 (1H, d, J = 14.7 Hz), 5.18 (1H, brs), 7.38 (1H, dd, J = 8.7, 2.3 Hz), 7.58-7.67 (2H, m), 8.88 (2H, brs). MS (ESI+): [M+]+ 274.1 C) [(3RS) -3- (3,4-Dichlorophenyl) azepan-3-yl] methanol hydrochloride tert-butyl (3RS) -3- (3,4-dichlorophenyl) -3- (hydroxymethyl) azepan- The title compound was obtained in the same manner as in Step B of Example 1 using 1-carboxylate.
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.42-1.57 (1H, m), 1.73 (3H, d, J = 4.9 Hz), 1.92 (1H, dd, J = 14.7, 9.8 Hz), 2.04- 2.18 (1H, m), 2.87-2.99 (1H, m), 3.05-3.19 (1H, m), 3.37-3.51 (3H, m), 3.63 (1H, d, J = 14.7 Hz), 5.18 (1H, brs), 7.38 (1H, dd, J = 8.7, 2.3 Hz), 7.58-7.67 (2H, m), 8.88 (2H, brs). MS (ESI +): [M +] + 274.1
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000089
試験例１
（１）ヒトドーパミントランスポーター発現プラスミドの構築
　特開平5-076385記載のpTB1411に含まれるSRαプロモーターは、制限酵素HindIII(タカラバイオ社製)で切断し、平滑末端化後、さらに制限酵素EcoRI(タカラバイオ社製)で切断し、断片化した。一方、pCIベクターは、制限酵素BglII(タカラバイオ社製)で切断し、T4DNAポリメラーゼで平滑末端化後、さらに制限酵素EcoRI(タカラバイオ社製)で切断した。このサイトにSRαプロモーター断片を挿入して、pCI-SRαを作製した。次いで、pCI-SRαを制限酵素ClaI(タカラバイオ社製)で切断後、平滑末端化したサイトに、pGFP-C1(東洋紡社製)を制限酵素Bsu36I(第一化学薬品社製)で切断後、平滑末端化した1.63Kbの断片を挿入し、pMSRα neoを作製した。ヒトドーパミントランスポーターcDNAは、ヒト黒質cDNAライブラリーよりPCRにより増幅し、pCRIIベクター（Invitrogen社製）に挿入した。塩基配列を確認・修正後、pMSRα neoにサブクローニングし、ヒトドーパミントランスポーター発現プラスミドを構築した。 Test example 1
(1) Construction of human dopamine transporter expression plasmid The SRα promoter contained in pTB1411 described in JP-A-5-076385 is cleaved with restriction enzyme HindIII (manufactured by Takara Bio Inc.), blunt-ended, and further subjected to restriction enzyme EcoRI (Takara (Manufactured by Bio Inc.) and fragmented. On the other hand, the pCI vector was cleaved with the restriction enzyme BglII (Takara Bio), blunt-ended with T4 DNA polymerase, and further cleaved with the restriction enzyme EcoRI (Takara Bio). An SRα promoter fragment was inserted into this site to prepare pCI-SRα. Next, after cleaving pCI-SRα with restriction enzyme ClaI (Takara Bio), blunt-ended sites, pGFP-C1 (Toyobo) after cleavage with restriction enzyme Bsu36I (Daiichi Kagaku), A blunt-ended 1.63 Kb fragment was inserted to prepare pMSRα neo. Human dopamine transporter cDNA was amplified by PCR from a human substantia nigra cDNA library and inserted into a pCRII vector (Invitrogen). After confirming and correcting the nucleotide sequence, it was subcloned into pMSRα neo to construct a human dopamine transporter expression plasmid.
（２）ヒトモノアミン発現細胞の作製
　ヒトセロトニントランスポーターcDNAは、ヒト脳cDNAライブラリーよりPCRにより増幅し、pCRII-TOPOベクター（Invitrogen社製）に挿入した。塩基配列を確認・修正後、pcDNA３．１ベクター（Invitrogen社製）にサブクローニングし、ヒトセロトニントランスポーター発現プラスミドを構築した。ヒトノルエピネフリントランスポーターcDNAは、Invitrogen社より購入し、塩基配列を確認・修正後、pcDNA３．１ベクターにサブクローニングし、ヒトノルエピネフリントランスポーター発現プラスミドを構築した。
　これら作製したモノアミントランスポーター発現プラスミドを、FuGENE6（Roche Diagnostics社製）を用い、添付のプロトコールに従いCHO-K1細胞に導入し、それぞれの発現細胞を樹立した。 (2) Preparation of human monoamine-expressing cells Human serotonin transporter cDNA was amplified by PCR from a human brain cDNA library and inserted into a pCRII-TOPO vector (Invitrogen). After confirming and correcting the base sequence, it was subcloned into pcDNA3.1 vector (manufactured by Invitrogen) to construct a human serotonin transporter expression plasmid. Human norepinephrine transporter cDNA was purchased from Invitrogen, and after confirming and correcting the nucleotide sequence, it was subcloned into pcDNA3.1 vector to construct a human norepinephrine transporter expression plasmid.
These prepared monoamine transporter expression plasmids were introduced into CHO-K1 cells using FuGENE6 (Roche Diagnostics) according to the attached protocol to establish each expression cell.
（３）ヒトセロトニントランスポーターに対する阻害作用
　ヒトセロトニントランスポーター阻害活性の測定にはヒトセロトニントランスポーターを安定発現したCHO細胞を用いた。特に記載が無い限り、これらのCHO細胞は、10%牛胎児血清(MOREGATE)を含むHam/F12培地(Invitrogen)を用いて培養した。
　ほぼコンフルエントになるまで培養した細胞を、PBS (Invitrogen)を用いてリンスした後、Trypsin/EDTA (Invitrogen)を用いて剥がし、遠心操作にて回収した。得られた細胞の数を測定し、培地1 mLあたり3×105個の細胞が含まれるように希釈し、96 well white plate (Corning)に1穴あたり100 μLずつ分注後、CO2培養器にて一晩培養した。
　次に、アッセイバッファー（126 mM NaCl, 4.95 mM KCl, 1.26 mM KH2PO4, 1.26 mM MgSO4, 10 mM HEPES, 2.32 mM CaCl2, 5.52 mM Glucose, 0.5% BSA）を調製し、細胞プレートの培地を除去した後、80 μLずつアッセイバッファーを添加した。また試験化合物をアッセイバッファーにて終濃度の10倍濃度となるように希釈し、ポリプロピレン製96 well plateに分注した。その希釈した試験化合物を10 μLずつ細胞プレートに分注した。[3H]-5-ヒドロキシトリプタミン（GE Healthcare）をアッセイバッファーにて200 nMとなるように希釈し、それを細胞プレートに10 μLずつ分注した。[3H]-5-ヒドロキシトリプタミンを添加してから20分経過したところで、アッセイバッファーを吸引除去し、PBS (Invitrogen)で1穴あたり150 μL、2回洗浄した。Microscinti20（PerkinElmer）を1穴あたり100 μLずつ分注し、30分前後攪拌した。放射活性はTopCount（PerkinElmer）で測定した。
　各化合物の10 μMの阻害活性を、10 μMのParoxetine（セロトニントランスポーター阻害剤）の阻害活性を100%とする相対活性値として算出した。その結果を以下の表２－１に示す。 (3) Inhibitory effect on human serotonin transporter For the measurement of human serotonin transporter inhibitory activity, CHO cells stably expressing human serotonin transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE).
