WO2009128262A1 - Quinolone derivative and use thereof - Google Patents

Quinolone derivative and use thereof Download PDF

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Publication number
WO2009128262A1
WO2009128262A1 PCT/JP2009/001737 JP2009001737W WO2009128262A1 WO 2009128262 A1 WO2009128262 A1 WO 2009128262A1 JP 2009001737 W JP2009001737 W JP 2009001737W WO 2009128262 A1 WO2009128262 A1 WO 2009128262A1
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optionally substituted
group
substituent
atom
compound
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PCT/JP2009/001737
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French (fr)
Japanese (ja)
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永井克典
樽井直樹
錦見裕司
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武田薬品工業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a quinolone derivative having excellent neurokinin 2 receptor antagonist activity and use thereof.
  • NK1 neurokinin 1
  • NK2 neurokinin 2
  • NK3 neurokinin 3
  • SP substance P
  • NAA neurokinin A
  • NKB neurokinin B
  • NK2 receptor antagonists are considered useful for the prevention and treatment of neurokinin A-dependent diseases.
  • digestive diseases eg, functional gastrointestinal diseases, irritable bowel syndrome, functional dyspepsia, gastroesophageal reflux disease, defecation disorder, constipation, diarrhea, malabsorption, indigestion, gastritis, duodenal inflammation, Reflux esophagitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, gastric ulcer, peptic ulcer, gastrointestinal disease due to H.
  • pyroli infection pain (eg, visceral pain, abdominal pain, stomach pain, swelling, somatic) Pain, neuropathic pain, migraine, neuralgia, pruritus), central nervous system disorders (eg, depression, anxiety, schizophrenia, dementia, obsessive compulsive disorder, panic disorder, Alzheimer's disease), lung disease (eg , Asthma, chronic obstructive pulmonary disease, cough), urological diseases (eg, dysuria, frequent urination, incontinence), vomiting, inflammation or allergic diseases (eg, atopy, dermatitis, herpes, psoriasis, asthma, bronchitis) Chronic obstructive pulmonary disease, epilepsy, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc., obesity, cardiovascular disease (eg, angina, hypertension, heart failure, thrombosis) It is considered useful
  • NK2 receptor selective peptide antagonists of the NK2 receptor are known (Br. J. Pharmacol., 1990, 100, 588-592 and International Publication No. WO 97/31941).
  • these known peptidic NK2 antagonists have low activity and are metabolically unstable, so that it is difficult to provide them as practical preventives or therapeutics.
  • Selective non-peptide NK2 receptor antagonists include SR 48968 (Brit. J. Pharmacol. 1992, 105, 77), GR-159897 (Bioorg. Med. Chem. Lett. 1994, 4, vol. 1951), CP 96345 (Science, 1991, 251; ⁇ 435), RP 67580 (Proc. Nat. Acad. Sci. 1991, 88, 10208), ZD 7944 (Abstracts of Papers, Part 1, 214th. NATIONAL Meeting of the American Chemical Society, Las Vegas, NV, September 7-11, 1997, MEDI 264), International Publication No. WO02 / No. 8547, WO WO02 / 38548 Patent, WO WO02 / 083663 Patent, and such as those described in WO WO02 / 083 664 is known.
  • Examples of the compound having a 10-membered nitrogen-containing heterocyclic ring include quinoxaline compounds having the following general formula in International Publication WO 2004/096780.
  • NK3 receptor has been pointed out to be associated with central diseases, particularly depression (Pharmacol. Biochem. Behav., 83 (2006), 533-539, Nature Rev. Drug Discov., 967-975. , 5 2005). Therefore, a compound having a binding action to the NK3 receptor is considered promising as a therapeutic agent for such central diseases.
  • the NK2 receptor is considered to be related to various diseases, it is considered that an effective pharmaceutical can be created if the NK2 receptor binding agent can regulate the signal signal transmission process via the NK2 receptor. .
  • the NK2 receptor binding agent which has an excellent affinity for the NK2 receptor and is superior in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety, and stability, has an excellent therapeutic effect. Can be expected. However, at present, none of them has been found to be excellent in affinity for the NK2 receptor and sufficiently satisfactory in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety, and stability. Therefore, development of a compound that has excellent NK2 receptor binding activity and is sufficiently satisfactory as a pharmaceutical product is eagerly desired.
  • a 1 and A 2 are the same or different and each represents an optionally substituted aromatic group;
  • Ring B represents a phenyl group which may have a substituent,
  • R represents a hydrogen atom or an optionally substituted hydrocarbon group;
  • R 1 is absent, represents a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified,
  • X 1 represents a methylene group which may have a substituent,
  • X 2 represents an ethylene group which may have a substituent,
  • Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized.
  • a 1 and A 2 may have a phenyl group which may have a substituent, Y is a carbon atom having no substituent, Is a double bond, R is a hydrogen atom, X 1 is methylene (—CH 2 —), and X 2 is ethylene (—CH 2 CH 2 —), the substituent on the B ring is C 1- Not 2 alkyl, C 1-2 alkoxy or C 1-2 alkylenedioxy. )] Or a salt thereof is a novel compound.
  • the present invention [1] Formula (I) [Where: Is a single bond or a double bond, A 1 and A 2 are the same or different and each represents an optionally substituted aromatic group, Ring B represents a phenyl group which may have a substituent, R represents a hydrogen atom or a hydrocarbon group which may have a substituent, R 1 represents a hydrogen atom, an alkyl group which may have a substituent, a carboxyl group, or a carboxyl group which may be esterified; X 1 represents a methylene group which may have a substituent, X 2 represents an ethylene group which may have a substituent, Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized.
  • a neurokinin (NK) receptor antagonist comprising a compound represented by the formula: [2] The antagonist according to [1], which is a neurokinin 2 (NK2) receptor antagonist; [3] The antagonist of the above-mentioned [1], which is a prophylactic / therapeutic agent for digestive organ diseases or central diseases; [4] The antagonist of the above-mentioned [3], wherein the digestive organ disease is a functional digestive tract disease; [5] The antagonist according to the above [4], wherein the functional gastrointestinal tract disease is irritable bowel syndrome or functional dyspepsia; [6] The antagonist of the above-mentioned [3], wherein the central disease is depression or anxiety; [7] Formula (I) [Where: Is a single bond or a double bond, A 1 and A 2 are the same or different and each represents an optionally substituted aromatic group, Ring B represents a phenyl group which may have a substituent, R represents a hydrogen atom or an optionally substituted hydrocarbon group; R 1 is absent, represents
  • a 1 and A 2 are optionally substituted phenyl groups, Y is a carbon atom having no substituent, Is a double bond, R is a hydrogen atom, X 1 is methylene (—CH 2 —), and X 2 is ethylene (—CH 2 CH 2 —), the substituent on the B ring is C 1- Not 2 alkyl, C 1-2 alkoxy or C 1-2 alkylenedioxy.
  • R is a hydrogen atom; R 1 is absent or is a hydrogen atom; X 1 is methylene (—CH 2 —); X 2 is ethylene optionally having hydroxy (—CH 2 CH 2 —) (in other words, ethylene optionally substituted with hydroxy (—CH 2 CH 2 —)); Y is an unsubstituted carbon atom (CH or CH 2 ) or an oxygen atom; Is a single bond or a double bond; A 1 may have 1 to 3 substituents each selected from a halogen atom, and (1) a C 6-10 aryl group or (2) a ring atom as a nitrogen atom in addition to a carbon atom, A 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 heteroatoms selected from a sulfur atom and an oxygen atom; A 2 has 1 to 3 substituents each selected from a halogen atom, cyano, lower (C 1-6 ) alkoxy, lower (C
  • Ring B is selected from (1) a halogen atom, (2) lower (C 1-6 ) alkoxy, (3) lower (C 1-6 ) alkoxy-carbonyl, (4) carboxyl, (5) carbamoyl and hydroxy Mono- or di-lower (C 1-6 ) alkylcarbamoyl optionally substituted with a substituent, and (6) phenyl optionally substituted with 1 to 4 substituents selected from carbamoyl
  • the compound (I) of the present invention, a salt thereof and a prodrug thereof are particularly useful as a preventive or therapeutic agent for irritable bowel syndrome and the like because of having NK2 receptor binding activity and low toxicity.
  • a 1 and A 2 are the same or different and each represents an aromatic group which may have a substituent.
  • Examples of the “aromatic group” of the “aromatic group optionally having a substituent” represented by A 1 and A 2 include an aryl group and an aromatic heterocyclic group.
  • aryl group examples include C 6-10 aryl groups such as phenyl, 1-naphthyl, and 2-naphthyl. Of these, phenyl and the like are preferable.
  • aromatic heterocyclic group for example, as a ring-constituting atom, 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom are used. Examples thereof include 5- to 14-membered (monocyclic, bicyclic or tricyclic) aromatic heterocyclic groups having 5 (preferably 1 to 3).
  • pyrrolyl eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • furyl eg, 2-furyl, 3-furyl
  • thienyl eg, 2-thienyl, 3-thienyl
  • oxazolyl eg, 2 -Oxazolyl, 4-oxazolyl, 5-oxazolyl
  • isoxazolyl eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl
  • thiazolyl isothiazolyl, imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), Pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,
  • aromatic ring of the “optionally substituted aromatic ring” represented by A 1 and A 2 is, for example, 1 to the maximum number of substituents in the following substituent group A that can be substituted by 1 to More preferably, it may have 1 to 3, more preferably 1, at a substitutable position.
  • Substituent group A (1) a halogen atom (eg, fluorine, chlorine, bromine, iodine); (2) C 1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, propylenedioxy, etc.); (3) Nitro; (4) Cyano; (5) optionally esterified carboxyl [eg, carboxyl, optionally substituted lower (C 1-6 ) alkoxy-carbonyl, optionally substituted C 6-14 aryloxy-carbonyl, substituted Optionally substituted C 7-16 aralkyloxy-carbonyl, optionally substituted silyloxy-carbonyl (eg, TMS-O—CO—, TES—O—CO—, TBS—O—CO—, TIPS—O—) CO-, TBDPS-O-CO-) etc.];
  • a halogen atom eg, fluorine, chlorine, bromine, iodine
  • C 1-3 alkylenedioxy e
  • An optionally substituted amino group [eg, amino, optionally substituted mono- or di-lower (C 1-6 ) alkylamino, optionally substituted mono- or di-C 3 -8 cycloalkylamino, optionally substituted mono- or di-C 6-14 arylamino, optionally substituted mono- or di-C 7-16 aralkylamino, optionally substituted heterocycle Group-amino, optionally substituted C 6-14 aryl-carbonylamino, formylamino, optionally substituted lower (C 1-6 ) alkyl-carbonylamino, optionally substituted C 3-8 cycloalkyl - carbonyl amino, optionally substituted heterocycle - carbonylamino, optionally substituted lower (C 1-6) alkoxy - carbonyl amino, is substituted Which may be C 3-8 cycloalkoxy - carbonylamino, optionally substituted heterocyclic group - oxycarbonylamino, substituents may carbam
  • the "optionally substituted lower (C 1-6) alkoxy - carbonyl" of “optionally carboxyl which may be esterified” and “lower (C 1-6) alkoxy - carbonyl "" Includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
  • C 6-14 aryloxy-carbonyl of “ optionally substituted C 6-14 aryloxy-carbonyl” as (5) “optionally esterified carboxyl” of substituent group A, An example is phenoxycarbonyl.
  • C 7-16 aralkyloxy-carbonyl of the “ optionally substituted C 7-16 aralkyloxy-carbonyl” as the (5) “optionally esterified carboxyl” in the substituent group A
  • examples include benzyloxycarbonyl and phenethyloxycarbonyl.
  • lower (C 1-6 ) alkyl in (6) “optionally substituted lower (C 1-6 ) alkyl” of substituent group A include, for example, methyl, ethyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
  • the "lower (C 2-6) alkenyl” in the substituent group A (7) the “optionally substituted lower (C 2-6) alkenyl", for example vinyl, 1-propen-1-yl, 2 -Propen-1-yl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like.
  • C 3-8 cycloalkyl in the group (9) “optionally substituted C 3-8 cycloalkyl” in Substituent Group A include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Substituent Group A (10) of the "optionally substituted C 6-14 aryl" as “C 6-14 aryl” include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl 4-biphenylyl, 2-anthryl and the like.
  • the C 6-14 aryl may be partially saturated, and examples of the partially saturated C 6-14 aryl include tetrahydronaphthyl.
  • C 7-16 aralkyl in Substituent Group A (11) "optionally substituted C 7-16 aralkyl", for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl) and the like.
  • C 6-14 aryl-C 2-6 alkenyl of (12) “optionally substituted C 6-14 aryl-C 2-6 alkenyl” in Substituent group A include styryl and the like. .
  • heterocyclic group of (13) “optionally substituted heterocyclic group” in the substituent group A examples include, for example, 1 to 3 types selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, Examples include 3 to 14 membered (monocyclic, bicyclic or tricyclic) heterocyclic groups containing 1 to 5 heteroatoms.
  • Examples thereof include pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrazolyl ( Examples, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (Eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), Triazolyl (1
  • lower (C 1-6 ) alkoxy of (15) “optionally substituted lower (C 1-6 ) alkoxy” in substituent group A include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Examples include isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.
  • C 3-8 cycloalkoxy in Substituent Group A (16) “optionally substituted C 3-8 cycloalkoxy” includes for example cyclopropyl, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like .
  • C 6-14 aryloxy in (17) “optionally substituted C 6-14 aryloxy” in Substituent Group A include, for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like. Can be mentioned.
  • C 7-16 aralkyloxy of (18) “optionally substituted C 7-16 aralkyloxy” in Substituent Group A include benzyloxy, phenethyloxy and the like.
  • lower (C 1-6 ) alkyl-carbonyloxy of (19) “optionally substituted lower (C 1-6 ) alkyl-carbonyloxy” in Substituent Group A include, for example, acetoxy, propionyloxy and the like Is mentioned.
  • Substituent Group A "optionally substituted lower (C 1-6) alkoxy - carbonyl oxy""lower (C 1-6) alkoxy - carbonyloxy” as is, for example, methoxycarbonyloxy, ethoxy Examples include carbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like.
  • Substituent group A (21) "optionally substituted mono - lower (C 1-6) alkyl - carbamoyloxy" in the “mono - lower (C 1-6) alkyl - carbamoyloxy” as, for example methyl Carbamoyloxy, ethylcarbamoyloxy and the like can be mentioned.
  • Substituent group A (22) may be substituted di - lower (C 1-6) alkyl - carbamoyloxy" in the "di - lower (C 1-6) alkyl - carbamoyloxy" as, for example, dimethyl Carbamoyloxy, diethylcarbamoyloxy and the like can be mentioned.
  • C 6-14 aryl-carbonyloxy in (23) “optionally substituted C 6-14 aryl-carbonyloxy” in substituent group A include benzoyloxy, naphthylcarbonyloxy and the like. .
  • heterocyclic group of the above-mentioned “optionally substituted heterocyclic group” may be used. And the like. Specific examples include 5- to 14-membered heterocyclic-oxy containing 1 to 3 types and 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
  • “Aromatic heterocyclic oxy” of “optionally substituted aromatic oxy” as “(25) optionally substituted heterocyclic oxy” in substituent group A includes, for example, other than carbon atoms 1 to 3 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, and 3 to 14-membered aromatic heterocyclic-oxy containing 1 to 5 heteroatoms.
  • lower (C 1-6 ) alkylthio of (27) “optionally substituted lower (C 1-6 ) alkylthio” in substituent group A include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, and sec-butylthio and tert-butylthio.
  • C 3-8 cycloalkylthio in (28) “optionally substituted C 3-8 cycloalkylthio” in substituent group A include cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. Can be mentioned.
  • C 7-16 aralkylthio of the substituent (30) “optionally substituted C 7-16 aralkylthio” include benzylthio, phenethylthio and the like.
  • lower (C 1-6 ) alkyl-carbonyl of (32) “optionally substituted lower (C 1-6 ) alkyl-carbonyl” in Substituent Group A include acetyl, propionyl, pivaloyl and the like. Can be mentioned.
  • C 6-14 aryl-carbonyl in (34) “optionally substituted C 6-14 aryl-carbonyl” in Substituent Group A include benzoyl, 1-naphthoyl, 2-naphthoyl and the like. It is done.
  • C 7-16 aralkyl-carbonyl of (35) “optionally substituted C 7-16 aralkyl-carbonyl” in Substituent Group A include phenylacetyl, 3-phenylpropionyl and the like.
  • heterocyclic moiety of (36) “optionally substituted heterocycle-carbonyl” in Substituent Group A include “heterocyclic group” in the above (13) “optionally substituted heterocyclic group”.
  • “optionally substituted 3- to 14-membered heterocyclic-carbonyl containing 1 to 3, 1 to 5 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom” More specifically, for example, picolinoyl, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, 1-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl, Aziridin-1-ylcarbonyl, aziridin-2-ylcarbonyl, azetidin-1-ylcarbonyl, azetidin-2-ylcarbonyl, pyrrolidin-1-ylcarbonyl,
  • Examples of (37) “optionally substituted lower (C 1-6 ) alkylsulfonyl” in Substituent Group A include methylsulfonyl, ethylsulfonyl and the like.
  • C 3-8 cycloalkylsulfonyl of (38) “optionally substituted C 3-8 cycloalkylsulfonyl” in Substituent Group A include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, and the like. Etc.
  • C 6-14 arylsulfonyl in the (39) “optionally substituted C 6-14 arylsulfonyl” in the substituent group A include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like. Can be mentioned.
  • Examples of (40) “optionally substituted lower (C 1-6 ) alkylsulfinyl” in Substituent Group A include methylsulfinyl, ethylsulfinyl and the like.
  • C 3-8 cycloalkylsulfinyl in (41) “optionally substituted C 3-8 cycloalkylsulfinyl” in Substituent Group A include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, and the like. Etc.
  • C 6-14 arylsulfinyl in Substituent Group A (42) "optionally substituted C 6-14 arylsulfinyl", for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl is Can be mentioned.
  • “-carbamoyl” include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and the like.
  • (C 1-6 ) alkylamino include methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like.
  • “carbonylamino” include acetylamino, propionylamino, pivaloylamino and the like.
  • heterocyclic group of the “heterocyclic group-amino” of the “optionally substituted heterocyclic group-amino” as the (49) “optionally substituted amino group” of the substituent group A
  • heterocyclic group of the above-mentioned “optionally substituted heterocyclic group” is used, and examples thereof include 2-pyridyl-amino and the like.
  • Heterocycle-carbonyl of “heterocycle-carbonylamino” of “optionally substituted heterocycle-carbonylamino” as (49) “optionally substituted amino group” in substituent group A is The same “heterocycle-carbonyl” of the above-mentioned “optionally substituted heterocycle-carbonyl” is used, and examples thereof include pyridyl-carbonylamino.
  • heterocyclic group of the “heterocyclic group-oxycarbonylamino” of the “optionally substituted heterocyclic group-oxycarbonylamino” as the “optionally substituted amino group” in the substituent group A (49)
  • heterocyclic group of “-oxycarbonyl”
  • those similar to the “heterocyclic group” of the above-mentioned “optionally substituted heterocyclic group” can be used, for example, 2-pyridyl-oxycarbonylamino and the like. Can be mentioned.
  • Heterocyclic group-sulfonyl of “Heterocyclic group-sulfonylamino” of “Optionally substituted heterocyclic group-sulfonylamino” as (49) “Optionally substituted amino group” in Substituent group A
  • the same “heterocyclic group” as the above-mentioned “optionally substituted heterocyclic group” is used, and examples thereof include 2-pyridyl-sulfonylamino.
  • “carbonylamino” include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like.
  • “Lower (C 1-6 ) alkylsulfonylamino” of “optionally substituted lower (C 1-6 ) alkylsulfonylamino” as (49) “optionally substituted amino group” in substituent group A "" Includes, for example, methylsulfonylamino, ethylsulfonylamino and the like.
  • carbonylamino C 3-8 cycloalkoxy in - “carbonylamino optionally substituted C 3-8 also be cycloalkoxy" as the substituent group A (49) the "optionally substituted amino group” Examples thereof include cyclopropoxycarbonylamino, cyclopentyloxycarbonylamino, cyclohexyloxycarbonylamino and the like.
  • arylamino include phenylamino, diphenylamino and the like.
  • “aralkylamino” include benzylamino and the like.
  • C 6-14 aryl-carbonylamino of “optionally substituted C 6-14 aryl-carbonylamino” as (49) “optionally substituted amino group” in substituent group A, Examples include benzoylamino and naphthoylamino.
  • C 6-14 arylsulfonylamino of “ optionally substituted C 6-14 arylsulfonylamino” as (49) “optionally substituted amino group” in substituent group A includes, for example, phenyl Examples include sulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino and the like.
  • Substituents in Substituent Group A “Optionally substituted lower (C 1-6 ) alkoxy-carbonyl”, (6) “optionally substituted lower (C 1-6 ) alkyl”, (7) “Lower (C 2-6 ) alkenyl optionally substituted”, (8) “optionally substituted lower (C 2-6 ) alkynyl”, (15) “optionally substituted lower (C 1-6 ) alkoxy”, (19) “optionally substituted lower (C 1-6 ) alkyl-carbonyloxy”, (20) “optionally substituted lower (C 1-6 ) alkoxy-carbonyloxy”, (21) “optionally substituted mono-lower (C 1-6 ) alkyl-carbamoyloxy”, (22) “Di-lower (C 1-6 ) alkyl-carbamoyloxy optionally substituted”, (27) “Lower (C 1-6 ) alkylthio optionally substituted", (32) "Lower (C 1-6 ) alkyl
  • Halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • Hydroxy Nitro
  • Cyano
  • C 6-14 aryl (wherein the C 6-14 aryl is a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono- or di-C 1-6 alkylamino, mono- or Di-C 6-14 arylamino, mono- or di-C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl -Carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio , C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl Mono -
  • C 6-14 aryloxy (the C 6-14 aryloxy is a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono- or di-C 1-6 alkylamino, mono -Or di-C 6-14 arylamino, mono- or di-C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 Cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1- 6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thio Rubamoiru, mono - or di -
  • C 7-16 aralkyloxy (wherein the C 7-16 aralkyloxy is a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono- or di-C 1-6 alkylamino, mono -Or di-C 6-14 arylamino, mono- or di-C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 Cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1- 6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, Okarubamoiru, mono
  • heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, furyl, pyridyl, thienyl, Pyrrolidino, 1-piperidinyl, 4-piperidyl, piperazyl, 1-morpholinyl, 4-thiomorpholinyl, azepan-1-yl, azocan-1-yl, azonan-1-yl, 3,4-dihydroisoquinolin-2-yl, etc.)
  • the heterocyclic group is a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 aryl.
  • Optionally substituted amino group [eg C 1-6 alkyl, C 2-6 alkenyl, C 6-14 aryl, C 7-16 aralkyl, heterocyclic group and heterocyclic-lower (C 1-6 ) alkyl
  • Group and heterocycle-C 1-6 alkyl are each a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl (but not alkyl and alkenyl substituents), mono- or di- -C 1-6 alkylamino, mono - or di -C 6-14 arylamino, mono- - or di -C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1- Alkoxy, formyl, C 1-6
  • C 3-8 cycloalkyl C 1-6 alkoxy (wherein the C 1-6 alkoxy is a halogen atom, hydroxy, amino, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 arylamino, C 3-8 cycloalkyl) C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C 1 -6 alkyl - carbamoyl, mono - or di -C 6
  • Mono- or di-C 6-14 aryl-carbamoyl eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.
  • aryl-carbamoyl eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.
  • nitrogen, sulfur and oxygen atoms in addition to carbon atoms Mono- or di-5 to 7-membered heterocycle-carbamoyl containing 1 to 4 heteroatoms (eg 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl)
  • Such 2-pyridylcarbamoyl, 3-pyri
  • substituent of the substituent group A “Optionally substituted C 6-14 aryloxy-carbonyl”, “Optionally substituted C 7-16 aralkyloxy-carbonyl”, (9) “optionally substituted C 3-8 cycloalkyl”, (10) “optionally substituted C 6-14 aryl”, (11) “C 7-16 aralkyl which may be substituted”, (12) “optionally substituted C 6-14 aryl-C 2-6 alkenyl”, (13) “optionally substituted heterocyclic group”, (16) “C 3-8 cycloalkoxy which may be substituted”, (17) “optionally substituted C 6-14 aryloxy”, (18) "C 7-16 aralkyloxy which may be substituted”, (23) “optionally substituted C 6-14 aryl-carbonyloxy”, (24) "optionally substituted mono- or di-C 6-14 aryl-carbamoyloxy", (25) “optionally substituted heterocyclic oxy”, “optionally substituted aromatic heterocyclic oxy”,
  • Substituent B ′ group C 1-6 alkyl (wherein the C 1-6 alkyl is a halogen atom, hydroxy, cyano, amino, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 arylamino) Mono- or di-C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl-carbonyl, C 6-14 aryl -Carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C
  • C 2-6 alkenyl (wherein the C 2-6 alkenyl is a halogen atom, hydroxy, cyano, amino, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 arylamino, mono- or di) -C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7 -16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, carbamoyl, thiocarbamoyl, mono- - or di -C 1-6 al
  • C 2-6 alkynyl (wherein C 2-6 alkynyl is a halogen atom, hydroxy, cyano, amino, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 arylamino, mono- or di) -C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7 -16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, carbamoyl, thiocarbamoyl, mono- - or di -C 1-6
  • the “substituent” of the “optionally substituted aromatic ring” represented by A 1 is preferably a halogen atom or the like.
  • a 1 (1) a C 6-10 aryl group (eg, phenyl) or (2) a ring-constituting atom each optionally having 1 to 3 substituents selected from halogen atoms, 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom (eg, 2-thienyl, etc.) Of thienyl) is preferred.
  • the “substituent” of the “optionally substituted aromatic ring” represented by A 2 is preferably a halogen atom (particularly a fluorine atom).
  • a 2 has 1 to 3 substituents each selected from a halogen atom, cyano, lower (C 1-6 ) alkoxy, lower (C 1-6 ) alkyl-carbonylamino and C 1-6 alkyl.
  • C 6-10 aryl group eg, phenyl
  • 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom
  • a 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 atoms eg, pyridyl such as 3-pyridyl, pyrazole such as 1H-pyrazol-4-yl
  • pyridyl such as 3-pyridyl
  • pyrazole such as 1H-pyrazol-4-yl
  • ring B represents a phenyl group which may have a substituent.
  • the “substituent” of the “phenyl group optionally having substituent (s)” represented by ring B is “the aromatic group optionally having substituent (s)” represented by A 1 and A 2.
  • the same group as “substituent” can be mentioned.
  • the number of the “substituents” is 1 to 4, preferably 1 to 3, more preferably 1 or 2.
  • the “substituent” of the “optionally substituted phenyl group” represented by ring B includes (1) a halogen atom, (5) an optionally esterified carboxyl, (14) Hydroxy, (15) optionally substituted lower (C 1-6 ) alkoxy, and (44) an optionally substituted carbamoyl group are preferred.
  • Ring B is selected from (1) halogen atom, (2) lower (C 1-6 ) alkoxy, (3) lower (C 1-6 ) alkoxy-carbonyl, (4) carboxyl, (5) carbamoyl and hydroxy Optionally substituted mono- or di-lower (C 1-6 ) alkylcarbamoyl and (6) phenyl optionally substituted with 1 to 4 substituents selected from carbamoyl Is preferred.
  • substituents that the ring B phenyl may have, there are a fluorine atom, a chlorine atom, a bromine atom, a methyl group, and a methoxy group. The 7th position is preferred.
  • R represents a hydrogen atom or an optionally substituted hydrocarbon group.
  • the “hydrocarbon group” of the “hydrocarbon group optionally having substituents” represented by R is preferably one having 1 to 20 carbon atoms. Examples thereof include, for example, “lower (C 1-6 ) alkyl” of (6) “optionally substituted lower (C 1-6 ) alkyl” in substituent group A; (7) “Lower (C 2-6 ) alkenyl” of “optionally substituted lower (C 2-6 ) alkenyl”; (8) “Lower (C 2-6 ) alkynyl” of “optionally substituted lower (C 2-6 ) alkynyl”; (9) “C 3-8 cycloalkyl” of “ optionally substituted C 3-8 cycloalkyl”; (10) “C 6-14 aryl” of “ optionally substituted C 6-14 aryl”; (11) “C 7-16 aralkyl” of “ optionally substituted C 7-16 a
  • Examples of the “substituent” of the “hydrocarbon group optionally having substituent (s)” represented by R include substituents selected from the substituent group A.
  • the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R is “lower (C 1-6 ) alkyl”, “lower (C 2-6 ) alkenyl”.
  • lower (C 2-6 ) alkynyl among the substituents selected from the substituent group A, (6) “optionally substituted lower (C 1-6 ) alkyl”; (7) “optionally substituted lower (C 2-6 ) alkenyl”; (8) “optionally substituted lower (C 2-6 ) alkynyl”; Substituents other than (11) “optionally substituted C 7-16 aralkyl”; and (12) “ optionally substituted C 6-14 aryl-C 2-6 alkenyl” are preferred.
  • the number of “substituents” in the “hydrocarbon group optionally having substituent (s)” represented by R is preferably 0 (unsubstituted) to 5, more preferably 0 (unsubstituted) to 1 It is a piece.
  • R is preferably hydrogen.
  • R 1 is absent or represents a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified.
  • Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized.
  • formula (I) Is a single bond
  • R 1 represents a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified
  • Y represents a carbon atom which may have a substituent
  • the nitrogen atom which may have a substituent, the oxygen atom, or the sulfur atom which may be oxidized is shown.
  • formula (I) Is a double bond Compound (I) is represented by formula (Ib): R 1 is not present, and Y represents a carbon atom which may have a substituent or a nitrogen atom which may have a substituent.
  • R 1 examples include, for example, (6) “optionally substituted lower (C 1-6 ) alkyl” in the above substituent group A. Similar groups are mentioned.
  • R 1 examples include the same groups as (5) “optionally esterified carboxyl” in the above-mentioned Substituent group A.
  • R 1 is preferably a hydrogen atom.
  • substituent of the “carbon atom optionally having substituent (s)” represented by Y examples include the substituent of the substituent group A and oxo.
  • substituent of the “nitrogen atom which may have a substituent” represented by Y include the substituents of the substituent group A.
  • Y is preferably an unsubstituted carbon atom (CH or CH 2 ), an oxygen atom, or an unsubstituted nitrogen atom (N or NH), more preferably an unsubstituted carbon atom or an oxygen atom, Particularly preferred is an unsubstituted carbon atom.
  • Y is an unsubstituted carbon atom, and Is a double bond.
  • X 1 represents a methylene group which may have a substituent.
  • Examples of the “substituent” of the “methylene group optionally having substituent (s)” represented by X 1 include a substituent selected from Substituent Group A and oxo.
  • the number of “substituents” in the “methylene group optionally having substituent (s)” represented by X 1 is preferably 0 (unsubstituted) to 1 and more preferably 0 (unsubstituted) ).
  • X 2 represents an ethylene group (dimethylene group) which may have a substituent.
  • Examples of the “substituent” of the “ethylene group optionally having substituent (s)” represented by X 2 include substituents of the substituent group A and oxo.
  • the “substituent” is preferably hydroxy.
  • the number of “substituents” in the “optionally substituted ethylene group” represented by X 2 is preferably 0 (unsubstituted) to 2 and more preferably 0 (unsubstituted) ).
  • R is a hydrogen atom; R 1 is absent or is a hydrogen atom; X 1 is methylene (—CH 2 —); X 2 is ethylene (—CH 2 CH 2 —) optionally having hydroxy; Y is an unsubstituted carbon atom (CH or CH 2 ) or an oxygen atom (preferably an unsubstituted carbon atom); Is a single bond or a double bond (preferably a double bond); A 1 may have 1 to 3 substituents each selected from halogen atoms, (1) a C 6-10 aryl group (eg, phenyl) or (2) a carbon atom as a ring member atom In addition, a 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (eg, thienyl such as 2-thienyl) ); A 2 has
  • C 6-10 aryl group eg, phenyl
  • 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom 1 to 3 5- or 6-membered aromatic monocyclic heterocyclic group (eg, pyridyl such as 3-pyridyl, pyrazole such as 1H-pyrazol-4-yl)
  • Ring B is selected from (1) halogen atom, (2) lower (C 1-6 ) alkoxy, (3) lower (C 1-6 ) alkoxy-carbonyl, (4) carboxyl, (5) carbamoyl and hydroxy Mono- or di-lower (C 1-6 ) alkylcarbamoyl optionally substituted with a substituent, and (6) phenyl optionally substituted with 1 to 4 substituents selected from carbamoyl Compound or salt thereof.
  • C 6-10 aryl group of A 2 eg, phenyl
  • a 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 atoms eg, pyridyl such as 3-pyridyl, pyrazole such as 1H-pyrazol-4-yl
  • a fluorine atom is particularly preferable.
  • the substituent that the phenyl of B ring may have is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, or a methoxy group, and the substitution position of such substituent is the 6-position and / or the 7-position. Is preferred.
  • R is a hydrogen atom;
  • X 1 is methylene (—CH 2 —);
  • X 2 is ethylene (—CH 2 CH 2 —);
  • Y is an unsubstituted carbon atom; Is a double bond;
  • a 1 is an optionally substituted C 6-10 aryl group (eg, phenyl);
  • a 2 may have a substituent, each of which is a C 6-10 aryl group (eg, phenyl), or a ring-constituting atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom
  • a 5- to 14-membered (monocyclic, bicyclic or tricyclic) aromatic heterocyclic group eg, 3-pyridyl having 1 to 5 (preferably 1 to 3) heteroatoms;
  • a compound or salt thereof is a hydrogen atom;
  • X 1 is methylene (—CH 2 —);
  • X 2 is ethylene (
  • R is a hydrogen atom
  • X 1 is methylene (—CH 2 —);
  • X 2 is ethylene (—CH 2 CH 2 —);
  • Y is an unsubstituted carbon atom; Is a double bond;
  • a 1 is phenyl optionally having 1 to 3 substituents selected from halogen atoms; 1-3 substituents optionally having respectively a C 6-10 aryl group (e.g., phenyl) that A 2 is selected from halogen atom or a ring-constituting atom, a nitrogen atom in addition to carbon atom, a sulfur atom
  • a compound or salt thereof which is a 5- or 6-membered aromatic monocyclic heterocyclic group (eg, 3-pyridyl) having 1 to 3 heteroatoms selected from oxygen atoms and 1 to 3 heteroatoms.
  • Examples of the salt of compound (I) 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.
  • the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine.
  • salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid 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, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done. Of these, pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • compound (I) has an isomer such as a tautomer, an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one of the isomers or a mixture is included in the compound of the present invention. Is included. Furthermore, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I).
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.
  • Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I).
  • a compound labeled or substituted with an isotope eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc. is also encompassed in compound (I).
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and a means known per se, for example, It can be easily purified by separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, distillation, chromatography and the like. Or when the compound in a formula is marketed, a commercial item can also be used as it is.
  • Compound (III) can be produced from compound (II) in Step 1 by a reduction reaction according to a known method or the like.
  • P represents a hydrogen atom or a protecting group.
  • the protecting group include C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-trimethyl, etc.), phenyl, trityl or silyl (optionally substituted).
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • TIPS triisopropylsilyl
  • TDPS tert-butyldiphenylsilyl
  • substituents include halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), silicon (eg, 2- (trimethylsilyl) ethyl), formyl, C 1-6 alkyl-carbonyl (eg, acetyl, propionyl, butyl) Carbonyl, etc.), C 1-6 alkoxy-carbonyl (eg ethoxycarbonyl, isopropyloxycarbonyl etc.), nitro, C 1-6 alkyl (eg methyl, ethyl, tert-butyl etc.), C 6-10 aryl (eg Phenyl, naphthyl, etc.) are used, and the number of substituents is 1 to 3.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • silicon eg, 2- (trimethylsilyl) ethyl
  • formyl eg, C 1-6 al
  • metal hydrides such as sodium borohydride and lithium aluminum hydride, and boranes such as borane tetrahydrofuran complex are used.
  • the amount of the reducing agent to be used is about 0.5 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (II).
  • an acid catalyst may be added together with the reducing agent.
  • a protonic acid for example, acetic acid, trifluoroacetic acid, etc.
  • a Lewis acid for example, p-toluenesulfonic acid, etc.
  • Such a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols such as water, methanol, ethanol, and propanol
  • hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, and mesitylene
  • Organic acids such as acetic acid, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether and diisopropyl ether, anilines such as N, N-dimethylaniline and N, N-diethylaniline, dichloromethane, chloroform, four Halogenated hydrocarbons such as carbon chloride and 1,2-dichloroethane or a mixed solvent thereof are used.
  • the reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to 12 hours.
  • the reaction temperature is usually about 0 to about 120 ° C., preferably about 25 to about 60 ° C.
  • Compound (II) which is commercially available, can be used as it is, or can be produced according to a known method or a method analogous thereto.
  • the target compound (II) is obtained from 2-nitrobenzaldehyde, 2-aminobenzaldehyde, or 2-nitrophenol corresponding to the compound (II) according to a known method (eg, US Pat. No. 6,329,389).
  • Compound IV (III) can be used as it is when commercially available, or can be produced according to a known method or a method analogous thereto.
  • N-acetylaniline corresponding to compound (III) is converted into 4-chloro-formylquinoline according to a known method (eg, Synletter, page 251, 2001, etc.) and then reacted with hydrochloric acid.
  • the target compound (III) is obtained.
  • step 2 compound (V) is obtained by using compound (III) and compound (IV) according to the method described in New Experimental Chemistry Course, Vol. 14-III, pages 1380 to 1385 (published by Maruzen Co., Ltd.). Accordingly, it can be produced by a reductive amination reaction.
  • L represents a hydrogen atom or a substituent selected from substituent group A. Examples of the substituent include alkyl.
  • metal hydrides such as sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride, and boranes such as borane tetrahydrofuran complex are used.
  • the amount of the reducing agent to be used is about 0.5 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (III).
  • an acid catalyst may be added together with the reducing agent.
  • a protonic acid for example, acetic acid, trifluoroacetic acid, etc.
  • a Lewis acid for example, p-toluenesulfonic acid, etc.
  • This reaction is advantageously carried out without solvent or using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols such as water, methanol, ethanol and propanol
  • hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene and mesitylene, formic acid and acetic acid.
  • Organic acids such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether and other ethers, N, N-dimethylaniline, anilines such as N, N-diethylaniline, dichloromethane, chloroform, tetrachloride Halogenated hydrocarbons such as carbon and 1,2-dichloroethane or mixed solvents thereof are used.
  • the reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to 12 hours.
  • the reaction temperature is usually about 0 to about 120 ° C., preferably about 25 to about 60 ° C.
  • Step 3 is a method of synthesizing compound (I) from compound (V) by acylation with compound (VI) in the presence of an appropriate condensing agent and, if necessary, a base according to a known method.
  • the amount of compound (VI) to be used is about 1 mol to 2 mol, preferably about 1 mol to 1.2 mol, per 1 mol of compound (V).
  • the amount of the condensing agent to be used is about 1 to 10 mol, preferably about 1 to 1.2 mol, per 1 mol of compound (VI).
  • Examples of the condensing agent include carbodiimides (CDI (ie, N, N′-carbonylimidazole) and the like).
  • Examples of the base include inorganic bases such as sodium hydride, sodium hydroxide and potassium hydroxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylamino.
  • Tertiary amines such as pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, ammonia or a mixture of two or more of these are used.
  • This reaction is advantageously carried out without solvent or using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols such as water, methanol, ethanol and propanol
  • hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene and mesitylene, formic acid and acetic acid.
  • Organic acids such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether and other ethers, N, N-dimethylaniline, anilines such as N, N-diethylaniline, dichloromethane, chloroform, tetrachloride Halogenated hydrocarbons such as carbon and 1,2-dichloroethane or mixed solvents thereof are used.
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 10 ° C. to 40 ° C.
  • the reaction time is usually 1 hour to 100 hours, preferably 1 hour to 24 hours.
  • Compound (I) can also be obtained by reacting compound (V) with a reactive derivative of compound (VI) (such as isocyanate).
  • step 4 compound (VII) is converted into compound (II).
  • the amount of compound (IV) to be used is about 1 mol to 10 mol, preferably about 1 mol to 3 mol, per 1 mol of compound (II).
  • the amount of the ketone used is about 1 mol to 10 mol, preferably about 1 mol to 3 mol, per mol of the compound (II) used.
  • This reaction is advantageously carried out without solvent or using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols such as water, methanol, ethanol and propanol
  • hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene and mesitylene, formic acid and acetic acid.
  • Organic acids such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether and other ethers, N, N-dimethylaniline, anilines such as N, N-diethylaniline, dichloromethane, chloroform, tetrachloride Halogenated hydrocarbons such as carbon and 1,2-dichloroethane or mixed solvents thereof are used.
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 60 ° C.
  • the reaction time is usually 1 hour to 100 hours, preferably 1 hour to 24 hours.
  • compound (V) can be produced from compound (VII) by decarboxylation of the carboxylic acid synthesized by removing and protecting the P site according to a known method or the like. .
  • compound (V) can be produced by decarboxylating carboxylic acid synthesized from compound (VII) by hydrolyzing the COOP site.
  • an acid catalyst may be added.
  • the acid catalyst a protonic acid (for example, hydrochloric acid, trifluoroacetic acid, etc.) and a Lewis acid (for example, p-toluenesulfonic acid, etc.) can be used.
  • the reaction temperature is usually 30 ° C. to 150 ° C., preferably 50 ° C. to 100 ° C.
  • the reaction time is usually 1 hour to 100 hours, preferably 1 hour to 24 hours.
  • a method for removing the protecting group a known or equivalent method is used. For example, a method of treating with acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like. Alternatively, a reduction reaction is used.
  • a hydrolysis method a known method or a method equivalent thereto is used.
  • a method of treating with an acid, a base, an enzyme or the like is used.
  • Step 6 is a method of synthesizing compound (VIII) from compound (VII) by acylation with compound (VI) in the presence of an appropriate condensing agent and, if necessary, a base according to a known method. The same method as 3 is used.
  • Step 7 is a method of synthesizing compound (I) from compound (VIII) by decarboxylating carboxylic acid synthesized by deprotecting and removing the P site according to a known method or the like. The same method as in step 5 is used. Alternatively, it is a method of synthesizing compound (I) from compound (VIII) by decarboxylating carboxylic acid synthesized by hydrolyzing the COOP site according to a known method, etc. The method is used.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated (for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated).
  • the compound of the present invention having an excellent NK2 receptor antagonistic activity is effective against mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.).
  • mammals eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.
  • functional digestive tract disease irritable bowel syndrome, functional dyspepsia, gastroesophageal reflux disease, defecation disorder, constipation, diarrhea, dyspepsia, gastritis, gastric ulcer, ulcerative colitis, Crohn's disease
  • Pain eg, visceral pain, somatic pain, neuropathic pain, migraine, neuralgia, pruritus
  • central nervous system diseases eg, depression, anxiety, schizophrenia, dementia, obsessive-compulsive disorder, panic disorder
  • lung diseases eg, asthma, chronic obstructive pulmonary disease, cough
  • urological diseases eg, dys
  • the compound of the present invention has an excellent NK3 receptor binding action, and is useful as a preventive or therapeutic agent for diseases of the central nervous system, particularly depression and anxiety.
  • the compounds of the present invention Compared with conventional NK2 receptor antagonists, the compounds of the present invention have markedly superior antagonistic activity, also have NK3 receptor binding activity, and excellent metabolic stability. Excellent therapeutic effects can be expected at doses.
  • the compound of the present invention has low toxicity (for example, it is superior as a pharmaceutical from the viewpoint of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), and it is used as it is as a pharmaceutical.
  • a pharmaceutical composition mixed with a pharmaceutically acceptable carrier or the like mammals (eg, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc. ) Can be safely administered orally or parenterally.
  • Parenter includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, etc. Includes direct lesion administration.
  • the dose of the compound of the present invention varies depending on the administration route, symptoms and the like.
  • a patient with irritable bowel syndrome adult, body weight 40 to 80 kg, eg 60 kg
  • 0.001 to 1000 mg / kg body weight preferably 0.01 to 100 mg / kg body weight per day, more preferably 0.1 to 10 mg / kg body weight per day.
  • This amount can be administered in 1 to 3 divided doses per day.
  • a dosage form when the compound of the present invention is used as a pharmaceutical composition tablets (eg, sugar-coated tablets, film-coated tablets, orally disintegrating tablets), films (eg, orally disintegrating film), pills, capsules , Granules, fine granules, powders, syrups, emulsions, suspensions, injections, sustained-release injections, inhalants, ointments and the like. These preparations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia).
  • the pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier, etc., but the compound of the present invention is usually 0.01 to 100% (w / w), preferably 0.1 to Contains 95% (w / w).
  • various organic or inorganic carriers conventionally used as starting materials are used. These include excipients, lubricants, binders and disintegrants in solid formulations, It is blended as a tonicity agent, a buffering agent, a soothing agent, etc., such as a solvent, a solubilizing agent, a suspending agent in a liquid preparation. Further, if necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used.
  • the compound of the present invention can be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).
  • concomitant drugs include NK2 receptor antagonistic activity and NK3 receptor binding activity even when used as a single agent, the effect thereof can be obtained by further combining with one or more concomitant drugs (multi-drug combination). Can be further enhanced.
  • Diabetes therapeutic agent eg, animal insulin preparation extracted from bovine or porcine pancreas; human insulin preparation genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin fragment Or a derivative (eg, INS-1 etc.), an insulin resistance enhancer (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or a maleate thereof, JTT-501, MCC-555, YM-440, GI-262570, KRP-297, FK-614, CS-011, etc.), ⁇ -glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), sulfonylurea agents (eg, , Tolbutamide, glibenclam
  • Aldose reductase inhibitors eg, torrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minalrestat (ARI-509), CT-112, etc.
  • nerve Nutritional factors eg, NGF, NT-3, etc.
  • AGE inhibitors eg, ALT-945, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT-766), EXO-226, etc.
  • reactive oxygen scavenging Drugs eg, thioctic acid, etc.
  • cerebral vasodilators eg, tiapride, etc.
  • Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or their salts (eg, sodium salt, etc.)), squalene synthase inhibition Or a fibrate compound having a triglyceride lowering effect (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.).
  • cholesterol synthesis inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or their salts (eg, sodium salt, etc.)
  • squalene synthase inhibition Or a fibrate compound having a triglyceride lowering effect (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.).
  • Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonist (eg, losartan, candesartan cilexetil, etc.), calcium antagonist (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine) Etc.), clonidine etc.
  • Angiotensin converting enzyme inhibitor eg, captopril, enalapril, delapril, etc.
  • angiotensin II antagonist eg, losartan, candesartan cilexetil, etc.
  • calcium antagonist eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine
  • Anti-obesity agents Central nervous system anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampifepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, etc.), pancreatic lipase inhibition Drugs (eg, orlistat, etc.), ⁇ 3 agonists (eg, CL-316243, sr-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.), peptide appetite suppressants (eg, leptin, CNTF (hair) , Etc.), cholecystokinin agonists (eg, Lynchtripto, FPL-15849, etc.).
  • ⁇ 3 agonists eg, CL-316243, sr-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.
  • Diuretics Xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclo Thiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, etacrine Acid, piretanide, bumetanide, furosemide etc.
  • Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plants Derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide, etc., among others, 5-fluorouracil derivatives such as furtulon or neoflutulon.
  • Alkylating agents eg, cyclophosphamide, ifosfamide, etc.
  • antimetabolites eg, methotrexate, 5-fluorouracil, etc.
  • anticancer antibiotics eg, mitomycin, adriamycin, etc.
  • plants Derived anticancer agents eg, vincristine, vindesine
  • Immunotherapeutic agents Microorganism-derived or bacteria-derived components (eg, muramyl dipeptide derivatives, picibanil etc.), immunopotentiating polysaccharides (eg lentinan, schizophyllan, krestin etc.), cytokines obtained by genetic engineering techniques (Eg, interferon, interleukin (IL), etc.), colony stimulating agents (eg, granulocyte colony stimulating factor, erythropoietin, etc.), such as IL-1, IL-2, IL-12, among others.
  • IL-1 eg, muramyl dipeptide derivatives, picibanil etc.
  • immunopotentiating polysaccharides eg lentinan, schizophyllan, krestin etc.
  • cytokines obtained by genetic engineering techniques
  • IL interleukin
  • colony stimulating agents eg, granulocyte colony stimulating factor, erythropoietin, etc.
  • Anti-inflammatory agents Steroids (eg, dexamethasone, etc.), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.)
  • Gastrointestinal disease therapeutic agent Irritable bowel syndrome therapeutic agent (serotonin antagonist (eg, alosetron, ramosetron, etc.), serotonin agonist (eg, tegaserod, etc.), water secretion promoter (eg, rubiprostone, linaclotide, etc.) , Calcium antagonists (eg, arterapamil), peripheral opioid agonists (eg, asimadoline)); anti-constipation drugs (serotonin agonists (eg, tegaserod), etc.
  • statonin antagonist eg, alosetron, ramosetron, etc.
  • serotonin agonist eg, tegaserod, etc.
  • water secretion promoter eg, rubiprostone, linaclotide, etc.
  • Calcium antagonists eg, arterapamil
  • peripheral opioid agonists eg, asimadoline
  • anti-constipation drugs
  • antidiarrheal drugs peripheral opioid agonists (eg, lopemin), polycarbophil calcium, etc.); laxatives; gastrointestinal motility drugs (serotonin agonists (eg, domperidone, metoclopramide, itopride, mosapride) Gastric acid secretion inhibitors (proton pump inhibitors (eg, omeprazole, lansops) Razol, etc.), histamine H 2 inhibitors (eg, cimetidine, ranitidine, etc.); antacids (aluminum hydroxide, sodium bicarbonate, etc.); mucosal protective agents (polaprezinc, ecabet sodium, rebamipide, teprenone, etc.); Drugs (anticholinergic drugs (butyl scopolamine, etc.)); stomach digestive drugs (gentian, assembly, diastase, etc.) (12) Others Glycation inhibitors
  • Benzodiazepines phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg, apomorphine), anticholinergics, ⁇ 1 receptor blockers (eg, tamsulosin), muscle relaxants (eg, baclofen, etc.) , Potassium channel openers (eg, nicorandil), calcium channel blockers (eg, nifedipine), Alzheimer's disease prevention / treatment (eg, donepezil, rivastigmine, galantamine), Parkinson's disease (eg, L-dopa), Antithrombotic drugs (eg, aspirin, cilostazol), NK2 receptor antagonist, HIV feeling Lowering agents (e.g., saquinavir, zidovudine, lamivudine, nevirapine), chronic obstructive pulmonary disease therapeutic agent (e.g., salmeterol, tiotropium bromide (
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be 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 mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • dosage forms include, for example, (1) Administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) Identical of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug Co-administration by route of administration, (3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference, (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention ⁇ the concomitant drug) Or
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or (and) the concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a pharmaceutical composition such as a tablet (sugar-coated tablet). , Including film-coated tablets), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained-release agents, and the like, which can be oral or parenteral ( (Eg, topical, rectal, intravenous, etc.).
  • the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight, preferably about 0, based on the whole preparation.
  • the range is about 1 to 50% by weight, and more preferably about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is in the range of about 0.5 to 20% by weight.
  • the content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by weight, preferably about 10 to 90% by weight based on the whole preparation. % Range.
  • the same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • the dose of the concomitant drug of the present invention varies depending on the type, age, weight, symptoms, dosage form, administration method, administration period, etc. of the compound of the present invention. ) About 0.01 to about 1000 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 1 day per day 0.1 to about 100 mg / kg, especially about 0.1 to about 50 mg / kg per day, especially about 1.5 to about 30 mg / kg per day, once to several times a day Divide orally.
  • the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.
  • 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 and nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually in the range of about 0.001 to 2000 mg / kg body weight of the mammal, preferably about 0.01 to 500 mg, more preferably, for example, by oral administration.
  • the dose is in the range of about 0.1 to 100 mg, which is usually administered once to 4 times a day.
  • the concomitant drug of the present invention When the concomitant drug of the present invention is administered, it may be administered at the same time as the compound of the present invention. However, after the concomitant drug is administered, the compound of the present invention may be administered. A concomitant drug may be administered after administration. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when administering a concomitant drug first, within 1 minute to 3 days after administration of the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day after administration of the compound of the present invention, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. A method is mentioned.
  • N-bromosuccinimide 29 g was added to a mixture of 2-amino-5-bromobenzaldehyde 2-aminobenzaldehyde (19.7 g) and N, N′-dimethylformamide (300 ml) at room temperature, and the mixture was stirred for 1 hour. . 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 magnesium sulfate, filtered and concentrated.
  • 6-Bromo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid A mixture of ethyl 6-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylate (20 g) and ethanol (200 ml) 1N Aqueous sodium hydroxide solution (200 ml) was added at room temperature, and the mixture was stirred at 70 ° C. for 2 hr. The reaction mixture was ice-cooled, and 6N aqueous hydrochloric acid solution (45 ml) was added. The precipitate was collected by filtration and dried to give the title compound (14 g) as a solid.
  • the reaction mixture was concentrated, 8N aqueous sodium hydroxide solution (200 ml) was added to the residue at room temperature, and the mixture was stirred for 4 hr.
  • the reaction mixture was ice-cooled, and 6N aqueous hydrochloric acid (300 ml) was added. The precipitate was collected by filtration and dried to give the title compound (14 g) as a solid.
  • the mixture was concentrated to about half, neutralized with saturated sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (eluted with a mixed solution of hexane and ethyl acetate having a mixing ratio of 80:20 to 0: 100) to give the title compound (862 mg) as amorphous.
  • N, N′-carbonyldiimidazole was added under ice-cooling and at room temperature. Stir for 5 hours.
  • N- [5-( ⁇ [2- (4-Fluorophenyl) ethyl] [(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl) methyl] carbamoyl ⁇ amino) pyridin-2-yl N, N′-carbonyldiimidazole was added to a mixture of acetamide 2-acetamido-5-aminopyridine (0.15 g), triethylamine (0.40 g) and THF (5 ml) under ice-cooling, and at room temperature for 5 hours. Stir.
  • Example 1 (1) 10.0 g of the compound of Example 1 (2) Lactose 70.0g (3) Corn starch 50.0g (4) 7.0g soluble starch (5) Magnesium stearate 3.0 g
  • Example 1 The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) were granulated with 70 ml of an aqueous solution of soluble starch (7.0 g as soluble starch), dried, lactose (70.0 g) and corn starch ( (Lactose, corn starch, soluble starch, and magnesium stearate are all conforming to the 14th revised Japanese Pharmacopoeia). The mixture is compressed to obtain tablets.
  • hNK2 receptor-expressing CHO cells (Euroscreen) were treated with 400 ⁇ g / mL geneticin, 100 U / mL penicillin, 100 ⁇ g / mL streptomycin and 10 The cells were cultured in HAM-F12 medium containing% inactivated serum. The medium was removed, and the adherent cells were washed with PBS, PBS containing 5 mM EDTA was added, and the cells were detached from the flask.
  • Cells are collected by centrifugation, suspended in suspension buffer A (15 mM Tris-HCl (pH 7.5), 2 mM MgCl2, 0.3 mM EDTA, 1 mM EGTA), disrupted with a Polytron homogenizer (Kinematica), Centrifugation was performed at 800 ⁇ for 10 minutes, and the supernatant was collected and ultracentrifuged at 100000 ⁇ g for 25 minutes. The precipitate fraction is suspended in suspension buffer B (7.5 mM Tris-HCl (pH 7.5), 12.5 mM MgCl2, 0.3 mM EDTA, 1 mM, EDTA, 250 mM sucrose) and frozen as a receptor preparation (-80 C).
  • measurement buffer 50 mM Tris-HCl (pH 7.4), 0.02% bovine serum albumin, 2 ⁇ g / mL chymostatin, 40 ⁇ g / mL bacitracin, 40 ⁇ g / mL APMSF, 3 mM MnCl2
  • measurement buffer 50 mM Tris-HCl (pH 7.4), 0.02% bovine serum albumin, 2 ⁇ g / mL chymostatin, 40 ⁇ g / mL bacitracin, 40 ⁇ g / mL APMSF, 3 mM MnCl2
  • GF / C Unifilter plate
  • cell harvester Perkin Elmer
  • bovine serum albumin The cells were washed 5 times with 50 mM Tris-HCl (pH 7.4) buffer solution (250 ⁇ L).
  • the GF / C filter plate was dried, 20 ⁇ L of microcinch-0 (Perkin Elmer) was added, and the radioactivity was measured with a top count (Perkin Elmer).
  • the GF / C filter plate used was immersed in 0.3% polyethyleneimine for one day. The specific binding amount is indicated by a value obtained by subtracting the non-specific binding amount from the total binding amount.
  • the binding inhibitory activity of the test compound is expressed as a ratio of the value obtained by subtracting the measured value when the test compound is added from the total binding amount to the specific binding amount.
  • the inhibition rate at 1 ⁇ M of the compounds of Examples 5, 6, 7, 10 and 11 was 90% or more.
  • the compound of the present invention has NK2 receptor binding activity and little toxicity, it is particularly useful as a preventive or therapeutic agent for irritable bowel syndrome and the like.

