WO2009128262A1 - Dérivé de quinolone et son utilisation - Google Patents

Dérivé de quinolone et son utilisation Download PDF

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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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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

L’invention concerne un composé qui présente une excellente activité de liaison au récepteur NK2. Le composé est satisfaisant en tant que produit pharmaceutique. L’invention concerne spécifiquement un antagoniste du récepteur de neurokinine, qui contient un composé représenté par la formule (I) ou un de ses sels. Dans la formule (I), --- représente une simple liaison ou une double liaison; A1 et A2 peuvent être identiques ou différents, et chacun représente un groupe aromatique éventuellement substitué; le cycle B représente un groupe phényle éventuellement substitué; R représente un atome d’hydrogène ou un groupe hydrocarbure éventuellement substitué; R1 peut ne pas exister, ou représente un atome d’hydrogène, un groupe alkyle éventuellement substitué ou un groupe carboxyle éventuellement estérifié; X1 représente un groupe méthylène éventuellement substitué; X2 représente un groupe éthylène éventuellement substitué; et Y représente un atome de carbone éventuellement substitué, un atome d’azote éventuellement substitué, un atome d’oxygène ou un atome de soufre éventuellement oxydé.
PCT/JP2009/001737 2008-04-15 2009-04-15 Dérivé de quinolone et son utilisation WO2009128262A1 (fr)

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CN113264879A (zh) * 2021-05-27 2021-08-17 上海科技大学 一种基于喹诺酮结构的光控配体及其应用
CN113453682A (zh) * 2019-03-07 2021-09-28 赛伯克斯股份有限公司 选择性地抑制β-葡糖醛酸糖苷酶和减轻与药物治疗引起的腹泻有关的副作用的化合物、组合物和方法
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
JP7570607B2 (ja) 2022-10-25 2024-10-22 広東省農業科学院蚕業与農産品加工研究所 リパーゼ阻害活性を有する米糠アルカロイドおよびその薬用塩またはエステル化誘導体、並びにその調製方法および応用

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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 (zh) * 2019-03-07 2021-09-28 赛伯克斯股份有限公司 选择性地抑制β-葡糖醛酸糖苷酶和减轻与药物治疗引起的腹泻有关的副作用的化合物、组合物和方法
EP3934644A4 (fr) * 2019-03-07 2022-12-07 Symberix, Inc. Composés, compositions et procédés d'inhibition sélective de beta-glucuronidases et de soulagement d'effets secondaires associés à la diarrhée induite par un traitement médicamenteux
CN113264879A (zh) * 2021-05-27 2021-08-17 上海科技大学 一种基于喹诺酮结构的光控配体及其应用
CN113264879B (zh) * 2021-05-27 2023-02-10 上海科技大学 一种基于喹诺酮结构的光控配体及其应用
JP7570607B2 (ja) 2022-10-25 2024-10-22 広東省農業科学院蚕業与農産品加工研究所 リパーゼ阻害活性を有する米糠アルカロイドおよびその薬用塩またはエステル化誘導体、並びにその調製方法および応用

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