Cells cultured until almost confluent were rinsed with PBS (Invitrogen), then detached with Trypsin / EDTA (Invitrogen), and collected by centrifugation. Count the number of cells obtained, dilute to contain 3 × 10 5 cells per mL of medium, dispense 100 μL per well into a 96 well white plate (Corning), and culture with CO 2 Incubated overnight in a vessel.
Next, prepare the assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH 2 PO 4 , 1.26 mM MgSO 4 , 10 mM HEPES, 2.32 mM CaCl 2 , 5.52 mM Glucose, 0.5% BSA) After removing the medium, 80 μL of assay buffer was added. Further, the test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 μL of the diluted test compound was dispensed into the cell plate. [3H] -5-hydroxytryptamine (GE Healthcare) was diluted to 200 nM with an assay buffer, and 10 μL was dispensed onto the cell plate. After 20 minutes from the addition of [3H] -5-hydroxytryptamine, the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 μL per well. Microscinti20 (PerkinElmer) was dispensed at 100 μL per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer).
The 10 μM inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 10 μM Paroxetine (serotonin transporter inhibitor) as 100%. The results are shown in Table 2-1 below.
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000090
　また、各化合物の1 μMの阻害活性を、10 μMのParoxetine(セロトニントランスポーター阻害剤)の阻害活性を100%とする相対活性値として算出した。その結果を以下の表２－２に示す。 In addition, 1 μM inhibitory activity of each compound was calculated as a relative activity value where the inhibitory activity of 10 μM Paroxetine (a serotonin transporter inhibitor) was 100%. The results are shown in Table 2-2 below.
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000091
試験例２　ヒトノルエピネフリントランスポーターに対する阻害作用
　ヒトノルエピネフリントランスポーター阻害活性の測定にはヒトノルエピネフリントランスポーターを安定発現したCHO細胞を用いた。特に記載が無い限り、これらのCHO細胞は10%牛胎児血清(MOREGATE)を含むHam/F12培地(Invitrogen)を用いて培養した。
　ほぼコンフルエントになるまで培養した細胞を、PBS (Invitrogen)を用いてリンスした後、Trypsin/EDTA (Invitrogen)を用いて剥がし、遠心操作にて回収した。得られた細胞の数を測定し、培地1 mLあたり3×105個の細胞が含まれるように希釈し、96 well white plate (Corning)に1穴あたり100 μLずつ分注後、CO2培養器にて一晩培養した。
　次にアッセイバッファー（126 mM NaCl, 4.95 mM KCl, 1.26 mM KH2PO4, 1.26 mM MgSO4, 10 mM HEPES, 2.32 mM CaCl2, 5.52 mM Glucose, 0.5% BSA）を調製し、細胞プレートの培地を除去した後、80 μLずつアッセイバッファーを添加した。また試験化合物をアッセイバッファーにて終濃度の10倍濃度となるように希釈し、ポリプロピレン製96 well plateに分注した。その希釈した試験化合物を10 μLずつ細胞プレートに分注した。[3H]-ノルエピネフリン（GE Healthcare）をアッセイバッファーにて200 nMとなるように希釈し、それを細胞プレートに10 μLずつ分注した。[3H]-ノルエピネフリンを添加してから45分経過したところで、アッセイバッファーを吸引除去し、PBS (Invitrogen)で1穴あたり150 μL、2回洗浄した。Microscinti20（PerkinElmer）を1穴あたり100 μLずつ分注し、30分前後攪拌した。放射活性はTopCount（PerkinElmer）で測定した。
　各化合物の10 μMの阻害活性を、10 μMのDMI（ノルエピネフリントランスポーター阻害剤）の阻害活性を100%とする相対活性値として算出した。その結果を以下の表３－１に示す。 Test Example 2 Inhibitory Action on Human Norepinephrine Transporter For measurement of human norepinephrine transporter inhibitory activity, CHO cells stably expressing human norepinephrine transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE).
Cells cultured until almost confluent were rinsed with PBS (Invitrogen), then detached with Trypsin / EDTA (Invitrogen), and collected by centrifugation. Count the number of cells obtained, dilute to contain 3 × 10 5 cells per mL of medium, dispense 100 μL per well into a 96 well white plate (Corning), and culture with CO 2 Incubated overnight in a vessel.
Next, prepare assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH 2 PO 4 , 1.26 mM MgSO 4 , 10 mM HEPES, 2.32 mM CaCl 2 , 5.52 mM Glucose, 0.5% BSA) Then, 80 μL of assay buffer was added. Further, the test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 μL of the diluted test compound was dispensed into the cell plate. [3H] -norepinephrine (GE Healthcare) was diluted to 200 nM with an assay buffer, and 10 μL was dispensed onto the cell plate. 45 minutes after the addition of [3 H] -norepinephrine, the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 μL per well. Microscinti20 (PerkinElmer) was dispensed at 100 μL per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer).
The 10 μM inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 10 μM DMI (norepinephrine transporter inhibitor) as 100%. The results are shown in Table 3-1 below.
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000092
　また、各化合物の1 μMの阻害活性を、10 μMのDMI(ノルエピネフリントランスポーター阻害剤)の阻害活性を100%とする相対活性値として算出した。その結果を以下の表３－２に示す。 Also, the 1 μM inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 10 μM DMI (norepinephrine transporter inhibitor) as 100%. The results are shown in Table 3-2 below.
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000093
試験例３　ヒトドーパミントランスポーターに対する阻害作用
　ヒトドーパミントランスポーター阻害活性の測定にはヒトドーパミントランスポーターを安定発現したCHO細胞を用いた。特に記載が無い限り、これらのCHO細胞は10%牛胎児血清(MOREGATE)を含むHam/F12培地(Invitrogen)を用いて培養した。
　アッセイ前日に、ほぼコンフルエントになるまで培養した細胞を、PBS (Invitrogen)を用いてリンスした後、Trypsin/EDTA (Invitrogen)を用いて剥がし、遠心操作にて回収した。得られた細胞の数を測定し、培地1 mLあたり3×105個の細胞が含まれるように希釈し、96 well white plate (Corning)に1穴あたり100 μLずつ分注後、CO2培養器にて一晩培養した。
　試験当日にアッセイバッファー（126 mM NaCl, 4.95 mM KCl, 1.26 mM KH2PO4, 1.26 mM MgSO4, 10 mM HEPES, 2.32 mM CaCl2, 5.52 mM Glucose, 0.5% BSA）を調製し、細胞プレートの培地を除去した後、80 μLずつアッセイバッファーを添加した。また試験化合物をアッセイバッファーにて終濃度の10倍濃度となるように希釈し、ポリプロピレン製96 well plateに分注した。その希釈した試験化合物を10 μLずつ細胞プレートに分注した。アッセイバッファーで[3H]-ドーパミン（GE Healthcare）を200 nMとなるように希釈し、またコールドのドーパミンを10 μMとなるように希釈した。それを細胞プレートに10 μLずつ分注した。[3H]-ドーパミンを添加してから60分経過したところで、アッセイバッファーを吸引除去し、PBS (Invitrogen)で1穴あたり150 μL、2回洗浄した。Microscinti20（PerkinElmer）を1穴あたり100 μLずつ分注し、30分前後攪拌した。放射活性はTopCount（PerkinElmer）で測定した。
　各化合物の10 μMの阻害活性を、100 μMのNomifensine（ドーパミントランスポーター阻害剤）の阻害活性を100%とする相対活性値として算出した。その結果を以下の表４－１に示す。 Test Example 3 Inhibitory action on human dopamine transporter For the measurement of human dopamine transporter inhibitory activity, CHO cells stably expressing human dopamine transporter were used. Unless otherwise stated, these CHO cells were cultured using Ham / F12 medium (Invitrogen) containing 10% fetal calf serum (MOREGATE).