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Abstract

Disclosed is a compound having excellent NK2 receptor binding activity. The compound is satisfactory as a pharmaceutical product. Specifically disclosed is a neurokinin receptor antagonist containing a compound represented by formula (I) or a salt thereof. In formula (I), --- represents a single bond or a double bond; A1 and A2 may be the same or different, and each represents an optionally substituted aromatic group; ring B represents an optionally substituted phenyl group; R represents a hydrogen atom or an optionally substituted hydrocarbon group; R1 may not exist, or represents a hydrogen atom, an optionally substituted alkyl group or an optionally esterified carboxyl group; X1 represents an optionally substituted methylene group; X2 represents an optionally substituted ethylene group; and Y represents an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom, or an optionally oxidized sulfur atom.

Description

キノロン誘導体およびその用途Quinolone derivatives and uses thereof
　本発明は、優れたニューロキニン２受容体拮抗活性を有するキノロン誘導体およびその用途に関する。 The present invention relates to a quinolone derivative having excellent neurokinin 2 receptor antagonist activity and use thereof.
　生体内にはニューロキニン１（ＮＫ１）受容体、ニューロキニン２（ＮＫ２）受容体、ニューロキニン３（ＮＫ３）受容体が存在する。これらにタキキニンとして知られている神経ペプチドであるサブスタンスＰ（ＳＰ）、ニューロキニンＡ（ＮＫＡ）、ニューロキニンＢ（ＮＫＢ）がそれぞれ主に結合し、さまざまな生理作用を発揮することが知られている。 In the living body, there are a neurokinin 1 (NK1) receptor, a neurokinin 2 (NK2) receptor, and a neurokinin 3 (NK3) receptor. It is known that substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), which are neuropeptides known as tachykinins, mainly bind to each other and exert various physiological functions. Yes.
　したがって、ＮＫ２受容体の拮抗薬は、ニューロキニンＡ依存性の疾患の予防や治療に有用であると考えられる。特に、消化器疾患（例、機能性消化管疾患、過敏性腸症候群、機能性ディスペプシア（Ｆｕｎｃｔｉｏｎａｌ　ｄｙｓｐｅｐｓｉａ）、胃食道逆流症、排便障害、便秘、下痢、吸収不良、消化不良、胃炎、十二指腸炎、逆流性食道炎、炎症性腸疾患、潰瘍性大腸炎、クローン病、胃潰瘍、消化性潰瘍、Ｈ．ｐｙｒｏｌｉ感染による消化器疾患）、痛み（例、内臓痛、腹痛、胃痛、むねやけ、体性痛、神経因性疼痛、偏頭痛、神経痛、掻痒）、中枢神経系の疾患（例、うつ、不安、統合失調症、認知症、強迫神経症、恐慌性障害、アルツハイマー病）、肺疾患（例、喘息、慢性閉塞性肺疾患、咳）、泌尿器疾患（例、排尿障害、頻尿、尿失禁）、嘔吐、炎症もしくはアレルギー性疾患（例、アトピー、皮膚炎、ヘルペス、乾癬、喘息、気管支炎、慢性閉塞性肺疾患、喀痰、鼻炎、リウマチ関節炎、変形性関節症、骨粗鬆症、多発性硬化症、結膜炎、膀胱炎など）、肥満、循環器疾患（例、狭心症、高血圧、心不全、血栓症など）、免疫異常、癌、ＨＩＶ感染症、心血管疾患、日光皮膚炎、性的機能不全、運動失調などの疾患の予防・治療剤に有用であると考えられる。 Therefore, NK2 receptor antagonists are considered useful for the prevention and treatment of neurokinin A-dependent diseases. In particular, digestive diseases (eg, functional gastrointestinal diseases, irritable bowel syndrome, functional dyspepsia, gastroesophageal reflux disease, defecation disorder, constipation, diarrhea, malabsorption, indigestion, gastritis, duodenal inflammation, Reflux esophagitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, gastric ulcer, peptic ulcer, gastrointestinal disease due to H. pyroli infection, pain (eg, visceral pain, abdominal pain, stomach pain, swelling, somatic) Pain, neuropathic pain, migraine, neuralgia, pruritus), central nervous system disorders (eg, depression, anxiety, schizophrenia, dementia, obsessive compulsive disorder, panic disorder, Alzheimer's disease), lung disease (eg , Asthma, chronic obstructive pulmonary disease, cough), urological diseases (eg, dysuria, frequent urination, incontinence), vomiting, inflammation or allergic diseases (eg, atopy, dermatitis, herpes, psoriasis, asthma, bronchitis) Chronic obstructive pulmonary disease, epilepsy, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc., obesity, cardiovascular disease (eg, angina, hypertension, heart failure, thrombosis) It is considered useful as a preventive / therapeutic agent for diseases such as immune abnormalities, cancer, HIV infection, cardiovascular disease, sun dermatitis, sexual dysfunction and ataxia.
　一方、ＮＫ２受容体の選択的ペプチド拮抗剤が知られている（Ｂｒ. Ｊ. Ｐｈａｒｍａｃｏｌ．，１９９０年, １００巻, ５８８－５９２頁および国際公開第ＷＯ９７／３１９４１号）。しかしながら、これら公知のペプチド性ＮＫ２拮抗薬は、活性が弱く、また、代謝的に不安定であることから、実用的な予防薬又は治療薬として供するのは難しい。 On the other hand, selective peptide antagonists of the NK2 receptor are known (Br. J. Pharmacol., 1990, 100, 588-592 and International Publication No. WO 97/31941). However, these known peptidic NK2 antagonists have low activity and are metabolically unstable, so that it is difficult to provide them as practical preventives or therapeutics.
　選択的非ペプチド系ＮＫ２受容体拮抗薬としては、ＳＲ ４８９６８（Ｂｒｉｔ. Ｊ. Ｐｈａｒｍａｃｏｌ. １９９２年、１０５巻、 ７７頁）、ＧＲ－１５９８９７（Ｂｉｏｏｒｇ. Ｍｅｄ. Ｃｈｅｍ. Ｌｅｔｔ. １９９４年, ４巻, １９５１頁）、ＣＰ ９６３４５（Ｓｃｉｅｎｃｅ, １９９１年, ２５１巻, ４３５頁）、ＲＰ　６７５８０（Ｐｒｏｃ．Ｎａｔ．Ａｃａｄ．Ｓｃｉ．１９９１， ８８巻, １０２０８頁）、ＺＤ　７９４４（Ａｂｓｔｒａｃｔｓ　ｏｆ　Ｐａｐｅｒｓ， Ｐａｒｔ　１，２１４ｔｈ　ＮＡＴＩＯＮＡＬ　Ｍｅｅｔｉｎｇ　ｏｆ　ｔｈｅ　Ａｍｅｒｉｃａｎ　Ｃｈｅｍｉｃａｌ　Ｓｏｃｉｅｔｙ，Ｌａｓ　Ｖｅｇａｓ， ＮＶ，Ｓｅｐｔ　７－１１，１９９７年，ＭＥＤＩ　２６４）、国際公開第ＷＯ０２／３８５４７号、国際公開第ＷＯ０２／３８５４８号、国際公開第ＷＯ０２／０８３６６３号、および国際公開第ＷＯ０２／０８３６６４号に記載されているものなどが知られている。 Selective non-peptide NK2 receptor antagonists include SR 48968 (Brit. J. Pharmacol. 1992, 105, 77), GR-159897 (Bioorg. Med. Chem. Lett. 1994, 4, vol. 1951), CP 96345 (Science, 1991, 251; 巻 435), RP 67580 (Proc. Nat. Acad. Sci. 1991, 88, 10208), ZD 7944 (Abstracts of Papers, Part 1, 214th. NATIONAL Meeting of the American Chemical Society, Las Vegas, NV, September 7-11, 1997, MEDI 264), International Publication No. WO02 / No. 8547, WO WO02 / 38548 Patent, WO WO02 / 083663 Patent, and such as those described in WO WO02 / 083 664 is known.
　また、１０員の含窒素複素環を有する化合物としては、例えば、国際公開ＷＯ２００４／０９６７８０号に下記の一般式のキノキサリン化合物が記載されている。
Examples of the compound having a 10-membered nitrogen-containing heterocyclic ring include quinoxaline compounds having the following general formula in International Publication WO 2004/096780.
　また、ＮＫ３受容体は、中枢疾患、特にうつとの関連性が指摘されている（Ｐｈａｒｍａｃｏｌ． Ｂｉｏｃｈｅｍ． Ｂｅｈａｖ．， ８３（２００６）， ５３３－５３９、Ｎａｔｕｒｅ Ｒｅｖ． Ｄｒｕｇ Ｄｉｓｃｏｖ．， ４， ９６７－９７５， ２００５）。したがって、ＮＫ３受容体に結合作用を示す化合物は、かかる中枢疾患の治療薬として有望と考えられる。 In addition, the NK3 receptor has been pointed out to be associated with central diseases, particularly depression (Pharmacol. Biochem. Behav., 83 (2006), 533-539, Nature Rev. Drug Discov., 967-975. , ５ 2005). Therefore, a compound having a binding action to the NK3 receptor is considered promising as a therapeutic agent for such central diseases.
国際公開第ＷＯ９７／３１９４１号International Publication No. WO 97/31941 国際公開第ＷＯ０２／３８５４７号International Publication No. WO02 / 38547 国際公開第ＷＯ０２／３８５４８号International Publication No. WO02 / 38548 国際公開第ＷＯ０２／０８３６６３号International Publication No. WO02 / 083663 国際公開第ＷＯ０２／０８３６６４号International Publication No. WO02 / 083664 国際公開第ＷＯ２００４／０９６７８０号International Publication No. WO2004 / 096780
　ＮＫ２受容体は種々の疾患に関連していると考えられるので、ＮＫ２受容体結合剤により、ＮＫ２受容体を介する情報シグナルの伝達過程を調節することができれば、有効な医薬品が創出できると考えられる。さらに、ＮＫ２受容体に対する親和性に優れ、薬効発現、薬物動態、溶解性、他の医薬品との相互作用、安全性、安定性の点で優れたＮＫ２受容体結合剤は、治療上優れた効果を期待することができる。しかしながら、現状では、ＮＫ２受容体に対する親和性に優れ、薬効発現、薬物動態、溶解性、他の医薬品との相互作用、安全性、安定性の点で十分満足できるものが見いだされていない。そこで、優れたＮＫ２受容体結合活性を有し、医薬品として十分満足できる化合物の開発が切望されている。 Since the NK2 receptor is considered to be related to various diseases, it is considered that an effective pharmaceutical can be created if the NK2 receptor binding agent can regulate the signal signal transmission process via the NK2 receptor. . Furthermore, the NK2 receptor binding agent, which has an excellent affinity for the NK2 receptor and is superior in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety, and stability, has an excellent therapeutic effect. Can be expected. However, at present, none of them has been found to be excellent in affinity for the NK2 receptor and sufficiently satisfactory in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety, and stability. Therefore, development of a compound that has excellent NK2 receptor binding activity and is sufficiently satisfactory as a pharmaceutical product is eagerly desired.
　本発明者らは、種々検討した結果、式（Ｉ） As a result of various studies, the present inventors have found that the formula (I)
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
［式中、
Figure JPOXMLDOC01-appb-C000003
 は単結合または二重結合を、
Ａ１およびＡ２は同一または異なって置換基を有していてもよい芳香族基を示し、
Ｂ環は置換基を有していてもよいフェニル基を示し、
Ｒは水素原子または置換基を有していてもよい炭化水素基を示し、
Ｒ１は、存在しないか、あるいは水素原子、置換基を有していてもよいアルキル基、またはエステル化されていてもよいカルボキシル基を示し、
Ｘ１は置換基を有していてもよいメチレン基を示し、
Ｘ２は置換基を有していてもよいエチレン基を示し、
Ｙは置換基を有していてもよい炭素原子、置換基を有していてもよい窒素原子示し、酸素原子または酸化されていてもよい硫黄原子を示す。］で表される化合物（本明細書中、化合物（I)と称する場合がある。）またはその塩が予想外にもＮＫ２受容体結合剤としての優れた性質を有しており、医薬として十分満足できるものであることを見出し、これらの知見に基づいて本発明を完成した。
　なお、化合物（I)のうち、式（Ｉ）
Figure JPOXMLDOC01-appb-C000004
 ［式中、
Figure JPOXMLDOC01-appb-C000005
 は単結合または二重結合を、
Ａ１およびＡ２は同一または異なって置換基を有していてもよい芳香族基を、
Ｂ環は置換基を有していてもよいフェニル基を、
Ｒは水素原子または置換基を有していてもよい炭化水素基を、
Ｒ１は、存在しないか、あるいは水素原子、置換基を有していてもよいアルキル基、またはエステル化されていてもよいカルボキシル基を示し、
Ｘ１は置換基を有していてもよいメチレン基を、
Ｘ２は置換基を有していてもよいエチレン基を、
Ｙは置換基を有していてもよい炭素原子、置換基を有していてもよい窒素原子、酸素原子または酸化されていてもよい硫黄原子を示す。
（ただし、Ａ１およびＡ２が置換基を有していてもよいフェニル基を、
Ｙが置換基を有しない炭素原子を、
Figure JPOXMLDOC01-appb-C000006
 が二重結合を、Ｒが水素原子を、Ｘ１がメチレン（－ＣＨ２－）を、Ｘ２がエチレン（－ＣＨ２ＣＨ２－）を示すとき、Ｂ環の置換基は、Ｃ１－２アルキル、Ｃ１－２アルコキシまたはＣ１－２アルキレンジオキシではない。）］で表される化合物またはその塩は、新規の化合物である。
　すなわち、本発明は、
［１］　式（Ｉ）
Figure JPOXMLDOC01-appb-C000007
 ［式中、
Figure JPOXMLDOC01-appb-C000008
 は単結合または二重結合を、
Ａ１およびＡ２は同一または異なって置換基を有していてもよい芳香族基を、
Ｂ環は置換基を有していてもよいフェニル基を示し、
Ｒは水素原子または置換基を有していてもよい炭化水素基を、
Ｒ１は水素原子、置換基を有していてもよいアルキル基、またはカルボキシル基、またはエステル化されていてもよいカルボキシル基を示し、
Ｘ１は置換基を有していてもよいメチレン基を示し、
Ｘ２は置換基を有していてもよいエチレン基を示し、
Ｙは置換基を有していてもよい炭素原子、置換基を有していてもよい窒素原子、酸素原子または酸化されていてもよい硫黄原子を示す。］で表される化合物またはその塩を含有してなるニューロキニン（ＮＫ）受容体拮抗剤；
［２］ニューロキニン２（ＮＫ２）受容体拮抗剤である上記［１］記載の拮抗剤；
［３］消化器疾患または中枢疾患の予防・治療剤である上記［１］記載の拮抗剤；
［４］消化器疾患が、機能性消化管疾患である上記［３］記載の拮抗剤；
［５］機能性消化管疾患が、過敏性腸症候群または機能性ディスペプシア（Ｆｕｎｃｔｉｏｎａｌ　ｄｙｓｐｅｐｓｉａ）である上記［４］記載の拮抗剤；
［６］中枢疾患がうつまたは不安である上記［３］記載の拮抗剤；
［７］　式（Ｉ）
Figure JPOXMLDOC01-appb-C000009
 ［式中、
Figure JPOXMLDOC01-appb-C000010
 は単結合または二重結合を、
Ａ１およびＡ２は同一または異なって置換基を有していてもよい芳香族基を、
Ｂ環は置換基を有していてもよいフェニル基を示し、
Ｒは水素原子または置換基を有していてもよい炭化水素基を示し、
Ｒ１は、存在しないか、あるいは水素原子、置換基を有していてもよいアルキル基、またはエステル化されていてもよいカルボキシル基を示し、
Ｘ１は置換基を有していてもよいメチレン基を示し、
Ｘ２は置換基を有していてもよいエチレン基を示し、
Ｙは置換基を有していてもよい炭素原子、置換基を有していてもよい窒素原子、酸素原子または酸化されていてもよい硫黄原子を示す。］で表される化合物
（ただし、Ａ１およびＡ２が置換基を有していてもよいフェニル基を、
Ｙが置換基を有しない炭素原子を、
Figure JPOXMLDOC01-appb-C000011
 が二重結合を、Ｒが水素原子を、Ｘ１がメチレン（－ＣＨ２－）を、Ｘ２がエチレン（－ＣＨ２ＣＨ２－）を示すとき、Ｂ環の置換基は、Ｃ１－２アルキル、Ｃ１－２アルコキシまたはＣ１－２アルキレンジオキシではない。）またはその塩；
[８] Ｒが水素原子であり； 
Ｒ１は存在しないか、あるいは水素原子であり；
Ｘ１がメチレン（－ＣＨ２－）であり； 
Ｘ２がヒドロキシを有していてもよいエチレン（－ＣＨ２ＣＨ２－）（換言すれば、ヒドロキシで置換されていてもよいエチレン（－ＣＨ２ＣＨ２－））であり；
Ｙが無置換の炭素原子（ＣＨまたはＣＨ２）または酸素原子であり； 
Figure JPOXMLDOC01-appb-C000012
 が単結合または二重結合であり；
Ａ１がハロゲン原子から選択される１～３個の置換基をそれぞれ有していてもよい、(1)Ｃ６－１０アリール基または(2)環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基であり；
Ａ２がハロゲン原子、シアノ、低級（Ｃ１－６）アルコキシ、低級（Ｃ１－６）アルキル－カルボニルアミノおよびC1-6アルキルから選択される１～３個の置換基をそれぞれ有していてもよい、(1)Ｃ６－１０アリール基または(2)環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基であり；
B環が(1)ハロゲン原子、(2)低級（Ｃ１－６）アルコキシ、(3)低級（Ｃ１－６）アルコキシ－カルボニル、(4)カルボキシル、(5)カルバモイルおよびヒドロキシから選択される置換基で置換されていてもよいモノ－またはジ－低級（Ｃ１－６）アルキルカルバモイル、および(6)カルバモイルから選択される１～４個の置換基で置換されていてもよいフェニルである上記[７]記載の化合物またはその塩；
[９]３－（４－シアノフェニル）－１－［２－（４－フルオロフェニル）エチル］－１－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］尿素、
Ｎ－［２－（４－フルオロフェニル）エチル］－Ｎ’－（６－フルオロピリジン－３－イル）－Ｎ－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］尿素、
１－［２－（４－フルオロフェニル）エチル］－１－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－３－（６－メトキシピリジン－３－イル）尿素、
１－［（６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－３－フェニル－１－（２－フェニルエチル）尿素、もしくは
２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボン酸メチル、またはそれらの塩；
［１０］上記［７］記載の化合物のプロドラッグ；
［１１］上記［７］記載の化合物もしくはその塩またはそのプロドラッグを含有してなる医薬；
［１２］哺乳動物に対し、上記［７］記載の化合物もしくはその塩またはそのプロドラッグの有効量を投与することを特徴とする消化器疾患または中枢疾患の予防・治療方法；
［１３］消化器疾患が、機能性消化管疾患である上記［１２］記載の予防・治療方法；
［１４］機能性消化管疾患が、過敏性腸症候群または機能性ディスペプシア（Ｆｕｎｃｔｉｏｎａｌ　ｄｙｓｐｅｐｓｉａ）である上記［１３］記載の予防・治療方法；
［１５］中枢疾患がうつまたは不安である上記［１２］記載の予防・治療方法；
［１６］消化器疾患または中枢疾患の予防・治療剤を製造するための上記［７］記載の化合物もしくはその塩またはそのプロドラッグの使用；
［１７］消化器疾患が、機能性消化管疾患である上記［１６］記載の使用；
［１８］機能性消化管疾患が、過敏性腸症候群または機能性ディスペプシア（Ｆｕｎｃｔｉｏｎａｌ　ｄｙｓｐｅｐｓｉａ）である上記［１７］記載の使用；および
［１９］中枢疾患がうつまたは不安である上記［１６］記載の使用等を提供する。 [Where:
Figure JPOXMLDOC01-appb-C000003
 Is a single bond or a double bond,
A 1 and A 2 are the same or different and each represents an optionally substituted aromatic group;
Ring B represents a phenyl group which may have a substituent,
R represents a hydrogen atom or an optionally substituted hydrocarbon group;
R 1 is absent, represents a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified,
X 1 represents a methylene group which may have a substituent,
X 2 represents an ethylene group which may have a substituent,
Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized. ] (Sometimes referred to as compound (I) in the present specification) or a salt thereof unexpectedly has excellent properties as an NK2 receptor binding agent, and is sufficient as a pharmaceutical. The present invention was found to be satisfactory, and the present invention was completed based on these findings.
Of the compounds (I), formula (I)
Figure JPOXMLDOC01-appb-C000004
 [Where:
Figure JPOXMLDOC01-appb-C000005
 Is a single bond or a double bond,
A 1 and A 2 are the same or different and each represents an optionally substituted aromatic group,
Ring B represents a phenyl group which may have a substituent,
R represents a hydrogen atom or a hydrocarbon group which may have a substituent,
R 1 is absent, represents a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified,
X 1 represents a methylene group which may have a substituent,
X 2 represents an ethylene group which may have a substituent,
Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized.
(However, A 1 and A 2 may have a phenyl group which may have a substituent,
Y is a carbon atom having no substituent,
Figure JPOXMLDOC01-appb-C000006
 Is a double bond, R is a hydrogen atom, X 1 is methylene (—CH 2 —), and X 2 is ethylene (—CH 2 CH 2 —), the substituent on the B ring is C 1- Not 2 alkyl, C 1-2 alkoxy or C 1-2 alkylenedioxy. )] Or a salt thereof is a novel compound.
That is, the present invention
[1] Formula (I)
Figure JPOXMLDOC01-appb-C000007
 [Where:
Figure JPOXMLDOC01-appb-C000008
 Is a single bond or a double bond,
A 1 and A 2 are the same or different and each represents an optionally substituted aromatic group,
Ring B represents a phenyl group which may have a substituent,
R represents a hydrogen atom or a hydrocarbon group which may have a substituent,
R 1 represents a hydrogen atom, an alkyl group which may have a substituent, a carboxyl group, or a carboxyl group which may be esterified;
X 1 represents a methylene group which may have a substituent,
X 2 represents an ethylene group which may have a substituent,
Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized. A neurokinin (NK) receptor antagonist comprising a compound represented by the formula:
[2] The antagonist according to [1], which is a neurokinin 2 (NK2) receptor antagonist;
[3] The antagonist of the above-mentioned [1], which is a prophylactic / therapeutic agent for digestive organ diseases or central diseases;
[4] The antagonist of the above-mentioned [3], wherein the digestive organ disease is a functional digestive tract disease;
[5] The antagonist according to the above [4], wherein the functional gastrointestinal tract disease is irritable bowel syndrome or functional dyspepsia;
[6] The antagonist of the above-mentioned [3], wherein the central disease is depression or anxiety;
[7] Formula (I)
Figure JPOXMLDOC01-appb-C000009
 [Where:
Figure JPOXMLDOC01-appb-C000010
 Is a single bond or a double bond,
A 1 and A 2 are the same or different and each represents an optionally substituted aromatic group,
Ring B represents a phenyl group which may have a substituent,
R represents a hydrogen atom or an optionally substituted hydrocarbon group;
R 1 is absent, represents a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified,
X 1 represents a methylene group which may have a substituent,
X 2 represents an ethylene group which may have a substituent,
Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized. (Wherein, A 1 and A 2 are optionally substituted phenyl groups,
Y is a carbon atom having no substituent,
Figure JPOXMLDOC01-appb-C000011
 Is a double bond, R is a hydrogen atom, X 1 is methylene (—CH 2 —), and X 2 is ethylene (—CH 2 CH 2 —), the substituent on the B ring is C 1- Not 2 alkyl, C 1-2 alkoxy or C 1-2 alkylenedioxy. ) Or a salt thereof;
[8] R is a hydrogen atom;
R 1 is absent or is a hydrogen atom;
X 1 is methylene (—CH 2 —);
X 2 is ethylene optionally having hydroxy (—CH 2 CH 2 —) (in other words, ethylene optionally substituted with hydroxy (—CH 2 CH 2 —));
Y is an unsubstituted carbon atom (CH or CH 2 ) or an oxygen atom;
Figure JPOXMLDOC01-appb-C000012
 Is a single bond or a double bond;
A 1 may have 1 to 3 substituents each selected from a halogen atom, and (1) a C 6-10 aryl group or (2) a ring atom as a nitrogen atom in addition to a carbon atom, A 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 heteroatoms selected from a sulfur atom and an oxygen atom;
A 2 has 1 to 3 substituents each selected from a halogen atom, cyano, lower (C 1-6 ) alkoxy, lower (C 1-6 ) alkyl-carbonylamino and C 1-6 alkyl. (1) C 6-10 aryl group or (2) 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom Having a 5- or 6-membered aromatic monocyclic heterocyclic group;
Ring B is selected from (1) a halogen atom, (2) lower (C 1-6 ) alkoxy, (3) lower (C 1-6 ) alkoxy-carbonyl, (4) carboxyl, (5) carbamoyl and hydroxy Mono- or di-lower (C 1-6 ) alkylcarbamoyl optionally substituted with a substituent, and (6) phenyl optionally substituted with 1 to 4 substituents selected from carbamoyl The compound or salt thereof according to [7] above;
[9] 3- (4-Cyanophenyl) -1- [2- (4-fluorophenyl) ethyl] -1-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl) methyl ]urea,
N- [2- (4-Fluorophenyl) ethyl] -N ′-(6-fluoropyridin-3-yl) -N-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl ) Methyl] urea,
1- [2- (4-Fluorophenyl) ethyl] -1-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl) methyl] -3- (6-methoxypyridine-3- Yl) urea,
1-[(6-Bromo-2-oxo-1,2-dihydroquinolin-3-yl) methyl] -3-phenyl-1- (2-phenylethyl) urea or 2-oxo-3-{[( Phenylcarbamoyl) (2-phenylethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxylate, or a salt thereof;
[10] A prodrug of the compound according to [7] above;
[11] A medicament comprising the compound according to [7] above or a salt thereof or a prodrug thereof;
[12] A method for the prophylaxis or treatment of digestive system diseases or central diseases, which comprises administering an effective amount of the compound according to [7] above or a salt thereof or a prodrug thereof to a mammal;
[13] The prevention / treatment method according to the above [12], wherein the digestive organ disease is a functional digestive tract disease;
[14] The prevention / treatment method according to the above [13], wherein the functional gastrointestinal tract disease is irritable bowel syndrome or functional dyspepsia;
[15] The prevention / treatment method according to the above [12], wherein the central disease is depression or anxiety;
[16] Use of the compound of the above-mentioned [7], a salt thereof or a prodrug thereof for producing a prophylactic / therapeutic agent for digestive system diseases or central diseases;
[17] The use according to [16] above, wherein the digestive system disease is a functional digestive tract disease;
[18] The use according to [17] above, wherein the functional gastrointestinal disease is irritable bowel syndrome or functional dyspepsia; and [19] the above [16], wherein the central disease is depression or anxiety Provide use etc.
　本発明の化合物（Ｉ）、その塩およびそのプロドラッグは、ＮＫ２受容体結合活性を有し、毒性も少ないため、過敏性腸症候群などの予防または治療剤として特に有用である。 The compound (I) of the present invention, a salt thereof and a prodrug thereof are particularly useful as a preventive or therapeutic agent for irritable bowel syndrome and the like because of having NK2 receptor binding activity and low toxicity.
　以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
　以下、式（Ｉ）中の記号を説明する。
　式（Ｉ）中、Ａ１およびＡ２は同一または異なって置換基を有していてもよい芳香族基を示す。
　Ａ１およびＡ２で示される「置換基を有していてもよい芳香族基」の「芳香族基」としては、例えば、アリール基、および芳香族複素環基が挙げられる。 Hereinafter, symbols in formula (I) will be described.
In formula (I), A 1 and A 2 are the same or different and each represents an aromatic group which may have a substituent.
Examples of the “aromatic group” of the “aromatic group optionally having a substituent” represented by A 1 and A 2 include an aryl group and an aromatic heterocyclic group.
　当該「アリール基」としては、例えば、フェニル、1-ナフチル、および2-ナフチルのようなＣ６－１０アリール基が挙げられる。なかでも、フェニル等が好ましい。 Examples of the “aryl group” include C 6-10 aryl groups such as phenyl, 1-naphthyl, and 2-naphthyl. Of these, phenyl and the like are preferable.
　当該「芳香族複素環基」としては、特に断りのない限り、例えば、環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし５個（好ましくは１ないし３個）有する、５ないし１４員（単環、２環又は３環式）の芳香族複素環基が挙げられる。 As the “aromatic heterocyclic group”, unless otherwise specified, for example, as a ring-constituting atom, 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom are used. Examples thereof include 5- to 14-membered (monocyclic, bicyclic or tricyclic) aromatic heterocyclic groups having 5 (preferably 1 to 3).
　このような「芳香族複素環基」としては、
例えば、ピロリル（例、１－ピロリル、２－ピロリル、３－ピロリル）、フリル（例、２－フリル、３－フリル）、チエニル（例、２－チエニル、３－チエニル）、オキサゾリル（例、２－オキサゾリル、４－オキサゾリル、５－オキサゾリル）、イソオキサゾリル（例、３－イソオキサゾリル、４－イソオキサゾリル、５－イソオキサゾリル）、チアゾリル、イソチアゾリル、イミダゾリル（例、１－イミダゾリル、２－イミダゾリル、４－イミダゾリル）、ピラゾリル（例、１－ピラゾリル、３－ピラゾリル、４－ピラゾリル）、１，２，３－オキサジアゾリル、１，２，４－オキサジアゾリル、１，３，４－オキサジアゾリル、フラザニル、１，２，３－チアジアゾリル、１，２，４－チアジアゾリル、１，３，４－チアジアゾリル、１，２，３－トリアゾリル、１，２，４－トリアゾリル、テトラゾリル、ピリジル（例、２－ピリジル、３－ピリジル、４－ピリジル）、ピリダジニル（例、３－ピリダジニル、４－ピリダジニル）、ピリミジニル（例、２－ピリミジニル、４－ピリミジニル、５－ピリミジニル）、ピラジニル、トリアジニル等の５または６員の芳香族単環式複素環基、および、
例えば、ベンゾフラニル、イソベンゾフラニル、ベンゾ［ｂ］チエニル、インドリル、３Ｈ－インドリル、インドリニル、イソインドリル、イソインドリニル、１Ｈ－インダゾリル、ベンズイミダゾリル、ベンゾオキサゾリル、１，２－ベンゾイソオキサゾリル、２，１－ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾピラニル、１，２－ベンゾイソチアゾリル、１Ｈ－ベンゾトリアゾリル、キノリル、イソキノリル、シンノリニル、キナゾリニル、キノキサリニル、フタラジニル、ナフチリジニル、プリニル、ブテリジニル、カルバゾリル、α－カルボリニル、β－カルボリニル、γ－カルボリニル、アクリジニル（ａｃｒｙｄｉｎｙｌ）、フェノキサジニル、フェノチアジニル、フェナジニル、フェノキサチイニル、チアントレニル、フェナントリジニル（ｐｈｅｎａｔｈｒｉｄｉｎｙｌ）、フェナントロリニル（ｐｈｅｎａｔｈｒｏｌｉｎｙｌ）、インドリジニル、ピロロ［１，２－ｂ］ピリダジニル、ピラゾロ［１，５－ａ］ピリジル、イミダゾ［１，２－ａ］ピリジル、イミダゾ［１，５－ａ］ピリジル、イミダゾ［１，２－ｂ］ピリダジニル、イミダゾ［１，２－ａ］ピリミジニル、１，２，４－トリアゾロ［４，３－ａ］ピリジル、１，２，４－トリアゾロ［４，３－ｂ］ピリダジニル、１，４－ベンズオキサジニル等の８ないし１２員の芳香族縮合複素環基（好ましくは、前記した５または６員の芳香族単環式複素環基がベンゼン環と縮合した複素環あるいは前記した５または６員の芳香族単環式複素環基の同一または異なった複素環２個が縮合した複素環）等が挙げられる。
　なかでも、当該「芳香族複素環基」としては、Ａ１については、２－チエニル等が好ましい。
　なかでも、当該「芳香族複素環基」としては、Ａ２については、３－ピリジル等がより好ましい。 As such an “aromatic heterocyclic group”,
For example, pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), oxazolyl (eg, 2 -Oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl, isothiazolyl, imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), Pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, , 2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and the like 5- or 6-membered aromatic monocyclic heterocyclic group, and
For example, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, 3H-indolyl, indolinyl, isoindolyl, isoindolinyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, 2 , 1-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α -Carborinyl, β-Carborinyl, γ-Carborinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thiantreni , Phenanthridinyl (phenathridinyl), phenanthrolinyl (phenathrolinyl), indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1,2,4 -8- to 12-membered aromatic condensed heterocyclic group such as triazolo [4,3- b ] pyridazinyl, 1,4-benzoxazinyl (preferably the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic ring A heterocycle in which the group is condensed with a benzene ring or two identical or different heterocycles of the 5- or 6-membered aromatic monocyclic heterocyclic group mentioned above are condensed Heterocycle) and the like have.
Among these, as the “aromatic heterocyclic group”, A 1 is preferably 2-thienyl or the like.
Among these, as the “aromatic heterocyclic group”, A 2 is more preferably 3-pyridyl or the like.
　Ａ１およびＡ２で示される「置換基を有していてもよい芳香環」の「芳香環」は、それぞれ、例えば、下記の置換基Ａ群の置換基を、１～置換可能な最大数、より好ましくは１～３個、更に好ましく１個、置換可能な位置に有していてもよい。
［置換基Ａ群］
（１）ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素）；
（２）Ｃ１－３アルキレンジオキシ（例、メチレンジオキシ、エチレンジオキシ、プロピレンジオキシなど）；
（３）ニトロ；
（４）シアノ；
（５）エステル化されていてもよいカルボキシル〔例、カルボキシル、置換されていてもよい低級（Ｃ１－６）アルコキシ－カルボニル、置換されていてもよいＣ６－１４アリールオキシ－カルボニル、置換されていてもよいＣ７－１６アラルキルオキシ－カルボニル、置換されていてもよいシリルオキシ－カルボニル（例、ＴＭＳ－Ｏ－ＣＯ－、ＴＥＳ－Ｏ－ＣＯ－、ＴＢＳ－Ｏ－ＣＯ－、ＴＩＰＳ－Ｏ－ＣＯ－、ＴＢＤＰＳ－Ｏ－ＣＯ－）など〕； The “aromatic ring” of the “optionally substituted aromatic ring” represented by A 1 and A 2 is, for example, 1 to the maximum number of substituents in the following substituent group A that can be substituted by 1 to More preferably, it may have 1 to 3, more preferably 1, at a substitutable position.
[Substituent group A]
(1) a halogen atom (eg, fluorine, chlorine, bromine, iodine);
(2) C 1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, propylenedioxy, etc.);
(3) Nitro;
(4) Cyano;
(5) optionally esterified carboxyl [eg, carboxyl, optionally substituted lower (C 1-6 ) alkoxy-carbonyl, optionally substituted C 6-14 aryloxy-carbonyl, substituted Optionally substituted C 7-16 aralkyloxy-carbonyl, optionally substituted silyloxy-carbonyl (eg, TMS-O—CO—, TES—O—CO—, TBS—O—CO—, TIPS—O—) CO-, TBDPS-O-CO-) etc.];
（６）置換されていてもよい低級（Ｃ１－６）アルキル；
（７）置換されていてもよい低級（Ｃ２－６）アルケニル；
（８）置換されていてもよい低級（Ｃ２－６）アルキニル；
（９）置換されていてもよいＣ３－８シクロアルキル；
（１０）置換されていてもよいＣ６－１４アリール；
（１１）置換されていてもよいＣ７－１６アラルキル；
（１２）置換されていてもよいＣ６－１４アリール－Ｃ２－６アルケニル； (6) optionally substituted lower (C 1-6 ) alkyl;
(7) optionally substituted lower (C 2-6 ) alkenyl;
(8) optionally substituted lower (C 2-6 ) alkynyl;
(9) optionally substituted C 3-8 cycloalkyl;
(10) optionally substituted C 6-14 aryl;
(11) optionally substituted C 7-16 aralkyl;
(12) optionally substituted C 6-14 aryl-C 2-6 alkenyl;
（１３）置換されていてもよい複素環基； (13) an optionally substituted heterocyclic group;
（１４）ヒドロキシ；
（１５）置換されていてもよい低級（Ｃ１－６）アルコキシ；
（１６）置換されていてもよいＣ３－８シクロアルコキシ；
（１７）置換されていてもよいＣ６－１４アリールオキシ；
（１８）置換されていてもよいＣ７－１６アラルキルオキシ；
（１９）置換されていてもよい低級（Ｃ１－６）アルキル－カルボニルオキシ；
（２０）置換されていてもよい低級（Ｃ１－６）アルコキシ－カルボニルオキシ；
（２１）置換されていてもよいモノ－低級（Ｃ１－６）アルキル－カルバモイルオキシ；
（２２）置換されていてもよいジ－低級（Ｃ１－６）アルキル－カルバモイルオキシ；
（２３）置換されていてもよいＣ６－１４アリール－カルボニルオキシ；
（２４）置換されていてもよいモノ－又はジ－Ｃ６－１４アリール－カルバモイルオキシ；
（２５）置換されていてもよい複素環オキシ（例、置換されていてもよい芳香族複素環オキシ）； (14) hydroxy;
(15) optionally substituted lower (C 1-6 ) alkoxy;
(16) optionally substituted C 3-8 cycloalkoxy;
(17) optionally substituted C 6-14 aryloxy;
(18) optionally substituted C 7-16 aralkyloxy;
(19) optionally substituted lower (C 1-6 ) alkyl-carbonyloxy;
(20) optionally substituted lower (C 1-6 ) alkoxy-carbonyloxy;
(21) optionally substituted mono-lower (C 1-6 ) alkyl-carbamoyloxy;
(22) optionally substituted di-lower (C 1-6 ) alkyl-carbamoyloxy;
(23) optionally substituted C 6-14 aryl-carbonyloxy;
(24) optionally substituted mono- or di-C 6-14 aryl-carbamoyloxy;
(25) optionally substituted heterocyclic oxy (eg, optionally substituted aromatic heterocyclic oxy);
（２６）メルカプト；
（２７）置換されていてもよい低級（Ｃ１－６）アルキルチオ；
（２８）置換されていてもよいＣ３－８シクロアルキルチオ；
（２９）置換されていてもよいＣ６－１４アリールチオ；
（３０）置換されていてもよいＣ７－１６アラルキルチオ； (26) Mercapto;
(27) optionally substituted lower (C 1-6 ) alkylthio;
(28) optionally substituted C 3-8 cycloalkylthio;
(29) optionally substituted C 6-14 arylthio;
(30) optionally substituted C 7-16 aralkylthio;
（３１）ホルミル；
（３２）置換されていてもよい低級（Ｃ１－６）アルキル－カルボニル；
（３３）置換されていてもよいＣ３－８シクロアルキル－カルボニル；
（３４）置換されていてもよいＣ６－１４アリール－カルボニル；
（３５）置換されていてもよいＣ７－１６アラルキル－カルボニル；
（３６）置換されていてもよい複素環－カルボニル； (31) formyl;
(32) optionally substituted lower (C 1-6 ) alkyl-carbonyl;
(33) optionally substituted C 3-8 cycloalkyl-carbonyl;
(34) optionally substituted C 6-14 aryl-carbonyl;
(35) optionally substituted C 7-16 aralkyl-carbonyl;
(36) optionally substituted heterocycle-carbonyl;
（３７）置換されていてもよい低級（Ｃ１－６）アルキルスルホニル；
（３８）置換されていてもよいＣ３－８シクロアルキルスルホニル；
（３９）置換されていてもよいＣ６－１４アリールスルホニル；
（４０）置換されていてもよい低級（Ｃ１－６）アルキルスルフィニル；
（４１）置換されていてもよいＣ３－８シクロアルキルスルフィニル；
（４２）置換されていてもよいＣ６－１４アリールスルフィニル；
（４３）スルホ；
（４４）スルファモイル；
（４５）スルフィナモイル；
（４６）スルフェナモイル；
（４７）チオカルバモイル； (37) optionally substituted lower (C 1-6 ) alkylsulfonyl;
(38) optionally substituted C 3-8 cycloalkylsulfonyl;
(39) optionally substituted C 6-14 arylsulfonyl;
(40) optionally substituted lower (C 1-6 ) alkylsulfinyl;
(41) optionally substituted C 3-8 cycloalkylsulfinyl;
(42) optionally substituted C 6-14 arylsulfinyl;
(43) Sulfo;
(44) Sulfamoyl;
(45) Sulfinamoyl;
(46) Sulfenamoyl;
(47) Thiocarbamoyl;
（４８）置換されていてもよいカルバモイル基〔例、置換されていてもよい低級（Ｃ１－６）アルキル－カルバモイルなど〕； (48) an optionally substituted carbamoyl group [eg, optionally substituted lower (C 1-6 ) alkyl-carbamoyl and the like];
（４９）置換されていてもよいアミノ基［例、アミノ、置換されていてもよいモノ－又はジ－低級（Ｃ１－６）アルキルアミノ、置換されていてもよいモノ－又はジ－Ｃ３－８シクロアルキルアミノ、置換されていてもよいモノ－又はジ－Ｃ６－１４アリールアミノ、置換されていてもよいモノ－又はジ－Ｃ７－１６アラルキルアミノ、置換されていてもよい複素環基－アミノ、置換されていてもよいＣ６－１４アリール－カルボニルアミノ、ホルミルアミノ、置換されていてもよい低級（Ｃ１－６）アルキル－カルボニルアミノ、置換されていてもよいＣ３－８シクロアルキル－カルボニルアミノ、置換されていてもよい複素環－カルボニルアミノ、置換されていてもよい低級（Ｃ１－６）アルコキシ－カルボニルアミノ、置換されていてもよいＣ３－８シクロアルコキシ－カルボニルアミノ、置換されていてもよい複素環基－オキシカルボニルアミノ、置換基を有していてもよいカルバモイルアミノ基、置換されていてもよい低級（Ｃ１－６）アルキルスルホニルアミノ、置換されていてもよいＣ３－８シクロアルキル－スルホニルアミノ、置換されていてもよい複素環基－スルホニルアミノ、置換されていてもよいＣ６－１４アリールスルホニルアミノ］ (49) An optionally substituted amino group [eg, amino, optionally substituted mono- or di-lower (C 1-6 ) alkylamino, optionally substituted mono- or di-C 3 -8 cycloalkylamino, optionally substituted mono- or di-C 6-14 arylamino, optionally substituted mono- or di-C 7-16 aralkylamino, optionally substituted heterocycle Group-amino, optionally substituted C 6-14 aryl-carbonylamino, formylamino, optionally substituted lower (C 1-6 ) alkyl-carbonylamino, optionally substituted C 3-8 cycloalkyl - carbonyl amino, optionally substituted heterocycle - carbonylamino, optionally substituted lower (C 1-6) alkoxy - carbonyl amino, is substituted Which may be C 3-8 cycloalkoxy - carbonylamino, optionally substituted heterocyclic group - oxycarbonylamino, substituents may carbamoylamino group optionally having, optionally substituted lower (C 1-6 ) alkylsulfonylamino, optionally substituted C 3-8 cycloalkyl-sulfonylamino, optionally substituted heterocyclic group-sulfonylamino, optionally substituted C 6-14 arylsulfonylamino ]
　置換基Ａ群の（５）「エステル化されていてもよいカルボキシル」としての「置換されていてもよい低級（Ｃ１－６）アルコキシ－カルボニル」の「低級（Ｃ１－６）アルコキシ－カルボニル」としては、例えば、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、ｔｅｒｔ-ブトキシカルボニルなどが挙げられる。
　置換基Ａ群の（５）「エステル化されていてもよいカルボキシル」としての「置換されていてもよいＣ６－１４アリールオキシ－カルボニル」の「Ｃ６－１４アリールオキシ－カルボニル」としては、例えばフェノキシカルボニルなどが挙げられる。
　置換基Ａ群の（５）「エステル化されていてもよいカルボキシル」としての「置換されていてもよいＣ７－１６アラルキルオキシ－カルボニル」の「Ｃ７－１６アラルキルオキシ－カルボニル」としては、例えばベンジルオキシカルボニル、フェネチルオキシカルボニルなどが挙げられる。 In the Substituent Group A (5) the "optionally substituted lower (C 1-6) alkoxy - carbonyl" of "optionally carboxyl which may be esterified" and "lower (C 1-6) alkoxy - carbonyl "" Includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
As “C 6-14 aryloxy-carbonyl” of “ optionally substituted C 6-14 aryloxy-carbonyl” as (5) “optionally esterified carboxyl” of substituent group A, An example is phenoxycarbonyl.
As the “C 7-16 aralkyloxy-carbonyl” of the “ optionally substituted C 7-16 aralkyloxy-carbonyl” as the (5) “optionally esterified carboxyl” in the substituent group A, Examples include benzyloxycarbonyl and phenethyloxycarbonyl.
　置換基Ａ群の（６）「置換されていてもよい低級（Ｃ１－６）アルキル」の「低級（Ｃ１－６）アルキル」としては、例えばメチル、エチル、イソプロピル、ブチル、イソブチル、ｓｅｃ-ブチル、ｔｅｒｔ-ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシルなどが挙げられる。 Examples of “lower (C 1-6 ) alkyl” in (6) “optionally substituted lower (C 1-6 ) alkyl” of substituent group A include, for example, methyl, ethyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
　置換基Ａ群の（７）「置換されていてもよい低級（Ｃ２－６）アルケニル」の「低級（Ｃ２－６）アルケニル」としては、例えばビニル、１－プロペン－１－イル、２－プロペン－１－イル、イソプロペニル、２－ブテン－１－イル、４－ペンテン－１－イル、５－へキセン－１－イルなどが挙げられる。 As the "lower (C 2-6) alkenyl" in the substituent group A (7) the "optionally substituted lower (C 2-6) alkenyl", for example vinyl, 1-propen-1-yl, 2 -Propen-1-yl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like.
　置換基Ａ群の（８）「置換されていてもよい低級（Ｃ２－６）アルキニル」の「低級（Ｃ２－６）アルキニル」としては、例えばエチニル、１－プロピン－１－イル、２－プロピン－１－イル、４－ペンチン－１－イル、５－へキシン－１－イルなどが挙げられる。 Examples of “lower (C 2-6 ) alkynyl” of (8) “optionally substituted lower (C 2-6 ) alkynyl” in Substituent Group A include, for example, ethynyl, 1-propyn-1-yl, 2 -Propin-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl and the like.
　置換基Ａ群の（９）「置換されていてもよいＣ３－８シクロアルキル」の「Ｃ３－８シクロアルキル」としては、例えばシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルなどが挙げられる。 Examples of “C 3-8 cycloalkyl” in the group (9) “optionally substituted C 3-8 cycloalkyl” in Substituent Group A include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
　置換基Ａ群の（１０）「置換されていてもよいＣ６－１４アリール」の「Ｃ６－１４アリール」としては、例えばフェニル、１－ナフチル、２－ナフチル、２－ビフェニリル、３－ビフェニリル、４－ビフェニリル、２－アンスリルなどが挙げられる。該Ｃ６－１４アリールは、部分的に飽和されていてもよく、部分的に飽和されたＣ６－１４アリールとしては、例えばテトラヒドロナフチルなどが挙げられる。 In the Substituent Group A (10) of the "optionally substituted C 6-14 aryl" as "C 6-14 aryl" include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl 4-biphenylyl, 2-anthryl and the like. The C 6-14 aryl may be partially saturated, and examples of the partially saturated C 6-14 aryl include tetrahydronaphthyl.
　置換基Ａ群の（１１）「置換されていてもよいＣ７－１６アラルキル」の「Ｃ７－１６アラルキル」としては、例えばベンジル、フェネチル、ジフェニルメチル、１－ナフチルメチル、２－ナフチルメチル、２，２－ジフェニルエチル、３－フェニルプロピル、４－フェニルブチル、５－フェニルペンチル、２－ビフェニリルメチル、３－ビフェニリルメチル、４－ビフェニリルメチル）などが挙げられる。 As "C 7-16 aralkyl" in Substituent Group A (11) "optionally substituted C 7-16 aralkyl", for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl) and the like.
　置換基Ａ群の（１２）「置換されていてもよいＣ６－１４アリール－Ｃ２－６アルケニル」の「Ｃ６－１４アリール－Ｃ２－６アルケニル」としては、例えばスチリルなどが挙げられる。 Examples of “C 6-14 aryl-C 2-6 alkenyl” of (12) “optionally substituted C 6-14 aryl-C 2-6 alkenyl” in Substituent group A include styryl and the like. .
　置換基Ａ群の（１３）「置換されていてもよい複素環基」の「複素環基」としては、例えば、炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる１ないし３種、１ないし５個のヘテロ原子を含む３ないし１４員（単環、２環又は３環式）複素環基が挙げられる。その例としては、ピロリル（例、１－ピロリル、２－ピロリル、３－ピロリル）、フリル（例、２－フリル、３－フリル）、チエニル（例、２－チエニル、３－チエニル）、ピラゾリル（例、１－ピラゾリル、３－ピラゾリル、４－ピラゾリル）、イミダゾリル（例、１－イミダゾリル、２－イミダゾリル、４－イミダゾリル）、イソオキサゾリル（例、３－イソオキサゾリル、４－イソオキサゾリル、５－イソオキサゾリル）、オキサゾリル（例、２－オキサゾリル、４－オキサゾリル、５－オキサゾリル）、イソチアゾリル（例、３－イソチアゾリル、４－イソチアゾリル、５－イソチアゾリル）、チアゾリル（例、２－チアゾリル、４－チアゾリル、５－チアゾリル）、トリアゾリル（１，２，３－トリアゾール－４－イル、１，２，４－トリアゾール－３－イル）、オキサジアゾリル（１，２，４－オキサジアゾール－３－イル、１，２，４－オキサジアゾール－５－イル）、チアジアゾリル（１，２，４－チアジアゾール－３－イル、１，２，４－チアジアゾール－５－イル）、テトラゾリル、ピリジル（例、２－ピリジル、３－ピリジル、４－ピリジル）、ピリダジニル（例、３－ピリダジニル、４－ピリダジニル）、ピリミジニル（例、２－ピリミジニル、４－ピリミジニル、５－ピリミジニル）、ピラジニル、イソインドリル（例、１－イソインドリル、２－イソインドリル、３－イソインドリル、４－イソインドリル、５－イソインドリル、６－イソインドリル、７－イソインドリル）、インドリル（例、１－インドリル、２－インドリル、３－インドリル、４－インドリル、５－インドリル、６－インドリル、７－インドリル）、ベンゾ［ｂ］フラニル（例、２－ベンゾ［ｂ］フラニル、３－ベンゾ［ｂ］フラニル、４－ベンゾ［ｂ］フラニル、５－ベンゾ［ｂ］フラニル、６－ベンゾ［ｂ］フラニル、７－ベンゾ［ｂ］フラニル）、ベンゾ［ｃ］フラニル（例、１－ベンゾ［ｃ］フラニル、４－ベンゾ［ｃ］フラニル、５－ベンゾ［ｃ］フラニル）、ベンゾ［ｂ］チエニル、（例、２－ベンゾ［ｂ］チエニル、３－ベンゾ［ｂ］チエニル、４－ベンゾ［ｂ］チエニル、５－ベンゾ［ｂ］チエニル、６－ベンゾ［ｂ］チエニル、７－ベンゾ［ｂ］チエニル）、ベンゾ［ｃ］チエニル（例、１－ベンゾ［ｃ］チエニル、４－ベンゾ［ｃ］チエニル、５－ベンゾ［ｃ］チエニル）、インダゾリル（例、１－インダゾリル、２－インダゾリル、３－インダゾリル、４－インダゾリル、５－インダゾリル、６－インダゾリル、７－インダゾリル）、ベンゾイミダゾリル（例、１－ベンゾイミダゾリル、２－ベンゾイミダゾリル、４－ベンゾイミダゾリル、５－ベンゾイミダゾリル）、１，２－ベンゾイソオキサゾリル（例、１，２－ベンゾイソオキサゾール－３－イル、１，２－ベンゾイソオキサゾール－４－イル、１，２－ベンゾイソオキサゾール－５－イル、１，２－ベンゾイソオキサゾール－６－イル、１，２－ベンゾイソオキサゾール－７－イル）、ベンゾオキサゾリル（例、２－ベンゾオキサゾリル、４－ベンゾオキサゾリル、５－ベンゾオキサゾリル、６－ベンゾオキサゾリル、７－ベンゾオキサゾリル）、１，２－ベンゾイソチアゾリル（例、１，２－ベンゾイソチアゾール－３－イル、１，２－ベンゾイソチアゾール－４－イル、１，２－ベンゾイソチアゾール－５－イル、１，２－ベンゾイソチアゾール－６－イル、１，２－ベンゾイソチアゾール－７－イル）、ベンゾチアゾリル（例、２－ベンゾチアゾリル、４－ベンゾチアゾリル、５－ベンゾチアゾリル、６－ベンゾチアゾリル、７－ベンゾチアゾリル）、イソキノリル（例、１－イソキノリル、３－イソキノリル、４－イソキノリル、５－イソキノリル）、キノリル（例、２－キノリル、３－キノリル、４－キノリル、５－キノリル、８－キノリル）、シンノリニル（例、３－シンノリニル、４－シンノリニル、５－シンノリニル、６－シンノリニル、７－シンノリニル、８－シンノリニル）、フタラジニル（例、１－フタラジニル、４－フタラジニル、５－フタラジニル、６－フタラジニル、７－フタラジニル、８－フタラジニル）、キナゾリニル（例、２－キナゾリニル、４－キナゾリニル、５－キナゾリニル、６－キナゾリニル、７－キナゾリニル、８－キナゾリニル）、キノキサリニル（例、２－キノキサリニル、３－キノキサリニル、５－キノキサリニル、６－キノキサリニル、７－キノキサリニル、８－キノキサリニル）、ピラゾロ［１，５－ａ］ピリジル（ピラゾロ［１，５－ａ］ピリジン－２－イル、ピラゾロ［１，５－ａ］ピリジン－３－イル、ピラゾロ［１，５－ａ］ピリジン－４－イル、ピラゾロ［１，５－ａ］ピリジン－５－イル、ピラゾロ［１，５－ａ］ピリジン－６－イル、ピラゾロ［１，５－ａ］ピリジン－７－イル）、イミダゾ［１，２－ａ］ピリジル（イミダゾ［１，２－ａ］ピリジン－２－イル、イミダゾ［１，２－ａ］ピリジン－３－イル、イミダゾ［１，２－ａ］ピリジン－５－イル、イミダゾ［１，２－ａ］ピリジン－６－イル、イミダゾ［１，２－ａ］ピリジン－７－イル、イミダゾ［１，２－ａ］ピリジン－８－イル）などの芳香族複素環基；
例えばオキサゾリジニル（例、イミダゾリニル（例、１－イミダゾリニル、２－イミダゾリニル、４－イミダゾリニル）、アジリジニル（例、１－アジリジニル、２－アジリジニル）、アゼチジニル（例、１－アゼチジニル、２－アゼチジニル）、ピロリジニル（例、１－ピロリジニル、２－ピロリジニル、３－ピロリジニル）、ピペリジニル（例、１－ピペリジニル、２－ピペリジニル、３－ピペリジニル）、アゼパニル（例、１－アゼパニル、２－アゼパニル、３－アゼパニル、４－アゼパニル）、アゾカニル（例、１－アゾカニル、２－アゾカニル、３－アゾカニル、４－アゾカニル）、ピペラジニル（例、１，４－ピペラジン－１－イル、１，４－ピペラジン－２－イル）、ジアゼパニル（例、１，４－ジアゼパン－１－イル、１，４－ジアゼパン－２－イル、１，４－ジアゼパン－５－イル、１，４－ジアゼパン－６－イル）、ジアゾカニル（１，４－ジアゾカン－１－イル、１，４－ジアゾカン－２－イル、１，４－ジアゾカン－５－イル、１，４－ジアゾカン－６－イル、１，５－ジアゾカン－１－イル、１，５－ジアゾカン－２－イル、１，５－ジアゾカン－３－イル）、１－モルホリニル、４－チオモルホリニル、２－オキサゾリジニルなどの非芳香族複素環基；
前記の芳香族複素環基の一部が水素化された複素環基（例えば、インドリル、ジヒドロキノリルなどの複素環基）；
前記の非芳香族複素環基の一部が脱水素化された複素環基（例えば、ジヒドロフラニル）などが挙げられる。 Examples of the “heterocyclic group” of (13) “optionally substituted heterocyclic group” in the substituent group A include, for example, 1 to 3 types selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, Examples include 3 to 14 membered (monocyclic, bicyclic or tricyclic) heterocyclic groups containing 1 to 5 heteroatoms. Examples thereof include pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrazolyl ( Examples, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (Eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), Triazolyl (1,2,3-triazol-4-yl, 1,2, -Triazol-3-yl), oxadiazolyl (1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl), thiadiazolyl (1,2,4-thiadiazole-3) -Yl, 1,2,4-thiadiazol-5-yl), tetrazolyl, pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl ( Examples, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, isoindolyl (eg, 1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), In-drill (eg 1-in-drill, 2-in-drill, 3-in-drill, 4 Indolyl, 5-indolyl, 6-indolyl, 7-indolyl), benzo [b] furanyl (eg, 2-benzo [b] furanyl, 3-benzo [b] furanyl, 4-benzo [b] furanyl, 5-benzo [B] furanyl, 6-benzo [b] furanyl, 7-benzo [b] furanyl), benzo [c] furanyl (eg, 1-benzo [c] furanyl, 4-benzo [c] furanyl, 5-benzo [ c] furanyl), benzo [b] thienyl, (eg, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [ b] thienyl, 7-benzo [b] thienyl), benzo [c] thienyl (eg, 1-benzo [c] thienyl, 4-benzo [c] thienyl, 5-benzo [c] thienyl), indazolyl (eg, 1- Indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzoimidazolyl (eg, 1-benzoimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), 1, 2-benzoisoxazolyl (eg, 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2- Benzoisoxazol-6-yl, 1,2-benzisoxazol-7-yl), benzoxazolyl (eg, 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6 -Benzoxazolyl, 7-benzoxazolyl), 1,2-benzisothiazoly (Eg, 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl 1,2-benzisothiazol-7-yl), benzothiazolyl (eg, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl) , 4-isoquinolyl, 5-isoquinolyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), cinnolinyl (eg, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl) 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), phthalazinyl (eg 1-phthalazinyl, 4-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 7-phthalazinyl, 8-phthalazinyl), quinazolinyl (eg, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8 -Quinazolinyl), quinoxalinyl (eg, 2-quinoxalinyl, 3-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, 8-quinoxalinyl), pyrazolo [1,5-a] pyridyl (pyrazolo [1,5-a ] Pyridin-2-yl, pyrazolo [1,5-a] pyridin-3-yl, pyrazolo [1,5-a] pyridin-4-yl, pyrazolo [1,5-a] pyridin-5-yl, pyrazolo [1,5-a] pyridin-6-yl, pyrazolo [1,5-a] pyridin-7-yl), Imidazo [1,2-a] pyridyl (imidazo [1,2-a] pyridin-2-yl, imidazo [1,2-a] pyridin-3-yl, imidazo [1,2-a] pyridine-5- Aromatic heterocycles such as yl, imidazo [1,2-a] pyridin-6-yl, imidazo [1,2-a] pyridin-7-yl, imidazo [1,2-a] pyridin-8-yl) Group;
For example, oxazolidinyl (eg, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl (eg, 1-aziridinyl, 2-aziridinyl), azetidinyl (eg, 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (eg Examples, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl), azepanyl (eg, 1-azepanyl, 2-azepanyl, 3-azepanyl, 4- Azepanyl), azocanyl (eg, 1-azocanyl, 2-azocanyl, 3-azocanyl, 4-azocanyl), piperazinyl (eg, 1,4-piperazin-1-yl, 1,4-piperazin-2-yl), diazepanyl (Eg, 1,4-diazepan-1-yl, 1, -Diazepan-2-yl, 1,4-diazepan-5-yl, 1,4-diazepan-6-yl), diazocanyl (1,4-diazocan-1-yl, 1,4-diazocan-2-yl, 1,4-diazocan-5-yl, 1,4-diazocan-6-yl, 1,5-diazocan-1-yl, 1,5-diazocan-2-yl, 1,5-diazocan-3-yl) Non-aromatic heterocyclic groups such as 1-morpholinyl, 4-thiomorpholinyl, 2-oxazolidinyl;
A heterocyclic group in which a part of the aromatic heterocyclic group is hydrogenated (for example, a heterocyclic group such as indolyl or dihydroquinolyl);
Examples thereof include a heterocyclic group in which a part of the non-aromatic heterocyclic group is dehydrogenated (for example, dihydrofuranyl).
　置換基Ａ群の（１５）「置換されていてもよい低級（Ｃ１－６）アルコキシ」の「低級（Ｃ１－６）アルコキシ」としては、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、ペンチルオキシ、ヘキシルオキシなどが挙げられる。 Examples of “lower (C 1-6 ) alkoxy” of (15) “optionally substituted lower (C 1-6 ) alkoxy” in substituent group A include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Examples include isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.