On the day before the assay, the cells cultured until they were almost confluent were rinsed with PBS (Invitrogen), detached with Trypsin / EDTA (Invitrogen), and collected by centrifugation. Count the number of cells obtained, dilute to contain 3 × 10 5 cells per mL of medium, dispense 100 μL per well into a 96 well white plate (Corning), and culture with CO 2 Incubated overnight in a vessel.
Prepare assay buffer (126 mM NaCl, 4.95 mM KCl, 1.26 mM KH 2 PO 4 , 1.26 mM MgSO 4 , 10 mM HEPES, 2.32 mM CaCl 2 , 5.52 mM Glucose, 0.5% BSA) on the day of the test. After removing the medium, 80 μL of assay buffer was added. Further, the test compound was diluted with an assay buffer so as to have a concentration 10 times the final concentration, and dispensed into a 96-well plate made of polypropylene. 10 μL of the diluted test compound was dispensed into the cell plate. [3H] -Dopamine (GE Healthcare) was diluted to 200 nM with assay buffer, and cold dopamine was diluted to 10 μM. 10 μL was dispensed onto the cell plate. When 60 minutes had elapsed since the addition of [3 H] -dopamine, the assay buffer was removed by aspiration and washed twice with PBS (Invitrogen) at 150 μL per well. Microscinti20 (PerkinElmer) was dispensed at 100 μL per well and stirred for about 30 minutes. Radioactivity was measured with TopCount (PerkinElmer).
The 10 μM inhibitory activity of each compound was calculated as a relative activity value with the inhibitory activity of 100 μM Nomifensine (dopamine transporter inhibitor) as 100%. The results are shown in Table 4-1 below.
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
　また、各化合物の1 μMの阻害活性を、100 μMのNomifensine(ドーパミントランスポーター阻害剤)の阻害活性を100%とする相対活性値として算出した。その結果を以下の表４－２に示す。 In addition, 1 μM inhibitory activity of each compound was calculated as a relative activity value where the inhibitory activity of 100 μM Nomifensine (dopamine transporter inhibitor) was 100%. The results are shown in Table 4-2 below.
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
試験例４　尿道抵抗上昇作用の測定
　ラットを用いた尿道抵抗上昇作用の測定は、松本ら（ＰＣＴ／ＪＰ２００８／７０８０９）の方法に倣い、修正して、次のようにして行った。すなわち、ＳＤ雌性ラット（日本クレア）へ、イソフルラン（１．０％；Ａｂｂｏｔｔ）を用いて麻酔をし、排尿反射を消失させるために脊髄をＴｈ８－９で切断した。開腹後、膀胱内圧測定用および生理食塩水注入用のカテーテル（ＰＥ－１００；Ｃｌａｙ　Ａｄａｍｓ）を膀胱に挿入した。その後、ラットの開腹部は、アロンアルファＡ「三共」（Ｄａｉｉｃｈｉ　Ｓａｎｋｙｏ）を用いて閉じた。カテーテルを挿入したラットを、ボールマンケージ（ＫＮ－３２６　ボールマンケージ　ＩＩＩ型；Ｎａｔｓｕｍｅ）へ固定した。膀胱内圧測定用カテーテルは、圧トランスデユーサー（ＲＥＦ６８５６４０；Ｎｉｈｏｎ　Ｋｏｄｅｎ）、アンプ（ＲＰＭ-６００８Ｍ；Ｎｉｈｏｎ　Ｋｏｄｅｎ）、多チャンネルデーター解析装置（ＭＰ１５０；Ｂｉｏｐａｃｋ）を介してコンピューターに接続し、膀胱内圧の変化を１００　ｓａｍｐｌｅｓ／秒の頻度でハードディスクに記録した。生理食塩水注入用のカテーテルは、Ｅｖａｎｓ　Ｂｌｕｅ（Ｗａｋｏ）を用いて着色した生理食塩水を満たした５０ ｍＬ　シリンジ（Ｔｅｒｕｍｏ）へ接続した。そして、生理食塩水を接続した５０ ｍＬシリンジより、インフュージョンポンプ（Ｋｄｓ１００；ＫＤＳｃｉｅｎｔｉｆｉｃ）を用いて、０．１　ｍＬ／秒の速度で膀胱内へ注入し、尿道口から生理食塩水の漏出が観察されたときに注入を停止し、膀胱内の生理食塩水を排出させた。生理食塩水を膀胱内へ注入し漏出するまでの最大圧をＬＰＰ（Ｌｅａｋ　ｐｏｉｎｔ　ｐｒｅｓｓｕｒｅ）値とした。ＬＰＰ値が安定するまで測定を繰り返し、連続して安定した３回のＬＰＰ値の平均を結果とした。また、薬物の作用は、動物をボールマンケージへ固定した１時間後から測定を始め、ＬＰＰ値（Ｐｒｅ値）を測定した後に、薬物を静脈内投与し、１０分後に、再びＬＰＰ値（Ｐｏｓｔ値）を測定し、薬物による尿道抵抗上昇作用は、ＬＰＰ値（Ｐｏｓｔ値）とＬＰＰ値（Ｐｒｅ値）の差で表した。薬物は、生理食塩水を溶媒として用いて、１．０　ｍＬ／ｋｇの割合で静脈内投与した。溶媒に比較した薬物による尿道抵抗上昇作用の有意差検定は、Ｗｉｌｌｉａｍｓ検定を用いた。
　実施例１２の化合物０．３　ｍｇ／ｋｇ、実施例１２の化合物１．０　ｍｇ／ｋｇおよび溶媒をラットへ投与し、上述した方法において、尿道抵抗上昇作用を測定した。以下の表５－１に示すように、実施例１２の化合物を投与したラットにおいて、溶媒投与に比べて、用量依存的かつ有意な尿道抵抗上昇作用を示した。 Test Example 4 Measurement of urethral resistance increasing action The measurement of urethral resistance increasing action using rats was carried out as follows in accordance with the method of Matsumoto et al. (PCT / JP2008 / 70809). That is, SD female rats (CLEA Japan) were anesthetized with isoflurane (1.0%; Abbott), and the spinal cord was cut with Th8-9 to eliminate the micturition reflex. After laparotomy, a catheter (PE-100; Clay Adams) for measuring intravesical pressure and injecting physiological saline was inserted into the bladder. The rat laparotomy was then closed using Aron Alpha A “Sankyo” (Daiichi Sankyo). The rat with the inserted catheter was fixed to a ball man cage (KN-326 ball man cage type III; Natsume). The intravesical pressure measurement catheter is connected to a computer via a pressure transducer (REF 695640; Nihon Koden), an amplifier (RPM-6008M; Nihon Koden), and a multi-channel data analyzer (MP150; Biopack) to change the intravesical pressure. Was recorded on the hard disk at a frequency of 100 samples / second. The saline injection catheter was connected to a 50 mL syringe (Terumo) filled with colored saline using Evans Blue (Wako). Then, the infusion pump (Kds100; KD Scientific) was used to inject into the bladder at a rate of 0.1 mL / second from a 50 mL syringe connected with physiological saline, and the leakage of physiological saline was observed from the urethral orifice. When infused, the infusion was stopped and saline in the bladder was drained. The maximum pressure until physiological saline was injected into the bladder and leaked was defined as an LPP (Leak point pressure) value. The measurement was repeated until the LPP value was stabilized, and the result was an average of three consecutive LPP values that were stable. The action of the drug was measured 1 hour after the animal was fixed to the Ballman cage, the LPP value (Pre value) was measured, the drug was administered intravenously, 10 minutes later, the LPP value (Post) Value) was measured, and the urethral resistance increasing action by the drug was expressed by the difference between the LPP value (Post value) and the LPP value (Pre value). The drug was intravenously administered at a rate of 1.0 mL / kg using physiological saline as a solvent. The Williams test was used for the significant difference test of the urethral resistance increasing action by the drug compared to the solvent.
The compound of Example 12 (0.3 mg / kg), the compound of Example 12 (1.0 mg / kg) and a solvent were administered to rats, and the effect of increasing urethral resistance was measured by the method described above. As shown in Table 5-1 below, the rats administered with the compound of Example 12 showed a dose-dependent and significant effect of increasing urethral resistance as compared with the solvent administration.
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000096
　また、実施例29の化合物0．3 mg／kg、1．0 mg／kg、3．0 mg／kgおよび溶媒をラットへ投与し、上述した方法において、尿道抵抗上昇作用を測定した。以下の表５－２に示すように、実施例29の化合物を投与したラットにおいて、溶媒投与に比べて、用量依存的かつ有意な尿道抵抗上昇作用を示した。 Further, the compound of Example 29, 0.3 mg / kg, 1.0 mg / kg, 3.0 mg / kg, and a solvent were administered to rats, and the urethral resistance increasing action was measured by the method described above. As shown in Table 5-2 below, the rat administered with the compound of Example 29 showed a dose-dependent and significant effect of increasing urethral resistance as compared with the solvent administration.
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000097
　また、実施例40の化合物1．0 mg／kg、3．0 mg／kgおよび溶媒をラットへ投与し、上述した方法において、尿道抵抗上昇作用を測定した。以下の表５－３に示すように、実施例40の化合物を投与したラットにおいて、溶媒投与に比べて、用量依存的かつ有意な尿道抵抗上昇作用を示した。 Further, the compound of Example 40 (1.0 mg / kg, 3.0 mg / kg) and a solvent were administered to rats, and the effect of increasing urethral resistance was measured by the method described above. As shown in Table 5-3 below, the rats administered with the compound of Example 40 showed a dose-dependent and significant effect of increasing urethral resistance as compared with vehicle administration.
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
製剤例１
　化合物（Ｉ’）を含有する医薬は、例えば、以下の処方によって製造することができる。
１．カプセル剤
（１）実施例１で得られた化合物 　４０ｍｇ
（２）ラクトース 　　　　　　　　７０ｍｇ
（３）微結晶セルロース 　　　　　　９ｍｇ
（４）ステアリン酸マグネシウム 　　１ｍｇ
１カプセル 　　　　　　　　　　１２０ｍｇ
　（１）、（２）、（３）および（４）の１／２を混和した後、顆粒化する。これに残りの（４）を加えて全体をゼラチンカプセルに封入する。 Formulation Example 1
The pharmaceutical containing compound (I ') can be manufactured by the following prescription, for example.
1. Capsule (1) 40 mg of the compound obtained in Example 1
(2) Lactose 70mg
(3) Microcrystalline cellulose 9mg
(4) Magnesium stearate 1mg
1 capsule 120mg
After mixing 1/2 of (1), (2), (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
２．錠剤
（１）実施例１で得られた化合物 　４０ｍｇ
（２）ラクトース 　　　　　　　　５８ｍｇ
（３）コーンスターチ 　　　　　　１８ｍｇ
（４）微結晶セルロース 　　　　３．５ｍｇ
（５）ステアリン酸マグネシウム ０．５ｍｇ
１錠 　　　　　　　　　　　　　１２０ｍｇ
　（１）、（２）、（３）、（４）の２／３および（５）の１／２を混和した後、顆粒化する。残りの（４）および（５）をこの顆粒に加えて錠剤に加圧成型する。 2. Tablet (1) Compound obtained in Example 1 40 mg
(2) Lactose 58mg
(3) Corn starch 18mg
(4) Microcrystalline cellulose 3.5mg
(5) Magnesium stearate 0.5mg
1 tablet 120mg
After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
製剤例２
　日局注射用蒸留水５０ｍＬに実施例１で得られた化合物５０ｍｇを溶解した後、日局注射用蒸留水を加えて１００ｍＬとする。この溶液を滅菌条件下でろ過し、次にこの溶液１ｍＬずつを取り、滅菌条件下、注射用バイアルに充填し、凍結乾燥して密閉する。 Formulation Example 2
After dissolving 50 mg of the compound obtained in Example 1 in 50 mL of JP injection distilled water, JP JP distilled water is added to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.
　本願発明の化合物またはそのプロドラッグは、優れたモノアミン（セロトニン、ノルエピネフリン、ドーパミン等）再取り込み阻害活性を有するため、例えば、うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮および腹圧性尿失禁等の安全な予防または治療薬として有用である。 Since the compound of the present invention or a prodrug thereof has an excellent monoamine (serotonin, norepinephrine, dopamine, etc.) reuptake inhibitory activity, for example, depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, It is useful as a safe preventive or therapeutic agent for pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia and stress urinary incontinence.
　本出願は、日本で出願された特願２０１１－１３２８９６を基礎としており、その内容は本明細書にすべて包含されるものである。 This application is based on Japanese Patent Application No. 2011-132896 filed in Japan, the contents of which are incorporated in full herein.