　置換基Ａ群の（１６）「置換されていてもよいＣ３－８シクロアルコキシ」の「Ｃ３－８シクロアルコキシ」としては、例えばシクロプロポキシ、シクロブトキシ、シクロペンチルオキシ、シクロヘキシルオキシなどが挙げられる。 As the "C 3-8 cycloalkoxy" in Substituent Group A (16) "optionally substituted C 3-8 cycloalkoxy" includes for example cyclopropyl, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like .
　置換基Ａ群の（１７）「置換されていてもよいＣ６－１４アリールオキシ」の「Ｃ６－１４アリールオキシ」としては、例えば、フェニルオキシ、１－ナフチルオキシ、２－ナフチルオキシなどが挙げられる。 Examples of “C 6-14 aryloxy” in (17) “optionally substituted C 6-14 aryloxy” in Substituent Group A include, for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like. Can be mentioned.
　置換基Ａ群の（１８）「置換されていてもよいＣ７－１６アラルキルオキシ」の「Ｃ７－１６アラルキルオキシ」としては、例えば、ベンジルオキシ、フェネチルオキシなどが挙げられる。 Examples of “C 7-16 aralkyloxy” of (18) “optionally substituted C 7-16 aralkyloxy” in Substituent Group A include benzyloxy, phenethyloxy and the like.
　置換基Ａ群の（１９）「置換されていてもよい低級（Ｃ１－６）アルキル－カルボニルオキシ」の「低級（Ｃ１－６）アルキル－カルボニルオキシ」としては、例えばアセトキシ、プロピオニルオキシなどが挙げられる。 Examples of “lower (C 1-6 ) alkyl-carbonyloxy” of (19) “optionally substituted lower (C 1-6 ) alkyl-carbonyloxy” in Substituent Group A include, for example, acetoxy, propionyloxy and the like Is mentioned.
　置換基Ａ群の（２０）「置換されていてもよい低級（Ｃ１－６）アルコキシ－カルボニルオキシ」の「低級（Ｃ１－６）アルコキシ－カルボニルオキシ」としては、例えばメトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、ブトキシカルボニルオキシなどが挙げられる。 In the Substituent Group A (20) "optionally substituted lower (C 1-6) alkoxy - carbonyl oxy""lower (C 1-6) alkoxy - carbonyloxy" as is, for example, methoxycarbonyloxy, ethoxy Examples include carbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like.
　置換基Ａ群の（２１）「置換されていてもよいモノ－低級（Ｃ１－６）アルキル－カルバモイルオキシ」の「モノ－低級（Ｃ１－６）アルキル－カルバモイルオキシ」としては、例えばメチルカルバモイルオキシ、エチルカルバモイルオキシなどが挙げられる。 Substituent group A (21) "optionally substituted mono - lower (C 1-6) alkyl - carbamoyloxy" in the "mono - lower (C 1-6) alkyl - carbamoyloxy" as, for example methyl Carbamoyloxy, ethylcarbamoyloxy and the like can be mentioned.
　置換基Ａ群の（２２）「置換されていてもよいジ－低級（Ｃ１－６）アルキル－カルバモイルオキシ」の「ジ－低級（Ｃ１－６）アルキル－カルバモイルオキシ」としては、例えばジメチルカルバモイルオキシ、ジエチルカルバモイルオキシなどが挙げられる。 Substituent group A (22) "may be substituted di - lower (C 1-6) alkyl - carbamoyloxy" in the "di - lower (C 1-6) alkyl - carbamoyloxy" as, for example, dimethyl Carbamoyloxy, diethylcarbamoyloxy and the like can be mentioned.
　置換基Ａ群の（２３）「置換されていてもよいＣ６－１４アリール－カルボニルオキシ」の「Ｃ６－１４アリール－カルボニルオキシ」としては、例えば、ベンゾイルオキシ、ナフチルカルボニルオキシなどが挙げられる。 Examples of “C 6-14 aryl-carbonyloxy” in (23) “optionally substituted C 6-14 aryl-carbonyloxy” in substituent group A include benzoyloxy, naphthylcarbonyloxy and the like. .
　置換基Ａ群の（２４）「置換されていてもよいモノ－又はジ－Ｃ６－１４アリール－カルバモイルオキシ」の「モノ－又はジ－Ｃ６－１４アリール－カルバモイルオキシ」としては、例えば、フェニルカルバモイルオキシ、ナフチルカルバモイルオキシなどが挙げられる。 "- or di -C 6-14 aryl - mono carbamoyloxy" in the substituent group A (24) "carbamoyloxy optionally substituted mono- - - or di -C 6-14 aryl" includes, for example, Examples include phenylcarbamoyloxy and naphthylcarbamoyloxy.
　置換基Ａ群の（２５）「置換されていてもよい複素環オキシ」の「複素環オキシ」の複素環部分としては、前述の「置換されていてもよい複素環基」の「複素環基」と同様のものが挙げられる。具体的には、例えば、炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる１ないし３種、１ないし５個のヘテロ原子を含む５ないし１４員複素環－オキシなどが挙げられる。 As the heterocyclic moiety of “heterocyclic oxy” of (25) “optionally substituted heterocyclic oxy” in substituent group A, “heterocyclic group” of the above-mentioned “optionally substituted heterocyclic group” may be used. And the like. Specific examples include 5- to 14-membered heterocyclic-oxy containing 1 to 3 types and 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
　置換基Ａ群の（２５）置換されていてもよい複素環オキシ」としての「置換されていてもよい芳香族「複素環オキシ」の「芳香族複素環オキシ」としては、例えば、炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる１ないし３種、１ないし５個のヘテロ原子を含む３ないし１４員芳香族複素環－オキシなどが挙げられる。 “Aromatic heterocyclic oxy” of “optionally substituted aromatic oxy” as “(25) optionally substituted heterocyclic oxy” in substituent group A includes, for example, other than carbon atoms 1 to 3 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, and 3 to 14-membered aromatic heterocyclic-oxy containing 1 to 5 heteroatoms.
　置換基Ａ群の（２７）「置換されていてもよい低級（Ｃ１－６）アルキルチオ」の「低級（Ｃ１－６）アルキルチオ」としては、例えばメチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、ｓｅｃ-ブチルチオ、ｔｅｒｔ-ブチルチオなどが挙げられる。 Examples of “lower (C 1-6 ) alkylthio” of (27) “optionally substituted lower (C 1-6 ) alkylthio” in substituent group A include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, and sec-butylthio and tert-butylthio.
　置換基Ａ群の（２８）「置換されていてもよいＣ３－８シクロアルキルチオ」の「Ｃ３－８シクロアルキルチオ」としては、例えばシクロプロピルチオ、シクロブチルチオ、シクロペンチルチオ、シクロヘキシルチオなどが挙げられる。 Examples of “C 3-8 cycloalkylthio” in (28) “optionally substituted C 3-8 cycloalkylthio” in substituent group A include cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. Can be mentioned.
　置換基Ａ群の（２９）「置換されていてもよいＣ６－１４アリールチオ」の「Ｃ６－１４アリールチオ」としては、例えばフェニルチオ、１－ナフチルチオ、２－ナフチルチオなどが挙げられる。 In the Substituent Group A (29) of the "optionally substituted C 6-14 arylthio" as the "C 6-14 arylthio", such as phenylthio, 1-naphthylthio, 2-naphthylthio.
　置換基Ａ群の（３０）「置換されていてもよいＣ７－１６アラルキルチオ」の「Ｃ７－１６アラルキルチオ」としては、例えばベンジルチオ、フェネチルチオなどが挙げられる。 Examples of “C 7-16 aralkylthio ” of the substituent (30) “optionally substituted C 7-16 aralkylthio” include benzylthio, phenethylthio and the like.
　置換基Ａ群の（３２）「置換されていてもよい低級（Ｃ１－６）アルキル－カルボニル」の「低級（Ｃ１－６）アルキル－カルボニル」としては、例えばアセチル、プロピオニル、ピバロイルなどが挙げられる。 Examples of “lower (C 1-6 ) alkyl-carbonyl” of (32) “optionally substituted lower (C 1-6 ) alkyl-carbonyl” in Substituent Group A include acetyl, propionyl, pivaloyl and the like. Can be mentioned.
　置換基Ａ群の（３３）「置換されていてもよいＣ３－８シクロアルキル－カルボニル」の「Ｃ３－８シクロアルキル－カルボニル」としては、例えばシクロプロピルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニルなどが挙げられる。 In the Substituent Group A (33) "optionally substituted C 3-8 cycloalkyl - carbonyl" for - as the "C 3-8 cycloalkylcarbonyl", for example cyclopropylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl Can be mentioned.
　置換基Ａ群の（３４）「置換されていてもよいＣ６－１４アリール－カルボニル」の「Ｃ６－１４アリール－カルボニル」としては、例えば、ベンゾイル、１－ナフトイル、２－ナフトイルなどが挙げられる。 Examples of “C 6-14 aryl-carbonyl” in (34) “optionally substituted C 6-14 aryl-carbonyl” in Substituent Group A include benzoyl, 1-naphthoyl, 2-naphthoyl and the like. It is done.
　置換基Ａ群の（３５）「置換されていてもよいＣ７－１６アラルキル－カルボニル」の「Ｃ７－１６アラルキル－カルボニル」としては、例えば、フェニルアセチル、３－フェニルプロピオニルなどが挙げられる。 Examples of “C 7-16 aralkyl-carbonyl” of (35) “optionally substituted C 7-16 aralkyl-carbonyl” in Substituent Group A include phenylacetyl, 3-phenylpropionyl and the like.
　置換基Ａ群の（３６）「置換されていてもよい複素環－カルボニル」の複素環部分としては、前記の（１３）「置換されていてもよい複素環基」の「複素環基」と同様のものが挙げられる。具体的には、「置換されていてもよい、炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる１ないし３種、１ないし５個のヘテロ原子を含む３ないし１４員複素環－カルボニル」が挙げられ、より具体的には、例えば、ピコリノイル、ニコチノイル、イソニコチノイル、２－テノイル、３－テノイル、２－フロイル、３－フロイル、１－モルホリニルカルボニル、４－チオモルホリニルカルボニル、アジリジン－１－イルカルボニル、アジリジン－２－イルカルボニル、アゼチジン－１－イルカルボニル、アゼチジン－２－イルカルボニル、ピロリジン－１－イルカルボニル、ピロリジン－２－イルカルボニル、ピロリジン－３－イルカルボニル、ピペリジン－１－イルカルボニル、ピペリジン－２－イルカルボニル、ピペリジン－３－イルカルボニル、アゼパン－１－イルカルボニル、アゼパン－２－イルカルボニル、アゼパン－３－イルカルボニル、アゼパン－４－イルカルボニル、アゾカン－１－イルカルボニル、アゾカン－２－イルカルボニル、アゾカン－３－イルカルボニル、アゾカン－４－イルカルボニル、１，４－ピペラジン－１－イルカルボニル、１，４－ピペラジン－２－イルカルボニル、１，４－ジアゼパン－１－イルカルボニル、１，４－ジアゼパン－２－イルカルボニル、１，４－ジアゼパン－５－イルカルボニル、１，４－ジアゼパン－６－イルカルボニル、１，４－ジアゾカン－１－イルカルボニル、１，４－ジアゾカン－２－イルカルボニル、１，４－ジアゾカン－５－イルカルボニル、１，４－ジアゾカン－６－イルカルボニル、１，５－ジアゾカン－１－イルカルボニル、１，５－ジアゾカン－２－イルカルボニル、１，５－ジアゾカン－３－イルカルボニルなどが挙げられる。 Examples of the heterocyclic moiety of (36) “optionally substituted heterocycle-carbonyl” in Substituent Group A include “heterocyclic group” in the above (13) “optionally substituted heterocyclic group”. The same thing is mentioned. Specifically, “optionally substituted 3- to 14-membered heterocyclic-carbonyl containing 1 to 3, 1 to 5 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom” More specifically, for example, picolinoyl, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, 1-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl, Aziridin-1-ylcarbonyl, aziridin-2-ylcarbonyl, azetidin-1-ylcarbonyl, azetidin-2-ylcarbonyl, pyrrolidin-1-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl, piperidine -1-ylcarbonyl, piperidin-2-ylcarbonyl, piperidine 3-ylcarbonyl, azepan-1-ylcarbonyl, azepan-2-ylcarbonyl, azepan-3-ylcarbonyl, azepan-4-ylcarbonyl, azocan-1-ylcarbonyl, azocan-2-ylcarbonyl, azocan-3 -Ylcarbonyl, azocan-4-ylcarbonyl, 1,4-piperazin-1-ylcarbonyl, 1,4-piperazin-2-ylcarbonyl, 1,4-diazepan-1-ylcarbonyl, 1,4-diazepan- 2-ylcarbonyl, 1,4-diazepan-5-ylcarbonyl, 1,4-diazepan-6-ylcarbonyl, 1,4-diazocan-1-ylcarbonyl, 1,4-diazocan-2-ylcarbonyl, 1 , 4-diazocan-5-ylcarbonyl, 1,4-diazocan-6-ylcarbonyl, 1, - diazocan-1-ylcarbonyl, 1,5-diazocan-2-ylcarbonyl, 1,5-diazocan-3-ylcarbonyl and the like.
　置換基Ａ群の（３７）「置換されていてもよい低級（Ｃ１－６）アルキルスルホニル」としては、例えば、メチルスルホニル、エチルスルホニルなどが挙げられる。 Examples of (37) “optionally substituted lower (C 1-6 ) alkylsulfonyl” in Substituent Group A include methylsulfonyl, ethylsulfonyl and the like.
　置換基Ａ群の（３８）「置換されていてもよいＣ３－８シクロアルキルスルホニル」の「Ｃ３－８シクロアルキルスルホニル」としては、例えば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、シクロヘキシルスルホニルなどが挙げられる。 Examples of “C 3-8 cycloalkylsulfonyl” of (38) “optionally substituted C 3-8 cycloalkylsulfonyl” in Substituent Group A include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, and the like. Etc.
　置換基Ａ群の（３９）「置換されていてもよいＣ６－１４アリールスルホニル」の「Ｃ６－１４アリールスルホニル」としては、例えば、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などが挙げられる。 Examples of the “C 6-14 arylsulfonyl” in the (39) “optionally substituted C 6-14 arylsulfonyl” in the substituent group A include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like. Can be mentioned.
　置換基Ａ群の（４０）「置換されていてもよい低級（Ｃ１－６）アルキルスルフィニル」としては、例えば、メチルスルフィニル、エチルスルフィニルなどが挙げられる。 Examples of (40) “optionally substituted lower (C 1-6 ) alkylsulfinyl” in Substituent Group A include methylsulfinyl, ethylsulfinyl and the like.
　置換基Ａ群の（４１）「置換されていてもよいＣ３－８シクロアルキルスルフィニル」の「Ｃ３－８シクロアルキルスルフィニル」としては、例えばシクロプロピルスルフィニル、シクロブチルスルフィニル、シクロペンチルスルフィニル、シクロヘキシルスルフィニルなどが挙げられる。 Examples of “C 3-8 cycloalkylsulfinyl” in (41) “optionally substituted C 3-8 cycloalkylsulfinyl” in Substituent Group A include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, and the like. Etc.
　置換基Ａ群の（４２）「置換されていてもよいＣ６－１４アリールスルフィニル」の「Ｃ６－１４アリールスルフィニル」としては、例えば、フェニルスルフィニル、１－ナフチルスルフィニル、２－ナフチルスルフィニルなどが挙げられる。 The "C 6-14 arylsulfinyl" in Substituent Group A (42) "optionally substituted C 6-14 arylsulfinyl", for example, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl is Can be mentioned.
　置換基Ａ群の（４８）「置換基をされていてもよいカルバモイル基」としての「置換されていてもよい低級（Ｃ１－６）アルキル－カルバモイル」の「低級（Ｃ１－６）アルキル－カルバモイル」としては、例えば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などが挙げられる。 “Lower (C 1-6 ) alkyl” of “optionally substituted lower (C 1-6 ) alkyl-carbamoyl” as (48) “optionally substituted carbamoyl group” in substituent group A Examples of “-carbamoyl” include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよいモノ－又はジ－低級（Ｃ１－６）アルキルアミノ」の「モノ－又はジ－低級（Ｃ１－６）アルキルアミノ」としては、例えばメチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノなどが挙げられる。 “Mono- or di-lower” of “optionally substituted mono- or di-lower (C 1-6 ) alkylamino” as (49) “optionally substituted amino group” in Substituent Group A Examples of (C 1-6 ) alkylamino ”include methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよい低級（Ｃ１－６）アルキル－カルボニルアミノ」の「低級（Ｃ１－６）アルキル－カルボニルアミノ」としては、例えばアセチルアミノ、プロピオニルアミノ、ピバロイルアミノなどが挙げられる。 “Lower (C 1-6 ) alkyl-” of “optionally substituted lower (C 1-6 ) alkyl-carbonylamino” as (49) “optionally substituted amino group” in substituent group A Examples of “carbonylamino” include acetylamino, propionylamino, pivaloylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよい複素環基－アミノ」の「複素環基－アミノ」の「複素環基」としては、上記した「置換されていてもよい複素環基」の「複素環基」と同様のものが用いられ、例えば２－ピリジル－アミノなどが挙げられる。 As the “heterocyclic group” of the “heterocyclic group-amino” of the “optionally substituted heterocyclic group-amino” as the (49) “optionally substituted amino group” of the substituent group A, The same “heterocyclic group” of the above-mentioned “optionally substituted heterocyclic group” is used, and examples thereof include 2-pyridyl-amino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよい複素環－カルボニルアミノ」の「複素環－カルボニルアミノ」の「複素環－カルボニル」としては、上記した「置換されていてもよい複素環－カルボニル」の「複素環－カルボニル」と同様のものが用いられ、例えばピリジル－カルボニルアミノなどが挙げられる。 “Heterocycle-carbonyl” of “heterocycle-carbonylamino” of “optionally substituted heterocycle-carbonylamino” as (49) “optionally substituted amino group” in substituent group A is The same “heterocycle-carbonyl” of the above-mentioned “optionally substituted heterocycle-carbonyl” is used, and examples thereof include pyridyl-carbonylamino.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよい複素環基－オキシカルボニルアミノ」の「複素環基－オキシカルボニルアミノ」の「複素環基－オキシカルボニル」の「複素環基」としては、上記した「置換されていてもよい複素環基」の「複素環基」と同様のものが用いられ、例えば２－ピリジル－オキシカルボニルアミノなどが挙げられる。 The “heterocyclic group” of the “heterocyclic group-oxycarbonylamino” of the “optionally substituted heterocyclic group-oxycarbonylamino” as the “optionally substituted amino group” in the substituent group A (49) As the “heterocyclic group” of “-oxycarbonyl”, those similar to the “heterocyclic group” of the above-mentioned “optionally substituted heterocyclic group” can be used, for example, 2-pyridyl-oxycarbonylamino and the like. Can be mentioned.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよい複素環基－スルホニルアミノ」の「複素環基－スルホニルアミノ」の「複素環基－スルホニル」の「複素環基」としては、上記した「置換されていてもよい複素環基」の「複素環基」と同様のものが用いられ、例えば２－ピリジル－スルホニルアミノなどが挙げられる。 “Heterocyclic group-sulfonyl” of “Heterocyclic group-sulfonylamino” of “Optionally substituted heterocyclic group-sulfonylamino” as (49) “Optionally substituted amino group” in Substituent group A As the “heterocyclic group”, the same “heterocyclic group” as the above-mentioned “optionally substituted heterocyclic group” is used, and examples thereof include 2-pyridyl-sulfonylamino.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよい低級（Ｃ１－６）アルコキシ－カルボニルアミノ」の「低級（Ｃ１－６）アルコキシ－カルボニルアミノ」としては、例えば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、ブトキシカルボニルアミノなどが挙げられる。 “Lower (C 1-6 ) alkoxy-” of “optionally substituted lower (C 1-6 ) alkoxy-carbonylamino” as (49) “optionally substituted amino group” in substituent group A Examples of “carbonylamino” include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよい低級（Ｃ１－６）アルキルスルホニルアミノ」の「低級（Ｃ１－６）アルキルスルホニルアミノ」としては、例えばメチルスルホニルアミノ、エチルスルホニルアミノなどが挙げられる。 “Lower (C 1-6 ) alkylsulfonylamino” of “optionally substituted lower (C 1-6 ) alkylsulfonylamino” as (49) “optionally substituted amino group” in substituent group A "" Includes, for example, methylsulfonylamino, ethylsulfonylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよいモノ－又はジ－Ｃ３－８シクロアルキルアミノ」の「モノ－又はジ－Ｃ３－８シクロアルキルアミノ」としては、例えばシクロプロピルアミノ、シクロペンチルアミノ、シクロヘキシルアミノなどが挙げられる。 The “mono- or di-C 3 3- ” of “ optionally substituted mono- or di-C 3-8 cycloalkylamino” as (49) “optionally substituted amino group” in Substituent Group A Examples of “ 8 cycloalkylamino” include cyclopropylamino, cyclopentylamino, cyclohexylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよいＣ３－８シクロアルキル－カルボニルアミノ」の「Ｃ３－８シクロアルキル－カルボニルアミノ」としては、例えばシクロプロピルカルボニルアミノ、シクロペンチルカルボニルアミノ、シクロヘキシルカルボニルアミノなどが挙げられる。 As - "carbonylamino C 3-8 cycloalkyl" of the - "carbonylamino optionally substituted C 3-8 cycloalkyl" as a substituent group A (49) "optionally substituted amino group" Examples include cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよいＣ３－８シクロアルコキシ－カルボニルアミノ」の「Ｃ３－８シクロアルコキシ－カルボニルアミノ」としては、例えばシクロプロポキシカルボニルアミノ、シクロペンチルオキシカルボニルアミノ、シクロヘキシルオキシカルボニルアミノなどが挙げられる。 As - "carbonylamino C 3-8 cycloalkoxy" in - "carbonylamino optionally substituted C 3-8 also be cycloalkoxy" as the substituent group A (49) the "optionally substituted amino group" Examples thereof include cyclopropoxycarbonylamino, cyclopentyloxycarbonylamino, cyclohexyloxycarbonylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよいＣ３－８シクロアルキル－スルホニルアミノ」の「Ｃ３－８シクロアルキル－スルホニルアミノ」としては、例えばシクロプロピルスルホニルアミノ、シクロペンチルスルホニルアミノ、シクロヘキシルスルホニルアミノなどが挙げられる。 As - "sulfonylamino C 3-8 cycloalkyl" of the - "sulfonylamino optionally substituted C 3-8 cycloalkyl" as a substituent group A (49) "optionally substituted amino group" Examples include cyclopropylsulfonylamino, cyclopentylsulfonylamino, cyclohexylsulfonylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよいモノ－又はジ－Ｃ６－１４アリールアミノ」の「モノ－又はジ－Ｃ６－１４アリールアミノ」としては、例えばフェニルアミノ、ジフェニルアミノなどが挙げられる。 “Mono- or di-C 6-14 ” of “ optionally substituted mono- or di-C 6-14 arylamino” as (49) “optionally substituted amino group” in Substituent Group A Examples of “arylamino” include phenylamino, diphenylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよいモノ－又はジ－Ｃ７－１６アラルキルアミノ」の「モノ－又はジ－Ｃ７－１６アラルキルアミノ」としては、例えばベンジルアミノなどが挙げられる。 “Mono- or di-C 7-16 ” of “ optionally substituted mono- or di-C 7-16 aralkylamino” as (49) “optionally substituted amino group” in Substituent Group A Examples of “aralkylamino” include benzylamino and the like.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよいＣ６－１４アリール－カルボニルアミノ」の「Ｃ６－１４アリール－カルボニルアミノ」としては、例えばベンゾイルアミノ、ナフトイルアミノなどが挙げられる。 As “C 6-14 aryl-carbonylamino” of “ optionally substituted C 6-14 aryl-carbonylamino” as (49) “optionally substituted amino group” in substituent group A, Examples include benzoylamino and naphthoylamino.
　置換基Ａ群の（４９）「置換されていてもよいアミノ基」としての「置換されていてもよいＣ６－１４アリールスルホニルアミノ」の「Ｃ６－１４アリールスルホニルアミノ」としては、例えばフェニルスルホニルアミノ、２－ナフチルスルホニルアミノ、１－ナフチルスルホニルアミノなどが挙げられる。 “C 6-14 arylsulfonylamino” of “ optionally substituted C 6-14 arylsulfonylamino” as (49) “optionally substituted amino group” in substituent group A includes, for example, phenyl Examples include sulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino and the like.
　置換基Ａ群の置換基：
「置換されていてもよい低級（Ｃ１－６）アルコキシ－カルボニル」、
（６）「置換されていてもよい低級（Ｃ１－６）アルキル」、
（７）「置換されていてもよい低級（Ｃ２－６）アルケニル」、
（８）「置換されていてもよい低級（Ｃ２－６）アルキニル」、
（１５）「置換されていてもよい低級（Ｃ１－６）アルコキシ」、
（１９）「置換されていてもよい低級（Ｃ１－６）アルキル－カルボニルオキシ」、
（２０）「置換されていてもよい低級（Ｃ１－６）アルコキシ－カルボニルオキシ」、
（２１）「置換されていてもよいモノ－低級（Ｃ１－６）アルキル－カルバモイルオキシ」、
（２２）「置換されていてもよいジ－低級（Ｃ１－６）アルキル－カルバモイルオキシ」、
（２７）「置換されていてもよい低級（Ｃ１－６）アルキルチオ」、
（３２）「置換されていてもよい低級（Ｃ１－６）アルキル－カルボニル」、
（３７）「置換されていてもよい低級（Ｃ１－６）アルキルスルホニル」、
（４０）「置換されていてもよい低級（Ｃ１－６）アルキルスルフィニル」、
「置換されていてもよいモノ－又はジ－低級（Ｃ１－６）アルキルアミノ」、
「置換されていてもよい低級（Ｃ１－６）アルキル－カルボニルアミノ」、
「置換されていてもよい低級（Ｃ１－６）アルコキシ－カルボニルアミノ」、
および「置換されていてもよい低級（Ｃ１－６）アルキルスルホニルアミノ」における、
「低級（Ｃ１－６）アルコキシ－カルボニル」、
（６）「低級（Ｃ１－６）アルキル」、
（７）「低級（Ｃ２－６）アルケニル」、
（８）「低級（Ｃ２－６）アルキニル」、
（１５）「低級（Ｃ１－６）アルコキシ」、
（１９）「低級（Ｃ１－６）アルキル－カルボニルオキシ」、
（２０）「低級（Ｃ１－６）アルコキシ－カルボニルオキシ」、
（２１）「モノ－低級（Ｃ１－６）アルキル－カルバモイルオキシ」、
（２２）「ジ－低級（Ｃ１－６）アルキル－カルバモイルオキシ」、
（２７）「低級（Ｃ１－６）アルキルチオ」、
（３２）「低級（Ｃ１－６）アルキル－カルボニル」、
（３７）「低級（Ｃ１－６）アルキルスルホニル」、
（４０）「低級（Ｃ１－６）アルキルスルフィニル」、
「置換されていてもよい低級（Ｃ１－６）アルキル－カルバモイル」、
「モノ－又はジ－低級（Ｃ１－６）アルキルアミノ」、
「低級（Ｃ１－６）アルキル－カルボニルアミノ」、
「低級（Ｃ１－６）アルコキシ－カルボニルアミノ」、および
「低級（Ｃ１－６）アルキルスルホニルアミノ」は、
例えば、下記の置換基Ｂ群から選択される置換基を１～置換可能な最大数、より好ましくは１～３個、更に好ましく１個、置換可能な位置に有していてもよい。 Substituents in Substituent Group A:
“Optionally substituted lower (C 1-6 ) alkoxy-carbonyl”,
(6) “optionally substituted lower (C 1-6 ) alkyl”,
(7) "Lower (C 2-6 ) alkenyl optionally substituted",
(8) “optionally substituted lower (C 2-6 ) alkynyl”,
(15) “optionally substituted lower (C 1-6 ) alkoxy”,
(19) "optionally substituted lower (C 1-6 ) alkyl-carbonyloxy",
(20) “optionally substituted lower (C 1-6 ) alkoxy-carbonyloxy”,
(21) “optionally substituted mono-lower (C 1-6 ) alkyl-carbamoyloxy”,
(22) "Di-lower (C 1-6 ) alkyl-carbamoyloxy optionally substituted",
(27) "Lower (C 1-6 ) alkylthio optionally substituted",
(32) "Lower (C 1-6 ) alkyl-carbonyl optionally substituted",
(37) "optionally substituted lower (C 1-6 ) alkylsulfonyl",
(40) "optionally substituted lower (C 1-6 ) alkylsulfinyl",
“Optionally substituted mono- or di-lower (C 1-6 ) alkylamino”,
“Optionally substituted lower (C 1-6 ) alkyl-carbonylamino”,
“Optionally substituted lower (C 1-6 ) alkoxy-carbonylamino”,
And “optionally substituted lower (C 1-6 ) alkylsulfonylamino”
“Lower (C 1-6 ) alkoxy-carbonyl”,
(6) “Lower (C 1-6 ) alkyl”,
(7) “Lower (C 2-6 ) alkenyl”,
(8) “Lower (C 2-6 ) alkynyl”,
(15) “Lower (C 1-6 ) alkoxy”,
(19) “Lower (C 1-6 ) alkyl-carbonyloxy”,
(20) "Lower (C 1-6 ) alkoxy-carbonyloxy",
(21) "Mono-lower (C 1-6 ) alkyl-carbamoyloxy",
(22) "Di-lower (C 1-6 ) alkyl-carbamoyloxy",
(27) "Lower (C 1-6 ) alkylthio",
(32) "Lower (C 1-6 ) alkyl-carbonyl",
(37) "Lower (C 1-6 ) alkylsulfonyl",
(40) "Lower (C 1-6 ) alkylsulfinyl",
“Optionally substituted lower (C 1-6 ) alkyl-carbamoyl”,
“Mono- or di-lower (C 1-6 ) alkylamino”,
“Lower (C 1-6 ) alkyl-carbonylamino”,
“Lower (C 1-6 ) alkoxy-carbonylamino” and “Lower (C 1-6 ) alkylsulfonylamino”
For example, a substituent selected from the following substituent group B may have 1 to the maximum number that can be substituted, more preferably 1 to 3, and even more preferably 1 at a substitutable position.
［置換基Ｂ群］
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）；
ヒドロキシ；
ニトロ；
シアノ； [Substituent group B]
Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom);
Hydroxy;
Nitro;
Cyano;
Ｃ６－１４アリール（該Ｃ６－１４アリールはハロゲン原子、ヒドロキシ、シアノ、アミノ、ハロゲン化されていてもよいＣ１－６アルキル、モノ－又はジ－Ｃ１－６アルキルアミノ、モノ－又はジ－Ｃ６－１４アリールアミノ、モノ－又はジ－Ｃ７－１６アラルキルアミノ、Ｃ３－８シクロアルキル、Ｃ１－６アルコキシ、ホルミル、Ｃ１－６アルキル－カルボニル、Ｃ３－８シクロアルキル－カルボニル、Ｃ６－１４アリール－カルボニル、Ｃ７－１６アラルキル－カルボニル、Ｃ１－６アルコキシ－カルボニル、Ｃ６－１４アリールオキシ－カルボニル、Ｃ７－１６アラルキルオキシ－カルボニル、Ｃ１－６アルキルチオ、Ｃ１－６アルキルスルフィニル、Ｃ１－６アルキルスルホニル、カルバモイル、チオカルバモイル、モノ－又はジ－Ｃ１－６アルキル－カルバモイル、モノ－又はジ－Ｃ６－１４アリール－カルバモイルなどで置換されていてもよい）； C 6-14 aryl (wherein the C 6-14 aryl is a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono- or di-C 1-6 alkylamino, mono- or Di-C 6-14 arylamino, mono- or di-C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl -Carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio , C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl Mono - or di -C 1-6 alkyl - carbamoyl, mono - or di -C 6-14 aryl - carbamoyl and the like may be substituted);
Ｃ６－１４アリールオキシ（該Ｃ６－１４アリールオキシはハロゲン原子、ヒドロキシ、シアノ、アミノ、ハロゲン化されていてもよいＣ１－６アルキル、モノ－又はジ－Ｃ１－６アルキルアミノ、モノ－又はジ－Ｃ６－１４アリールアミノ、モノ－又はジ－Ｃ７－１６アラルキルアミノ、Ｃ３－８シクロアルキル、Ｃ１－６アルコキシ、ホルミル、Ｃ１－６アルキル－カルボニル、Ｃ３－８シクロアルキル－カルボニル、Ｃ６－１４アリール－カルボニル、Ｃ７－１６アラルキル－カルボニル、Ｃ１－６アルコキシ－カルボニル、Ｃ６－１４アリールオキシ－カルボニル、Ｃ７－１６アラルキルオキシ－カルボニル、Ｃ１－６アルキルチオ、Ｃ１－６アルキルスルフィニル、Ｃ１－６アルキルスルホニル、カルバモイル、チオカルバモイル、モノ－又はジ－Ｃ１－６アルキル－カルバモイル、モノ－又はジ－Ｃ６－１４アリール－カルバモイルなどで置換されていてもよい）； C 6-14 aryloxy (the C 6-14 aryloxy is a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono- or di-C 1-6 alkylamino, mono -Or di-C 6-14 arylamino, mono- or di-C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 Cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1- 6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thio Rubamoiru, mono - or di -C 1-6 alkyl - carbamoyl, mono - or di -C 6-14 aryl - carbamoyl and the like may be substituted);
Ｃ７－１６アラルキルオキシ（該Ｃ７－１６アラルキルオキシはハロゲン原子、ヒドロキシ、シアノ、アミノ、ハロゲン化されていてもよいＣ１－６アルキル、モノ－又はジ－Ｃ１－６アルキルアミノ、モノ－又はジ－Ｃ６－１４アリールアミノ、モノ－又はジ－Ｃ７－１６アラルキルアミノ、Ｃ３－８シクロアルキル、Ｃ１－６アルコキシ、ホルミル、Ｃ１－６アルキル－カルボニル、Ｃ３－８シクロアルキル－カルボニル、Ｃ６－１４アリール－カルボニル、Ｃ７－１６アラルキル－カルボニル、Ｃ１－６アルコキシ－カルボニル、Ｃ６－１４アリールオキシ－カルボニル、Ｃ７－１６アラルキルオキシ－カルボニル、Ｃ１－６アルキルチオ、Ｃ１－６アルキルスルフィニル、Ｃ１－６アルキルスルホニル、カルバモイル、チオカルバモイル、モノ－又はジ－Ｃ１－６アルキル－カルバモイル、モノ－又はジ－Ｃ６－１４アリール－カルバモイルなどで置換されていてもよい）； C 7-16 aralkyloxy (wherein the C 7-16 aralkyloxy is a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono- or di-C 1-6 alkylamino, mono -Or di-C 6-14 arylamino, mono- or di-C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 Cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1- 6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, Okarubamoiru, mono - or di -C 1-6 alkyl - carbamoyl, mono - or di -C 6-14 aryl - carbamoyl and the like may be substituted);
炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる１又は２種、１ないし４個のヘテロ原子を含むモノ－又はジ－５ないし１０員複素環基（例、フリル、ピリジル、チエニル、ピロリジノ、１－ピペリジニル、４－ピペリジル、ピペラジル、１－モルホリニル、４－チオモルホリニル、アゼパン－１－イル、アゾカン－１－イル、アゾナン－１－イル、３，４－ジヒドロイソキノリン－２－イルなど）（該複素環基はハロゲン原子、ヒドロキシ、シアノ、アミノ、ハロゲン化されていてもよいＣ１－６アルキル、モノ－又はジ－Ｃ１－６アルキルアミノ、モノ－又はジ－Ｃ６－１４アリールアミノ、モノ－又はジ－Ｃ７－１６アラルキルアミノ、Ｃ３－８シクロアルキル、Ｃ１－６アルコキシ、ホルミル、Ｃ１－６アルキル－カルボニル、Ｃ３－８シクロアルキル－カルボニル、Ｃ６－１４アリール－カルボニル、Ｃ７－１６アラルキル－カルボニル、Ｃ１－６アルコキシ－カルボニル、Ｃ６－１４アリールオキシ－カルボニル、Ｃ７－１６アラルキルオキシ－カルボニル、Ｃ１－６アルキルチオ、Ｃ１－６アルキルスルフィニル、Ｃ１－６アルキルスルホニル、カルバモイル、チオカルバモイル、モノ－又はジ－Ｃ１－６アルキル－カルバモイル、モノ－又はジ－Ｃ６－１４アリール－カルバモイルなどで置換されていてもよい）； Mono- or di-5- to 10-membered heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (eg, furyl, pyridyl, thienyl, Pyrrolidino, 1-piperidinyl, 4-piperidyl, piperazyl, 1-morpholinyl, 4-thiomorpholinyl, azepan-1-yl, azocan-1-yl, azonan-1-yl, 3,4-dihydroisoquinolin-2-yl, etc.) (The heterocyclic group is a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 aryl. Amino, mono- or di-C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl- Carbonyl, C 3-8 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy -Carbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C 1-6 alkyl-carbamoyl, mono- or di-C 6-14 Optionally substituted with aryl-carbamoyl etc.);
置換されていてもよいアミノ基〔例えば、Ｃ１－６アルキル、Ｃ２－６アルケニル、Ｃ６－１４アリール、Ｃ７－１６アラルキル、複素環基および複素環－低級（Ｃ１－６）アルキルから成る群から選ばれる１または２個の置換基で置換されていてもよいアミノ基（該Ｃ１－６アルキル、Ｃ２－６アルケニル、Ｃ６－１４アリール、Ｃ７－１６アラルキル、複素環基および複素環－Ｃ１－６アルキルはそれぞれハロゲン原子、ヒドロキシ、シアノ、アミノ、ハロゲン化されていてもよいＣ１－６アルキル（但し、アルキルおよびアルケニルの置換基ではない）、モノ－又はジ－Ｃ１－６アルキルアミノ、モノ－又はジ－Ｃ６－１４アリールアミノ、モノ－又はジ－Ｃ７－１６アラルキルアミノ、Ｃ３－８シクロアルキル、Ｃ１－６アルコキシ、ホルミル、Ｃ１－６アルキル－カルボニル、Ｃ３－８シクロアルキル－カルボニル、Ｃ６－１４アリール－カルボニル、Ｃ７－１６アラルキル－カルボニル、Ｃ１－６アルコキシ－カルボニル、Ｃ３－８シクロアルコキシ－カルボニル、Ｃ６－１４アリールオキシ－カルボニル、Ｃ７－１６アラルキルオキシ－カルボニル、Ｃ１－６アルキルチオ、Ｃ３－８シクロアルキルチオ、Ｃ１－６アルキルスルフィニル、Ｃ３－８シクロアルキルスルフィニル、Ｃ１－６アルキルスルホニル、Ｃ３－８シクロアルキルスルホニル、カルバモイル、チオカルバモイル、モノ－又はジ－Ｃ１－６アルキル－カルバモイル、モノ－又はジ－Ｃ６－１４アリール－カルバモイルなどで置換されていてもよい。なお、「複素環」および「複素環－低級（Ｃ１－６）アルキル」の「複素環」は前述の「置換されていてもよい複素環基」の「複素環基」と同様のものが挙げられる。〕； Optionally substituted amino group [eg C 1-6 alkyl, C 2-6 alkenyl, C 6-14 aryl, C 7-16 aralkyl, heterocyclic group and heterocyclic-lower (C 1-6 ) alkyl An amino group which may be substituted with one or two substituents selected from the group consisting of (C 1-6 alkyl, C 2-6 alkenyl, C 6-14 aryl, C 7-16 aralkyl, heterocyclic ring) Group and heterocycle-C 1-6 alkyl are each a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl (but not alkyl and alkenyl substituents), mono- or di- -C 1-6 alkylamino, mono - or di -C 6-14 arylamino, mono- - or di -C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1- Alkoxy, formyl, C 1-6 alkyl - carbonyl, C 3-8 cycloalkyl - carbonyl, C 6-14 aryl - carbonyl, C 7-16 aralkyl - carbonyl, C 1-6 alkoxy - carbonyl, C 3-8 cycloalkyl Alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio, C 3-8 cycloalkylthio, C 1-6 alkylsulfinyl, C 3-8 cycloalkylsulfinyl, Substituted with C 1-6 alkylsulfonyl, C 3-8 cycloalkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C 1-6 alkyl-carbamoyl, mono- or di-C 6-14 aryl-carbamoyl, etc. Note that “heterocycle” and Heterocyclic - "heterocycle lower (C 1-6) alkyl", "include those similar to the" heterocyclic group "of the" optionally substituted heterocyclic group "described above];.
Ｃ３－８シクロアルキル；
Ｃ１－６アルコキシ（該Ｃ１－６アルコキシはハロゲン原子、ヒドロキシ、アミノ、モノ－又はジ－Ｃ１－６アルキルアミノ、モノ－又はジ－Ｃ６－１４アリールアミノ、Ｃ３－８シクロアルキル、Ｃ１－６アルコキシ、ホルミル、Ｃ１－６アルキル－カルボニル、Ｃ３－８シクロアルキル－カルボニル、Ｃ６－１４アリール－カルボニル、Ｃ７－１６アラルキル－カルボニル、Ｃ１－６アルコキシ－カルボニル、Ｃ６－１４アリールオキシ－カルボニル、Ｃ７－１６アラルキルオキシ－カルボニル、Ｃ１－６アルキルチオ、Ｃ１－６アルキルスルフィニル、Ｃ１－６アルキルスルホニル、カルバモイル、チオカルバモイル、モノ－又はジ－Ｃ１－６アルキル－カルバモイル、モノ－又はジ－Ｃ６－１４アリール－カルバモイルなどで置換されていてもよい）； C 3-8 cycloalkyl;
C 1-6 alkoxy (wherein the C 1-6 alkoxy is a halogen atom, hydroxy, amino, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 arylamino, C 3-8 cycloalkyl) C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C 1 -6 alkyl - carbamoyl, mono - or di -C 6-14 aryl - carbamoyl May be substituted with etc.);
ホルミル；
Ｃ１－６アルキル－カルボニル（例、アセチル）；
Ｃ３－８シクロアルキル－カルボニル；
Ｃ６－１４アリール－カルボニル；
Ｃ７－１６アラルキル－カルボニル；
Ｃ１－６アルコキシ－カルボニル；
Ｃ６－１４アリールオキシ－カルボニル；
Ｃ７－１６アラルキルオキシ－カルボニル；
Ｃ１－６アルキルチオ；
Ｃ１－６アルキルスルフィニル；
Ｃ１－６アルキルスルホニル；
カルバモイル；
チオカルバモイル；
モノ－Ｃ１－６アルキル－カルバモイル（例、メチルカルバモイル、エチルカルバモイルなど）；
ジ－Ｃ１－６アルキル－カルバモイル（例、ジメチルカルバモイル、ジエチルカルバモイル、エチルメチルカルバモイルなど）； Formyl;
C 1-6 alkyl-carbonyl (eg acetyl);
C 3-8 cycloalkyl-carbonyl;
C 6-14 aryl-carbonyl;
C 7-16 aralkyl-carbonyl;
C 1-6 alkoxy-carbonyl;
C 6-14 aryloxy-carbonyl;
C 7-16 aralkyloxy-carbonyl;
C 1-6 alkylthio;
C 1-6 alkylsulfinyl;
C 1-6 alkylsulfonyl;
Carbamoyl;
Thiocarbamoyl;
Mono-C 1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.);
Di-C 1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.);
モノ－又はジ－Ｃ６－１４アリール－カルバモイル（例、フェニルカルバモイル、１－ナフチルカルバモイル、２－ナフチルカルバモイルなど）；および
炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる１又は２種、１ないし４個のヘテロ原子を含むモノ－又はジ－５ないし７員複素環－カルバモイル（例、２－ピリジルカルバモイル、３－ピリジルカルバモイル、４－ピリジルカルバモイル、２－チエニルカルバモイル、３－チエニルカルバモイルなど）。 Mono- or di-C 6-14 aryl-carbamoyl (eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.); and one or two selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Mono- or di-5 to 7-membered heterocycle-carbamoyl containing 1 to 4 heteroatoms (eg 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl) Such).
　また、　置換基Ａ群の置換基：
「置換されていてもよいＣ６－１４アリールオキシ－カルボニル」、
「置換されていてもよいＣ７－１６アラルキルオキシ－カルボニル」、
（９）「置換されていてもよいＣ３－８シクロアルキル」、
（１０）「置換されていてもよいＣ６－１４アリール」、
（１１）「置換されていてもよいＣ７－１６アラルキル」、
（１２）「置換されていてもよいＣ６－１４アリール－Ｃ２－６アルケニル」、
（１３）「置換されていてもよい複素環基」、
（１６）「置換されていてもよいＣ３－８シクロアルコキシ」、
（１７）「置換されていてもよいＣ６－１４アリールオキシ」、
（１８）「置換されていてもよいＣ７－１６アラルキルオキシ」、
（２３）「置換されていてもよいＣ６－１４アリール－カルボニルオキシ」、
（２４）「置換されていてもよいモノ－又はジ－Ｃ６－１４アリール－カルバモイルオキシ」、
（２５）「置換されていてもよい複素環オキシ」、「置換されていてもよい芳香族複素環オキシ」、
（２８）「置換されていてもよいＣ３－８シクロアルキルチオ」、
（２９）「置換されていてもよいＣ６－１４アリールチオ」、
（３０）「置換されていてもよいＣ７－１６アラルキルチオ」、
（３３）「置換されていてもよいＣ３－８シクロアルキル－カルボニル」、
（３４）「置換されていてもよいＣ６－１４アリール－カルボニル」、
（３５）「置換されていてもよいＣ７－１６アラルキル－カルボニル」、
（３６）「置換されていてもよい複素環－カルボニル」、
（３８）「置換されていてもよいＣ３－８シクロアルキルスルホニル」、
（３９）「置換されていてもよいＣ６－１４アリールスルホニル」、
（４１）「置換されていてもよいＣ３－８シクロアルキルスルフィニル」、
（４２）「置換されていてもよいＣ６－１４アリールスルフィニル」、
（４８）「置換されていてもよいカルバモイル基」、および
（４９）「置換されていてもよいアミノ基」
における、
「Ｃ６－１４アリールオキシ－カルボニル」、
「Ｃ７－１６アラルキルオキシ－カルボニル」、
（９）「Ｃ３－８シクロアルキル」、
（１０）「Ｃ６－１４アリール」、
（１１）「Ｃ７－１６アラルキル」、
（１２）「Ｃ６－１４アリール－Ｃ２－６アルケニル」、
（１３）「複素環基」、
（１６）「Ｃ３－８シクロアルコキシ」、
（１７）「Ｃ６－１４アリールオキシ」、
（１８）「Ｃ７－１６アラルキルオキシ」、
（２３）「Ｃ６－１４アリール－カルボニルオキシ」、
（２４）「モノ－又はジ－Ｃ６－１４アリール－カルバモイルオキシ」、
（２５）「複素環オキシ」、「芳香族複素環オキシ）」、
（２８）「Ｃ３－８シクロアルキルチオ」、
（３１）「Ｃ６－１４アリールチオ」、
（３２）「Ｃ７－１６アラルキルチオ」、
（３３）「Ｃ３－８シクロアルキル－カルボニル」、
（３４）「Ｃ６－１４アリール－カルボニル」、
（３５）「Ｃ７－１６アラルキル－カルボニル」、
（３６）「複素環－カルボニル」、
（３８）「Ｃ３－８シクロアルキルスルホニル」、
（３９）「Ｃ６－１４アリールスルホニル」、
（４１）「Ｃ３－８シクロアルキルスルフィニル」、
（４２）「Ｃ６－１４アリールスルフィニル」、
（４８）「カルバモイル基」、および
（４９）「アミノ基」は、それぞれ、例えば、上記の置換基Ｂ群および下記の置換基Ｂ’群から選択される置換基を１～置換可能な最大数、より好ましくは１～３個、更に好ましく１個、置換可能な位置に有していてもよい。 In addition, the substituent of the substituent group A:
“Optionally substituted C 6-14 aryloxy-carbonyl”,
“Optionally substituted C 7-16 aralkyloxy-carbonyl”,
(9) “optionally substituted C 3-8 cycloalkyl”,
(10) “optionally substituted C 6-14 aryl”,
(11) “C 7-16 aralkyl which may be substituted”,
(12) “optionally substituted C 6-14 aryl-C 2-6 alkenyl”,
(13) "optionally substituted heterocyclic group",
(16) “C 3-8 cycloalkoxy which may be substituted”,
(17) “optionally substituted C 6-14 aryloxy”,
(18) "C 7-16 aralkyloxy which may be substituted",
(23) “optionally substituted C 6-14 aryl-carbonyloxy”,
(24) "optionally substituted mono- or di-C 6-14 aryl-carbamoyloxy",
(25) “optionally substituted heterocyclic oxy”, “optionally substituted aromatic heterocyclic oxy”,
(28) "C 3-8 cycloalkylthio which may be substituted",
(29) "C 6-14 arylthio optionally substituted",
(30) "C 7-16 aralkylthio optionally substituted",
(33) "C 3-8 cycloalkyl-carbonyl optionally substituted",
(34) the "optionally substituted C 6-14 aryl - carbonyl",
(35) "C 7-16 aralkyl-carbonyl optionally substituted",
(36) "optionally substituted heterocycle-carbonyl",
(38) "C 3-8 cycloalkylsulfonyl which may be substituted",
(39) "C 6-14 arylsulfonyl optionally substituted",
(41) "C 3-8 cycloalkylsulfinyl optionally substituted",
(42) "C 6-14 arylsulfinyl optionally substituted",
(48) “optionally substituted carbamoyl group” and (49) “optionally substituted amino group”
In
“C 6-14 aryloxy-carbonyl”,
“C 7-16 aralkyloxy-carbonyl”,
(9) “C 3-8 cycloalkyl”,
(10) “C 6-14 aryl”,
(11) "C 7-16 aralkyl",
(12) “C 6-14 aryl-C 2-6 alkenyl”,
(13) “heterocyclic group”,
(16) “C 3-8 cycloalkoxy”,
(17) “C 6-14 aryloxy”,
(18) “C 7-16 aralkyloxy”,
(23) “C 6-14 aryl-carbonyloxy”,
(24) "Mono- or di-C 6-14 aryl-carbamoyloxy",
(25) “heterocyclic oxy”, “aromatic heterocyclic oxy” ”,
(28) “C 3-8 cycloalkylthio”,
(31) "C 6-14 arylthio",
(32) “C 7-16 aralkylthio”,
(33) "C 3-8 cycloalkyl - carbonyl",
(34) "C 6-14 aryl-carbonyl",
(35) “C 7-16 aralkyl-carbonyl”,
(36) "Heterocycle-carbonyl",
(38) "C 3-8 cycloalkylsulfonyl",
(39) "C 6-14 arylsulfonyl",
(41) “C 3-8 cycloalkylsulfinyl”,
(42) "C 6-14 arylsulfinyl",
(48) “carbamoyl group” and (49) “amino group” each represent, for example, 1 to the maximum number of substituents selected from the above-mentioned substituent group B and the following substituent group B ′. More preferably, it may have 1 to 3, more preferably 1, at a substitutable position.
置換基Ｂ’群
Ｃ１－６アルキル（該Ｃ１－６アルキルはハロゲン原子、ヒドロキシ、シアノ、アミノ、モノ－又はジ－Ｃ１－６アルキルアミノ、モノ－又はジ－Ｃ６－１４アリールアミノ、モノ－又はジ－Ｃ７－１６アラルキルアミノ、Ｃ３－８シクロアルキル、Ｃ１－６アルコキシ、ホルミル、Ｃ１－６アルキル－カルボニル、Ｃ３－８シクロアルキル－カルボニル、Ｃ６－１４アリール－カルボニル、Ｃ７－１６アラルキル－カルボニル、Ｃ１－６アルコキシ－カルボニル、Ｃ６－１４アリールオキシ－カルボニル、Ｃ７－１６アラルキルオキシ－カルボニル、Ｃ１－６アルキルチオ、Ｃ１－６アルキルスルフィニル、Ｃ１－６アルキルスルホニル、カルバモイル、チオカルバモイル、モノ－又はジ－Ｃ１－６アルキル－カルバモイル、モノ－又はジ－Ｃ６－１４アリール－カルバモイルなどで置換されていてもよい）； Substituent B ′ group C 1-6 alkyl (wherein the C 1-6 alkyl is a halogen atom, hydroxy, cyano, amino, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 arylamino) Mono- or di-C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl-carbonyl, C 6-14 aryl -Carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or di-C 1-6 alkyl-cal Optionally substituted with bamoyl, mono- or di-C 6-14 aryl-carbamoyl);
Ｃ２－６アルケニル（該Ｃ２－６アルケニルはハロゲン原子、ヒドロキシ、シアノ、アミノ、モノ－又はジ－Ｃ１－６アルキルアミノ、モノ－又はジ－Ｃ６－１４アリールアミノ、モノ－又はジ－Ｃ７－１６アラルキルアミノ、Ｃ３－８シクロアルキル、Ｃ１－６アルコキシ、ホルミル、Ｃ１－６アルキル－カルボニル、Ｃ３－８シクロアルキル－カルボニル、Ｃ６－１４アリール－カルボニル、Ｃ７－１６アラルキル－カルボニル、Ｃ１－６アルコキシ－カルボニル、Ｃ６－１４アリールオキシ－カルボニル、Ｃ７－１６アラルキルオキシ－カルボニル、Ｃ１－６アルキルチオ、Ｃ１－６アルキルスルフィニル、Ｃ１－６アルキルスルホニル、カルバモイル、チオカルバモイル、モノ－又はジ－Ｃ１－６アルキル－カルバモイル、モノ－又はジ－Ｃ６－１４アリール－カルバモイルなどで置換されていてもよい）； C 2-6 alkenyl (wherein the C 2-6 alkenyl is a halogen atom, hydroxy, cyano, amino, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 arylamino, mono- or di) -C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7 -16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, carbamoyl, thiocarbamoyl, mono- - or di -C 1-6 alkyl - Karubamoi , Mono - or di -C 6-14 aryl - may be substituted carbamoyl, etc.);
Ｃ２－６アルキニル（該Ｃ２－６アルキニルはハロゲン原子、ヒドロキシ、シアノ、アミノ、モノ－又はジ－Ｃ１－６アルキルアミノ、モノ－又はジ－Ｃ６－１４アリールアミノ、モノ－又はジ－Ｃ７－１６アラルキルアミノ、Ｃ３－８シクロアルキル、Ｃ１－６アルコキシ、ホルミル、Ｃ１－６アルキル－カルボニル、Ｃ３－８シクロアルキル－カルボニル、Ｃ６－１４アリール－カルボニル、Ｃ７－１６アラルキル－カルボニル、Ｃ１－６アルコキシ－カルボニル、Ｃ６－１４アリールオキシ－カルボニル、Ｃ７－１６アラルキルオキシ－カルボニル、Ｃ１－６アルキルチオ、Ｃ１－６アルキルスルフィニル、Ｃ１－６アルキルスルホニル、カルバモイル、チオカルバモイル、モノ－又はジ－Ｃ１－６アルキル－カルバモイル、モノ－又はジ－Ｃ６－１４アリール－カルバモイルなどで置換されていてもよい）。 C 2-6 alkynyl (wherein C 2-6 alkynyl is a halogen atom, hydroxy, cyano, amino, mono- or di-C 1-6 alkylamino, mono- or di-C 6-14 arylamino, mono- or di) -C 7-16 aralkylamino, C 3-8 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-8 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7 -16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, carbamoyl, thiocarbamoyl, mono- - or di -C 1-6 alkyl - Karubamoi , Mono - or di -C 6-14 aryl - or the like may be substituted by carbamoyl).
　Ａ１で示される「置換基を有していてもよい芳香環」の「置換基」としては、ハロゲン原子等が好ましい。
　Ａ１としては、ハロゲン原子から選択される１～３個の置換基をそれぞれ有していてもよい、(1)Ｃ６－１０アリール基（例、フェニル）または(2)環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基（例、２－チエニルなどのチエニル）が好ましい。 The “substituent” of the “optionally substituted aromatic ring” represented by A 1 is preferably a halogen atom or the like.
As A 1 , (1) a C 6-10 aryl group (eg, phenyl) or (2) a ring-constituting atom each optionally having 1 to 3 substituents selected from halogen atoms, 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom (eg, 2-thienyl, etc.) Of thienyl) is preferred.
　Ａ２で示される「置換基を有していてもよい芳香環」の「置換基」としては、ハロゲン原子（特に、フッ素原子）等が好ましい。
　Ａ２としては、ハロゲン原子、シアノ、低級（Ｃ１－６）アルコキシ、低級（Ｃ１－６）アルキル－カルボニルアミノおよびＣ１－６アルキルから選択される１～３個の置換基をそれぞれ有していてもよい、(1)Ｃ６－１０アリール基（例、フェニル）または(2)環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基（例、３－ピリジルなどのピリジル、１Ｈ－ピラゾール－４－イルなどのピラゾール）が好ましい。 The “substituent” of the “optionally substituted aromatic ring” represented by A 2 is preferably a halogen atom (particularly a fluorine atom).
A 2 has 1 to 3 substituents each selected from a halogen atom, cyano, lower (C 1-6 ) alkoxy, lower (C 1-6 ) alkyl-carbonylamino and C 1-6 alkyl. (1) C 6-10 aryl group (eg, phenyl) or (2) 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom A 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 atoms (eg, pyridyl such as 3-pyridyl, pyrazole such as 1H-pyrazol-4-yl) is preferable.
　式（Ｉ）中、Ｂ環は置換基を有していてもよいフェニル基を示す。
　Ｂ環で示される「置換基を有していてもよいフェニル基」の「置換基」としては、Ａ１およびＡ２で示される「置換基を有していてもよい芳香族基」の「置換基」と同様の基が挙げられる。該「置換基」の数は１～４個、好ましくは１～３個、より好ましくは１または２個である。
　なかでも、Ｂ環で示される「置換基を有していてもよいフェニル基」の「置換基」としては、（１）ハロゲン原子、（５）エステル化されていてもよいカルボキシル、（１４）ヒドロキシ、（１５）置換されていてもよい低級（Ｃ１－６）アルコキシ、および（４４）置換基を有していてもよいカルバモイル基等が好ましい。
　Ｂ環としては、(1)ハロゲン原子、(2)低級（Ｃ１－６）アルコキシ、(3)低級（Ｃ１－６）アルコキシ－カルボニル、(4)カルボキシル、(5)カルバモイルおよびヒドロキシから選択される置換基で置換されていてもよいモノ－またはジ－低級（Ｃ１－６）アルキルカルバモイル、および(6)カルバモイルから選択される１～４個の置換基で置換されていてもよいフェニルが好ましい。
　上記した中でも、Ｂ環のフェニルが有していてもよい「置換基」としては、フッ素原子、塩素原子、臭素原子、メチル基、メトキシ基であり、かかる置換基の置換位置としては６位および／または７位が好ましい。 In formula (I), ring B represents a phenyl group which may have a substituent.
The “substituent” of the “phenyl group optionally having substituent (s)” represented by ring B is “the aromatic group optionally having substituent (s)” represented by A 1 and A 2. The same group as “substituent” can be mentioned. The number of the “substituents” is 1 to 4, preferably 1 to 3, more preferably 1 or 2.
Among them, the “substituent” of the “optionally substituted phenyl group” represented by ring B includes (1) a halogen atom, (5) an optionally esterified carboxyl, (14) Hydroxy, (15) optionally substituted lower (C 1-6 ) alkoxy, and (44) an optionally substituted carbamoyl group are preferred.
Ring B is selected from (1) halogen atom, (2) lower (C 1-6 ) alkoxy, (3) lower (C 1-6 ) alkoxy-carbonyl, (4) carboxyl, (5) carbamoyl and hydroxy Optionally substituted mono- or di-lower (C 1-6 ) alkylcarbamoyl and (6) phenyl optionally substituted with 1 to 4 substituents selected from carbamoyl Is preferred.
Among the above-mentioned, as the “substituent” that the ring B phenyl may have, there are a fluorine atom, a chlorine atom, a bromine atom, a methyl group, and a methoxy group. The 7th position is preferred.
　式（Ｉ）中、Ｒは水素原子、または置換基を有していてもよい炭化水素基を示す。
　Ｒで示される「置換基を有していてもよい炭化水素基」の「炭化水素基」としては、炭素数１～２０のものが好ましい。その例としては、例えば、置換基Ａ群の
（６）「置換されていてもよい低級（Ｃ１－６）アルキル」の「低級（Ｃ１－６）アルキル」；
（７）「置換されていてもよい低級（Ｃ２－６）アルケニル」の「低級（Ｃ２－６）アルケニル」；
（８）「置換されていてもよい低級（Ｃ２－６）アルキニル」の「低級（Ｃ２－６）アルキニル」；
（９）「置換されていてもよいＣ３－８シクロアルキル」の「Ｃ３－８シクロアルキル」；
（１０）「置換されていてもよいＣ６－１４アリール」の「Ｃ６－１４アリール」；
（１１）「置換されていてもよいＣ７－１６アラルキル」の「Ｃ７－１６アラルキル」；および
（１２）「置換されていてもよいＣ６－１４アリール－Ｃ２－６アルケニル」の「Ｃ６－１４アリール－Ｃ２－６アルケニル」と同様の基が挙げられる。
　Ｒで示される「置換基を有していてもよい炭化水素基」の「置換基」としては、置換基Ａ群から選ばれる置換基が挙げられる。
　ここで、Ｒで示される「置換基を有していてもよい炭化水素基」の「炭化水素基」が、「低級（Ｃ１－６）アルキル」、「低級（Ｃ２－６）アルケニル」、または「低級（Ｃ２－６）アルキニル」である場合、置換基Ａ群から選ばれる置換基のうち、
（６）「置換されていてもよい低級（Ｃ１－６）アルキル」；
（７）「置換されていてもよい低級（Ｃ２－６）アルケニル」；
（８）「置換されていてもよい低級（Ｃ２－６）アルキニル」；
（１１）「置換されていてもよいＣ７－１６アラルキル」；および
（１２）「置換されていてもよいＣ６－１４アリール－Ｃ２－６アルケニル」以外の置換基が好ましい。
　Ｒで示される「置換基を有していてもよい炭化水素基」の「置換基」の数は、好ましくは０個（無置換）～５個、更に好ましくは０個（無置換）～１個である。
　Ｒとしては、水素が好ましい In formula (I), R represents a hydrogen atom or an optionally substituted hydrocarbon group.
The “hydrocarbon group” of the “hydrocarbon group optionally having substituents” represented by R is preferably one having 1 to 20 carbon atoms. Examples thereof include, for example, “lower (C 1-6 ) alkyl” of (6) “optionally substituted lower (C 1-6 ) alkyl” in substituent group A;
(7) “Lower (C 2-6 ) alkenyl” of “optionally substituted lower (C 2-6 ) alkenyl”;
(8) “Lower (C 2-6 ) alkynyl” of “optionally substituted lower (C 2-6 ) alkynyl”;
(9) “C 3-8 cycloalkyl” of “ optionally substituted C 3-8 cycloalkyl”;
(10) “C 6-14 aryl” of “ optionally substituted C 6-14 aryl”;
(11) “C 7-16 aralkyl” of “ optionally substituted C 7-16 aralkyl”; and (12) “ optionally substituted C 6-14 aryl-C 2-6 alkenyl” And a group similar to “C 6-14 aryl-C 2-6 alkenyl”.
Examples of the “substituent” of the “hydrocarbon group optionally having substituent (s)” represented by R include substituents selected from the substituent group A.
Here, the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R is “lower (C 1-6 ) alkyl”, “lower (C 2-6 ) alkenyl”. Or “lower (C 2-6 ) alkynyl”, among the substituents selected from the substituent group A,
(6) “optionally substituted lower (C 1-6 ) alkyl”;
(7) “optionally substituted lower (C 2-6 ) alkenyl”;
(8) “optionally substituted lower (C 2-6 ) alkynyl”;
Substituents other than (11) “optionally substituted C 7-16 aralkyl”; and (12) “ optionally substituted C 6-14 aryl-C 2-6 alkenyl” are preferred.
The number of “substituents” in the “hydrocarbon group optionally having substituent (s)” represented by R is preferably 0 (unsubstituted) to 5, more preferably 0 (unsubstituted) to 1 It is a piece.
R is preferably hydrogen.
　式（Ｉ）中、Ｒ１は、存在しないか、あるいは水素原子、置換基を有していてもよいアルキル基、またはエステル化されていてもよいカルボキシル基を示す。
　式（Ｉ）中、Ｙは置換基を有していてもよい炭素原子、置換基を有していてもよい窒素原子、酸素原子または酸化されていてもよい硫黄原子を示す。
　式（Ｉ）中、
Figure JPOXMLDOC01-appb-C000013
 は単結合または二重結合を示す。なかでも、好ましくは、二重結合である。

より詳しく説明すると、式（Ｉ）中の
Figure JPOXMLDOC01-appb-C000014
 が単結合
Figure JPOXMLDOC01-appb-C000015
 であるとき、化合物（Ｉ）は式（Ｉａ）
Figure JPOXMLDOC01-appb-I000001

で表され、Ｒ１は、水素原子、置換基を有していてもよいアルキル基、またはエステル化されていてもよいカルボキシル基を示し、Ｙは置換基を有していてもよい炭素原子、置換基を有していてもよい窒素原子、酸素原子または酸化されていてもよい硫黄原子を示す。
　
一方、式（Ｉ）中の
Figure JPOXMLDOC01-appb-C000016
 が二重結合
Figure JPOXMLDOC01-appb-C000017
 であるとき、化合物（Ｉ）は式（Ｉｂ）：
Figure JPOXMLDOC01-appb-C000018
 で表され、Ｒ１は、存在せず、Ｙは置換基を有していてもよい炭素原子または置換基を有していてもよい窒素原子を示す。 In the formula (I), R 1 is absent or represents a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified.
In formula (I), Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized.
In formula (I),
Figure JPOXMLDOC01-appb-C000013
 Represents a single bond or a double bond. Of these, a double bond is preferable.

More specifically, in formula (I)
Figure JPOXMLDOC01-appb-C000014
 Is a single bond
Figure JPOXMLDOC01-appb-C000015
 Where compound (I) is of formula (Ia)
Figure JPOXMLDOC01-appb-I000001

R 1 represents a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified, Y represents a carbon atom which may have a substituent, The nitrogen atom which may have a substituent, the oxygen atom, or the sulfur atom which may be oxidized is shown.

On the other hand, in formula (I)
Figure JPOXMLDOC01-appb-C000016
 Is a double bond
Figure JPOXMLDOC01-appb-C000017
 Compound (I) is represented by formula (Ib):
Figure JPOXMLDOC01-appb-C000018
 R 1 is not present, and Y represents a carbon atom which may have a substituent or a nitrogen atom which may have a substituent.
　Ｒ１で示される「置換基を有していてもよいアルキル基」としては、例えば、前記の置換基Ａ群における（６）「置換されていてもよい低級（Ｃ１－６）アルキル」と同様の基が挙げられる。 Examples of the “optionally substituted alkyl group” represented by R 1 include, for example, (6) “optionally substituted lower (C 1-6 ) alkyl” in the above substituent group A. Similar groups are mentioned.
　Ｒ１で示される「エステル化されていてもよいカルボキシル基」としては、例えば、前記の置換基Ａ群における（５）「エステル化されていてもよいカルボキシル」と同様の基が挙げられる。
　化合物(Ｉ)が、式(Ｉａ)で表される場合、Ｒ１としては水素原子が好ましい。
　Ｙで示される、「置換基を有していてもよい炭素原子」の置換基としては、置換基Ａ群の置換基およびオキソが挙げられる。
Ｙで示される、「置換基を有していてもよい窒素原子」の置換基としては、置換基Ａ群の置換基が挙げられる。
　Ｙは、好ましくは、無置換の炭素原子（ＣＨまたはＣＨ２）、酸素原子、または無置換の窒素原子（ＮまたはＮＨ）であり、より好ましくは、無置換の炭素原子または酸素原子であり、特に好ましくは、無置換の炭素原子である。
　好ましくは、Ｙが、無置換の炭素原子であり、かつ
Figure JPOXMLDOC01-appb-C000019
が二重結合である。 Examples of the “optionally esterified carboxyl group” represented by R 1 include the same groups as (5) “optionally esterified carboxyl” in the above-mentioned Substituent group A.
When compound (I) is represented by the formula (Ia), R 1 is preferably a hydrogen atom.
Examples of the substituent of the “carbon atom optionally having substituent (s)” represented by Y include the substituent of the substituent group A and oxo.
Examples of the substituent of the “nitrogen atom which may have a substituent” represented by Y include the substituents of the substituent group A.
Y is preferably an unsubstituted carbon atom (CH or CH 2 ), an oxygen atom, or an unsubstituted nitrogen atom (N or NH), more preferably an unsubstituted carbon atom or an oxygen atom, Particularly preferred is an unsubstituted carbon atom.
Preferably Y is an unsubstituted carbon atom, and
Figure JPOXMLDOC01-appb-C000019
Is a double bond.
　式（Ｉ）中、Ｘ１は置換基を有していてもよいメチレン基を示す。
　Ｘ１で示される「置換基を有していてもよいメチレン基」の「置換基」としては、置換基Ａ群およびオキソから選ばれる置換基が挙げられる。Ｘ１で示される「置換基を有していてもよいメチレン基」の「置換基」の数は、好ましくは０個（無置換）～１個であり、更に好ましくは、０個（無置換）である。
　式（Ｉ）中、Ｘ２は置換基を有していてもよいエチレン基（ジメチレン基）を示す。
　Ｘ２で示される「置換基を有していてもよいエチレン基」の「置換基」としては、置換基Ａ群の置換基およびオキソが挙げられる。該「置換基」としてはヒドロキシが好ましい。Ｘ２で示される「置換基を有していてもよいエチレン基」の「置換基」の数は、好ましくは０個（無置換）～２個であり、更に好ましくは、０個（無置換）である。 In the formula (I), X 1 represents a methylene group which may have a substituent.
Examples of the “substituent” of the “methylene group optionally having substituent (s)” represented by X 1 include a substituent selected from Substituent Group A and oxo. The number of “substituents” in the “methylene group optionally having substituent (s)” represented by X 1 is preferably 0 (unsubstituted) to 1 and more preferably 0 (unsubstituted) ).
In the formula (I), X 2 represents an ethylene group (dimethylene group) which may have a substituent.
Examples of the “substituent” of the “ethylene group optionally having substituent (s)” represented by X 2 include substituents of the substituent group A and oxo. The “substituent” is preferably hydroxy. The number of “substituents” in the “optionally substituted ethylene group” represented by X 2 is preferably 0 (unsubstituted) to 2 and more preferably 0 (unsubstituted) ).
　式（Ｉ）の化合物またはその塩として好ましくは、次の化合物である。
[化合物Ａ]　 
Ｒが水素原子であり； 
Ｒ１は存在しないか、あるいは水素原子であり；
Ｘ１がメチレン（－ＣＨ２－）であり； 
Ｘ２がヒドロキシを有していてもよいエチレン（－ＣＨ２ＣＨ２－）であり；
Ｙが無置換の炭素原子（ＣＨまたはＣＨ２）または酸素原子であり（好ましくは無置換の炭素原子）； 
Figure JPOXMLDOC01-appb-C000020
 が単結合または二重結合であり（好ましくは二重結合）；
Ａ１がハロゲン原子から選択される１～３個の置換基をそれぞれ有していてもよい、(1)Ｃ６－１０アリール基（例、フェニル）または(2)環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基（例、２－チエニルなどのチエニル）であり；
Ａ２がハロゲン原子、シアノ、低級（Ｃ１－６）アルコキシ、低級（Ｃ１－６）アルキル－カルボニルアミノおよびＣ１－６アルキルから選択される１～３個の置換基をそれぞれ有していてもよい、(1)Ｃ６－１０アリール基（例、フェニル）または(2)環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基（例、３－ピリジルなどのピリジル、１Ｈ-ピラゾール－４－イルなどのピラゾール）であり；
Ｂ環が(1)ハロゲン原子、(2)低級（Ｃ１－６）アルコキシ、(3)低級（Ｃ１－６）アルコキシ－カルボニル、(4)カルボキシル、(5)カルバモイルおよびヒドロキシから選択される置換基で置換されていてもよいモノ－またはジ－低級（C1-6）アルキルカルバモイル、および(6)カルバモイルから選択される１～４個の置換基で置換されていてもよいフェニルである化合物またはその塩。

　ここで、Ａ２の(1)Ｃ６－１０アリール基（例、フェニル）または(2)環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基（例、３－ピリジルなどのピリジル、１H-ピラゾール－４－イルなどのピラゾール）が有していてもよい置換基としては特にフッ素原子が好ましい。
　また、Ｂ環のフェニルが有していてもよい置換基としては、フッ素原子、塩素原子、臭素原子、メチル基、メトキシ基であり、かかる置換基の置換位置としては６位および／または７位が好ましい。
［化合物Ｂ］
Ｒが水素原子であり； 
Ｘ１がメチレン（－ＣＨ２－）であり； 
Ｘ２がエチレン（－ＣＨ２ＣＨ２－）であり；
Ｙが無置換の炭素原子であり； 
Figure JPOXMLDOC01-appb-C000021
 が二重結合であり；
Ａ１が置換基を有していてもよいＣ６－１０アリール基（例、フェニル）であり；
Ａ２が、置換基をそれぞれ有していてもよい、Ｃ６－１０アリール基（例、フェニル）、または環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし５個（好ましくは１ないし３個）有する、５ないし１４員（単環、２環又は３環式）の芳香族複素環基（例、３－ピリジル）である化合物またはその塩。 The following compounds are preferred as the compound of formula (I) or a salt thereof.
[Compound A]
R is a hydrogen atom;
R 1 is absent or is a hydrogen atom;
X 1 is methylene (—CH 2 —);
X 2 is ethylene (—CH 2 CH 2 —) optionally having hydroxy;
Y is an unsubstituted carbon atom (CH or CH 2 ) or an oxygen atom (preferably an unsubstituted carbon atom);
Figure JPOXMLDOC01-appb-C000020
 Is a single bond or a double bond (preferably a double bond);
A 1 may have 1 to 3 substituents each selected from halogen atoms, (1) a C 6-10 aryl group (eg, phenyl) or (2) a carbon atom as a ring member atom In addition, a 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (eg, thienyl such as 2-thienyl) );
A 2 has 1 to 3 substituents each selected from a halogen atom, cyano, lower (C 1-6 ) alkoxy, lower (C 1-6 ) alkyl-carbonylamino and C 1-6 alkyl. (1) C 6-10 aryl group (eg, phenyl) or (2) 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom 1 to 3 5- or 6-membered aromatic monocyclic heterocyclic group (eg, pyridyl such as 3-pyridyl, pyrazole such as 1H-pyrazol-4-yl);
Ring B is selected from (1) halogen atom, (2) lower (C 1-6 ) alkoxy, (3) lower (C 1-6 ) alkoxy-carbonyl, (4) carboxyl, (5) carbamoyl and hydroxy Mono- or di-lower (C 1-6 ) alkylcarbamoyl optionally substituted with a substituent, and (6) phenyl optionally substituted with 1 to 4 substituents selected from carbamoyl Compound or salt thereof.