Claims (17)

  1. 　式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
    〔式中、環Ａは、置換基を有するベンゼン環、または置換基を有していてもよい５～６員芳香族複素環を示す；
    Figure JPOXMLDOC01-appb-C000002
    で表される基は、
    Figure JPOXMLDOC01-appb-C000003
    （式中、環Ｂ１、環Ｂ２または環Ｂ３は、さらに置換基を有していてもよい；
    Figure JPOXMLDOC01-appb-C000004
    は、単結合または二重結合を示す；
    Ｘ１、Ｘ２およびＸ３のいずれか１つは－ＮＨ－を示し、他の２つは各々独立して－ＣＲ２Ｒ３－（Ｒ２およびＲ３は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。）で表される基を示す；
    環Ｂが環Ｂ１または環Ｂ２である場合、Ｒ１は、ヒドロキシ基、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示し、
    環Ｂが環Ｂ３である場合、Ｒ１は、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、（ａ）ハロゲン原子、（ｂ）Ｃ１－６アルコキシ基、（ｃ）－Ｓ－Ｒ１ａ、（ｄ）－ＳＯ２－Ｒ１ａ、（ｅ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｆ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｇ）－ＮＨ－ＣＯ－Ｒ１ａ、（ｈ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｉ）－ＮＨ－ＳＯ２－Ｒ１ａ、（ｊ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）および（ｋ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル（式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す；
    ただし、環Ｂ１、環Ｂ２または環Ｂ３の環構成原子である窒素原子に結合した水素原子は置換されない。）で表される基を示す；
    また、環Ａ上の置換基同士が結合して、環Ａと共に、置換基を有していてもよい８～１０員芳香族縮合環を形成してもよい。〕で表される化合物
    （ただし、（１）式：
    Figure JPOXMLDOC01-appb-C000005
    （式中、Ｒｘ１は水素原子またはメチル基を示し、Ｒｘ２は－ＣＨ２－ＣＯ－Ｎ（ＣＨ３）－ＣＨＲａ１－Ｒａ２（Ｒａ１は水素原子またはメチル基を、Ｒａ２はハロゲン原子およびトリフルオロメチル基から選択される２個の置換基で３，５－置換されたフェニル基を示す。）で表される基を示し、Ｒｘ３は水素原子またはフッ素原子を示す。）で表される化合物、
    （２）式（Ｉ）中、
    Figure JPOXMLDOC01-appb-C000006
    で表される基が、
    Figure JPOXMLDOC01-appb-C000007
    （式中、Ｒ１は上記と同義を表す。）で表される基である化合物、
    （３）［４－（４－フルオロフェニル）アゼパン－４－イル］酢酸、
    （４）３－アミノ－Ｎ－｛［４－（３－フルオロフェニル）アゼパン－４－イル］メチル｝ピラジン－２－カルボキサミド、
    （５）Ｎ－｛［４－（３－フルオロフェニル）アゼパン－４－イル］メチル｝－２－メトキシベンズアミド、
    （６）４－（１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル）アゼパン－４－オール、
    （７）４－［１－（４－フルオロベンジル）－１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル］アゼパン－４－オール、
    （８）４－（４－クロロフェニル）アゼパン－４－オール、
    （９）２－［３－（３，４－ジクロロフェニル）アゼパン－３－イル］エタノール、
    （１０）４－（３－フルオロフェニル）－７－オキソアゼパン－４－カルボニトリル、
    （１１）４－（３－メトキシフェニル）－７－オキソアゼパン－４－カルボニトリル、
    （１２）３－（４－フルオロフェニル）アゼパン－３－オール、
    （１３）３－（３，４－ジクロロフェニル）－３－［３－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）プロピル］アゼパン、
    （１４）３－（３，４－ジクロロフェニル）－３－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］アゼパン、
    および
    （１５）２－［３－（３－メトキシフェニル）アゼパン－３－イル］エタノール
    を除く。）またはその塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000001
    [Wherein, ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent;
    Figure JPOXMLDOC01-appb-C000002
    The group represented by
    Figure JPOXMLDOC01-appb-C000003
    (In the formula, ring B 1 , ring B 2 or ring B 3 may further have a substituent;
    Figure JPOXMLDOC01-appb-C000004
    Represents a single bond or a double bond;
    Any one of X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or an optionally substituted C 1-6 alkyl group).
    When Ring B is Ring B 1 or Ring B 2 , R 1 is a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, a substituted C 1-6 alkyl A group, an optionally substituted C 1-6 alkoxy group, or an optionally substituted carbamoyl group,
    When ring B is ring B 3 , R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a C 1-6 alkoxy group (C) -S-R 1a , (d) -SO 2 -R 1a , (e) -SO 2 -N (R 1b ) (R 1c ), (f) -N (R 1b ) (R 1c ) (G) —NH—CO—R 1a , (h) —NH—CO—N (R 1b ) (R 1c ), (i) —NH—SO 2 —R 1a , (j) —NH—SO 2 —N (R 1b ) (R 1c ) and (k) 1H-pyrazol-1-yl optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group (wherein R 1a Is a C 1-6 alkyl group, R 1b and R 1c are each independently a hydrogen atom or C 1-6 A C 1-6 alkyl group substituted with 1 to 3 substituents selected from: a C 1-6 alkoxy group which may be substituted, or a carbamoyl group which may be substituted; Indicates;
    However, the hydrogen atom bonded to the nitrogen atom which is the ring constituent atom of ring B 1 , ring B 2 or ring B 3 is not substituted. ) Represents a group represented by
    In addition, substituents on ring A may be bonded to each other to form an 8- to 10-membered aromatic condensed ring which may have a substituent together with ring A. ] A compound represented by the formula (However, the formula (1):
    Figure JPOXMLDOC01-appb-C000005
    (Wherein R x1 represents a hydrogen atom or a methyl group, R x2 represents —CH 2 —CO—N (CH 3 ) —CHR a1 —R a2 (R a1 represents a hydrogen atom or a methyl group, and R a2 represents a halogen atom) 2 represents a 3,5-substituted phenyl group with two substituents selected from an atom and a trifluoromethyl group.), And R x3 represents a hydrogen atom or a fluorine atom. The compound represented,
    (2) In formula (I),
    Figure JPOXMLDOC01-appb-C000006
    The group represented by
    Figure JPOXMLDOC01-appb-C000007
    (Wherein R 1 represents the same meaning as described above),
    (3) [4- (4-Fluorophenyl) azepan-4-yl] acetic acid,
    (4) 3-amino-N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} pyrazine-2-carboxamide;
    (5) N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} -2-methoxybenzamide,
    (6) 4- (1H-imidazo [4,5-b] pyridin-2-yl) azepan-4-ol,
    (7) 4- [1- (4-Fluorobenzyl) -1H-imidazo [4,5-b] pyridin-2-yl] azepan-4-ol,
    (8) 4- (4-chlorophenyl) azepan-4-ol,
    (9) 2- [3- (3,4-Dichlorophenyl) azepan-3-yl] ethanol,
    (10) 4- (3-Fluorophenyl) -7-oxoazepane-4-carbonitrile,
    (11) 4- (3-methoxyphenyl) -7-oxoazepane-4-carbonitrile,
    (12) 3- (4-fluorophenyl) azepan-3-ol,
    (13) 3- (3,4-Dichlorophenyl) -3- [3- (tetrahydro-2H-pyran-2-yloxy) propyl] azepane,
    (14) 3- (3,4-dichlorophenyl) -3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] azepan,
    And (15) 2- [3- (3-methoxyphenyl) azepan-3-yl] ethanol. ) Or its salt.