Here, (1) C 6-10 aryl group of A 2 (eg, phenyl) or (2) 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom A 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 atoms (eg, pyridyl such as 3-pyridyl, pyrazole such as 1H-pyrazol-4-yl) may have As the substituent, a fluorine atom is particularly preferable.
Further, the substituent that the phenyl of B ring may have is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, or a methoxy group, and the substitution position of such substituent is the 6-position and / or the 7-position. Is preferred.
[Compound B]
R is a hydrogen atom;
X 1 is methylene (—CH 2 —);
X 2 is ethylene (—CH 2 CH 2 —);
Y is an unsubstituted carbon atom;
Figure JPOXMLDOC01-appb-C000021
 Is a double bond;
A 1 is an optionally substituted C 6-10 aryl group (eg, phenyl);
A 2 may have a substituent, each of which is a C 6-10 aryl group (eg, phenyl), or a ring-constituting atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom A 5- to 14-membered (monocyclic, bicyclic or tricyclic) aromatic heterocyclic group (eg, 3-pyridyl) having 1 to 5 (preferably 1 to 3) heteroatoms; A compound or salt thereof.
［化合物Ｃ］
Ｒが水素原子であり； 
Ｘ１がメチレン（－ＣＨ２－）であり； 
Ｘ２がエチレン（－ＣＨ２ＣＨ２－）であり；
Ｙが無置換の炭素原子であり； 
Figure JPOXMLDOC01-appb-C000022
 が二重結合であり；
Ａ１がハロゲン原子から選択される１～３個の置換基を有していてもよいフェニルであり；
Ａ２がハロゲン原子から選択される１～３個の置換基をそれぞれ有していてもよいＣ６－１０アリール基（例、フェニル）または環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基（例、３－ピリジル）である化合物またはその塩。 [Compound C]
R is a hydrogen atom;
X 1 is methylene (—CH 2 —);
X 2 is ethylene (—CH 2 CH 2 —);
Y is an unsubstituted carbon atom;
Figure JPOXMLDOC01-appb-C000022
 Is a double bond;
A 1 is phenyl optionally having 1 to 3 substituents selected from halogen atoms;
1-3 substituents optionally having respectively a C 6-10 aryl group (e.g., phenyl) that A 2 is selected from halogen atom or a ring-constituting atom, a nitrogen atom in addition to carbon atom, a sulfur atom And a compound or salt thereof which is a 5- or 6-membered aromatic monocyclic heterocyclic group (eg, 3-pyridyl) having 1 to 3 heteroatoms selected from oxygen atoms and 1 to 3 heteroatoms.
　化合物（Ｉ）の塩としては、例えば金属塩、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などが挙げられる。金属塩の好適な例としては、例えばナトリウム塩、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。有機塩基との塩の好適な例としては、例えばトリメチルアミン、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などとの塩が挙げられる。無機酸との塩の好適な例としては、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩が挙げられる。有機酸との塩の好適な例としては、例えばギ酸、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などとの塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えばアルギニン、リジン、オルニチンなどとの塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えばアスパラギン酸、グルタミン酸など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。例えば、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、カリウム塩など）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩、バリウム塩など）などの無機塩、アンモニウム塩など、また、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、リン酸など無機酸との塩、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などの有機酸との塩が挙げられる。 Examples of the salt of compound (I) 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. Preferable 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. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid 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, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), When the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, And salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
　化合物（Ｉ）が、互変異性体、光学異性体、立体異性体、位置異性体、回転異性体などの異性体を有する場合には、いずれか一方の異性体も混合物も本発明の化合物に包含される。さらに、化合物（Ｉ）に光学異性体が存在する場合には、ラセミ体から分割された光学異性体も化合物（Ｉ）に包含される。 When compound (I) has an isomer such as a tautomer, an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one of the isomers or a mixture is included in the compound of the present invention. Is included. Furthermore, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I).
　化合物（Ｉ）は、結晶であってもよく、結晶形が単一であっても結晶形混合物であっても化合物（Ｉ）に包含される。
　化合物（Ｉ）は、溶媒和物（例えば、水和物など）であっても、無溶媒和物であってもよく、いずれも化合物（Ｉ）に包含される。
　同位元素（例、２Ｈ，３Ｈ，１４Ｃ，３５Ｓ，１２５Ｉなど）などで標識または置換された化合物も、化合物（Ｉ）に包含される。 Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.
Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I).
A compound labeled or substituted with an isotope (eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc.) is also encompassed in compound (I).
［製造方法］
　本発明の化合物（Ｉ）の製造法を、以下に説明する。
　本発明の化合物（Ｉ）は、例えば以下の反応式で示される方法またはこれに準じた方法などにより得られる。反応式中の化合物の各記号は、前記と同意義を示す。なお、式中の化合物は、塩を形成している場合も含み、このような塩としては、例えば化合物（Ｉ）の塩と同様のものなどが挙げられる。また、各工程で得られた化合物は反応液のままか粗製物として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、例えば、抽出、濃縮、中和、濾過、蒸留、再結晶、蒸留、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、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。 [Production method]
The production method of compound (I) of the present invention will be described below.
Compound (I) of the present invention can be obtained, for example, by the method shown by the following reaction formula or a method analogous thereto. Each symbol of the compound in the reaction formula has the same meaning as described above. In addition, the compound in a formula also includes the case where it forms the salt, As such a salt, the thing similar to the salt of compound (I) etc. are mentioned, for example. In addition, the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and a means known per se, for example, It can be easily purified by separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, distillation, chromatography and the like. Or when the compound in a formula is marketed, a commercial item can also be used as it is.
　以下にその反応式の略図を示した。化合物（ＩＩＩ）は、工程１で、化合物（ＩＩ）より、公知の方法等に準じて、還元反応によって製造することができる。化合物（ＩＩ）中、Ｐは水素原子または保護基を示す。保護基としては、例えばそれぞれ置換基を有していてもよいＣ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、tert-ブチル、２－トリメチルなど）、フェニル、トリチルもしくはシリル（例、トリメチルシリル（ＴＭＳ）、トリエチルシリル（ＴＥＳ）、tert-ブチルジメチルシリル（ＴＢＳ（ＴＢＤＭＳ））、トリイソプロピルシリル（ＴＩＰＳ）、tert-ブチルジフェニルシリル（ＴＢＤＰＳ））などが用いられる。これらの置換基としては、ハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素など）、ケイ素（例えば、２－（トリメチルシリル）エチル）、ホルミル、Ｃ1-6アルキル－カルボニル（例えば、アセチル、プロピオニル、ブチルカルボニルなど）、Ｃ1-6アルコキシ－カルボニル（例えば、エトキシカルボニル、イソプロピロキシカルボニルなど）、ニトロ、Ｃ１－６アルキル（例えば、メチル、エチル、ｔｅｒｔ－ブチルなど）、Ｃ６－１０アリール（例えば、フェニル、ナフチルなど）などが用いられ、置換基の数は１ないし３個である。 A schematic diagram of the reaction formula is shown below. Compound (III) can be produced from compound (II) in Step 1 by a reduction reaction according to a known method or the like. In compound (II), P represents a hydrogen atom or a protecting group. Examples of the protecting group include C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-trimethyl, etc.), phenyl, trityl or silyl (optionally substituted). Examples include trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS (TBDMS)), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS)) and the like. These substituents include halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), silicon (eg, 2- (trimethylsilyl) ethyl), formyl, C 1-6 alkyl-carbonyl (eg, acetyl, propionyl, butyl) Carbonyl, etc.), C 1-6 alkoxy-carbonyl (eg ethoxycarbonyl, isopropyloxycarbonyl etc.), nitro, C 1-6 alkyl (eg methyl, ethyl, tert-butyl etc.), C 6-10 aryl (eg Phenyl, naphthyl, etc.) are used, and the number of substituents is 1 to 3.
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　還元剤としては、水素化ホウ素ナトリウム、水素化リチウムアルミニウムなどの金属水素化物類、ボランテトラヒドロフラン錯体などのボラン類などが用いられる。還元剤の使用量は、それぞれ化合物（ＩＩ）１モルに対し、約０．５～約１０モル、好ましくは約１～約５モルである。また所望により還元剤とともに酸触媒を加えても良い。酸触媒としては、プロトン酸（たとえば、酢酸、トリフルオロ酢酸など）およびルイス酸（たとえば、ｐ－トルエンスルホン酸など）などを用いることができる。
　本反応は、無溶媒で行うか、反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては、反応が進行する限り特に限定されないが、例えば、水、メタノール、エタノール、プロパノールなどのアルコール類、シクロヘキサン、ヘキサン、ベンゼン、トルエン、キシレン、メシチレンなどの炭化水素類、ギ酸、酢酸などの有機酸類、テトラヒドロフラン、ジオキサン、１，２－ジメトキシエタン、ジエチルエーテル、ジイソプロピルエーテルなどのエーテル類、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンなどのアニリン類、ジクロロメタン、クロロホルム、四塩化炭素、１，２－ジクロロエタンなどのハロゲン化炭化水素類またはこれらの混合溶媒などが用いられる。
　反応時間は通常約１０分～約２４時間、好ましくは約３０分～１２時間である。反応温度は通常約０～約１２０℃、好ましくは約２５～約６０℃である。 As the reducing agent, metal hydrides such as sodium borohydride and lithium aluminum hydride, and boranes such as borane tetrahydrofuran complex are used. The amount of the reducing agent to be used is about 0.5 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (II). If desired, an acid catalyst may be added together with the reducing agent. As the acid catalyst, a protonic acid (for example, acetic acid, trifluoroacetic acid, etc.) and a Lewis acid (for example, p-toluenesulfonic acid, etc.) can be used.
This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as water, methanol, ethanol, and propanol, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, and mesitylene, formic acid, Organic acids such as acetic acid, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether and diisopropyl ether, anilines such as N, N-dimethylaniline and N, N-diethylaniline, dichloromethane, chloroform, four Halogenated hydrocarbons such as carbon chloride and 1,2-dichloroethane or a mixed solvent thereof are used.
The reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to 12 hours. The reaction temperature is usually about 0 to about 120 ° C., preferably about 25 to about 60 ° C.
　化合物（ＩＩ）は、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、公知の方法またはこれらに準じた方法に従って製造することもできる。例えば、化合物（ＩＩ）に相当する２－ニトロベンズアルデヒド、２－アミノベンズアルデヒド、あるいは２－ニトロフェノールより、公知の方法（例、特許ＵＳ６３２９３８９等）に従い、目的とする化合物（ＩＩ）を得る。 Compound (II), which is commercially available, can be used as it is, or can be produced according to a known method or a method analogous thereto. For example, the target compound (II) is obtained from 2-nitrobenzaldehyde, 2-aminobenzaldehyde, or 2-nitrophenol corresponding to the compound (II) according to a known method (eg, US Pat. No. 6,329,389).
　化合物 （ＩＩＩ）は、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、公知の方法またはこれらに準じた方法に従って製造することもできる。例えば、化合物（ＩＩＩ）に相当するＮ－アセチルアニリンより、公知の方法（例、シンレター、２５１頁、２００１年等）に従い、４－クロロ－ホルミルキノリンとした後、これを塩酸と反応させることにより目的とする化合物（ＩＩＩ）を得る。 Compound IV (III) can be used as it is when commercially available, or can be produced according to a known method or a method analogous thereto. For example, N-acetylaniline corresponding to compound (III) is converted into 4-chloro-formylquinoline according to a known method (eg, Synletter, page 251, 2001, etc.) and then reacted with hydrochloric acid. The target compound (III) is obtained.
　工程２で、化合物（Ｖ）は化合物（ＩＩＩ）と化合物（ＩＶ）を用いて、新実験化学講座、第１４－ＩＩＩ巻、１３８０頁～１３８５頁（丸善株式会社刊）に記載の方法等に準じて、還元アミノ化反応によって製造することができる。化合物（ＩＩＩ）中、Ｌは水素原子または置換基Ａ群から選ばれる置換基を示す。置換基としては、例えばアルキルなどが挙げられる。 In step 2, compound (V) is obtained by using compound (III) and compound (IV) according to the method described in New Experimental Chemistry Course, Vol. 14-III, pages 1380 to 1385 (published by Maruzen Co., Ltd.). Accordingly, it can be produced by a reductive amination reaction. In compound (III), L represents a hydrogen atom or a substituent selected from substituent group A. Examples of the substituent include alkyl.
　還元剤としては、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ナトリウムなどの金属水素化物類、ボランテトラヒドロフラン錯体などのボラン類などが用いられる。還元剤の使用量は、それぞれ化合物（ＩＩＩ）１モルに対し、約０．５～約１０モル、好ましくは約１～約５モルである。また所望により還元剤とともに酸触媒を加えても良い。酸触媒としては、プロトン酸（たとえば、酢酸、トリフルオロ酢酸など）およびルイス酸（たとえば、ｐ－トルエンスルホン酸など）などを用いることができる。
　本反応は、無溶媒で行うか、反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては、反応が進行する限り特に限定されないが、例えば水、メタノール、エタノール、プロパノールなどのアルコール類、シクロヘキサン、ヘキサン、ベンゼン、トルエン、キシレン、メシチレンなどの炭化水素類、ギ酸、酢酸などの有機酸類、テトラヒドロフラン、ジオキサン、１，２－ジメトキシエタン、ジエチルエーテル、ジイソプロピルエーテルなどのエーテル類、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンなどのアニリン類、ジクロロメタン、クロロホルム、四塩化炭素、１，２－ジクロロエタンなどのハロゲン化炭化水素類またはこれらの混合溶媒などが用いられる。
　反応時間は通常約１０分～約２４時間、好ましくは約３０分～１２時間である。反応温度は通常約０～約１２０℃、好ましくは約２５～約６０℃である。 As the reducing agent, metal hydrides such as sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride, and boranes such as borane tetrahydrofuran complex are used. The amount of the reducing agent to be used is about 0.5 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (III). If desired, an acid catalyst may be added together with the reducing agent. As the acid catalyst, a protonic acid (for example, acetic acid, trifluoroacetic acid, etc.) and a Lewis acid (for example, p-toluenesulfonic acid, etc.) can be used.
This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as water, methanol, ethanol and propanol, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene and mesitylene, formic acid and acetic acid. Organic acids such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether and other ethers, N, N-dimethylaniline, anilines such as N, N-diethylaniline, dichloromethane, chloroform, tetrachloride Halogenated hydrocarbons such as carbon and 1,2-dichloroethane or mixed solvents thereof are used.
The reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to 12 hours. The reaction temperature is usually about 0 to about 120 ° C., preferably about 25 to about 60 ° C.
　工程３は、化合物（Ｖ）から、公知の方法等に準じて、適当な縮合剤および必要により塩基の存在下、化合物（ＶＩ）でアシル化して化合物（Ｉ）を合成する方法である。化合物（ＶＩ）の使用量は、化合物（Ｖ）の使用量１モルに対して、約１モルないし２モル、好ましくは約１モルないし１．２モルである。縮合剤の使用量は、化合物（ＶＩ）の使用量１モルあたり、約１モルないし１０モル、好ましくは約１モルないし１．２モルである。 Step 3 is a method of synthesizing compound (I) from compound (V) by acylation with compound (VI) in the presence of an appropriate condensing agent and, if necessary, a base according to a known method. The amount of compound (VI) to be used is about 1 mol to 2 mol, preferably about 1 mol to 1.2 mol, per 1 mol of compound (V). The amount of the condensing agent to be used is about 1 to 10 mol, preferably about 1 to 1.2 mol, per 1 mol of compound (VI).
　縮合剤としては、たとえば、カルボジイミド類（ＣＤＩ（すなわち、Ｎ，Ｎ'－カルボニルイミダゾール）など）などがあげられる。塩基としては、たとえば、水素化ナトリウム、水酸化ナトリウム、水酸化カリウムなどの無機塩基類、ピリジン、ルチジンなどの芳香族アミン類、トリエチルアミン、トリプロピルアミン、トリブチルアミン、シクロヘキシルジメチルアミン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルピロリジン、Ｎ－メチルモルホリンなどの３級アミン類、アンモニアまたはこれら二種以上の混合物などが用いられる。
本反応は、無溶媒で行うか、反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては、反応が進行する限り特に限定されないが、例えば水、メタノール、エタノール、プロパノールなどのアルコール類、シクロヘキサン、ヘキサン、ベンゼン、トルエン、キシレン、メシチレンなどの炭化水素類、ギ酸、酢酸などの有機酸類、テトラヒドロフラン、ジオキサン、１，２－ジメトキシエタン、ジエチルエーテル、ジイソプロピルエーテルなどのエーテル類、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンなどのアニリン類、ジクロロメタン、クロロホルム、四塩化炭素、１，２－ジクロロエタンなどのハロゲン化炭化水素類またはこれらの混合溶媒などが用いられる。
反応温度は、通常０℃ないし１００℃、好ましくは１０℃ないし４０℃である。反応時間は通常１時間ないし１００時間、好ましくは１時間ないし２４時間である。また、化合物（Ｉ）は、化合物（Ｖ）を化合物（ＶＩ）の反応性誘導体（たとえば、イソシアネートなど）と反応させることによっても得ることができる。 Examples of the condensing agent include carbodiimides (CDI (ie, N, N′-carbonylimidazole) and the like). Examples of the base include inorganic bases such as sodium hydride, sodium hydroxide and potassium hydroxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylamino. Tertiary amines such as pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, ammonia or a mixture of two or more of these are used.
This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as water, methanol, ethanol and propanol, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene and mesitylene, formic acid and acetic acid. Organic acids such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether and other ethers, N, N-dimethylaniline, anilines such as N, N-diethylaniline, dichloromethane, chloroform, tetrachloride Halogenated hydrocarbons such as carbon and 1,2-dichloroethane or mixed solvents thereof are used.
The reaction temperature is generally 0 ° C. to 100 ° C., preferably 10 ° C. to 40 ° C. The reaction time is usually 1 hour to 100 hours, preferably 1 hour to 24 hours. Compound (I) can also be obtained by reacting compound (V) with a reactive derivative of compound (VI) (such as isocyanate).
　工程４で、化合物（ＶＩＩ）は、化合物（ＩＩ）における
Figure JPOXMLDOC01-appb-C000024
 が単結合でＲ１が水素である時、化合物（ＩＩ）から化合物（ＩＶ）を用いて、公知の方法等に準じて、ホルムアルデヒドなどのケトン存在下、マンニッヒ反応によって製造することができる。化合物（ＩＶ）の使用量は、化合物（ＩＩ）の使用量１モルに対して、約１モルないし１０モル、好ましくは約１モルないし３モルである。ケトンの使用量は、化合物（ＩＩ）の使用量１モルあたり、約１モルないし１０モル、好ましくは約１モルないし３モルである。 In step 4, compound (VII) is converted into compound (II).
Figure JPOXMLDOC01-appb-C000024
 Is a single bond and R 1 is hydrogen, it can be produced by Mannich reaction using compound (II) to compound (IV) in the presence of a ketone such as formaldehyde according to a known method. The amount of compound (IV) to be used is about 1 mol to 10 mol, preferably about 1 mol to 3 mol, per 1 mol of compound (II). The amount of the ketone used is about 1 mol to 10 mol, preferably about 1 mol to 3 mol, per mol of the compound (II) used.
　本反応は、無溶媒で行うか、反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては、反応が進行する限り特に限定されないが、例えば水、メタノール、エタノール、プロパノールなどのアルコール類、シクロヘキサン、ヘキサン、ベンゼン、トルエン、キシレン、メシチレンなどの炭化水素類、ギ酸、酢酸などの有機酸類、テトラヒドロフラン、ジオキサン、１，２－ジメトキシエタン、ジエチルエーテル、ジイソプロピルエーテルなどのエーテル類、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリンなどのアニリン類、ジクロロメタン、クロロホルム、四塩化炭素、１，２－ジクロロエタンなどのハロゲン化炭化水素類またはこれらの混合溶媒などが用いられる。
反応温度は、通常０℃ないし１００℃、好ましくは２０℃ないし６０℃である。反応時間は通常１時間ないし１００時間、好ましくは１時間ないし２４時間である。 This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as water, methanol, ethanol and propanol, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene and mesitylene, formic acid and acetic acid. Organic acids such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether and other ethers, N, N-dimethylaniline, anilines such as N, N-diethylaniline, dichloromethane, chloroform, tetrachloride Halogenated hydrocarbons such as carbon and 1,2-dichloroethane or mixed solvents thereof are used.
The reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 60 ° C. The reaction time is usually 1 hour to 100 hours, preferably 1 hour to 24 hours.
　工程５で、化合物（Ｖ）は化合物（ＶＩＩ）から、公知の方法等に準じて、Ｐ部位を脱保護して除去して合成したカルボン酸を脱炭酸化反応することによって製造することができる。あるいは、化合物（Ｖ）は化合物（ＶＩＩ）から、ＣＯＯＰ部位を加水分して合成したカルボン酸を脱炭酸化反応することによって製造することができる。所望により酸触媒を加えても良い。酸触媒としては、プロトン酸（たとえば、塩酸、トリフルオロ酢酸など）およびルイス酸（たとえば、ｐ－トルエンスルホン酸など）などを用いることができる。反応温度は、通常３０℃ないし１５０℃、好ましくは５０℃ないし１００℃である。反応時間は通常１時間ないし１００時間、好ましくは１時間ないし２４時間である。 In step 5, compound (V) can be produced from compound (VII) by decarboxylation of the carboxylic acid synthesized by removing and protecting the P site according to a known method or the like. . Alternatively, compound (V) can be produced by decarboxylating carboxylic acid synthesized from compound (VII) by hydrolyzing the COOP site. If desired, an acid catalyst may be added. As the acid catalyst, a protonic acid (for example, hydrochloric acid, trifluoroacetic acid, etc.) and a Lewis acid (for example, p-toluenesulfonic acid, etc.) can be used. The reaction temperature is usually 30 ° C. to 150 ° C., preferably 50 ° C. to 100 ° C. The reaction time is usually 1 hour to 100 hours, preferably 1 hour to 24 hours.
　保護基の除去方法としては、公知またはそれに準じる方法が用いられ、例えば酸、塩基、紫外光、ヒドラジン、フェニルヒドラジン、Ｎ－メチルジチオカルバミン酸ナトリウム、テトラブチルアンモニウムフルオリド、酢酸パラジウムなどで処理する方法または還元反応が用いられる。
加水分解の方法としては、公知またはそれに準じる方法が用いられ、例えば酸、塩基、酵素などで処理する方法が用いられる。　　　　　　 As a method for removing the protecting group, a known or equivalent method is used. For example, a method of treating with acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like. Alternatively, a reduction reaction is used.
As the hydrolysis method, a known method or a method equivalent thereto is used. For example, a method of treating with an acid, a base, an enzyme or the like is used.
　工程６は、化合物（ＶＩＩ）より、公知の方法等に準じて、適当な縮合剤および必要により塩基の存在下、化合物（ＶＩ）でアシル化して化合物（ＶＩＩＩ）を合成する方法であり、工程３と同様の方法が用いられる。 Step 6 is a method of synthesizing compound (VIII) from compound (VII) by acylation with compound (VI) in the presence of an appropriate condensing agent and, if necessary, a base according to a known method. The same method as 3 is used.
　工程７は、化合物（ＶＩＩＩ）より、公知の方法等に準じて、Ｐ部位を脱保護して除去して合成したカルボン酸を脱炭酸化反応することによって化合物（Ｉ）を合成する方法であり、工程５と同様の方法が用いられる。あるいは、化合物（ＶＩＩＩ）より、公知の方法等に準じて、ＣＯＯＰ部位を加水分して合成したカルボン酸を脱炭酸化反応することによって化合物（Ｉ）を合成する方法であり、工程５と同様の方法が用いられる。 Step 7 is a method of synthesizing compound (I) from compound (VIII) by decarboxylating carboxylic acid synthesized by deprotecting and removing the P site according to a known method or the like. The same method as in step 5 is used. Alternatively, it is a method of synthesizing compound (I) from compound (VIII) by decarboxylating carboxylic acid synthesized by hydrolyzing the COOP site according to a known method, etc. The method is used.
　いずれの場合にも、さらに所望により、公知の脱保護反応、アシル化反応、アルキル化反応、水素添加反応、酸化反応、還元反応、炭素鎖延長反応または置換基交換反応を、単独あるいはその二つ以上を組み合わせることにより、化合物（Ｉ）を合成することができる。 In any case, a known deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction or substituent exchange reaction may be carried out singly or in combination, as desired. By combining the above, compound (I) can be synthesized.
　化合物（Ｉ）またはその塩と同様に、化合物（Ｉ）またはその塩のプロドラッグとして用いてもよい。化合物（Ｉ）のプロドラッグは、生体内における生理条件下で酵素や胃酸など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、加水分解などを起こして化合物（Ｉ）に変化する化合物、胃酸など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いう。 Similarly to compound (I) or a salt thereof, it may be used as a prodrug of compound (I) or a salt thereof. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) by hydrolysis or the like due to gastric acid or the like.
　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（例えば、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など）；化合物（Ｉ）のヒドロキシル基がアシル化、アルキル化、りん酸化、ホウ酸化された化合物（例えば、化合物（Ｉ）のヒドロキシル基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、スクシニル化、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など）；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（例えば、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）；などが挙げられる。これらの化合物は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。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。 Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated (for example, 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 compounds, etc.); Compounds wherein the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated, dimethylaminomethylcarbonylated compounds, etc.); Compound (I) Compound in which carboxy group is esterified or amidated (for example, carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxy Carbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.); Is mentioned. These compounds can be produced from compound (I) by a known method. The prodrug of compound (I) is changed to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Pharmaceutical Development”, Volume 7, Molecular Design, pages 163 to 198. There may be.
　優れたＮＫ２受容体拮抗作用を有する本発明の化合物は、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、ヒトなど）に対して、例えば、消化器疾患（例、機能性消化管疾患、過敏性腸症候群、機能性ディスペプシア（Ｆｕｎｃｔｉｏｎａｌ　ｄｙｓｐｅｐｓｉａ）、胃食道逆流症、排便障害、便秘、下痢、消化不良、胃炎、胃潰瘍、潰瘍性大腸炎、クローン病）、痛み（例、内臓痛、体性痛、神経因性疼痛、偏頭痛、神経痛、掻痒）、中枢神経系の疾患（例、うつ、不安、統合失調症、認知症、強迫神経症、恐慌性障害、アルツハイマー病）、肺疾患（例、喘息、慢性閉塞性肺疾患、咳）、泌尿器疾患（例、排尿障害、頻尿、尿失禁）、嘔吐、炎症もしくはアレルギー性疾患（例、アトピー、皮膚炎、ヘルペス、乾癬、喘息、気管支炎、慢性閉塞性肺疾患、喀痰、鼻炎、リウマチ関節炎、変形性関節症、骨粗鬆症、多発性硬化症、結膜炎、膀胱炎など）、肥満、循環器疾患（例、狭心症、高血圧、心不全、血栓症など）、免疫異常、癌、ＨＩＶ感染症、心血管疾患、日光皮膚炎、性的機能不全、運動失調などの疾患の予防・治療剤として有用である。
　なかでも、機能性消化管疾患、さらにそのなかでも、過敏性腸症候群、機能性ディスペプシア（Ｆｕｎｃｔｉｏｎａｌ　ｄｙｓｐｅｐｓｉａ）の予防・治療剤として有用である。 The compound of the present invention having an excellent NK2 receptor antagonistic activity is effective against mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.). (Eg, functional digestive tract disease, irritable bowel syndrome, functional dyspepsia, gastroesophageal reflux disease, defecation disorder, constipation, diarrhea, dyspepsia, gastritis, gastric ulcer, ulcerative colitis, Crohn's disease), Pain (eg, visceral pain, somatic pain, neuropathic pain, migraine, neuralgia, pruritus), central nervous system diseases (eg, depression, anxiety, schizophrenia, dementia, obsessive-compulsive disorder, panic disorder) , Alzheimer's disease), lung diseases (eg, asthma, chronic obstructive pulmonary disease, cough), urological diseases (eg, dysuria, frequent urination, urinary incontinence), vomiting, inflammation or allergic diseases (eg, atopy, skin) Dermatitis, herpes, psoriasis, asthma, bronchitis, chronic obstructive pulmonary disease, sputum, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc.), obesity, cardiovascular disease ( Eg, angina pectoris, hypertension, heart failure, thrombosis), immune disorders, cancer, HIV infection, cardiovascular disease, sun dermatitis, sexual dysfunction, ataxia, etc. is there.
Among them, it is useful as a preventive / therapeutic agent for functional gastrointestinal diseases, and more particularly, irritable bowel syndrome and functional dyspepsia.
　さらに、本発明の化合物は優れたＮＫ３受容体結合作用をも有し、中枢神経系の疾患、なかでも、うつおよび不安の予防・治療剤として有用である。 Furthermore, the compound of the present invention has an excellent NK3 receptor binding action, and is useful as a preventive or therapeutic agent for diseases of the central nervous system, particularly depression and anxiety.
　本発明の化合物は、従来のＮＫ２受容体拮抗剤と比較し、顕著に優れた拮抗活性を有し、ＮＫ３受容体結合活性をも有し、代謝安定性に優れるので、上記疾患に対して低用量でかつ優れた治療効果が期待できる。 Compared with conventional NK2 receptor antagonists, the compounds of the present invention have markedly superior antagonistic activity, also have NK3 receptor binding activity, and excellent metabolic stability. Excellent therapeutic effects can be expected at doses.
　本発明の化合物は、毒性が低く（例えば、急性毒性、慢性毒性、遺伝毒性、生殖毒性、心毒性、薬物相互作用、癌原性等の点から医薬として、より優れている）、そのまま医薬として、または薬学的に許容される担体等と混合された医薬組成物として、哺乳動物（例えば、ヒト、サル、ウシ、ウマ、ブタ、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ヒツジ、ヤギ等）に対して、経口的、または非経口的に安全に投与できる。「非経口」には、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、腫瘍の近位などへの投与および直接的な病巣への投与を含む。 The compound of the present invention has low toxicity (for example, it is superior as a pharmaceutical from the viewpoint of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), and it is used as it is as a pharmaceutical. Or as a pharmaceutical composition mixed with a pharmaceutically acceptable carrier or the like, mammals (eg, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc. ) Can be safely administered orally or parenterally. “Parenteral” includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, etc. Includes direct lesion administration.
　本発明の化合物の投与量は、投与ルート、症状などによって異なるが、例えば、過敏性腸症候群の患者（成人、体重４０ないし８０ｋｇ、例えば６０ｋｇ）に経口投与する場合、例えば１日０．００１～１０００ｍｇ／ｋｇ体重、好ましくは1日０．０１～１００ｍｇ／ｋｇ体重、さらに好ましくは1日０．１～１０ ｍｇ／ｋｇ体重である。この量を１日１回～３回に分けて投与することができる。 The dose of the compound of the present invention varies depending on the administration route, symptoms and the like. For example, when administered orally to a patient with irritable bowel syndrome (adult, body weight 40 to 80 kg, eg 60 kg), for example, 0.001 to 1000 mg / kg body weight, preferably 0.01 to 100 mg / kg body weight per day, more preferably 0.1 to 10 mg / kg body weight per day. This amount can be administered in 1 to 3 divided doses per day.
　本発明の化合物を医薬組成物とする場合の剤形としては、錠剤（例：糖衣錠、フィルムコーティング錠、口腔内崩壊錠）、フィルム剤（例：口腔内崩壊フィルム剤）、丸剤、カプセル剤、顆粒剤、細粒剤、散剤、シロップ剤、乳剤、懸濁剤、注射剤、徐放性注射剤、吸入剤、軟膏剤等が挙げられる。これらの製剤は常法（例えば、日本薬局方記載の方法等）に従って調製される。
　本発明の医薬組成物は、剤型、投与方法、担体などにより異なるが、本発明の化合物を、製剤全量に対して通常０．０１～１００％（ｗ／ｗ）、好ましくは０．１～９５％（ｗ／ｗ）含有する。 As a dosage form when the compound of the present invention is used as a pharmaceutical composition, tablets (eg, sugar-coated tablets, film-coated tablets, orally disintegrating tablets), films (eg, orally disintegrating film), pills, capsules , Granules, fine granules, powders, syrups, emulsions, suspensions, injections, sustained-release injections, inhalants, ointments and the like. These preparations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia).
The pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier, etc., but the compound of the present invention is usually 0.01 to 100% (w / w), preferably 0.1 to Contains 95% (w / w).
　薬学的に許容される担体としては、製剤素材（ｓｔａｒｔｉｎｇ ｍａｔｅｒｉａｌ）として慣用されている各種有機あるいは無機担体が用いられ、これらは、固形製剤における賦形剤、滑沢剤、結合剤および崩壊剤、液状製剤における溶剤、溶解補助剤、懸濁化剤、など張化剤、緩衝剤および無痛化剤などとして配合される。また必要に応じて、防腐剤、抗酸化剤、着色剤、甘味剤などの製剤添加物を用いることもできる。 As the pharmaceutically acceptable carrier, various organic or inorganic carriers conventionally used as starting materials (starting materials) are used. These include excipients, lubricants, binders and disintegrants in solid formulations, It is blended as a tonicity agent, a buffering agent, a soothing agent, etc., such as a solvent, a solubilizing agent, a suspending agent in a liquid preparation. Further, if necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used.
　例えば、本発明の化合物は、他の活性成分（以下、併用薬物と略記する）と併用して使用することができる。
　本発明の化合物は、単剤として使用しても優れたＮＫ２受容体拮抗活性およびＮＫ３受容体の結合活性を示すが、さらに１以上の併用薬物と併用（多剤併用）することによって、その効果をより一層増強させることができる。 For example, the compound of the present invention can be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).
Although the compound of the present invention exhibits excellent NK2 receptor antagonistic activity and NK3 receptor binding activity even when used as a single agent, the effect thereof can be obtained by further combining with one or more concomitant drugs (multi-drug combination). Can be further enhanced.
　併用薬物としては、例えば、以下が挙げられる。
（１）糖尿病治療剤
　インスリン製剤（例、ウシまたは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または誘導体（例、ＩＮＳ－１など）など）、インスリン抵抗性増強剤（例、塩酸ピオグリタゾン、トログリタゾン、ロジグリタゾンまたはそのマレイン酸塩、ＪＴＴ－５０１、ＭＣＣ－５５５、ＹＭ－４４０、ＧＩ－２６２５７０、ＫＲＰ－２９７、ＦＫ－６１４、ＣＳ－０１１など）、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、エミグリテートなど）、ビグアナイド剤（例、フェンホルミン、メトホルミン、ブホルミンなど）、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、グリメピリドなど）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、ミチグリニドまたはそのカルシウム塩水和物、ＧＬＰ－１、ナテグリニドなど）、ジペプチジルペプチダーゼＩＶ阻害剤（例、ＮＶＰ－ＤＰＰ－２７８、ＰＴ－１００、Ｐ３２／９８など）、β3アゴニスト（例、ＣＬ－３１６２４３、ＳＲ－５８６１１－Ａ、ＵＬ－ＴＧ－３０７、ＡＪ－９６７７、ＡＺ４０１４０など）、アミリンアゴニスト（例、プラムリンチドなど）、ホスホチロシンホスファターゼ阻害剤（例、バナジン酸など）、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、グルカゴン拮抗剤など）、ＳＧＬＴ（すなわち、ｓｏｄｉｕｍ－ｇｌｕｃｏｓｅ ｃｏｔｒａｎｓｐｏｒｔｅｒ）阻害剤（例、Ｔ－１０９５など）など。 Examples of the concomitant drug include the following.
(1) Diabetes therapeutic agent Insulin preparation (eg, animal insulin preparation extracted from bovine or porcine pancreas; human insulin preparation genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin fragment Or a derivative (eg, INS-1 etc.), an insulin resistance enhancer (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or a maleate thereof, JTT-501, MCC-555, YM-440, GI-262570, KRP-297, FK-614, CS-011, etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), sulfonylurea agents (eg, , Tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.) and other insulin secretagogues (eg, repaglinide, senaglinide, mitiglinide or its calcium salt hydrate, GLP-1, Nateglinide, etc.), dipeptidyl peptidase IV inhibitors (eg, NVP-DPP-278, PT-100, P32 / 98, etc.), β3 agonists (eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9679, AZ40140, etc.), amylin agonist (eg, pramlintide, etc.), phosphotyrosine phosphatase inhibitor (eg, vanadic acid, etc.), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphine) Synthetase inhibitor, such as glucagon antagonists), SGLT (i.e., sodium-glucose cotransporter) inhibitors (e.g., such as T-1095) and the like.
（２）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）、ＣＴ－１１２など）、神経栄養因子(例、ＮＧＦ、ＮＴ－３など)、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(ＡＬＴ－７６６)、ＥＸＯ－２２６など)、活性酸素消去薬(例、チオクト酸など)、脳血管拡張剤(例、チアプリド（ｔｉａｐｕｒｉｄｅ）など)など。 (2) Agents for treating diabetic complications Aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minalrestat (ARI-509), CT-112, etc.), nerve Nutritional factors (eg, NGF, NT-3, etc.), AGE inhibitors (eg, ALT-945, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT-766), EXO-226, etc.), reactive oxygen scavenging Drugs (eg, thioctic acid, etc.), cerebral vasodilators (eg, tiapride, etc.), etc.
（３）抗高脂血剤
　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、セリバスタチンまたはそれらの塩（例、ナトリウム塩など）など）、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、シンフィブラート、クリノフィブラートなど）など。 (3) Antihyperlipidemic agents Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or their salts (eg, sodium salt, etc.)), squalene synthase inhibition Or a fibrate compound having a triglyceride lowering effect (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.).
（４）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、デラプリルなど）、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 シレキセチルなど）、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、ニカルジピンなど）、クロニジンなど。 (4) Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonist (eg, losartan, candesartan cilexetil, etc.), calcium antagonist (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine) Etc.), clonidine etc.
（５）抗肥満剤
　中枢神経性抗肥満薬（例、デクスフェンフルアミン、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など）、膵リパーゼ阻害薬（例、オルリスタットなど）、β３アゴニスト（例、ＣＬ－３１６２４３、ｓｒ－５８６１１－Ａ、ＵＬ－ＴＧ－３０７、ＡＪ－９６７７、ＡＺ４０１４０など）、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）など）、コレシストキニンアゴニスト（例、リンチトリプト、ＦＰＬ－１５８４９など）など。 (5) Anti-obesity agents Central nervous system anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampifepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, etc.), pancreatic lipase inhibition Drugs (eg, orlistat, etc.), β3 agonists (eg, CL-316243, sr-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.), peptide appetite suppressants (eg, leptin, CNTF (hair) , Etc.), cholecystokinin agonists (eg, Lynchtripto, FPL-15849, etc.).
（６）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など）、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、メチクロチアジドなど）、抗アルドステロン製剤（例、スピロノラクトン、トリアムテレンなど）、炭酸脱水酵素阻害剤（例、アセタゾラミドなど）、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、インダパミドなど）、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、フロセミドなど。 (6) Diuretics Xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclo Thiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, etacrine Acid, piretanide, bumetanide, furosemide etc.
（７）化学療法剤
　アルキル化剤（例、サイクロフォスファミド、イフォスファミドなど）、代謝拮抗剤（例、メソトレキセート、５－フルオロウラシルなど）、抗癌性抗生物質（例、マイトマイシン、アドリアマイシンなど）、植物由来抗癌剤（例、ビンクリスチン、ビンデシン、タキソールなど）、シスプラチン、カルボプラチン、エトポシドなど、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など。 (7) Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plants Derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide, etc., among others, 5-fluorouracil derivatives such as furtulon or neoflutulon.
（８）免疫療法剤
　微生物由来または細菌由来成分（例、ムラミルジペプチド誘導体、ピシバニールなど）、免疫増強活性のある多糖類（例、レンチナン、シゾフィラン、クレスチンなど）、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）など）、コロニー刺激剤（例、顆粒球コロニー刺激因子、エリスロポエチンなど）など、なかでもＩＬ－１、ＩＬ－２、ＩＬ－１２など。 (8) Immunotherapeutic agents Microorganism-derived or bacteria-derived components (eg, muramyl dipeptide derivatives, picibanil etc.), immunopotentiating polysaccharides (eg lentinan, schizophyllan, krestin etc.), cytokines obtained by genetic engineering techniques (Eg, interferon, interleukin (IL), etc.), colony stimulating agents (eg, granulocyte colony stimulating factor, erythropoietin, etc.), such as IL-1, IL-2, IL-12, among others.
（９）動物モデルや臨床使用で悪液質改善効果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（文献はいずれも上記と同様）、脂肪代謝改善剤（例、エイコサペンタエン酸など）（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、悪液質誘導因子であるＴＮＦ－α、ＬＩＦ、ＩＬ－６およびオンコスタチンＭに対する抗体など。 (9) Drugs that have been shown to improve cachexia in animal models and clinical use Progesterone derivatives (eg, megestrol acetate) [Journal of Clinical Oncology, Vol. 12, 213- 225, 1994], metoclopramide drugs, tetrahydrocannabinol drugs (the literature is the same as above), fat metabolism improvers (eg, eicosapentaenoic acid, etc.) (British Journal of Cancer (British Journal of Cancer) Cancer, 68, 314-318, 1993), growth hormone, IGF-1, antibodies to cachexia-inducing factors TNF-α, LIF, IL-6, and oncostatin M.
（１０）消炎剤
　ステロイド剤（例、デキサメサゾンなど）、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、ロフェコキシブなど）など。 (10) Anti-inflammatory agents Steroids (eg, dexamethasone, etc.), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.)
（１１）消化器系疾患治療剤