  2. 　式（Ｉ）
    Figure JPOXMLDOC01-appb-C000008
    〔式中、環Ａは、置換基を有するベンゼン環、または置換基を有していてもよい５～６員芳香族複素環を示す；
    Figure JPOXMLDOC01-appb-C000009
    で表される基は、
    Figure JPOXMLDOC01-appb-C000010
    （式中、環Ｂ１または環Ｂ２は、さらに置換基を有していてもよい；
    Figure JPOXMLDOC01-appb-C000011
    は、単結合または二重結合を示す；
    Ｘ１、Ｘ２およびＸ３のいずれか１つは－ＮＨ－を示し、他の２つは－ＣＲ２Ｒ３－（Ｒ２およびＲ３は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。）で表される基を示す；
    Ｒ１は、ヒドロキシ基、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す；
    ただし、環Ｂ１または環Ｂ２の環構成原子である窒素原子に結合した水素原子は置換されない。）で表される基を示す；
    また、環Ａ上の置換基同士が結合して、環Ａと共に、置換基を有していてもよい８～１０員芳香族縮合環を形成してもよい。〕で表される請求項１記載の化合物
    （ただし、（１）式：
    Figure JPOXMLDOC01-appb-C000012
    （式中、Ｒｘ１は水素原子またはメチル基を示し、Ｒｘ２は－ＣＨ２－ＣＯ－Ｎ（ＣＨ３）－ＣＨＲａ１－Ｒａ２（Ｒａ１は水素原子またはメチル基を、Ｒａ２はハロゲン原子およびトリフルオロメチル基から選択される２個の置換基で３，５－置換されたフェニル基を示す。）で表される基を示し、Ｒｘ３は水素原子またはフッ素原子を示す。）で表される化合物、
    （２）式（Ｉ）中、
    Figure JPOXMLDOC01-appb-C000013
    で表される基が、
    Figure JPOXMLDOC01-appb-C000014
    （式中、Ｒ１は上記と同義を表す。）で表される基である化合物、
    （３）［４－（４－フルオロフェニル）アゼパン－４－イル］酢酸、
    （４）３－アミノ－Ｎ－｛［４－（３－フルオロフェニル）アゼパン－４－イル］メチル｝ピラジン－２－カルボキサミド、
    （５）Ｎ－｛［４－（３－フルオロフェニル）アゼパン－４－イル］メチル｝－２－メトキシベンズアミド、
    （６）４－（１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル）アゼパン－４－オール、
    （７）４－［１－（４－フルオロベンジル）－１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル］アゼパン－４－オール、
    （８）４－（４－クロロフェニル）アゼパン－４－オール、
    （９）４－（３－フルオロフェニル）－７－オキソアゼパン－４－カルボニトリル、および
    （１０）４－（３－メトキシフェニル）－７－オキソアゼパン－４－カルボニトリル
    を除く。）またはその塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000008
    [Wherein, ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent;
    Figure JPOXMLDOC01-appb-C000009
    The group represented by
    Figure JPOXMLDOC01-appb-C000010
    (In the formula, ring B 1 or ring B 2 may further have a substituent;
    Figure JPOXMLDOC01-appb-C000011
    Represents a single bond or a double bond;
    Any one of X 1 , X 2 and X 3 represents —NH—, and the other two represent —CR 2 R 3 — (R 2 and R 3 are the same or different and each represents a hydrogen atom or a substituted Represents an optionally substituted C 1-6 alkyl group).
    R 1 represents a hydroxy group, a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, a substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group. Or an optionally substituted carbamoyl group;
    However, the hydrogen atom bonded to the nitrogen atom that is the ring constituent atom of ring B 1 or ring B 2 is not substituted. ) Represents a group represented by
    In addition, substituents on ring A may be bonded to each other to form an 8- to 10-membered aromatic condensed ring which may have a substituent together with ring A. The compound according to claim 1, represented by the formula (wherein formula (1):
    Figure JPOXMLDOC01-appb-C000012
    (Wherein R x1 represents a hydrogen atom or a methyl group, R x2 represents —CH 2 —CO—N (CH 3 ) —CHR a1 —R a2 (R a1 represents a hydrogen atom or a methyl group, and R a2 represents a halogen atom) 2 represents a 3,5-substituted phenyl group with two substituents selected from an atom and a trifluoromethyl group.), And R x3 represents a hydrogen atom or a fluorine atom. The compound represented,
    (2) In formula (I),
    Figure JPOXMLDOC01-appb-C000013
    The group represented by
    Figure JPOXMLDOC01-appb-C000014
    (Wherein R 1 represents the same meaning as described above),
    (3) [4- (4-Fluorophenyl) azepan-4-yl] acetic acid,
    (4) 3-amino-N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} pyrazine-2-carboxamide;
    (5) N-{[4- (3-fluorophenyl) azepan-4-yl] methyl} -2-methoxybenzamide,
    (6) 4- (1H-imidazo [4,5-b] pyridin-2-yl) azepan-4-ol,
    (7) 4- [1- (4-Fluorobenzyl) -1H-imidazo [4,5-b] pyridin-2-yl] azepan-4-ol,
    (8) 4- (4-chlorophenyl) azepan-4-ol,
    (9) 4- (3-Fluorophenyl) -7-oxoazepane-4-carbonitrile and (10) 4- (3-methoxyphenyl) -7-oxoazepane-4-carbonitrile are excluded. ) Or its salt.
  3. 　式（Ｉ）
    Figure JPOXMLDOC01-appb-C000015
    〔式中、環Ａは、置換基を有するベンゼン環、または置換基を有していてもよい５～６員芳香族複素環を示す；
    Figure JPOXMLDOC01-appb-C000016
    で表される基は、
    Figure JPOXMLDOC01-appb-C000017
    （式中、
    Figure JPOXMLDOC01-appb-C000018
    は、単結合または二重結合を示す；
    Ｘ１、Ｘ２およびＸ３のいずれか１つは－ＮＨ－を示し、他の２つは各々独立して－ＣＲ２Ｒ３－（Ｒ２およびＲ３は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。）で表される基を示す；
    環Ｂが環Ｂ１または環Ｂ２である場合、Ｒ１は、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、（ａ）ハロゲン原子、（ｂ）ヒドロキシ基、（ｃ）Ｃ１－６アルコキシ基、（ｄ）－Ｓ－Ｒ１ａ、（ｅ）－ＳＯ２－Ｒ１ａ、（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル（式中、Ｒ１ａはＣ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示し、
    環Ｂが環Ｂ３である場合、Ｒ１は、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、（ａ）ハロゲン原子、（ｂ）Ｃ１－６アルコキシ基、（ｃ）－Ｓ－Ｒ１ａ、（ｄ）－ＳＯ２－Ｒ１ａ、（ｅ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｆ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｇ）－ＮＨ－ＣＯ－Ｒ１ａ、（ｈ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｉ）－ＮＨ－ＳＯ２－Ｒ１ａ、（ｊ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）および（ｋ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル（式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す；
    ただし、環Ｂ１、環Ｂ２または環Ｂ３の環構成原子である窒素原子に結合した水素原子は置換されない。）を示し、環Ｂ１または環Ｂ３は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない。）で表される基を示す〕で表される請求項１に記載の化合物またはその塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000015
    [Wherein, ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent;
    Figure JPOXMLDOC01-appb-C000016
    The group represented by
    Figure JPOXMLDOC01-appb-C000017
    (Where
    Figure JPOXMLDOC01-appb-C000018
    Represents a single bond or a double bond;
    Any one of X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or an optionally substituted C 1-6 alkyl group).
    When Ring B is Ring B 1 or Ring B 2 , R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a hydroxy group (C) C 1-6 alkoxy group, (d) —S—R 1a , (e) —SO 2 —R 1a , (f) —SO 2 —N (R 1b ) (R 1c ), (g) -N (R 1b ) (R 1c ), (h) -NH-CO-R 1a , (i) -NH-CO-N (R 1b ) (R 1c ), (j) -NH-SO 2 -R 1a , (k) -NH—SO 2 —N (R 1b ) (R 1c ), and (l) 1H— optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group Pyrazol-1-yl (wherein R 1a is a C 1-6 alkyl group, R 1b and R 1c are Standing and represent a hydrogen atom or a C 1-6 alkyl group. 1 is selected from) to C 1-6 alkyl group substituted with three substituents, which may be substituted C 1-6 alkoxy group Or an optionally substituted carbamoyl group,
    When ring B is ring B 3 , R 1 is a cyano group, an optionally substituted carboxy group, an optionally substituted amino group, (a) a halogen atom, (b) a C 1-6 alkoxy group (C) -S-R 1a , (d) -SO 2 -R 1a , (e) -SO 2 -N (R 1b ) (R 1c ), (f) -N (R 1b ) (R 1c ) (G) —NH—CO—R 1a , (h) —NH—CO—N (R 1b ) (R 1c ), (i) —NH—SO 2 —R 1a , (j) —NH—SO 2 —N (R 1b ) (R 1c ) and (k) 1H-pyrazol-1-yl optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group (wherein R 1a Is a C 1-6 alkyl group, R 1b and R 1c are each independently a hydrogen atom or C 1-6 A C 1-6 alkyl group substituted with 1 to 3 substituents selected from: a C 1-6 alkoxy group which may be substituted, or a carbamoyl group which may be substituted; Indicates;
    However, the hydrogen atom bonded to the nitrogen atom which is the ring constituent atom of ring B 1 , ring B 2 or ring B 3 is not substituted. Ring B 1 or ring B 3 has no substituent other than ring A and R 1 , and ring B 2 is any of ring A, R 1 , X 1 , X 2 and X 3 . When has a substituent, it has no substituent other than the substituent. The compound or its salt of Claim 1 represented by these.
  4. 　式（Ｉ）
    Figure JPOXMLDOC01-appb-C000019
    〔式中、環Ａは、置換基を有するベンゼン環、または置換基を有していてもよい５～６員芳香族複素環を示す；
    Figure JPOXMLDOC01-appb-C000020
    で表される基は、
    Figure JPOXMLDOC01-appb-C000021
    （式中、
    Figure JPOXMLDOC01-appb-C000022
    は、単結合または二重結合を示す；
    Ｘ１、Ｘ２およびＸ３のいずれか１つは－ＮＨ－を示し、他の２つは各々独立して－ＣＲ２Ｒ３－（Ｒ２およびＲ３は、同一または異なって、水素原子または置換されていてもよいＣ１－６アルキル基を示す。）で表される基を示す；
    Ｒ１は、シアノ基、置換されていてもよいカルボキシ基、置換されていてもよいアミノ基、（ａ）ハロゲン原子、（ｂ）ヒドロキシ基、（ｃ）Ｃ１－６アルコキシ基、（ｄ）－Ｓ－Ｒ１ａ、（ｅ）－ＳＯ２－Ｒ１ａ、（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）および（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル（式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、置換されていてもよいＣ１－６アルコキシ基、または置換されていてもよいカルバモイル基を示す；
    ただし、環Ｂ１または環Ｂ２の環構成原子である窒素原子に結合した水素原子は置換されない。）を示し、環Ｂ１は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない。）で表される基を示す〕で表される請求項１記載の化合物またはその塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000019
    [Wherein, ring A represents a benzene ring having a substituent or a 5- to 6-membered aromatic heterocycle optionally having a substituent;
    Figure JPOXMLDOC01-appb-C000020
    The group represented by
    Figure JPOXMLDOC01-appb-C000021
    (Where
    Figure JPOXMLDOC01-appb-C000022
    Represents a single bond or a double bond;
    Any one of X 1 , X 2 and X 3 represents —NH—, and the other two independently represent —CR 2 R 3 — (R 2 and R 3 are the same or different and represent a hydrogen atom Or an optionally substituted C 1-6 alkyl group).
    R 1 is a cyano group, optionally carboxy group which may be substituted, an optionally substituted amino group, (a) a halogen atom, (b) a hydroxy group, (c) C 1-6 alkoxy group, (d) —S—R 1a , (e) —SO 2 —R 1a , (f) —SO 2 —N (R 1b ) (R 1c ), (g) —N (R 1b ) (R 1c ), (h) -NH-CO-R 1a , (i) -NH-CO-N (R 1b ) (R 1c ), (j) -NH-SO 2 -R 1a , (k) -NH-SO 2 -N (R 1b ) (R 1c ) and (l) 1H-pyrazol-1-yl optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group (wherein R 1a is C 1 -6 alkyl group, R 1b and R 1c are each independently a hydrogen atom or C 1-6 alkyl It 1 is selected from the representative.) Are shown three substituted with a substituent a C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group or an optionally substituted carbamoyl group, ;
    However, the hydrogen atom bonded to the nitrogen atom that is the ring constituent atom of ring B 1 or ring B 2 is not substituted. Ring B 1 has no substituent other than ring A and R 1 , and ring B 2 is a ring A, R 1 , and any one of X 1 , X 2 and X 3 is a substituent When it has, it has no substituent other than the substituent. The compound or its salt of Claim 1 represented by these.
  5. 　環Ａが、ハロゲン原子およびＣ１－６アルキル基から選択される１ないし３個の置換基で置換されたベンゼン環であり、
    Ｒ１が、
    （１）ヒドロキシ基、
    （２）Ｃ１－６アルコキシ－カルボニル基、
    （３）（ａ）ハロゲン原子、
    　　　（ｂ）ヒドロキシ基、
    　　　（ｃ）Ｃ１－６アルコキシ基、
    　　　（ｄ）－Ｓ－Ｒ１ａ、
    　　　（ｅ）－ＳＯ２－Ｒ１ａ、
    　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
    　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
    　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
    　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
    　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、
    　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および
    　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
    （式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルコキシ基、
    （４）（ａ）ハロゲン原子、
    　　　（ｂ）ヒドロキシ基、および
    　　　（ｃ）Ｃ１－６アルコキシ基
    から選択される１ないし３個の置換基で置換されてもよいモノ－またはジ－（Ｃ１－６アルキル－カルボニル）アミノ基、
    （５）Ｃ１－６アルキルスルホニルアミノ基、
    （６）スルファモイルアミノ基、または
    （７）（ａ）ハロゲン原子、
    　　　（ｂ）ヒドロキシ基、
    　　　（ｃ）Ｃ１－６アルコキシ基、
    　　　（ｄ）－Ｓ－Ｒ１ａ、
    　　　（ｅ）－ＳＯ２－Ｒ１ａ、
    　　　（ｆ）－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
    　　　（ｇ）－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
    　　　（ｈ）－ＮＨ－ＣＯ－Ｒ１ａ、
    　　　（ｉ）－ＮＨ－ＣＯ－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、
    　　　（ｊ）－ＮＨ－ＳＯ２－Ｒ１ａ、
    　　　（ｋ）－ＮＨ－ＳＯ２－Ｎ（Ｒ１ｂ）（Ｒ１ｃ）、および
    　　　（ｌ）カルボキシ基およびメチル基から選択される１ないし３個の置換基で置換されていてもよい１Ｈ－ピラゾール－１－イル
    （式中、Ｒ１ａは、Ｃ１－６アルキル基を、Ｒ１ｂおよびＲ１ｃは、それぞれ独立して水素原子またはＣ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基であり、
    環Ｂ１または環Ｂ３は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない請求項１に記載の化合物またはその塩。     Ring A is a benzene ring substituted with 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group,
    R 1 is
    (1) a hydroxy group,
    (2) a C 1-6 alkoxy-carbonyl group,
    (3) (a) a halogen atom,
    (B) a hydroxy group,
    (C) a C 1-6 alkoxy group,
    (D) -SR 1a ,
    (E) —SO 2 —R 1a ,
    (F) —SO 2 —N (R 1b ) (R 1c ),
    (G) -N (R 1b ) (R 1c ),
    (H) -NH-CO-R 1a ,
    (I) —NH—CO—N (R 1b ) (R 1c ),
    (J) —NH—SO 2 —R 1a ,
    (K) —NH—SO 2 —N (R 1b ) (R 1c ), and (l) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group 1 to 3 selected from 1-yl (wherein R 1a represents a C 1-6 alkyl group, and R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group). A C 1-6 alkoxy group substituted with one substituent,
    (4) (a) a halogen atom,
    (B) hydroxy groups, and (c) C 1-6 to 1 is selected from an alkoxy group which may be substituted with 1-3 substituents mono - or di - (C 1-6 alkyl - carbonyl) amino group,
    (5) a C 1-6 alkylsulfonylamino group,
    (6) a sulfamoylamino group, or (7) (a) a halogen atom,
    (B) a hydroxy group,
    (C) a C 1-6 alkoxy group,
    (D) -SR 1a ,
    (E) —SO 2 —R 1a ,
    (F) —SO 2 —N (R 1b ) (R 1c ),
    (G) -N (R 1b ) (R 1c ),
    (H) -NH-CO-R 1a ,
    (I) —NH—CO—N (R 1b ) (R 1c ),
    (J) —NH—SO 2 —R 1a ,
    (K) —NH—SO 2 —N (R 1b ) (R 1c ), and (l) 1H-pyrazole optionally substituted with 1 to 3 substituents selected from a carboxy group and a methyl group 1 to 3 selected from 1-yl (wherein R 1a represents a C 1-6 alkyl group, and R 1b and R 1c each independently represents a hydrogen atom or a C 1-6 alkyl group). A C 1-6 alkyl group substituted with one substituent,
    Ring B 1 or Ring B 3 has no substituents other than Ring A and R 1 , and Ring B 2 is a ring A, R 1 , and any one of X 1 , X 2 and X 3 is a substituent The compound or its salt of Claim 1 which does not have substituents other than the substituent when it has.