　過敏性腸症候群治療薬（セロトニン拮抗薬（例：アロセトロン、ラモセトロン等）、セロトニン作動薬（例：テガセロッド等）、水分泌促進薬（例：ルビプロストン、リナクロチド等）、カルシウム拮抗薬（例：アールベラパミル等）、末梢性オピオイド作動薬（例：アシマドリン等））；抗便秘薬（セロトニン作動薬（例：テガセロッド等）、ＣｌＣ２開口薬（例：ルビプロストン等）、ポリカルボフィルカルシウム等）；抗下痢薬（末梢性オピオイド作動薬（例：ロペミン）、ポリカルボフィルカルシウム等）；緩下剤；消化管運動促進薬（セロトニン作動薬（例：ドンペリドン、メトクロプラミド、イトプリド、モサプリド等））；胃酸分泌抑制薬（プロトンポンプ阻害薬（例：オメプラゾール、ランソプラゾール等）、ヒスタミンH2阻害薬（例：シメチジン、ラニチジン等））；制酸剤（水酸化アルミニウム、炭酸水素ナトリウム等）；粘膜保護薬（ポラプレジンク、エカベトナトリウム、レバミピド、テプレノン等）；鎮痙薬（抗コリン薬（ブチルスコポラミン等））；健胃消化薬（ゲンチアナ、センブリ、ジアスターゼ等）など。
（１２）その他
　糖化阻害剤(例、ＡＬＴ－７１１など)、神経再生促進薬(例、Ｙ－１２８、ＶＸ８５３、プロサプチド（ｐｒｏｓａｐｔｉｄｅ）など)、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、フルオキセチン（ｆｌｕｏｘｅｔｉｎｅ）、パロキセチン、ドキセピン、カルバマゼピンなどの抗うつ薬）、抗てんかん薬（例、ラモトリジン）、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、ＡＢＴ－５９４)、エンドセリン受容体拮抗薬（例、ＡＢＴ－６２７）、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、フルオキセチン（ｆｌｕｏｘｅｔｉｎｅ）、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、ＬＹ－３３３５３１)、抗不安薬（例、ベンゾジアゼピン類）、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）、抗コリン剤、α１受容体遮断薬（例、タムスロシン）、筋弛緩薬（例、バクロフェンなど）、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）、アルツハイマー病の予防・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）、抗血栓薬（例、アスピリン、シロスタゾール）、ＮＫ２受容体拮抗薬、ＨＩＶ感染症治療薬（例、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（例、サルメテロール、チオトロピウムブロミド（ｔｉｏｔｒｏｐｉｕｍ ｂｒｏｍｉｄｅ）、シロミラスト）など。 (11) Gastrointestinal disease therapeutic agent Irritable bowel syndrome therapeutic agent (serotonin antagonist (eg, alosetron, ramosetron, etc.), serotonin agonist (eg, tegaserod, etc.), water secretion promoter (eg, rubiprostone, linaclotide, etc.) , Calcium antagonists (eg, arterapamil), peripheral opioid agonists (eg, asimadoline)); anti-constipation drugs (serotonin agonists (eg, tegaserod), etc. Carbophil calcium, etc.); antidiarrheal drugs (peripheral opioid agonists (eg, lopemin), polycarbophil calcium, etc.); laxatives; gastrointestinal motility drugs (serotonin agonists (eg, domperidone, metoclopramide, itopride, mosapride) Gastric acid secretion inhibitors (proton pump inhibitors (eg, omeprazole, lansops) Razol, etc.), histamine H 2 inhibitors (eg, cimetidine, ranitidine, etc.); antacids (aluminum hydroxide, sodium bicarbonate, etc.); mucosal protective agents (polaprezinc, ecabet sodium, rebamipide, teprenone, etc.); Drugs (anticholinergic drugs (butyl scopolamine, etc.)); stomach digestive drugs (gentian, assembly, diastase, etc.)
(12) Others Glycation inhibitors (eg, ALT-711, etc.), nerve regeneration promoting drugs (eg, Y-128, VX853, prosapides, etc.), central nervous system drugs (eg, desipramine, amitriptyline, imipramine, Antidepressants such as fluoxetine, paroxetine, doxepin, carbamazepine), antiepileptic drugs (eg, lamotrigine), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, ABT-594), endothelin receptors Antagonists (eg, ABT-627), monoamine uptake inhibitors (eg, tramadol), indoleamine uptake inhibitors (eg, fluoxetine, paroxetine), narcotic analgesics (eg, morphine), GABA receptor agonists Drugs (eg, gabapentin) , GABA uptake inhibitors (e.g., tiagabine), alpha 2 receptor agonists (e.g., clonidine), local analgesics (e.g., capsaicin), protein kinase C inhibitors (e.g., LY-333531), anxiolytics (e.g. , Benzodiazepines), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg, apomorphine), anticholinergics, α 1 receptor blockers (eg, tamsulosin), muscle relaxants (eg, baclofen, etc.) , Potassium channel openers (eg, nicorandil), calcium channel blockers (eg, nifedipine), Alzheimer's disease prevention / treatment (eg, donepezil, rivastigmine, galantamine), Parkinson's disease (eg, L-dopa), Antithrombotic drugs (eg, aspirin, cilostazol), NK2 receptor antagonist, HIV feeling Lowering agents (e.g., saquinavir, zidovudine, lamivudine, nevirapine), chronic obstructive pulmonary disease therapeutic agent (e.g., salmeterol, tiotropium bromide (tiotropium bromide), cilomilast) and the like.
　本発明の化合物と併用薬物との併用に際しては、本発明の化合物と併用薬物の投与時期は限定されず、本発明の化合物と併用薬物とを、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じて決定すればよく、投与対象、投与ルート、疾患、組み合わせなどにより適宜選択することができる。 When the compound of the present invention is used in combination with the concomitant drug, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be 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.
　本発明の化合物と併用薬物の投与形態は、特に限定されず、投与時に、本発明の化合物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）本発明の化合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）本発明の化合物と併用薬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）本発明の化合物と併用薬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）本発明の化合物と併用薬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）本発明の化合物と併用薬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、本発明の化合物→併用薬物の順序での投与、あるいは逆の順序での投与）などが用いられる。以下、これらの投与形態をまとめて、本発明の併用剤と略記する。 The administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Such dosage forms include, for example,
(1) Administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) Identical of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug Co-administration by route of administration,
(3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference,
(4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention → the concomitant drug) Or administration in the reverse order). Hereinafter, these administration forms are collectively abbreviated as the combination agent of the present invention.
　本発明の併用剤は、毒性が低く、例えば、本発明の化合物または（および）前記併用薬物を公知の方法に従って、薬理学的に許容される担体と混合して医薬組成物、例えば錠剤（糖衣錠、フィルムコーティング錠を含む）、散剤、顆粒剤、カプセル剤、（ソフトカプセルを含む）、液剤、注射剤、坐剤、徐放剤などとすることができ、それらは、経口的または非経口的（例、局所、直腸、静脈など）に安全に投与することができる。 The concomitant drug of the present invention has low toxicity. For example, the compound of the present invention or (and) the concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a pharmaceutical composition such as a tablet (sugar-coated tablet). , Including film-coated tablets), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained-release agents, and the like, which can be oral or parenteral ( (Eg, topical, rectal, intravenous, etc.).
　本発明の併用剤の製造に用いられてもよい薬理学的に許容される担体としては、前記した本発明の医薬組成物に使用されるものと同様のものを使用することができる。 As the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention, the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
　本発明の併用剤における本発明の化合物と併用薬物との配合比は、投与対象、投与ルート、疾患などにより適宜選択することができる。 The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
　例えば、本発明の併用剤における本発明の化合物の含有量は、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９９．９重量％の範囲であり、好ましくは約０．１ないし５０重量％の範囲であり、さらに好ましくは約０．５ないし２０重量％程度の範囲である。 For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight, preferably about 0, based on the whole preparation. The range is about 1 to 50% by weight, and more preferably about 0.5 to 20% by weight.
　本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％の範囲であり、好ましくは約０．１ないし５０重量％の範囲であり、さらに好ましくは約０．５ないし２０重量％程度の範囲である。 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 in the range of about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is in the range of about 0.5 to 20% by weight.
　本発明の併用剤における担体など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％の範囲であり、好ましくは約１０ないし９０重量％程度の範囲である。 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 in the range of about 1 to 99.99% by weight, preferably about 10 to 90% by weight based on the whole preparation. % Range.
　本発明の化合物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。
　本発明の併用剤の投与量は、本発明の化合物の種類、年齢、体重、症状、剤形、投与方法、投与期間などにより異なるが、例えば、過敏性腸症候群の患者（成人、体重約６０kg）一人あたり、通常、本発明の化合物または併用薬物として、それぞれ、1日約０．０１～約１０００ mg/kg、好ましくは１日約０．０１～約１００mg/kg、より好ましくは１日約０．１～約１００ mg/kg、とりわけ１日約０．１～約５０mg/kgを、なかでも１日約１．５～約３０mg/kgの併用剤を、1日1回から数回に分けて経口投与する。もちろん、前記したように投与量は種々の条件で変動するので、前記投与量より少ない量で十分な場合もあり、また範囲を超えて投与する必要のある場合もある。 The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
The dose of the concomitant drug of the present invention varies depending on the type, age, weight, symptoms, dosage form, administration method, administration period, etc. of the compound of the present invention. ) About 0.01 to about 1000 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 1 day per day 0.1 to about 100 mg / kg, especially about 0.1 to about 50 mg / kg per day, especially about 1.5 to about 30 mg / kg per day, once to several times a day Divide orally. Of course, as described above, the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.
　併用薬物は、副作用が問題とならなければ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、間隔および医薬製剤の性質、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、薬物の量としては、通常、例えば経口投与で、哺乳動物１kg体重あたり約０．００１～２０００ ｍｇの範囲であり、好ましくは約０．０１～５００ｍｇの範囲であり、さらに好ましくは約０．１～１００ ｍｇ程度の範囲であり、これを通常１日１回～４回に分けて投与する。 ¡Any amount of the concomitant drug can be set as long as side effects are not 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 and nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although not limited, the amount of the drug is usually in the range of about 0.001 to 2000 mg / kg body weight of the mammal, preferably about 0.01 to 500 mg, more preferably, for example, by oral administration. The dose is in the range of about 0.1 to 100 mg, which is usually administered once to 4 times a day.
　本発明の併用剤を投与するに際しては、本発明の化合物と同時期に投与してもよいが、併用薬物の投与の後、本発明の化合物を投与してもよいし、本発明の化合物の投与後、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、剤形および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時間以内に本発明の化合物を投与する方法が挙げられる。本発明の化合物を先に投与する場合、本発明の化合物を投与した後、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。 When the concomitant drug of the present invention is administered, it may be administered at the same time as the compound of the present invention. However, after the concomitant drug is administered, the compound of the present invention may be administered. A concomitant drug may be administered after administration. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when administering a concomitant drug first, within 1 minute to 3 days after administration of the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day after administration of the compound of the present invention, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. A method is mentioned.
　以下に参考例、実施例、製剤例および実験例を挙げて、本発明を更に具体的に説明するが、これによって本発明が限定されるものではない。
　以下の参考例、実施例中の「室温」は通常約１０℃ないし約３５℃を示す。「％」は特記しない限り重量パーセントを示す。その他の本文中で用いられている略号は下記の意味を示す。ｓはシングレット（ｓｉｎｇｌｅｔ）、ｄはダブレット（ｄｏｕｂｌｅｔ）、ｔはトリプレット（ｔｒｉｐｌｅｔ）、ｑはカルテット（ｑｕａｒｔｅｔ）、ｍ はマルチプレット（ｍｕｌｔｉｐｌｅｔ）、ｂｒはブロード（ｂｒｏａｄ）、Ｊはカップリング定数（ｃｏｕｐｌｉｎｇ ｃｏｎｓｔａｎｔ）である。
下記実施例におけるＨＰＬＣおよびＭＳは以下の条件で測定した。
測定機器：ウォーターズ社　ＬＣ－ＭＳシステム
ＨＰＬＣ部：アジレント社　ＨＰ１１００
ＭＳ部：マイクロマス社　Quattro micro API
ＨＰＬＣ条件
カラム：ＣＡＰＣＥＬＬ ＰＡＫ Ｃ１８ＵＧ１２０、Ｓ－３μｍ、１．５×３５ｍｍ（資生堂）
溶媒：Ａ液；５ｍM酢酸アンモニウム含有２％アセトニトリル水、Ｂ液；５ｍM酢酸アンモニウム含有95％アセトニトリル水
グラジェントサイクル：０．００分（Ａ液/Ｂ液＝１００/0）、２．００分（Ａ液/Ｂ液＝０/１００）、３.００分（Ａ液/Ｂ液＝０/１００）、３.０１分（Ａ液/Ｂ液＝１００/０）、３.３０分（Ａ液/Ｂ液＝100/０）
注入量：２μＬ、流速：０．５ｍＬ/ｍｉｎ、検出法：ＵＶ２２０ｎｍ
ＭＳ条件　イオン化法：ＥＳＩ Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, Formulation Examples and Experimental Examples, but the present invention is not limited thereto.
“Room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. “%” Indicates weight percent unless otherwise specified. Other abbreviations used in the text have the following meanings. s is a singlet, d is a doublet, t is a triplet, q is a quartet, m is a multiplet, br is broad, and J is a coupling constant (coupling) constant).
HPLC and MS in the following examples were measured under the following conditions.
Measuring instrument: Waters LC-MS system HPLC part: Agilent HP1100
MS Department: Micromass Quattro micro API
HPLC condition column: CAPCELL PAK C18UG120, S-3 μm, 1.5 × 35 mm (Shiseido)
Solvent: Liquid A; 5 mM ammonium acetate-containing 2% acetonitrile water, liquid B; 5 mM ammonium acetate-containing 95% acetonitrile water gradient cycle: 0.00 minutes (liquid A / liquid B = 100/0), 2.00 minutes ( A liquid / B liquid = 0/100), 3.00 minutes (A liquid / B liquid = 0/100), 3.01 minutes (A liquid / B liquid = 100/0), 3.30 minutes (A liquid / B liquid = 100/0)
Injection volume: 2 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm
MS conditions Ionization method: ESI
参考例１
Figure JPOXMLDOC01-appb-C000025
 Reference example 1
Figure JPOXMLDOC01-appb-C000025
３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン　
２－オキソ－１，２－ジヒドロキノリン－３－カルバルデヒド（１．７３ｇ）とＴＨＦ（８０ｍｌ）とフェネチルアミン（１．２１ｇ）の混合物に、水素化トリアセトキシホウ素ナトリウム（４．２４ｇ）を室温で加え、１８時間攪拌した。反応液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。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物を再結晶（エタノール）して、表題化合物（１．６８ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．７６（４Ｈ，ｓ），３．６１（２Ｈ，ｓ），７．１０－７．６５（９Ｈ，ｍ），７．７７（１Ｈ，ｓ）． 3-{[(2-Phenylethyl) amino] methyl} quinolin-2 (1H) -one
To a mixture of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (1.73 g), THF (80 ml) and phenethylamine (1.21 g) was added sodium triacetoxyborohydride (4.24 g) at room temperature. The mixture was further stirred for 18 hours. A saturated aqueous sodium hydrogen carbonate solution 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, filtered and concentrated. The residue was recrystallized (ethanol) to give the title compound (1.68 g) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.76 (4H, s), 3.61 (2H, s), 7.10-7.65 (9H, m), 7.77 (1H, s ).
参考例２
Figure JPOXMLDOC01-appb-C000026
 Reference example 2
Figure JPOXMLDOC01-appb-C000026
３－（｛［２－（２－チエニル）エチル］アミノ｝メチル）キノリン－２（１Ｈ）－オン　
２－オキソ－１，２－ジヒドロキノリン－３－カルバルデヒド（３４６ｍｇ）とＴＨＦ（３０ｍｌ）と２－チオフェンエチルアミン（３０５ｍｇ）の混合物に、水素化トリアセトキシホウ素ナトリウム（８４８ｍｇ）を室温で加え、１８時間攪拌した。反応液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。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（混合比が７０対３０のヘキサンと酢酸エチルの混合溶液で溶出）で精製して、表題化合物（４７０ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．８０（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），２．９７（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．６２（２Ｈ，ｓ），６．８４－７．０２（７Ｈ，ｍ），７．８１（１Ｈ，ｓ）． 3-({[2- (2-Thienyl) ethyl] amino} methyl) quinolin-2 (1H) -one
To a mixture of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (346 mg), THF (30 ml) and 2-thiophenethylamine (305 mg) was added sodium triacetoxyborohydride (848 mg) at room temperature, Stir for hours. A saturated aqueous sodium hydrogen carbonate solution 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, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with a mixed solution of hexane and ethyl acetate having a mixing ratio of 70:30) to give the title compound (470 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.80 (2H, t, J = 7.5 Hz), 2.97 (2H, t, J = 7.5 Hz), 3.62 (2H, s) , 6.84-7.02 (7H, m), 7.81 (1H, s).
参考例３
Figure JPOXMLDOC01-appb-C000027
 Reference example 3
Figure JPOXMLDOC01-appb-C000027
３－｛［（２－ヒドロキシ－２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン
２－オキソ－１，２－ジヒドロキノリン－３－カルバルデヒド（３４６ｍｇ）と２－アミノ－１－フェニルエタノール（２８８ｍｇ）とＴＨＦ（１６ｍｌ）の混合物に水素化トリアセトキシほう素ナトリウム（８４８ｍｇ）を加え、室温で終夜攪拌した。反応液に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。抽出液を炭酸水素ナトリウム、飽和食塩水で順次洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物をエタノール－酢酸エチル（１：１）混合物で洗い、表題化合物（４３３ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．２７（１Ｈ，ｂｒｓ），２．６６（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），３．５４－３．７２（２Ｈ，ｍ），４．６８（１Ｈ，ｂｒｓ），５．２９（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．１６（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．１９－７．３９（７Ｈ，ｍ），７．４５（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６０（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），１１．７６（１Ｈ，ｂｒｓ）． 3-{[(2-Hydroxy-2-phenylethyl) amino] methyl} quinolin-2 (1H) -one 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (346 mg) and 2-amino-1 -Sodium triacetoxyborohydride (848 mg) was added to a mixture of phenylethanol (288 mg) and THF (16 ml), and the mixture was stirred at room temperature overnight. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was washed with ethanol-ethyl acetate (1: 1) mixture to give the title compound (433 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.27 (1H, brs), 2.66 (2H, d, J = 6.1 Hz), 3.54-3.72 (2H, m), 4 .68 (1H, brs), 5.29 (1H, d, J = 3.0 Hz), 7.16 (1H, t, J = 7.4 Hz), 7.19-7.39 (7H, m) 7.45 (1H, t, J = 7.8 Hz), 7.60 (1H, d, J = 8.0 Hz), 11.76 (1H, brs).
参考例４
Figure JPOXMLDOC01-appb-C000028
 Reference example 4
Figure JPOXMLDOC01-appb-C000028
３－（｛［２－（４－フルオロフェニル）エチル］アミノ｝メチル）－６－メトキシキノリン－２（１Ｈ）－オン　トリフルオロ酢酸塩
６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－カルバルデヒド（２．０３ｇ）と酢酸イソプロピル（１２０ｍｌ）と２－（４－フルオロフェニル）エタンアミン（１．４６ｇ）の混合物に、トリフルオロ酢酸（２．２８ｇ）と水素化トリアセトキシホウ素ナトリウム（２．９０ｇ）を室温で加え、７２時間攪拌した。反応液を濃縮した。残留物を酢酸エチルとヘキサンで洗浄し、ろ取し、表題化合物（３．７９ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．９０－２．９５（２Ｈ，ｍ），３．１０－３．１５（２Ｈ，ｍ），３．８０（３Ｈ，ｓ），４．０２（２Ｈ，ｓ），６．３２（１Ｈ，ｂｒｓ），７．１１－７．２３（４Ｈ，ｍ），７．２９－７．３３（３Ｈ，ｍ），７．９９（１Ｈ，ｓ），８．６７（１Ｈ，ｂｒｓ）． 3-({[2- (4-Fluorophenyl) ethyl] amino} methyl) -6-methoxyquinolin-2 (1H) -one trifluoroacetate 6-methoxy-2-oxo-1,2-dihydroquinoline- To a mixture of 3-carbaldehyde (2.03 g), isopropyl acetate (120 ml) and 2- (4-fluorophenyl) ethanamine (1.46 g), trifluoroacetic acid (2.28 g) and sodium triacetoxyborohydride ( 2.90 g) was added at room temperature and stirred for 72 hours. The reaction solution was concentrated. The residue was washed with ethyl acetate and hexane and collected by filtration to give the title compound (3.79 g) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.90-2.95 (2H, m), 3.10-3.15 (2H, m), 3.80 (3H, s), 4.02 (2H, s), 6.32 (1H, brs), 7.11-7.23 (4H, m), 7.29-7.33 (3H, m), 7.9 (1H, s), 8.67 (1H, brs).
参考例５
Figure JPOXMLDOC01-appb-C000029
 Reference Example 5
Figure JPOXMLDOC01-appb-C000029
２－アミノベンズアルデヒド
二酸化マンガン（７０．５ｇ）とトルエン（２００ｍｌ）の混合物に、（２－アミノフェニル）メタノール（２５ｇ）とアセトニトリル（２００ｍｌ）の混合溶液を０℃で加え、室温で２時間攪拌した。反応液をセライトろ過し、ろ液を濃縮した。残留物をシリカゲルカラムクロマトグラフィー（混合比が９０対１０から８０対２０のヘキサンと酢酸エチルの混合溶液で溶出）で精製し、表題化合物（１９．７ｇ）を油状物質として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：６．１１（２Ｈ，ｂｒｓ），６．６５（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），６．７１－６．７９（１Ｈ，ｍ），７．２８－７．３６（１Ｈ，ｍ），７．４８（１Ｈ，ｄｄ，Ｊ＝７．８、１．６Ｈｚ），９．８７（１Ｈ，ｓ）． To a mixture of 2-aminobenzaldehyde manganese dioxide (70.5 g) and toluene (200 ml), a mixed solution of (2-aminophenyl) methanol (25 g) and acetonitrile (200 ml) was added at 0 ° C. and stirred at room temperature for 2 hours. . The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluted with a mixed solution of hexane and ethyl acetate having a mixing ratio of 90:10 to 80:20) to give the title compound (19.7 g) as an oil.
1 H-NMR (CDCl 3 ) δ: 6.11 (2H, brs), 6.65 (1H, d, J = 8.5 Hz), 6.71-6.79 (1H, m), 7.28 -7.36 (1H, m), 7.48 (1H, dd, J = 7.8, 1.6 Hz), 9.87 (1H, s).
参考例６
Figure JPOXMLDOC01-appb-C000030
 Reference Example 6
Figure JPOXMLDOC01-appb-C000030
２－アミノ－５－ブロモベンズアルデヒド
２－アミノベンズアルデヒド（１９．７ｇ）とＮ、Ｎ’－ジメチルホルムアミド（３００ｍｌ）の混合物に、Ｎ－ブロモスクシイミド（２９ｇ）を室温で加え、１時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸マグネシウムで乾燥し、ろ過し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（混合比が９０対１０から８０対２０のヘキサンと酢酸エチルの混合溶液で溶出）で精製し、表題化合物（１６．２ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：６．１４（２Ｈ，ｂｒｓ），６．５７（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ），７．３７（１Ｈ，ｄｄ，Ｊ＝８．８，２．４Ｈｚ），７．５８（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），９．８０（１Ｈ，ｓ）． N-bromosuccinimide (29 g) was added to a mixture of 2-amino-5-bromobenzaldehyde 2-aminobenzaldehyde (19.7 g) and N, N′-dimethylformamide (300 ml) at room temperature, and the mixture was stirred for 1 hour. . 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 magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with a mixed solution of hexane and ethyl acetate having a mixing ratio of 90:10 to 80:20) to give the title compound (16.2 g) as a solid.
1 H-NMR (CDCl 3 ) δ: 6.14 (2H, brs), 6.57 (1H, d, J = 8.7 Hz), 7.37 (1H, dd, J = 8.8, 2. 4 Hz), 7.58 (1 H, d, J = 2.4 Hz), 9.80 (1 H, s).
参考例７
Figure JPOXMLDOC01-appb-C000031
 Reference Example 7
Figure JPOXMLDOC01-appb-C000031
６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－カルボン酸エチル
２－アミノ－５－ブロモベンズアルデヒド（１６．２ｇ）とテトラヒドロフラン（１２０ｍｌ）の混合物に、クロロホルミル酢酸エチル（２０．３ｇ）とテトラヒドロフラン（３０ｍｌ）の混合溶液（２００ｍｌ）を０℃で加え、２．５時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残渣（３６．１ｇ）とエタノール（２００ｍｌ）の混合物に、ナトリウムエトキシド（５．５１ｇ）を室温で加え、２０時間攪拌した。沈殿物をろ取し、乾燥し、表題化合物（２２ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２８（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．２３（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．１６（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ），７．５４（１Ｈ，ｄｄ，Ｊ＝８．９，２．５Ｈｚ），７．８７（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ），８．１８（１Ｈ，ｓ）． Ethyl 6-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylate A mixture of 2-amino-5-bromobenzaldehyde (16.2 g) and tetrahydrofuran (120 ml) was added to ethyl chloroformate (20.3 g). ) And tetrahydrofuran (30 ml) mixed solution (200 ml) was added at 0 ° C. and stirred for 2.5 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, filtered and concentrated. Sodium ethoxide (5.51 g) was added to a mixture of the residue (36.1 g) and ethanol (200 ml) at room temperature, and the mixture was stirred for 20 hours. The precipitate was collected by filtration and dried to give the title compound (22 g) as a solid.
1 H-NMR (CDCl 3 ) δ: 1.28 (3H, t, J = 7.2 Hz), 4.23 (2H, q, J = 7.2 Hz), 7.16 (1H, d, J = 8.7 Hz), 7.54 (1H, dd, J = 8.9, 2.5 Hz), 7.87 (1H, d, J = 2.3 Hz), 8.18 (1H, s).
参考例８
Figure JPOXMLDOC01-appb-C000032
 Reference Example 8
Figure JPOXMLDOC01-appb-C000032
６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－カルボン酸
６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－カルボン酸エチル（２０ｇ）とエタノール（２００ｍｌ）の混合物に、１Ｎ水酸化ナトリウム水溶液（２００ｍｌ）を室温で加え、７０℃で２時間攪拌した。反応液を氷冷し、６Ｎ塩酸水溶液（４５ｍｌ）を加えた。沈殿物をろ取し、乾燥し、表題化合物（１４ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：７．４５（１Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．９１（１Ｈ，ｄｄ，Ｊ＝８．９，２．３Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ），８．９３（１Ｈ，ｓ），１３．２４（１Ｈ，ｂｒｓ），１４．５６（１Ｈ，ｂｒｓ）． 6-Bromo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid A mixture of ethyl 6-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylate (20 g) and ethanol (200 ml) 1N Aqueous sodium hydroxide solution (200 ml) was added at room temperature, and the mixture was stirred at 70 ° C. for 2 hr. The reaction mixture was ice-cooled, and 6N aqueous hydrochloric acid solution (45 ml) was added. The precipitate was collected by filtration and dried to give the title compound (14 g) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 7.45 (1H, d, J = 8.9 Hz), 7.91 (1H, dd, J = 8.9, 2.3 Hz), 8.33 ( 1H, d, J = 2.3 Hz), 8.93 (1H, s), 13.24 (1H, brs), 14.56 (1H, brs).
参考例９
Figure JPOXMLDOC01-appb-C000033
 Reference Example 9
Figure JPOXMLDOC01-appb-C000033
６－ブロモ－３－（ヒドロキシメチル）キノリン－２（１Ｈ）－オン
６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－カルボン酸（１２ｇ）とテトラヒドロフラン（３００ｍｌ）とトリエチルアミン（１２．３ｍｌ）の混合物に、クロロ炭酸イソプロピル（１１．５ｇ）とテトラヒドロフラン（３０ｍｌ）の混合液を０℃で加え、０℃で０．５時間攪拌した。反応液に、水素化ホウ素ナトリウム（１６．８ｇ）と水（２００ｍｌ）の混合液を０℃で加え、２時間攪拌した。反応液を濃縮し、残留物に８Ｎ水酸化ナトリウム水溶液（２００ｍｌ）を室温で加え、４時間攪拌した。反応液を氷冷し、６Ｎ塩酸水溶液（３００ｍｌ）を加えた。沈殿物をろ取し、乾燥し、表題化合物（１４ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：４．４１（２Ｈ，ｄｄ，Ｊ＝５．５，１．７Ｈｚ），５．２６－５．３１（１Ｈ，ｍ），７．２５（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ），７．６０（１Ｈ，ｄｄ，Ｊ＝８．９，２．３Ｈｚ），７．８５（１Ｈ，ｓ），７．９７（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ），１１．９１（１Ｈ，ｓ）． 6-Bromo-3- (hydroxymethyl) quinolin-2 (1H) -one 6-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (12 g), tetrahydrofuran (300 ml) and triethylamine (12. 3 ml), a mixture of isopropyl chlorocarbonate (11.5 g) and tetrahydrofuran (30 ml) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 0.5 hour. A mixed solution of sodium borohydride (16.8 g) and water (200 ml) was added to the reaction solution at 0 ° C., and the mixture was stirred for 2 hours. The reaction mixture was concentrated, 8N aqueous sodium hydroxide solution (200 ml) was added to the residue at room temperature, and the mixture was stirred for 4 hr. The reaction mixture was ice-cooled, and 6N aqueous hydrochloric acid (300 ml) was added. The precipitate was collected by filtration and dried to give the title compound (14 g) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 4.41 (2H, dd, J = 5.5, 1.7 Hz), 5.26-5.31 (1H, m), 7.25 (1H, d, J = 8.7 Hz), 7.60 (1H, dd, J = 8.9, 2.3 Hz), 7.85 (1H, s), 7.97 (1H, d, J = 2.3 Hz) ), 11.91 (1H, s).
参考例１０
Figure JPOXMLDOC01-appb-C000034
 Reference Example 10
Figure JPOXMLDOC01-appb-C000034
６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－カルバルデヒド
６－ブロモ－３－（ヒドロキシメチル）キノリン－２（１Ｈ）－オン（１ｇ）とアセトニトリル（５０ｍｌ）の混合物に、二酸化マンガン（２ｇ）を加え、１９時間加熱還流した。反応液をセライトろ過し、テトラヒドロフランで洗浄し、ろ液を濃縮し、表題化合物（８４０ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：７．３０（１Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．８０（１Ｈ，ｄｄ，Ｊ＝８．９，２．３Ｈｚ），８．２０（１Ｈ，ｄ，Ｊ＝２．１Ｈｚ），８．４８（１Ｈ，ｓ），１０．２３（１Ｈ，ｓ），１２．３５（１Ｈ，ｓ）． A mixture of 6-bromo-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 6-bromo-3- (hydroxymethyl) quinolin-2 (1H) -one (1 g) and acetonitrile (50 ml) was added to carbon dioxide. Manganese (2 g) was added and heated to reflux for 19 hours. The reaction mixture was filtered through celite, washed with tetrahydrofuran, and the filtrate was concentrated to give the title compound (840 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 7.30 (1H, d, J = 8.9 Hz), 7.80 (1H, dd, J = 8.9, 2.3 Hz), 8.20 ( 1H, d, J = 2.1 Hz), 8.48 (1H, s), 10.23 (1H, s), 12.35 (1H, s).
参考例１１
Figure JPOXMLDOC01-appb-C000035
 Reference Example 11
Figure JPOXMLDOC01-appb-C000035
６－ブロモ－２－クロロキノリン－３－カルバルデヒド
ＤＭＦ（９．２ｇ）に塩化ホスホリル（３２ｍｌ）を氷冷下で加え、５分間攪拌した。４－ブロモアセトアニリド（１０．７ｇ）を加えて、７５℃で２４時間攪拌した。冷却後、水（３００ｍｌ）に注いで、０－１０℃で０．５時間攪拌した。析出した結晶を濾取し、水で洗浄し、表題化合物（３．５ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：７．９５（２Ｈ，ｓ），８．１５（１Ｈ，ｓ），８．６７（１Ｈ，ｓ），１０．５６（１Ｈ，ｓ）． Phosphoryl chloride (32 ml) was added to 6-bromo-2-chloroquinoline-3-carbaldehyde DMF (9.2 g) under ice-cooling and stirred for 5 minutes. 4-Bromoacetanilide (10.7 g) was added and stirred at 75 ° C. for 24 hours. After cooling, it was poured into water (300 ml) and stirred at 0-10 ° C. for 0.5 hour. The precipitated crystals were collected by filtration and washed with water to give the title compound (3.5 g) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 7.95 (2H, s), 8.15 (1H, s), 8.67 (1H, s), 10.56 (1H, s).
参考例１２
６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－カルバルデヒド
６－ブロモ－２－クロロキノリン－３－カルバルデヒド（３．５ｇ）と４Ｎ塩酸（６０ｍｌ）の混合物を、６時間加熱還流した。冷却後、析出した結晶を濾取し、水で洗浄し、表題化合物（２．８ｇ）を固体として得た。 Reference Example 12
A mixture of 6-bromo-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 6-bromo-2-chloroquinoline-3-carbaldehyde (3.5 g) and 4N hydrochloric acid (60 ml) was heated for 6 hours. Refluxed. After cooling, the precipitated crystals were collected by filtration and washed with water to give the title compound (2.8 g) as a solid.
参考例１３
Figure JPOXMLDOC01-appb-C000036
 Reference Example 13
Figure JPOXMLDOC01-appb-C000036
６－ブロモ－３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン　トリフルオロ酢酸塩
６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－カルバルデヒド（８００ｍｇ）と酢酸イソプロピル（４０ｍｌ）とフェネチルアミン（０．４２ｍｌ）の混合物に、トリフルオロ酢酸（０．４８ｍｌ）と水素化トリアセトキシホウ素ナトリウム（９１９ｍｇ）を室温で加え、６時間攪拌した。反応液を濃縮した。残留物を酢酸エチルとヘキサンで洗浄し、ろ取し、表題化合物（１．４３ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．８３－３．０１（２Ｈ，ｍ），３．０３－３．１９（２Ｈ，ｍ），３．９８（２Ｈ，ｓ），７．１２－７．４１（６Ｈ，ｍ），７．５８－７．７５（１Ｈ，ｍ），７．９７（２Ｈ，ｄ，Ｊ＝１３．８Ｈｚ）． 6-bromo-3-{[(2-phenylethyl) amino] methyl} quinolin-2 (1H) -one trifluoroacetate 6-bromo-2-oxo-1,2-dihydroquinoline-3-carbaldehyde ( To a mixture of 800 mg), isopropyl acetate (40 ml) and phenethylamine (0.42 ml), trifluoroacetic acid (0.48 ml) and sodium triacetoxyborohydride (919 mg) were added at room temperature and stirred for 6 hours. The reaction solution was concentrated. The residue was washed with ethyl acetate and hexane and collected by filtration to give the title compound (1.43 g) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.83-3.01 (2H, m), 3.03-3.19 (2H, m), 3.98 (2H, s), 7.12 -7.41 (6H, m), 7.58-7.75 (1H, m), 7.97 (2H, d, J = 13.8 Hz).
参考例１４
Figure JPOXMLDOC01-appb-C000037
 Reference Example 14
Figure JPOXMLDOC01-appb-C000037
ジメチル　［（２－ニトロフェニル）メチリデン］プロパンジオアート
２－ニトロベンズアルデヒド（２５ｇ）のメタノール（７５ｍｌ）溶液に、マロン酸ジメチル（２１．９ｇ）と酢酸（０．３ｍｌ）とピペリジン（３ｍｌ）を順次加え、２４時間加熱還流した。反応液を濃縮後、酢酸エチルを加え、水、１Ｎ塩酸、水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（混合比が７５対２５から５０対５０のヘキサンと酢酸エチルの混合溶液で溶出）で精製し、再結晶（ジイソプロピルエーテルとヘキサンの混合溶液）して、表題化合物（２７．１ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：３．６１（３Ｈ，ｓ），３．８９（３Ｈ，ｓ），７．４２（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．５２－７．６９（２Ｈ，ｍ），８．１８－８．２５（２Ｈ，ｍ）． Dimethyl [(2-nitrophenyl) methylidene] propanedioate 2-nitrobenzaldehyde (25 g) in methanol (75 ml), dimethyl malonate (21.9 g), acetic acid (0.3 ml) and piperidine (3 ml) sequentially In addition, the mixture was heated to reflux for 24 hours. The reaction mixture was concentrated, ethyl acetate was added, the mixture was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with a mixed solution of hexane and ethyl acetate having a mixing ratio of 75:25 to 50:50) and recrystallized (mixed solution of diisopropyl ether and hexane) to give the title compound ( 27.1 g) was obtained as a solid.
1 H-NMR (CDCl 3 ) δ: 3.61 (3H, s), 3.89 (3H, s), 7.42 (1H, d, J = 7.6 Hz), 7.52-7.69 (2H, m), 8.18-8.25 (2H, m).
参考例１５
Figure JPOXMLDOC01-appb-C000038
 Reference Example 15
Figure JPOXMLDOC01-appb-C000038
２－オキソ－１，２，３，４－テトラヒドロキノリン－３－カルボン酸メチル
ジメチル
［（２－ニトロフェニル）メチリデン］プロパンジオアート（１５．２ｇ）の酢酸エチル（５０ｍｌ）－メタノール（７５ｍｌ）溶液に、水素化ほう素ナトリウム（１．１０ｇ）を氷冷下で加え、同温で２０分間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を水、飽和食塩水で順次洗い、無水硫酸マグネシウムで乾燥し、ろ過し、濃縮した。残留物にＴＨＦ－メタノール（１：１，２００ｍｌ）と５％パラジウム炭素（３ｇ）を加え、１気圧の水素雰囲気下で終夜攪拌した。パラジウム炭素を濾去して得られた溶液に酢酸（０．５ｍｌ）を加え、６０℃で２時間攪拌し、濃縮した。残留物に酢酸エチルを加え、飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物を再結晶（酢酸エチルとヘキサンの混合溶液）して、表題化合物（９．０２ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：３．０７－３．２０（１Ｈ，ｍ），３．３２－３．４８（１Ｈ，ｍ），３．６５（１Ｈ，ｄｄ，Ｊ＝９．１，６．４Ｈｚ），３．７６（３Ｈ，ｓ），６．８１（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．０１（１Ｈ，ｔ，Ｊ＝７．６Ｈｚ），７．１３－７．２４（２Ｈ，ｍ），８．４６（１Ｈ，ｂｒｓ）． 2-Oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate methyldimethyl [(2-nitrophenyl) methylidene] propanedioate (15.2 g) in ethyl acetate (50 ml) -methanol (75 ml) To the mixture, sodium borohydride (1.10 g) was added under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. To the residue were added THF-methanol (1: 1, 200 ml) and 5% palladium carbon (3 g), and the mixture was stirred overnight under a hydrogen atmosphere of 1 atm. Acetic acid (0.5 ml) was added to the solution obtained by removing palladium on carbon, and the mixture was stirred at 60 ° C. for 2 hours and concentrated. Ethyl acetate was added to the residue, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was recrystallized (mixed solution of ethyl acetate and hexane) to give the title compound (9.02 g) as a solid.
1 H-NMR (CDCl 3 ) δ: 3.07-3.20 (1H, m), 3.32-3.48 (1H, m), 3.65 (1H, dd, J = 9.1, 6.4 Hz), 3.76 (3 H, s), 6.81 (1 H, d, J = 7.6 Hz), 7.01 (1 H, t, J = 7.6 Hz), 7.13-7. 24 (2H, m), 8.46 (1 H, brs).
参考例１６
Figure JPOXMLDOC01-appb-C000039
 Reference Example 16
Figure JPOXMLDOC01-appb-C000039
３－（｛［２－（４－フルオロフェニル）エチル］アミノ｝メチル）－２－オキソ－１，２，３，４－テトラヒドロキノリン－３－カルボン酸メチル
２－（４－フルオロフェニル）エタンアミン（１．３９ｇ）のエタノール（４ｍｌ）溶液に、３７％ホルマリン水溶液（０．８２ｇ）を加えて室温で３０分間攪拌した。反応液にエタノール（１２ｍｌ）と２－オキソ－１，２，３，４－テトラヒドロキノリン－３－カルボン酸メチル（１．０３ｇ）を加えて６０℃で３日間攪拌した。反応液に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。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（混合比が７０対３０から３０対７０のヘキサンと酢酸エチルの混合溶液で溶出）で精製して、表題化合物（１．６５ｇ）をアモルファスとして得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：２．５７－２．９１（４Ｈ，ｍ），３．０７（２Ｈ，ｓ），３．２５（２Ｈ，ｓ），３．６０（３Ｈ，ｓ），６．７３（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），６．９０－７．０３（４Ｈ，ｍ），７．０７－７．２１（４Ｈ，ｍ），７．９７（１Ｈ，ｓ）． 3-({[2- (4-Fluorophenyl) ethyl] amino} methyl) -2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate methyl 2- (4-fluorophenyl) ethanamine ( To a solution of 1.39 g) in ethanol (4 ml), 37% formalin aqueous solution (0.82 g) was added and stirred at room temperature for 30 minutes. Ethanol (12 ml) and methyl 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (1.03 g) were added to the reaction mixture, and the mixture was stirred at 60 ° C. for 3 days. An aqueous sodium hydrogen carbonate solution 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, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with a mixed solution of hexane and ethyl acetate having a mixing ratio of 70:30 to 30:70) to give the title compound (1.65 g) as amorphous.
1 H-NMR (CDCl 3 ) δ: 2.57-2.91 (4H, m), 3.07 (2H, s), 3.25 (2H, s), 3.60 (3H, s), 6.73 (1H, d, J = 8.0 Hz), 6.90-7.03 (4H, m), 7.07-7.21 (4H, m), 7.97 (1H, s).
参考例１７
Figure JPOXMLDOC01-appb-C000040
 Reference Example 17
Figure JPOXMLDOC01-appb-C000040
３－（｛［２－（４－フルオロフェニル）エチル］アミノ｝メチル）－３，４－ジヒドロキノリン－２（１Ｈ）－オン
３－（｛［２－（４－フルオロフェニル）エチル］アミノ｝メチル）－２－オキソ－１，２，３，４－テトラヒドロキノリン－３－カルボン酸メチル（１．６５ｇ）のＴＨＦ－メタノール（１：１，２０ｍｌ）溶液に、１Ｎ水酸化ナトリウム水溶液（９．２ｍｌ）を加え、室温で２時間攪拌した。反応液に１Ｎ塩酸（２０ｍｌ）を加え、６０℃で１時間攪拌した。約半量まで濃縮し、飽和炭酸水素ナトリウムを加えて中和し、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー（混合比が８０対２０から０対１００のヘキサンと酢酸エチルの混合溶液で溶出）で精製して、表題化合物（８６２ｍｇ）をアモルファスとして得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２２－１．３９（１Ｈ，ｍ），２．６１－３．０９（９Ｈ，ｍ），６．７１（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），６．９０－７．０５（３Ｈ，ｍ），７．０８－７．２２（４Ｈ，ｍ），７．７５（１Ｈ，ｂｒｓ）． 3-({[2- (4-Fluorophenyl) ethyl] amino} methyl) -3,4-dihydroquinolin-2 (1H) -one 3-({[2- (4-fluorophenyl) ethyl] amino} To a solution of methyl) -2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (1.65 g) in THF-methanol (1: 1, 20 ml), 1N aqueous sodium hydroxide solution (9. 2 ml) was added and stirred at room temperature for 2 hours. 1N Hydrochloric acid (20 ml) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 1 hr. The mixture was concentrated to about half, neutralized with saturated sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (eluted with a mixed solution of hexane and ethyl acetate having a mixing ratio of 80:20 to 0: 100) to give the title compound (862 mg) as amorphous.
1 H-NMR (CDCl 3 ) δ: 1.22-1.39 (1H, m), 2.61-3.09 (9H, m), 6.71 (1H, d, J = 7.6 Hz) 6.90-7.05 (3H, m), 7.08-7.22 (4H, m), 7.75 (1H, brs).
参考例１８
Figure JPOXMLDOC01-appb-C000041
 Reference Example 18
Figure JPOXMLDOC01-appb-C000041
（２－ニトロフェノキシ）マロン酸ジエチル
２－ニトロフェノール（６．９６ｇ）と水素化ナトリウム（６０％油性、２．０ｇ）とブロモマロン酸ジエチル（１１．９５ｇ）とＤＭＦ（１００ｍｌ）溶液の混合物を室温で４８時間攪拌した。反応液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。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（混合比が８５対１５から８０対２０のヘキサンと酢酸エチルの混合溶液で溶出）で精製して、表題化合物（１０．９７ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２９（６Ｈ，ｄ，Ｊ＝７．２Ｈｚ），４．２５－４．４０（４Ｈ，ｍ），５．２４（１Ｈ，ｓ），７．０５－７．２５（２Ｈ，ｍ），７．５０－７．６０（２Ｈ，ｍ）． (2-Nitrophenoxy) diethyl malonate 2-nitrophenol (6.96 g), sodium hydride (60% oily, 2.0 g), diethyl bromomalonate (11.95 g), and a solution of DMF (100 ml) at room temperature For 48 hours. A saturated aqueous sodium hydrogen carbonate solution 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, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with a mixed solution of hexane and ethyl acetate having a mixing ratio of 85:15 to 80:20) to give the title compound (10.97 g) as a solid.
1 H-NMR (CDCl 3 ) δ: 1.29 (6H, d, J = 7.2 Hz), 4.25-4.40 (4H, m), 5.24 (1H, s), 7.05 -7.25 (2H, m), 7.50-7.60 (2H, m).
参考例１９
Figure JPOXMLDOC01-appb-C000042
 Reference Example 19
Figure JPOXMLDOC01-appb-C000042
３－オキソ－３，４－ジヒドロ－２Ｈ－１，４－ベンゾオキサジン－２－カルボン酸エチル
（２－ニトロフェノキシ）マロン酸ジエチル（２９７ｍｇ）と１０％パラジウム炭素（１００ｍｇ）とメタノール（５ｍｌ）溶液の混合物を水素気流下、室温で２４時間攪拌した。パラジウム炭素を濾去して得られた溶液を濃縮した。残留物を再結晶（エーテルとヘキサンの混合溶液）して、表題化合物（１６２ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２７（３Ｈ，ｔ，Ｊ＝６．９Ｈｚ），４．１５－４．４０（２Ｈ，ｍ），５．２１（１Ｈ，ｓ），６．８０－７．１５（４Ｈ，ｍ），８．５０（１Ｈ，ｂｒｓ）．