  6. 　環Ａが、１ないし３個のハロゲン原子で置換されたベンゼン環であり、
    Ｒ１が、
    （１）（ａ）ヒドロキシ基、
    　　　（ｂ）－ＳＯ２－Ｒ１ａ、および
    　　　（ｃ）－ＮＨ－ＳＯ２－Ｒ１ａ
    （式中、Ｒ１ａは、Ｃ１－６アルキル基を表す。）から選択される１ないし３個の置換基で置換されたＣ１－６アルキル基、または
    （２）Ｃ１－６アルキルスルホニルアミノ基
    　　であり、
    環Ｂ１または環Ｂ３は、環ＡおよびＲ１以外の置換基を有さず、環Ｂ２は、環Ａ、Ｒ１、並びに、Ｘ１、Ｘ２およびＸ３のいずれかが置換基を有す場合はその置換基以外の置換基を有していない請求項１に記載の化合物またはその塩。     Ring A is a benzene ring substituted with 1 to 3 halogen atoms,
    R 1 is
    (1) (a) a hydroxy group,
    (B) —SO 2 —R 1a , and (c) —NH—SO 2 —R 1a
    (Wherein, R 1a is, C 1-6 alkyl group.) 1 is selected from to three substituted with a substituent a C 1-6 alkyl group or (2) C 1-6 alkylsulfonyl, An amino group,
    Ring B 1 or Ring B 3 has no substituents other than Ring A and R 1 , and Ring B 2 is a ring A, R 1 , and any one of X 1 , X 2 and X 3 is a substituent The compound or its salt of Claim 1 which does not have substituents other than the substituent when it has.
  7. 　（３Ｒ，４Ｒ）－３－（３－クロロ－４－フルオロフェニル）－４－［（メチルスルホニル）メチル］アゼパンまたはその塩。 (3R, 4R) -3- (3-chloro-4-fluorophenyl) -4-[(methylsulfonyl) methyl] azepane or a salt thereof.
  8. 　（３ＲＳ，４ＲＳ）－３－（３，４－ジクロロフェニル）－４－［（メチルスルホニル）メチル］アゼパンの光学活性体またはその塩。 (3RS, 4RS) -3- (3,4-dichlorophenyl) -4-[(methylsulfonyl) methyl] azepane optically active substance or a salt thereof.
  9. 　Ｎ－［（３Ｒ，４Ｒ）－３－（３，４－ジクロロフェニル）アゼパン－４－イル］メタンスルホンアミドまたはその塩。 N-[(3R, 4R) -3- (3,4-dichlorophenyl) azepan-4-yl] methanesulfonamide or a salt thereof.
  10. 　（１ＲＳ）－１－［（３ＳＲ，４ＲＲ）－３－（３，４－ジクロロフェニル）アゼパン－４－イル］エタン－１，２－ジオールまたはその塩。 (1RS) -1-[(3SR, 4RR) -3- (3,4-dichlorophenyl) azepan-4-yl] ethane-1,2-diol or a salt thereof.
  11. 　５－（３，４－ジクロロフェニル）－６－［（メチルスルホニル）メチル］－２，３，４，７－テトラヒドロ－１Ｈ－アゼピンまたはその塩。 5- (3,4-dichlorophenyl) -6-[(methylsulfonyl) methyl] -2,3,4,7-tetrahydro-1H-azepine or a salt thereof.
  12. 　請求項１記載の化合物またはその塩を含有する医薬。 A pharmaceutical comprising the compound according to claim 1 or a salt thereof.
  13. 　モノアミン再取り込み阻害薬である請求項１２記載の医薬。 The medicament according to claim 12, which is a monoamine reuptake inhibitor.
  14. 　うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮または腹圧性尿失禁の予防または治療薬である請求項１２記載の医薬。 Claims for prevention or treatment of depression, anxiety, attention deficit / hyperactivity disorder, menopause, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia or stress urinary incontinence Item 13. A medicine according to Item 12.
  15. 　哺乳動物に対して請求項１記載の化合物またはその塩の有効量を投与することを特徴とするうつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮または腹圧性尿失禁の予防・治療方法。 Depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, fecal incontinence characterized by administering an effective amount of the compound according to claim 1 or a salt thereof to a mammal A method for preventing and treating disuse muscle atrophy, muscle atrophy associated with cachexia or stress urinary incontinence.
  16. 　うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮または腹圧性尿失禁の予防・治療剤を製造するための、請求項１記載の化合物またはその塩の使用。 Manufactures preventive and therapeutic agents for depression, anxiety, attention deficit / hyperactivity disorder, climacteric disorder, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia or stress urinary incontinence Use of a compound according to claim 1 or a salt thereof for the purpose.
  17. 　うつ病、不安症、注意欠陥・多動性障害、更年期障害、疼痛、骨盤臓器脱、便失禁、廃用性筋萎縮、カヘキシアに伴う筋萎縮または腹圧性尿失禁の予防・治療に使用するための、請求項１記載の化合物またはその塩。 To be used for the prevention and treatment of depression, anxiety, attention deficit / hyperactivity disorder, menopause, pain, pelvic organ prolapse, fecal incontinence, disuse muscle atrophy, muscle atrophy associated with cachexia or stress urinary incontinence Or a salt thereof according to claim 1.
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