参考例２０ 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate ethyl (2-nitrophenoxy) diethyl malonate (297 mg), 10% palladium on carbon (100 mg) and methanol (5 ml) solution The mixture was stirred at room temperature for 24 hours under a hydrogen stream. The solution obtained by filtering off palladium on carbon was concentrated. The residue was recrystallized (mixed solution of ether and hexane) to give the title compound (162 mg) as a solid.
1 H-NMR (CDCl 3 ) δ: 1.27 (3H, t, J = 6.9 Hz), 4.15-4.40 (2H, m), 5.21 (1H, s), 6.80 -7.15 (4H, m), 8.50 (1H, brs).
Reference Example 20
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
２－（｛［２－（４－フルオロフェニル）エチル］アミノ｝メチル）－３－オキソ－３，４－ジヒドロ－２Ｈ－１，４－ベンゾオキサジン－２－カルボン酸エチル
２－（４－フルオロフェニル）エタンアミン（４１８ｍｇ）のエタノール（３ｍｌ）溶液に、３７％ホルマリン水溶液（０．２４ｍｌ）を加えて室温で３０分間攪拌した。反応液に３－オキソ－３，４－ジヒドロ－２Ｈ－１，４－ベンゾオキサジン－２－カルボン酸エチル（２２１ｍｇ）を加えて６０℃で１８時間攪拌した。反応液に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。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（混合比が７０対３０のヘキサンと酢酸エチルの混合溶液で溶出）で精製して、表題化合物（１６８ｍｇ）を油状物質として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．１５（３Ｈ，ｔ，Ｊ＝６．９Ｈｚ），２．７０－２．８０（２Ｈ，ｍ），２．８５－３．００（２Ｈ，ｍ），３．４４（１Ｈ，ｄ，Ｊ＝１２．６Ｈｚ），４．００－４．２５（２Ｈ，ｍ），６．７０－７．２０（８Ｈ，ｍ），７．２５（１Ｈ，ｓ），８．２８（１Ｈ，ｂｒｓ）． 2-({[2- (4-Fluorophenyl) ethyl] amino} methyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate 2- (4-fluoro To a solution of phenyl) ethanamine (418 mg) in ethanol (3 ml) was added 37% formalin aqueous solution (0.24 ml), and the mixture was stirred at room temperature for 30 minutes. Ethyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (221 mg) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 18 hours. An aqueous sodium hydrogen carbonate solution 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, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with a mixed solution of hexane and ethyl acetate having a mixing ratio of 70:30) to give the title compound (168 mg) as an oily substance.
1 H-NMR (CDCl 3 ) δ: 1.15 (3H, t, J = 6.9 Hz), 2.70-2.80 (2H, m), 2.85-3.00 (2H, m) , 3.44 (1H, d, J = 12.6 Hz), 4.00-4.25 (2H, m), 6.70-7.20 (8H, m), 7.25 (1H, s) , 8.28 (1H, brs).
参考例２１
Figure JPOXMLDOC01-appb-C000044
 Reference Example 21
Figure JPOXMLDOC01-appb-C000044
２－（｛［２－（４－フルオロフェニル）エチル］アミノ｝メチル）－３－オキソ－３，４－ジヒドロ－２Ｈ－１，４－ベンゾオキサジン－２－カルボン酸
２－（｛［２－（４－フルオロフェニル）エチル］アミノ｝メチル）－３－オキソ－３，４－ジヒドロ－２Ｈ－１，４－ベンゾオキサジン－２－カルボン酸エチル（１６８ｍｇ）のＴＨＦ－メタノール（１：１，２ｍｌ）溶液に、１Ｎ水酸化ナトリウム水溶液（１ｍｌ）を加え、室温で４時間攪拌した。反応液に１Ｎ塩酸（２ｍｌ）を加え、６０℃で１時間攪拌した。飽和炭酸水素ナトリウムを加えて中和し、酢酸エチルとメタノールで抽出した。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮して、表題化合物（４６ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．７０（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．８１（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．００－３．４０（２Ｈ，ｍ），６．６５－７．８０（８Ｈ，ｍ），１０．１２（１Ｈ，ｂｒｓ）． 2-({[2- (4-Fluorophenyl) ethyl] amino} methyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid 2-({[2- (4-Fluorophenyl) ethyl] amino} methyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (168 mg) in THF-methanol (1: 1, 2 ml ) 1N aqueous sodium hydroxide solution (1 ml) was added to the solution and stirred at room temperature for 4 hours. 1N Hydrochloric acid (2 ml) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 1 hr. Saturated sodium hydrogen carbonate was added for neutralization, and the mixture was extracted with ethyl acetate and methanol. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (46 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.70 (2H, t, J = 7.2 Hz), 2.81 (2H, t, J = 7.2 Hz), 3.00-3.40 ( 2H, m), 6.65-7.80 (8H, m), 10.12 (1H, brs).
実施例１
Figure JPOXMLDOC01-appb-C000045
 Example 1
Figure JPOXMLDOC01-appb-C000045
１－［（２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－３－フェニル－１－（２－フェニルエチル）尿素
３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン（１３９ｍｇ）とテトラヒドロフラン（２ｍｌ）とトリエチルアミン（０．１４ｍｌ）の混合物に、フェニルイソシアネート（０．０５４ｍｌ）を室温で加え、１０分間攪拌した。析出した結晶を濾取し、ジエチルエーテルで洗浄し、表題化合物（１７７ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．８０－２．９５（２Ｈ，ｍ），３．５０－３．７０（２Ｈ、ｍ），４．３９（２Ｈ，ｓ），６．９０－７．７５（１４Ｈ，ｍ），７．９１（１Ｈ，ｓ），９．５４（１Ｈ，ｓ）． 1-[(2-oxo-1,2-dihydroquinolin-3-yl) methyl] -3-phenyl-1- (2-phenylethyl) urea 3-{[(2-phenylethyl) amino] methyl} quinoline Phenyl isocyanate (0.054 ml) was added to a mixture of -2 (1H) -one (139 mg), tetrahydrofuran (2 ml) and triethylamine (0.14 ml) at room temperature and stirred for 10 minutes. The precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound (177 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.80-2.95 (2H, m), 3.50-3.70 (2H, m), 4.39 (2H, s), 6.90 -7.75 (14H, m), 7.91 (1H, s), 9.54 (1H, s).
実施例２
Figure JPOXMLDOC01-appb-C000046
 Example 2
Figure JPOXMLDOC01-appb-C000046
Ｎ－［（２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－Ｎ－（２－フェニルエチル）－Ｎ’－ピリジン－３－イル尿素
３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン（１３９ｍｇ）とテトラヒドロフラン（２ｍｌ）とトリエチルアミン（０．１４ｍｌ）の混合物に、ピリジン－３－イソシアン酸（６０ｍｇ）を室温で加え、３０分間攪拌した。析出した結晶を濾取し、ジエチルエーテルで洗浄し、表題化合物（１４９ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．３０－２．４５（２Ｈ，ｍ），３．５０－３．６５（２Ｈ、ｍ），４．３７（２Ｈ，ｓ），６．８０－７．７５（１３Ｈ，ｍ），７．８６（１Ｈ，ｓ），９．２３（１Ｈ，ｓ）． N-[(2-oxo-1,2-dihydroquinolin-3-yl) methyl] -N- (2-phenylethyl) -N′-pyridin-3-ylurea 3-{[(2-phenylethyl) Pyridine-3-isocyanic acid (60 mg) was added to a mixture of amino] methyl} quinolin-2 (1H) -one (139 mg), tetrahydrofuran (2 ml) and triethylamine (0.14 ml) at room temperature and stirred for 30 minutes. The precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound (149 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.30-2.45 (2H, m), 3.50-3.65 (2H, m), 4.37 (2H, s), 6.80 -7.75 (13H, m), 7.86 (1H, s), 9.23 (1H, s).
実施例３
Figure JPOXMLDOC01-appb-C000047
 Example 3
Figure JPOXMLDOC01-appb-C000047
Ｎ－［（２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－Ｎ’－フェニル－Ｎ－［２－（２－チエニル）エチル］尿素
３－（｛［２－（２－チエニル）エチル］アミノ｝メチル）キノリン－２（１Ｈ）－オン（１４０ｍｇ）とテトラヒドロフラン（２ｍｌ）とトリエチルアミン（０．１４ｍｌ）の混合物に、フェニルイソシアネート（０．０６２ｍｌ）を室温で加え、３０分間攪拌した。析出した結晶を濾取し、ジエチルエーテルで洗浄し、表題化合物（１６４ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：３．０９（２Ｈ，ｔ，Ｊ＝６．６Ｈｚ），３．５８（２Ｈ，ｔ，Ｊ＝６．６Ｈｚ），４．４１（２Ｈ，ｓ），６．８５－７．８０（１２Ｈ，ｍ），７．９２（１Ｈ，ｓ），９．５７（１Ｈ，ｓ）． N-[(2-oxo-1,2-dihydroquinolin-3-yl) methyl] -N′-phenyl-N- [2- (2-thienyl) ethyl] urea 3-({[2- (2- To a mixture of thienyl) ethyl] amino} methyl) quinolin-2 (1H) -one (140 mg), tetrahydrofuran (2 ml) and triethylamine (0.14 ml), phenyl isocyanate (0.062 ml) was added at room temperature and stirred for 30 minutes. did. The precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound (164 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 3.09 (2H, t, J = 6.6 Hz), 3.58 (2H, t, J = 6.6 Hz), 4.41 (2H, s) 6.85-7.80 (12H, m), 7.92 (1H, s), 9.57 (1H, s).
実施例４
Figure JPOXMLDOC01-appb-C000048
 Example 4
Figure JPOXMLDOC01-appb-C000048
３－（４－フルオロフェニル）－１－（２－ヒドロキシ－２－フェニルエチル）－１－［（２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］尿素
３－｛［（２－ヒドロキシ－２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン（２０３ｍｇ）とトリエチルアミン（０．１９ｍｌ）とＴＨＦ（４０ｍｌ）の混合物にイソシアン酸４－フルオロフェニル（８０μｌ）を－７８℃で加え、徐々に室温まで昇温後、室温で終夜攪拌した。不溶物を濾去して得られた溶液を約５ｍｌまで濃縮し攪拌した。析出した結晶を濾取し、ＴＨＦ、ＴＨＦ－ジエチルエーテル（１：１）、ジエチルエーテルで洗浄し、表題化合物（１４４ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：３．５０（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），４．３２－４．５１（２Ｈ，ｍ），４．８９－５．０３（１Ｈ，ｍ），５．９０（１Ｈ，ｂｒｓ），６．９７－７．５６（１２Ｈ，ｍ），７．６８（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ），７．７８（１Ｈ，ｓ），９．４５（１Ｈ，ｂｒｓ），１２．０５（１Ｈ，ｂｒｓ）． 3- (4-Fluorophenyl) -1- (2-hydroxy-2-phenylethyl) -1-[(2-oxo-1,2-dihydroquinolin-3-yl) methyl] urea 3-{[(2 -Hydroxy-2-phenylethyl) amino] methyl} quinolin-2 (1H) -one (203 mg), triethylamine (0.19 ml) and THF (40 ml) in a mixture of 4-fluorophenyl isocyanate (80 μl) at −78 The mixture was added at ° C, gradually warmed to room temperature, and stirred at room temperature overnight. The insoluble material was removed by filtration, and the resulting solution was concentrated to about 5 ml and stirred. The precipitated crystals were collected by filtration and washed with THF, THF-diethyl ether (1: 1), and diethyl ether to obtain the title compound (144 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 3.50 (2H, d, J = 5.7 Hz), 4.32-4.51 (2H, m), 4.89-5.03 (1H, m), 5.90 (1H, brs), 6.97-7.56 (12H, m), 7.68 (1H, d, J = 7.2 Hz), 7.78 (1H, s), 9 .45 (1H, brs), 12.05 (1H, brs).
実施例５
Figure JPOXMLDOC01-appb-C000049
 Example 5
Figure JPOXMLDOC01-appb-C000049
３－（４－シアノフェニル）－１－［２－（４－フルオロフェニル）エチル］－１－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］尿素
６－メトキシ－３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン　トリフルオロ酢酸塩（０．８８ｇ）とテトラヒドロフラン（３０ｍｌ）とトリエチルアミン（０．６０ｇ）の混合物に、４－シアノフェニルイソシアネート（０．３２ｇ）を室温で加え、１２０時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物を再結晶（ヘキサン－酢酸エチル）して、表題化合物（０．７０ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＤＯ－ｄ６）δ：２．８７（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．５３（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．８０（３Ｈ，ｓ），４．３９（２Ｈ，ｓ），７．０２（２Ｈ，ｔ，Ｊ＝８．７Ｈｚ），７．１７－７．３２（５Ｈ，ｍ），７．６３－７．７２（４Ｈ，ｍ），７．９１（１Ｈ，ｓ），１０．３８（１Ｈ，ｂｒｓ），１２．１７（１Ｈ，ｂｒｓ）． 3- (4-Cyanophenyl) -1- [2- (4-fluorophenyl) ethyl] -1-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl) methyl] urea 6 To a mixture of -methoxy-3-{[(2-phenylethyl) amino] methyl} quinolin-2 (1H) -one trifluoroacetate (0.88 g), tetrahydrofuran (30 ml) and triethylamine (0.60 g), 4-Cyanophenyl isocyanate (0.32 g) was added at room temperature and stirred for 120 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, filtered and concentrated. The residue was recrystallized (hexane-ethyl acetate) to give the title compound (0.70 g) as a solid.
1 H-NMR (DMDO-d 6 ) δ: 2.87 (2H, t, J = 7.2 Hz), 3.53 (2H, t, J = 7.2 Hz), 3.80 (3H, s) 4.39 (2H, s), 7.02 (2H, t, J = 8.7 Hz), 7.17-7.32 (5H, m), 7.63-7.72 (4H, m) , 7.91 (1H, s), 10.38 (1H, brs), 12.17 (1H, brs).
実施例６
Figure JPOXMLDOC01-appb-C000050
 Example 6
Figure JPOXMLDOC01-appb-C000050
Ｎ－［２－（４－フルオロフェニル）エチル］－Ｎ’－（６－フルオロピリジン－３－イル）－Ｎ－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］尿素
５－アミノ－２－フルオロピリジン（０．１１ｇ）とトリエチルアミン（０．４０ｇ）とＴＨＦ（５ｍｌ）の混合物に、Ｎ，Ｎ’－カルボニルジイミダゾールを氷冷下で加え、室温で５時間攪拌した。６－メトキシ－３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン　トリフルオロ酢酸塩（０．４４ｇ）とテトラヒドロフラン（１５ｍｌ）とトリエチルアミン（０．３０ｇ）の混合物を室温で加え、１８時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物を再結晶（酢酸エチル）して、表題化合物（０．２７ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＤＯ－ｄ６）δ：　２．８８（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．５５（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．７９（３Ｈ，ｓ），４．３９（２Ｈ，ｓ），７．０３－７．３０（８Ｈ，ｍ），８．０１－８．０６（１Ｈ，ｍ），８．２５（１Ｈ，ｓ），９．７３（１Ｈ，　ｂｒｓ），１２．０７（１Ｈ，ｂｒｓ）． N- [2- (4-Fluorophenyl) ethyl] -N ′-(6-fluoropyridin-3-yl) -N-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl ) Methyl] urea To a mixture of 5-amino-2-fluoropyridine (0.11 g), triethylamine (0.40 g) and THF (5 ml), N, N′-carbonyldiimidazole was added under ice-cooling and at room temperature. Stir for 5 hours. 6-Methoxy-3-{[(2-phenylethyl) amino] methyl} quinolin-2 (1H) -one A mixture of trifluoroacetate (0.44 g), tetrahydrofuran (15 ml) and triethylamine (0.30 g) Added at room temperature and stirred for 18 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, filtered and concentrated. The residue was recrystallized (ethyl acetate) to give the title compound (0.27 g) as a solid.
1 H-NMR (DMDO-d 6 ) δ: 2.88 (2H, t, J = 7.2 Hz), 3.55 (2H, t, J = 7.2 Hz), 3.79 (3H, s) , 4.39 (2H, s), 7.03-7.30 (8H, m), 8.01-8.06 (1H, m), 8.25 (1H, s), 9.73 (1H , Brs), 12.07 (1H, brs).
実施例７
Figure JPOXMLDOC01-appb-C000051
 Example 7
Figure JPOXMLDOC01-appb-C000051
１－［２－（４－フルオロフェニル）エチル］－１－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－３－（６－メトキシピリジン－３－イル）尿素
５－アミノ－２－メトキシピリジン（０．１２ｇ）とトリエチルアミン（０．４０ｇ）とＴＨＦ（５ｍｌ）の混合物に、Ｎ，Ｎ’－カルボニルジイミダゾールを氷冷下で加え、室温で５時間攪拌した。６－メトキシ－３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン　トリフルオロ酢酸塩（０．４４ｇ）とテトラヒドロフラン（１５ｍｌ）とトリエチルアミン（０．３０ｇ）の混合物を室温で加え、１８時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物を再結晶（ヘキサン－酢酸エチル）して、表題化合物（０．３２ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＤＯ－ｄ６）　δ：２．８７（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．５４（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．７９（３Ｈ，ｓ），３．８０（３Ｈ，ｓ），４．３７（２Ｈ，ｓ），６．７５（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．０６－７．３０（７Ｈ，ｍ），７．７５－７．８０（２Ｈ，ｍ），８．１７（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），９．３３（１Ｈ，ｂｒｓ），１２．０８（１Ｈ，ｂｒｓ）． 1- [2- (4-Fluorophenyl) ethyl] -1-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl) methyl] -3- (6-methoxypyridine-3- Yl) N, N′-carbonyldiimidazole was added to a mixture of urea 5-amino-2-methoxypyridine (0.12 g), triethylamine (0.40 g), and THF (5 ml) under ice-cooling. Stir for hours. 6-Methoxy-3-{[(2-phenylethyl) amino] methyl} quinolin-2 (1H) -one A mixture of trifluoroacetate (0.44 g), tetrahydrofuran (15 ml) and triethylamine (0.30 g) Added at room temperature and stirred for 18 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, filtered and concentrated. The residue was recrystallized (hexane-ethyl acetate) to give the title compound (0.32 g) as a solid.
1 H-NMR (DMDO-d 6 ) δ: 2.87 (2H, t, J = 7.2 Hz), 3.54 (2H, t, J = 7.2 Hz), 3.79 (3H, s) , 3.80 (3H, s), 4.37 (2H, s), 6.75 (1H, d, J = 9.0 Hz), 7.06-7.30 (7H, m), 7.75 -7.80 (2H, m), 8.17 (1H, d, J = 2.7 Hz), 9.33 (1H, brs), 12.08 (1H, brs).
実施例８
Figure JPOXMLDOC01-appb-C000052
 Example 8
Figure JPOXMLDOC01-appb-C000052
Ｎ－［５－（｛［２－（４－フルオロフェニル）エチル］［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］カルバモイル｝アミノ）ピリジン－２－イル］アセトアミド
２－アセトアミド－５－アミノピリジン（０．１５ｇ）とトリエチルアミン（０．４０ｇ）とＴＨＦ（５ｍｌ）の混合物に、Ｎ，Ｎ’－カルボニルジイミダゾールを氷冷下で加え、室温で５時間攪拌した。６－メトキシ－３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン　トリフルオロ酢酸塩（０．４４ｇ）とテトラヒドロフラン（１５ｍｌ）とトリエチルアミン（０．３０ｇ）の混合物を室温で加え、１８時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物を再結晶（ヘキサン－酢酸エチル）し、シリカゲルカラムクロマトグラフィー（混合比が８０対２０から５０対５０の酢酸エチルとメタノールの混合溶液で溶出）で精製し、再結晶（酢酸エチル）して、表題化合物（０．０３ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＤＯ－ｄ６）δ：２．０５（３Ｈ，ｓ），２．８７（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．５４（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．７９（３Ｈ，ｓ），４．３８（２Ｈ，ｓ），７．０３－７．３０（８Ｈ，ｍ），７．７８－７．８２（２Ｈ，ｍ），８．３９（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），９．５８（１Ｈ，ｂｒｓ），１０．３５（１Ｈ，ｂｒｓ），１２．０７（１Ｈ，ｂｒｓ）． N- [5-({[2- (4-Fluorophenyl) ethyl] [(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl) methyl] carbamoyl} amino) pyridin-2-yl N, N′-carbonyldiimidazole was added to a mixture of acetamide 2-acetamido-5-aminopyridine (0.15 g), triethylamine (0.40 g) and THF (5 ml) under ice-cooling, and at room temperature for 5 hours. Stir. 6-Methoxy-3-{[(2-phenylethyl) amino] methyl} quinolin-2 (1H) -one A mixture of trifluoroacetate (0.44 g), tetrahydrofuran (15 ml) and triethylamine (0.30 g) Added at room temperature and stirred for 18 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, filtered and concentrated. The residue was recrystallized (hexane-ethyl acetate), purified by silica gel column chromatography (eluting with a mixed solution of ethyl acetate and methanol having a mixing ratio of 80:20 to 50:50), and recrystallized (ethyl acetate). To give the title compound (0.03 g) as a solid.
1 H-NMR (DMDO-d 6 ) δ: 2.05 (3H, s), 2.87 (2H, t, J = 7.2 Hz), 3.54 (2H, t, J = 7.2 Hz) , 3.79 (3H, s), 4.38 (2H, s), 7.03-7.30 (8H, m), 7.78-7.82 (2H, m), 8.39 (1H) , D, J = 2.7 Hz), 9.58 (1H, brs), 10.35 (1H, brs), 12.07 (1H, brs).
実施例９
Figure JPOXMLDOC01-appb-C000053
 Example 9
Figure JPOXMLDOC01-appb-C000053
１－［２－（４－フルオロフェニル）エチル］－１－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－３－（１－メチル－１Ｈ－ピラゾール－４－イル）尿素
１－メチル－１Ｈ－ピラゾール－４－イルアミン（０．１０ｇ）とトリエチルアミン（０．４０ｇ）とＴＨＦ（５ｍｌ）の混合物に、Ｎ，Ｎ’－カルボニルジイミダゾールを氷冷下で加え、室温で２４時間攪拌した。６－メトキシ－３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン　トリフルオロ酢酸塩（０．４４ｇ）とテトラヒドロフラン（１５ｍｌ）とトリエチルアミン（０．３０ｇ）の混合物を室温で加え、１８時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物を再結晶（酢酸エチル）して、表題化合物（０．２１ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＤＯ－ｄ６）δ：２．８５（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．５３（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．７５（３Ｈ，ｓ），３．７６（３Ｈ，ｓ），４．３１（２Ｈ，ｓ），７．０５－７．１４（３Ｈ，ｍ），７．２４－７．３２（５Ｈ，ｍ），７．６３（１Ｈ，ｓ），７．７０（１Ｈ，ｓ），８．９０（１Ｈ，ｂｒｓ），１１．９１（１Ｈ，ｂｒｓ）． 1- [2- (4-Fluorophenyl) ethyl] -1-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl) methyl] -3- (1-methyl-1H-pyrazole -4-yl) urea To a mixture of 1-methyl-1H-pyrazol-4-ylamine (0.10 g), triethylamine (0.40 g) and THF (5 ml), N, N′-carbonyldiimidazole was cooled with ice. And stirred at room temperature for 24 hours. 6-Methoxy-3-{[(2-phenylethyl) amino] methyl} quinolin-2 (1H) -one A mixture of trifluoroacetate (0.44 g), tetrahydrofuran (15 ml) and triethylamine (0.30 g) Added at room temperature and stirred for 18 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, filtered and concentrated. The residue was recrystallized (ethyl acetate) to give the title compound (0.21 g) as a solid.
1 H-NMR (DMDO-d 6 ) δ: 2.85 (2H, t, J = 7.2 Hz), 3.53 (2H, t, J = 7.2 Hz), 3.75 (3H, s) , 3.76 (3H, s), 4.31 (2H, s), 7.05-7.14 (3H, m), 7.24-7.32 (5H, m), 7.63 (1H) , S), 7.70 (1H, s), 8.90 (1H, brs), 11.91 (1H, brs).
実施例１０
Figure JPOXMLDOC01-appb-C000054
 Example 10
Figure JPOXMLDOC01-appb-C000054
１－［（６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－３－フェニル－１－（２－フェニルエチル）尿素
６－ブロモ－３－｛［（２－フェニルエチル）アミノ］メチル｝キノリン－２（１Ｈ）－オン　トリフルオロ酢酸塩（１．３５ｇ）とテトラヒドロフラン（２０ｍｌ）とトリエチルアミン（０．９５ｍｌ）の混合物に、フェニルイソシアネート（０．３２ｍｌ）を室温で加え、１時間攪拌した。反応液をろ過し、ろ液を濃縮した。残留物を酢酸エチルとヘキサンで洗浄し、ろ取し、表題化合物（９６１ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．８３－２．９２（２Ｈ，ｍ），３．５４（２Ｈ，ｔ，Ｊ＝７．６Ｈｚ），４．３８（２Ｈ，ｓ），６．９４（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．０９－７．１７（１Ｈ，ｍ），７．２０－７．３３（７Ｈ，ｍ），７．４６（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．６５（１Ｈ，ｄｄ，Ｊ＝８．９，２．１Ｈｚ），７．８４（１Ｈ，ｓ），７．９８（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ），９．２９（１Ｈ，ｂｒｓ），１２．２４（１Ｈ，ｓ）． 1-[(6-Bromo-2-oxo-1,2-dihydroquinolin-3-yl) methyl] -3-phenyl-1- (2-phenylethyl) urea 6-bromo-3-{[(2- Phenylethyl) amino] methyl} quinolin-2 (1H) -one trifluoroacetate (1.35 g), tetrahydrofuran (20 ml) and triethylamine (0.95 ml) were mixed with phenyl isocyanate (0.32 ml) at room temperature. Added and stirred for 1 hour. The reaction solution was filtered and the filtrate was concentrated. The residue was washed with ethyl acetate and hexane and collected by filtration to give the title compound (961 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.83-2.92 (2H, m), 3.54 (2H, t, J = 7.6 Hz), 4.38 (2H, s), 6 .94 (1H, t, J = 7.4 Hz), 7.09-7.17 (1H, m), 7.20-7.33 (7H, m), 7.46 (2H, d, J = 7.6 Hz), 7.65 (1 H, dd, J = 8.9, 2.1 Hz), 7.84 (1 H, s), 7.98 (1 H, d, J = 2.3 Hz), 9. 29 (1H, brs), 12.24 (1H, s).
実施例１１
Figure JPOXMLDOC01-appb-C000055
 Example 11
Figure JPOXMLDOC01-appb-C000055
２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボン酸メチル
１－［（６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－３－フェニル－１－（２－フェニルエチル）尿素（５，１ｇ）とトリエチルアミン（２．９６ｍｌ）とＮ，Ｎ’－ジメチルホルムアミド（２００ｍｌ）とメタノール（２００ｍｌ）の混合物に、酢酸パラジウム（１２０ｍｇ）とビスジフェニルフォスフィノフェロセン（２９６ｍｇ）を室温で加え、一酸化炭素雰囲気下、８０℃、１３時間攪拌した。反応液を濃縮し、残渣に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸マグネシウムで乾燥し、ろ過し、濃縮した。残留物をメタノールで洗浄し、ろ取し、表題化合物（３．１２ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．８８（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．５６（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．８６（３Ｈ，ｓ），４．３８（２Ｈ，ｓ），６．９４（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．０６－７．１６（１Ｈ，ｍ），７．１９－７．２９（６Ｈ，ｍ），７．４１（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ），７．４４－７．４９（２Ｈ，ｍ），７．９８－８．１０（２Ｈ，ｍ），８．３８（１Ｈ，ｄ，Ｊ＝１．７Ｈｚ），９．２７（１Ｈ，ｂｒｓ），１２．４２（１Ｈ，ｂｒｓ）． 2-Oxo-3-{[(phenylcarbamoyl) (2-phenylethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxylate 1-[(6-bromo-2-oxo-1,2 -Dihydroquinolin-3-yl) methyl] -3-phenyl-1- (2-phenylethyl) urea (5,1 g), triethylamine (2.96 ml), N, N′-dimethylformamide (200 ml) and methanol ( 200 ml), palladium acetate (120 mg) and bisdiphenylphosphinoferrocene (296 mg) were added at room temperature, and the mixture was stirred at 80 ° C. for 13 hours in a carbon monoxide atmosphere. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was washed with methanol and collected by filtration to give the title compound (3.12 g) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.88 (2H, t, J = 7.5 Hz), 3.56 (2H, t, J = 7.5 Hz), 3.86 (3H, s) 4.38 (2H, s), 6.94 (1H, t, J = 7.3 Hz), 7.06-7.16 (1H, m), 7.19-7.29 (6H, m) , 7.41 (1H, d, J = 8.7 Hz), 7.44-7.49 (2H, m), 7.98-8.10 (2H, m), 8.38 (1H, d, J = 1.7 Hz), 9.27 (1H, brs), 12.42 (1H, brs).
実施例１２
Figure JPOXMLDOC01-appb-C000056
 Example 12
Figure JPOXMLDOC01-appb-C000056
２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボン酸
２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボン酸メチル（１．３６ｇ）とメタノール（４０ｍｌ）の混合物に、１Ｎ水酸化ナトリウム水溶液（４０ｍｌ）を室温で加え、７０℃で１時間攪拌した。反応液を放冷し、６Ｎ塩酸水溶液（５０ｍｌ）を加えた。沈殿物をろ取し、乾燥し、表題化合物（１。１４ｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．２８（２Ｈ，ｔ，Ｊ＝７．６Ｈｚ），３．５６（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），４．３８（２Ｈ，ｓ），６．９４（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．０８－７．１６（１Ｈ，ｍ），７．１９－７．２９（６Ｈ，ｍ），７．３９（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４６（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．９９－８．０７（２Ｈ，ｍ），８．３３（１Ｈ，ｄ，Ｊ＝１．９Ｈｚ），９．３４（１Ｈ，ｂｒｓ），１２．３９（１Ｈ，ｂｒｓ），１２．９３（１Ｈ，ｂｒｓ）． 2-oxo-3-{[(phenylcarbamoyl) (2-phenylethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxylic acid 2-oxo-3-{[(phenylcarbamoyl) (2-phenyl 1N aqueous sodium hydroxide solution (40 ml) was added to a mixture of ethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxylate (1.36 g) and methanol (40 ml) at room temperature. Stir for hours. The reaction mixture was allowed to cool, and 6N aqueous hydrochloric acid solution (50 ml) was added. The precipitate was collected by filtration and dried to give the title compound (1.14 g) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.28 (2H, t, J = 7.6 Hz), 3.56 (2H, t, J = 7.4 Hz), 4.38 (2H, s) 6.94 (1H, t, J = 7.4 Hz), 7.08-7.16 (1H, m), 7.19-7.29 (6H, m), 7.39 (1H, d, J = 8.3 Hz), 7.46 (2H, d, J = 7.6 Hz), 7.9-8.07 (2H, m), 8.33 (1H, d, J = 1.9 Hz), 9.34 (1H, brs), 12.39 (1H, brs), 12.93 (1H, brs).
実施例１３
Figure JPOXMLDOC01-appb-C000057
 Example 13
Figure JPOXMLDOC01-appb-C000057
Ｎ－（２－アミノ－２－オキソエチル）－２－オキソ－３－｛[｛フェニルカルバモイル｝（２－フェニルエチル）アミノ]メチル｝－１，２－ジヒドロキノリン－６－カルボキサミド
２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボン酸（５０ｍｇ）と１－エチル－３－（３’－ジメチルアミノプロピル）カルボジイミド塩酸塩（３４ｍｇ）と１－ヒドロキシベンゾトリアゾール（４３ｍｇ）とトリエチルアミン（０．０３１ｍｌ）とアセトニトリル（３ｍｌ）とＮ，Ｎ’－ジメチルホルムアミド（１ｍｌ）の混合物に、グリシンアミド塩酸塩（１８ｍｇ）を室温で加え、１時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸マグネシウムで乾燥し、ろ過し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（混合比が１００対０から８５対１５の酢酸エチルとメタノールの混合溶液で溶出）で精製し、表題化合物（４２ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．８８（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．５６（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），３．８２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），４．４１（２Ｈ，ｓ），６．９４（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．０４（１Ｈ，ｓ），７．１１－７．１８（１Ｈ，ｍ），７．２２－７．２８（６Ｈ，ｍ），７．３８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４６（２Ｈ，ｄ，Ｊ＝７．７Ｈｚ），７．８９（１Ｈ，ｍ），８．００（１Ｈ，ｄｄ，Ｊ＝８．７，１．９Ｈｚ），８．２７（１Ｈ，ｄ，Ｊ＝１．７Ｈｚ），８．６８（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），９．３０（１Ｈ，ｓ），１２．３４（１Ｈ，ｂｒｓ）． N- (2-amino-2-oxoethyl) -2-oxo-3-{[{phenylcarbamoyl} (2-phenylethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxamide 2-oxo-3 -{[(Phenylcarbamoyl) (2-phenylethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxylic acid (50 mg) and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (34 mg), 1-hydroxybenzotriazole (43 mg), triethylamine (0.031 ml), acetonitrile (3 ml) and N, N′-dimethylformamide (1 ml) were added with glycinamide hydrochloride (18 mg) at room temperature. Stir for 1 hour. 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 magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with a mixed solution of ethyl acetate and methanol having a mixing ratio of 100: 0 to 85:15) to give the title compound (42 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.88 (2H, t, J = 7.5 Hz), 3.56 (2H, t, J = 7.3 Hz), 3.82 (2H, d, J = 5.7 Hz), 4.41 (2H, s), 6.94 (1H, t, J = 7.3 Hz), 7.04 (1H, s), 7.11-7.18 (1H, m), 7.22-7.28 (6H, m), 7.38 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 7.7 Hz), 7.89 ( 1H, m), 8.00 (1H, dd, J = 8.7, 1.9 Hz), 8.27 (1H, d, J = 1.7 Hz), 8.68 (1H, t, J = 5) .9 Hz), 9.30 (1H, s), 12.34 (1H, brs).
実施例１４
Figure JPOXMLDOC01-appb-C000058
 Example 14
Figure JPOXMLDOC01-appb-C000058
２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボキサミド
２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボン酸（５０ｍｇ）と１－ヒドロキシベンゾトリアゾール－アンモニア複合体（２０ｍｇ）とＮ，Ｎ’－ジメチルホルムアミド（２ｍｌ）の混合物に、１－エチル－３－（３’－ジメチルアミノプロピル）カルボジイミド塩酸塩（２４ｍｇ）を室温で加え、１８時間攪拌した。反応液に水を加え、析出した結晶を濾取し、水で洗浄し、再結晶（エタノール）して、表題化合物（３０ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．８８（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．５６（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），４．４０（２Ｈ，ｓ），６．９１－６．９６（１Ｈ，ｍ），７．１１－７．４８（１１Ｈ，ｍ），７．８７（１Ｈ，ｓ），７．９８－８．０１（２Ｈ，ｍ），８．２４（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），９．３１（１Ｈ，ｂｒｓ），１２．３２（１Ｈ，ｂｒｓ）． 2-oxo-3-{[(phenylcarbamoyl) (2-phenylethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxamide 2-oxo-3-{[(phenylcarbamoyl) (2-phenylethyl ) Amino] methyl} -1,2-dihydroquinoline-6-carboxylic acid (50 mg), 1-hydroxybenzotriazole-ammonia complex (20 mg) and N, N′-dimethylformamide (2 ml) Ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (24 mg) was added at room temperature and stirred for 18 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and recrystallized (ethanol) to give the title compound (30 mg) as a solid.
1 H-NMR (DMSO-d 6 ) δ: 2.88 (2H, t, J = 7.5 Hz), 3.56 (2H, t, J = 7.5 Hz), 4.40 (2H, s) 6.91-6.96 (1H, m), 7.11-7.48 (11H, m), 7.87 (1H, s), 7.98-8.01 (2H, m), 8 .24 (1H, d, J = 1.5 Hz), 9.31 (1H, brs), 12.32 (1H, brs).
実施例１５
Figure JPOXMLDOC01-appb-C000059
 Example 15
Figure JPOXMLDOC01-appb-C000059
Ｎ－（２－ヒドロキシエチル）－Ｎ－メチル－２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボキサミド
２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボン酸（５０ｍｇ）と１－エチル－３－（３’－ジメチルアミノプロピル）カルボジイミド塩酸塩（２４ｍｇ）と１－ヒドロキシベンゾトリアゾール（２０ｍｇ）とＮ，Ｎ’－ジメチルホルムアミド（２ｍｌ）の混合物に、２－（メチルアミノ）エタノール（１１ｍｇ）を室温で加え、１８時間攪拌した。反応液に水を加え、析出した結晶を濾取し、水で洗浄し、再結晶（エタノール）して、表題化合物（１０ｍｇ）を固体として得た。１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ６）δ：２．８７（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），２．９９（３Ｈ，ｓ），３．４６－３．５７（６Ｈ，ｍ），４．３８（２Ｈ，ｓ），４．７５－４．７９（１Ｈ，ｍ），６．９３（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．１０－７．５８（１１Ｈ，ｍ），７．７９（１Ｈ，ｂｒｓ），７．９１（１Ｈ，ｓ），９．４０（１Ｈ，ｂｒｓ），１１．２８（１Ｈ，ｂｒｓ）． N- (2-hydroxyethyl) -N-methyl-2-oxo-3-{[(phenylcarbamoyl) (2-phenylethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxamide 2-oxo- 3-{[(Phenylcarbamoyl) (2-phenylethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxylic acid (50 mg) and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride 2- (Methylamino) ethanol (11 mg) was added to a mixture of the salt (24 mg), 1-hydroxybenzotriazole (20 mg) and N, N′-dimethylformamide (2 ml) at room temperature, and the mixture was stirred for 18 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and recrystallized (ethanol) to give the title compound (10 mg) as a solid. 1 H-NMR (DMSO-d 6 ) δ: 2.87 (2H, t, J = 7.5 Hz), 2.99 (3H, s), 3.46-3.57 (6H, m), 4 .38 (2H, s), 4.75-4.79 (1H, m), 6.93 (1H, t, J = 7.5 Hz), 7.10-7.58 (11H, m), 7 .79 (1H, brs), 7.91 (1H, s), 9.40 (1H, brs), 11.28 (1H, brs).
実施例１６
Figure JPOXMLDOC01-appb-C000060
 Example 16
Figure JPOXMLDOC01-appb-C000060
３－（４－フルオロフェニル）－１－［２－（４－フルオロフェニル）エチル］－１－［（２－オキソ－１，２，３，４－テトラヒドロキノリン－３－イル）メチル］尿素
３－（｛［２－（４－フルオロフェニル）エチル］アミノ｝メチル）－３，４－ジヒドロキノリン－２（１Ｈ）－オン（２９８ｍｇ）とトリエチルアミン（０．２８ｍｌ）とＴＨＦ（５ｍｌ）の混合物にイソシアン酸４－フルオロフェニル（０．１１ｍｌ）を氷冷下で加え、室温で１５分間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（混合比が８０対２０から５０対５０のヘキサンと酢酸エチルの混合溶液で溶出）で精製し、再結晶（ジエチルエーテル）して、表題化合物（３２９ｍｇ）を固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：２．４７－２．６３（１Ｈ，ｍ），２．７９－３．０８（４Ｈ，ｍ），３．２９－３．５２（２Ｈ，ｍ），３．５６－３．７２（１Ｈ，ｍ），３．８７（１Ｈ，ｄｄ，Ｊ＝１５．９，６．１Ｈｚ），６．７６（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），６．８７－７．０９（５Ｈ，ｍ），７．１３－７．２４（４Ｈ，ｍ），７．３２－７．４５（２Ｈ，ｍ），７．７８（１Ｈ，ｓ），８．７５（１Ｈ，ｂｒｓ）． 3- (4-Fluorophenyl) -1- [2- (4-fluorophenyl) ethyl] -1-[(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl) methyl] urea 3 To a mixture of-({[2- (4-fluorophenyl) ethyl] amino} methyl) -3,4-dihydroquinolin-2 (1H) -one (298 mg), triethylamine (0.28 ml) and THF (5 ml) 4-Fluorophenyl isocyanate (0.11 ml) was added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. 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, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with a mixed solution of hexane and ethyl acetate with a mixing ratio of 80:20 to 50:50) and recrystallized (diethyl ether) to give the title compound (329 mg) as a solid Obtained.
1 H-NMR (CDCl 3 ) δ: 2.47-2.63 (1H, m), 2.79-3.08 (4H, m), 3.29-3.52 (2H, m), 3 .56-3.72 (1H, m), 3.87 (1H, dd, J = 15.9, 6.1 Hz), 6.76 (1H, d, J = 7.6 Hz), 6.87- 7.09 (5H, m), 7.13-7.24 (4H, m), 7.32-7.45 (2H, m), 7.78 (1H, s), 8.75 (1H, brs).
実施例１７
Figure JPOXMLDOC01-appb-C000061
 Example 17
Figure JPOXMLDOC01-appb-C000061
Ｎ’－（４－フルオロフェニル）－Ｎ－［２－（４－フルオロフェニル）エチル］－Ｎ－［（３－オキソ－３，４－ジヒドロ－２Ｈ－１，４－ベンゾオキサジン－２－イル）メチル］尿素
２－（｛［２－（４－フルオロフェニル）エチル］アミノ｝メチル）－３－オキソ－３，４－ジヒドロ－２Ｈ－１，４－ベンゾオキサジン－２－カルボン酸（４４ｍｇ）とトリエチルアミン（０．０４１ｍｌ）とＴＨＦ（１ｍｌ）の混合物にイソシアン酸４－フルオロフェニル（０．０１７ｍｌ）を氷冷下で加え、室温で３０分間攪拌した。反応液にジエチルエーテルを加えた。析出した結晶を濾取し、ジエチルエーテルで洗浄し、結晶（１３０ｍｇ）を得た。結晶をＤＭＳＯに溶解させて放置して表題化合物を得た。
ＬＣ－ＭＳ：ｍ／ｚ　計算値４３８, 実測値４３８（ＭＨ＋）；保持時間：１．５９分． N ′-(4-fluorophenyl) -N- [2- (4-fluorophenyl) ethyl] -N-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl ) Methyl] urea 2-({[2- (4-fluorophenyl) ethyl] amino} methyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (44 mg) To a mixture of triethylamine (0.041 ml) and THF (1 ml) was added 4-fluorophenyl isocyanate (0.017 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Diethyl ether was added to the reaction solution. The precipitated crystals were collected by filtration and washed with diethyl ether to obtain crystals (130 mg). The crystals were dissolved in DMSO and left to give the title compound.
LC-MS: m / z calc. 438, found 438 (MH + ); retention time: 1.59 minutes.
製剤例１
　　（１）実施例１の化合物　　　　　　　　　　　　　１０.０g
　　（２）乳糖　　　　　　　　　　　　　　　　　　　７０.０g
　　（３）コーンスターチ　　　　　　　　　　　　　　５０.０g
　　（４）可溶性デンプン　　　　　　　　　　　　　　　７.０g
　　（５）ステアリン酸マグネシウム　　　　　　　　　　３.０g Formulation Example 1
(1) 10.0 g of the compound of Example 1
(2) Lactose 70.0g
(3) Corn starch 50.0g
(4) 7.0g soluble starch
(5) Magnesium stearate 3.0 g
　実施例１の化合物（１０.０ｇ）およびステアリン酸マグネシウム（３.０ｇ）を可溶性デンプンの水溶液７０ｍｌ（可溶性デンプンとして７.０ｇ）で顆粒化し、乾燥して、乳糖（７０.０ｇ）およびコーンスターチ（５０.０ｇ）と混合する（乳糖、コーンスターチ、可溶性デンプンおよびステアリン酸マグネシウムはいずれも第十四改正日本薬局方適合品）。混合物を圧縮して錠剤を得る。 The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) were granulated with 70 ml of an aqueous solution of soluble starch (7.0 g as soluble starch), dried, lactose (70.0 g) and corn starch ( (Lactose, corn starch, soluble starch, and magnesium stearate are all conforming to the 14th revised Japanese Pharmacopoeia). The mixture is compressed to obtain tablets.
実験例１
hNK2受容体発現CHO細胞の膜画分を用いたラジオリガンド受容体結合阻害活性
　hNK2受容体発現CHO細胞（ユーロスクリーン社製）を、400μg/mLジェネテシン、100U/mL ペニシリン、100μg/mLストレプトマイシンおよび10％非働化血清を含むHAM-F12培地で培養した。培地を除き、接着している細胞をPBSで洗浄し、5mM EDTAを含むPBSを添加して、細胞をフラスコから剥がした。遠心分離により細胞を回収し、懸濁用緩衝液A（15mM Tris-HCl(pH7.5)、2mM MgCl2、0.3mM EDTA、1mM EGTA）に懸濁し、ポリトロンホモジナイザー（キネマチカ社製）で破砕し、800×で10分間遠心分離し、その上清を回収して100000×gで25分間超遠心した。沈殿画分を懸濁用緩衝液B（7.5mM Tris-HCl(pH7.5) 、12.5mM MgCl2、0.3mM EDTA、1mM、EDTA、250mM スクロース）に懸濁し、受容体標品として凍結（-80℃）保存した。
　96ウェルマイクロアッセイプレートに、測定用緩衝液（50mM Tris-HCl(pH7.4)、0.02％牛血清アルブミン、2μg/mL キモスタチン、40μg/mL バシトラシン、40μg/mL APMSF、3mM MnCl2）50μLを添加した。そこに測定用緩衝液に懸濁した膜標品（20μg/mL）50μLを添加した。総結合量を調べるために、2%ジメチルスルホキシドを含む測定用緩衝液（50μL）を加え、非特異的結合量を調べるために、2%ジメチルスルホキシドを含む測定用バッファーで希釈した4μMの非標識NKA（ペプチド研究所株式会社製）溶液（50μL）を加え、試験化合物の結合阻害活性を調べるために測定用緩衝液で希釈した試験化合物（50μL、2%ジメチルスルホキシドを含む）を添加した。さらに各ウェルに400μMの[125I]-NKA（アマシャムバイオサイエンス社製）溶液（50μL）を添加した。
　室温で30分反応させた後、セルハーベスター（パーキンエルマー社製）を用いてユニフィルタープレート（GF/C）（パーキンエルマー社製）上で急速濾過して反応を停止し、0.02％牛血清アルブミンを含む50mM Tris-HCl(pH7.4)緩衝液（250μL）で細胞を5回洗浄した。GF/Cフィルタープレートを乾燥し、20μLのマイクロシンチ－０（パーキンエルマー社製）を添加し、トップカウント（パーキンエルマー社製）で放射活性を測定した。GF/Cフィルタープレートは、0.3％ポリエチレンイミンに一日間浸漬しておいたものを用いた。
　特異的結合量は、総結合量から非特異的結合量を減じて得られる値で示される。試験化合物の結合阻害活性は、総結合量から試験化合物を加えた場合の測定値を減じて得られる値の、特異的結合量の値に対する比率で示される。
　実施例の５、６、７、１０および１１の化合物の１μＭにおける阻害率は９０％以上であった。 Experimental example 1
Radioligand receptor binding inhibitory activity using membrane fraction of hNK2 receptor-expressing CHO cells. hNK2 receptor-expressing CHO cells (Euroscreen) were treated with 400 μg / mL geneticin, 100 U / mL penicillin, 100 μg / mL streptomycin and 10 The cells were cultured in HAM-F12 medium containing% inactivated serum. The medium was removed, and the adherent cells were washed with PBS, PBS containing 5 mM EDTA was added, and the cells were detached from the flask. Cells are collected by centrifugation, suspended in suspension buffer A (15 mM Tris-HCl (pH 7.5), 2 mM MgCl2, 0.3 mM EDTA, 1 mM EGTA), disrupted with a Polytron homogenizer (Kinematica), Centrifugation was performed at 800 × for 10 minutes, and the supernatant was collected and ultracentrifuged at 100000 × g for 25 minutes. The precipitate fraction is suspended in suspension buffer B (7.5 mM Tris-HCl (pH 7.5), 12.5 mM MgCl2, 0.3 mM EDTA, 1 mM, EDTA, 250 mM sucrose) and frozen as a receptor preparation (-80 C).
To a 96-well microassay plate, 50 μL of measurement buffer (50 mM Tris-HCl (pH 7.4), 0.02% bovine serum albumin, 2 μg / mL chymostatin, 40 μg / mL bacitracin, 40 μg / mL APMSF, 3 mM MnCl2) was added. . Thereto was added 50 μL of a membrane preparation (20 μg / mL) suspended in a measurement buffer. To determine the total amount of binding, add 4 μM unlabeled assay buffer (50 μL) containing 2% dimethyl sulfoxide and dilute with assay buffer containing 2% dimethyl sulfoxide to determine the amount of non-specific binding. NKA (Peptide Institute, Inc.) solution (50 μL) was added, and a test compound (50 μL, containing 2% dimethyl sulfoxide) diluted with a measurement buffer was added to examine the binding inhibitory activity of the test compound. Furthermore, 400 μM [125I] -NKA (Amersham Bioscience) solution (50 μL) was added to each well.
After 30 minutes of reaction at room temperature, the reaction was stopped by rapid filtration on a Unifilter plate (GF / C) (Perkin Elmer) using a cell harvester (Perkin Elmer), and 0.02% bovine serum albumin The cells were washed 5 times with 50 mM Tris-HCl (pH 7.4) buffer solution (250 μL). The GF / C filter plate was dried, 20 μL of microcinch-0 (Perkin Elmer) was added, and the radioactivity was measured with a top count (Perkin Elmer). The GF / C filter plate used was immersed in 0.3% polyethyleneimine for one day.
The specific binding amount is indicated by a value obtained by subtracting the non-specific binding amount from the total binding amount. The binding inhibitory activity of the test compound is expressed as a ratio of the value obtained by subtracting the measured value when the test compound is added from the total binding amount to the specific binding amount.
The inhibition rate at 1 μM of the compounds of Examples 5, 6, 7, 10 and 11 was 90% or more.
　本発明の化合物は、ＮＫ２受容体結合活性を有し、毒性も少ないため、過敏性腸症候群などの予防または治療剤として特に有用である。 Since the compound of the present invention has NK2 receptor binding activity and little toxicity, it is particularly useful as a preventive or therapeutic agent for irritable bowel syndrome and the like.

Claims (18)

  1. 　式（Ｉ）
    Figure JPOXMLDOC01-appb-C000062
     ［式中、
    Figure JPOXMLDOC01-appb-C000063
    は単結合または二重結合を示し、
    Ａ１およびＡ２は同一または異なって置換基を有していてもよい芳香族基を、
    Ｂ環は置換基を有していてもよいフェニル基を示し、
    Ｒは水素原子または置換基を有していてもよい炭化水素基を示し、
    Ｒ１は、存在しないか、あるいは水素原子、置換基を有していてもよいアルキル基、またはエステル化されていてもよいカルボキシル基を示し、
    Ｘ１は置換基を有していてもよいメチレン基を示し、
    Ｘ２は置換基を有していてもよいエチレン基を示し、
    Ｙは置換基を有していてもよい炭素原子、置換基を有していてもよい窒素原子、酸素原子または酸化されていてもよい硫黄原子を示す。
    ］で表される化合物またはその塩を含有してなるニューロキニン受容体拮抗剤。     Formula (I)
    Figure JPOXMLDOC01-appb-C000062
     [Where:
    Figure JPOXMLDOC01-appb-C000063
    Indicates a single bond or a double bond,
    A 1 and A 2 are the same or different and each represents an optionally substituted aromatic group,
    Ring B represents a phenyl group which may have a substituent,
    R represents a hydrogen atom or an optionally substituted hydrocarbon group;
    R 1 is absent, represents a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified,
    X 1 represents a methylene group which may have a substituent,
    X 2 represents an ethylene group which may have a substituent,
    Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized.
    ] The neurokinin receptor antagonist containing the compound or its salt represented by these.
  2. ニューロキニン２受容体拮抗剤である請求項１記載の拮抗剤。 The antagonist according to claim 1, which is a neurokinin 2 receptor antagonist.
  3. 消化器疾患または中枢疾患の予防・治療剤である請求項１記載の拮抗剤。 The antagonist according to claim 1, which is a prophylactic / therapeutic agent for digestive system diseases or central diseases.
  4. 消化器疾患が、機能性消化管疾患である請求項３記載の拮抗剤。 The antagonist according to claim 3, wherein the digestive system disease is a functional digestive tract disease.
  5. 機能性消化管疾患が、過敏性腸症候群または機能性ディスペプシアである請求項４記載の拮抗剤。 The antagonist according to claim 4, wherein the functional gastrointestinal disease is irritable bowel syndrome or functional dyspepsia.
  6. 中枢疾患がうつまたは不安である請求項３記載の拮抗剤。 The antagonist according to claim 3, wherein the central disease is depression or anxiety.
  7. 　式（Ｉ）
    Figure JPOXMLDOC01-appb-C000064
     ［式中、
    Figure JPOXMLDOC01-appb-C000065
     は単結合または二重結合を、
    Ａ１およびＡ２は同一または異なって置換基を有していてもよい芳香族基を、
    Ｂ環は置換基を有していてもよいフェニル基を、
    Ｒは水素原子または置換基を有していてもよい炭化水素基を、
    Ｒ１は、存在しないか、あるいは水素原子、置換基を有していてもよいアルキル基、またはエステル化されていてもよいカルボキシル基を示し、Ｘ１は置換基を有していてもよいメチレン基を、
    Ｘ２は置換基を有していてもよいエチレン基を、
    Ｙは置換基を有していてもよい炭素原子、置換基を有していてもよい窒素原子、酸素原子または酸化されていてもよい硫黄原子を示す。
    （ただし、Ａ１およびＡ２が置換基を有していてもよいフェニル基を、
    Ｙが置換基を有しない炭素原子を、
    Figure JPOXMLDOC01-appb-C000066
     が二重結合を、Ｒが水素原子を、Ｘ１がメチレン（－ＣＨ２－）を、Ｘ２がエチレン（－ＣＨ２ＣＨ２－）を示すとき、Ｂ環の置換基は、Ｃ１－２アルキル、Ｃ１－２アルコキシまたはＣ１－２アルキレンジオキシではない。）］で表される化合物
    またはその塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000064
     [Where:
    Figure JPOXMLDOC01-appb-C000065
     Is a single bond or a double bond,
    A 1 and A 2 are the same or different and each represents an optionally substituted aromatic group,
    Ring B represents a phenyl group which may have a substituent,
    R represents a hydrogen atom or a hydrocarbon group which may have a substituent,
    R 1 is a hydrogen atom, an alkyl group which may have a substituent, or a carboxyl group which may be esterified, and X 1 is a methylene which may have a substituent. Group
    X 2 represents an ethylene group which may have a substituent,
    Y represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, an oxygen atom or a sulfur atom which may be oxidized.
    (However, A 1 and A 2 may have a phenyl group which may have a substituent,
    Y is a carbon atom having no substituent,
    Figure JPOXMLDOC01-appb-C000066
     Is a double bond, R is a hydrogen atom, X 1 is methylene (—CH 2 —), and X 2 is ethylene (—CH 2 CH 2 —), the substituent on the B ring is C 1- Not 2 alkyl, C 1-2 alkoxy or C 1-2 alkylenedioxy. )] Or a salt thereof.
  8. Ｒが水素原子であり；
    Ｒ１は存在しないか、あるいは水素原子であり；
    Ｘ１がメチレン（－ＣＨ２－）であり；
    Ｘ２がヒドロキシを有していてもよいエチレン（－ＣＨ２ＣＨ２－）であり；
    Ｙが無置換の炭素原子（ＣＨまたはＣＨ２）または酸素原子であり；
    Figure JPOXMLDOC01-appb-C000067
     が単結合または二重結合であり；
    Ａ１がハロゲン原子から選択される１～３個の置換基をそれぞれ有していてもよい、（１）Ｃ６－１０アリール基または（２）環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基であり；
    Ａ２がハロゲン原子、シアノ、低級（Ｃ１－６）アルコキシ、低級（Ｃ１－６）アルキル－カルボニルアミノおよびＣ１－６アルキルから選択される１～３個の置換基をそれぞれ有していてもよい、（１）Ｃ６－１０アリール基または（２）環構成原子として、炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし３種のヘテロ原子を、１ないし３個有する、５または６員の芳香族単環式複素環基であり；
    Ｂ環が（１）ハロゲン原子、（２）低級（Ｃ１－６）アルコキシ、（３）低級（Ｃ１－６）アルコキシ－カルボニル、（４）カルボキシル、（５）カルバモイルおよびヒドロキシから選択される置換基で置換されていてもよいモノ－またはジ－低級（Ｃ１－６）アルキルカルバモイル、および（６）カルバモイルから選択される１～４個の置換基で置換されていてもよいフェニルである請求項７記載の化合物またはその塩。     R is a hydrogen atom;
    R 1 is absent or is a hydrogen atom;
    X 1 is methylene (—CH 2 —);
    X 2 is ethylene (—CH 2 CH 2 —) optionally having hydroxy;
    Y is an unsubstituted carbon atom (CH or CH 2 ) or an oxygen atom;
    Figure JPOXMLDOC01-appb-C000067
     Is a single bond or a double bond;
    A 1 may have 1 to 3 substituents each selected from a halogen atom, (1) a C 6-10 aryl group or (2) a ring atom as a nitrogen atom in addition to a carbon atom, A 5- or 6-membered aromatic monocyclic heterocyclic group having 1 to 3 heteroatoms selected from a sulfur atom and an oxygen atom;
    A 2 has 1 to 3 substituents each selected from a halogen atom, cyano, lower (C 1-6 ) alkoxy, lower (C 1-6 ) alkyl-carbonylamino and C 1-6 alkyl. (1) C 6-10 aryl group or (2) 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom Having a 5- or 6-membered aromatic monocyclic heterocyclic group;
    Ring B is selected from (1) halogen atom, (2) lower (C 1-6 ) alkoxy, (3) lower (C 1-6 ) alkoxy-carbonyl, (4) carboxyl, (5) carbamoyl and hydroxy Mono- or di-lower (C 1-6 ) alkylcarbamoyl optionally substituted with a substituent, and (6) phenyl optionally substituted with 1 to 4 substituents selected from carbamoyl The compound according to claim 7 or a salt thereof.
  9. ３－（４－シアノフェニル）－１－［２－（４－フルオロフェニル）エチル］－１－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］尿素、
    Ｎ－［２－（４－フルオロフェニル）エチル］－Ｎ’－（６－フルオロピリジン－３－イル）－Ｎ－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］尿素、
    １－［２－（４－フルオロフェニル）エチル］－１－［（６－メトキシ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－３－（６－メトキシピリジン－３－イル）尿素、
    １－［（６－ブロモ－２－オキソ－１，２－ジヒドロキノリン－３－イル）メチル］－３－フェニル－１－（２－フェニルエチル）尿素、もしくは
    ２－オキソ－３－｛［（フェニルカルバモイル）（２－フェニルエチル）アミノ］メチル｝－１，２－ジヒドロキノリン－６－カルボン酸メチル、またはそれらの塩。     3- (4-cyanophenyl) -1- [2- (4-fluorophenyl) ethyl] -1-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl) methyl] urea,
    N- [2- (4-Fluorophenyl) ethyl] -N ′-(6-fluoropyridin-3-yl) -N-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl ) Methyl] urea,
    1- [2- (4-Fluorophenyl) ethyl] -1-[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl) methyl] -3- (6-methoxypyridine-3- Yl) urea,
    1-[(6-Bromo-2-oxo-1,2-dihydroquinolin-3-yl) methyl] -3-phenyl-1- (2-phenylethyl) urea or 2-oxo-3-{[( Phenylcarbamoyl) (2-phenylethyl) amino] methyl} -1,2-dihydroquinoline-6-carboxylate, or a salt thereof.
  10. 請求項７記載の化合物もしくはその塩またはそのプロドラッグを含有してなる医薬。 A medicament comprising the compound according to claim 7 or a salt thereof or a prodrug thereof.
  11. 哺乳動物に対し、請求項７記載の化合物もしくはその塩またはそのプロドラッグの有効量を投与することを特徴とする消化器疾患または中枢疾患の予防・治療方法。 A method for the prophylaxis or treatment of digestive system diseases or central diseases, which comprises administering an effective amount of the compound according to claim 7 or a salt thereof or a prodrug thereof to a mammal.
  12. 消化器疾患が、機能性消化管疾患である請求項１１記載の予防・治療方法。 The method according to claim 11, wherein the digestive system disease is a functional digestive tract disease.
  13. 機能性消化管疾患が、過敏性腸症候群または機能性ディスペプシアである請求項１２記載の予防・治療方法。 The method according to claim 12, wherein the functional gastrointestinal disease is irritable bowel syndrome or functional dyspepsia.
  14. 中枢疾患がうつまたは不安である請求項１１記載の予防・治療方法。 The method according to claim 11, wherein the central disease is depression or anxiety.
  15. 消化器疾患または中枢疾患の予防・治療剤を製造するための請求項７記載の化合物もしくはその塩またはそのプロドラッグの使用。 Use of the compound according to claim 7 or a salt thereof or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for digestive system diseases or central diseases.
  16. 消化器疾患が、機能性消化管疾患である請求項１５記載の使用。 The use according to claim 15, wherein the digestive organ disease is a functional digestive tract disease.
  17. 機能性消化管疾患が、過敏性腸症候群または機能性ディスペプシアである請求項１６記載の使用。 The use according to claim 16, wherein the functional gastrointestinal disease is irritable bowel syndrome or functional dyspepsia.
  18. 中枢疾患がうつまたは不安である請求項１５記載の使用。 16. Use according to claim 15, wherein the central disease is depression or anxiety.
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CN113453682A (en) * 2019-03-07 2021-09-28 赛伯克斯股份有限公司 Compounds, compositions and methods for selectively inhibiting beta-glucuronidase and reducing side effects associated with drug therapy-induced diarrhea
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US12017994B2 (en) * 2017-09-08 2024-06-25 Symberix, Inc. Compounds, compositions, and methods for selectively inhibiting β-glucuronidases and alleviating side effects associated with drug treatment induced diarrhea
CN113453682A (en) * 2019-03-07 2021-09-28 赛伯克斯股份有限公司 Compounds, compositions and methods for selectively inhibiting beta-glucuronidase and reducing side effects associated with drug therapy-induced diarrhea
EP3934644A4 (en) * 2019-03-07 2022-12-07 Symberix, Inc. Compounds, compositions, and methods for selectively inhibiting beta-glucuronidases and alleviating side effects associated with drug treatment induced diarrhea
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CN113264879B (en) * 2021-05-27 2023-02-10 上海科技大学 Quinolone structure-based light-operated ligand and application thereof

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