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WO2019235572A1 - Solid cancer treatment agent and medicinal composition - Google Patents

Solid cancer treatment agent and medicinal composition Download PDF

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Publication number
WO2019235572A1
WO2019235572A1 PCT/JP2019/022540 JP2019022540W WO2019235572A1 WO 2019235572 A1 WO2019235572 A1 WO 2019235572A1 JP 2019022540 W JP2019022540 W JP 2019022540W WO 2019235572 A1 WO2019235572 A1 WO 2019235572A1
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Prior art keywords
group
optionally substituted
cancer
alkyl group
represented
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PCT/JP2019/022540
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French (fr)
Japanese (ja)
Inventor
北澤　諭
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富士フイルム株式会社
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Publication of WO2019235572A1 publication Critical patent/WO2019235572A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a treatment agent and a pharmaceutical composition for preventing or treating solid cancer.
  • Cancer is a major health problem in modern medicine and one of the leading causes of death in developed countries.
  • solid cancers including lung cancer, colon cancer and pancreatic cancer are the most commonly identified human cancers.
  • Patent Document 1 discloses a compound that has an excellent keratinocyte growth-inhibiting action and is useful for treatment such as prevention or treatment of a disease involving excessive proliferation of keratinocytes. There are no studies on treatment.
  • a treatment for solid cancer comprising a compound represented by the general formula (1) or a salt thereof.
  • G 1 is CH or a nitrogen atom
  • R 1 is a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-8 cycloalkyl group
  • R 2 is an optionally substituted bicyclic fused hydrocarbon ring group or an optionally substituted bicyclic heterocyclic group.
  • R 2 is an optionally substituted bicyclic fused hydrocarbon ring group
  • G 1 is a nitrogen atom
  • R 2 is represented by the general formula (2-1) or (2-2) (Where X 1 , X 2 and X 3 are the same or different and are CR 3 or a nitrogen atom;
  • R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group
  • R 4 is an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group,
  • a therapeutic agent for solid cancer comprising the compound or a salt thereof according to [1], wherein R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group.
  • R 2 is represented by the general formula (3-1) or (3-2) (Where X 1a , X 2a , and X 3a are the same or different and are CR 5 or a nitrogen atom; X 4 is CH or a nitrogen atom; R 4a is an optionally substituted C 1-6 alkyl group optionally, an optionally substituted aryl group or an optionally substituted aralkyl C 1-6 alkyl group; R 5 is a hydrogen atom, a halogen atom, an optionally substituted C 3-8 cycloalkenyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group.
  • R 2 is represented by the general formula (4-1) or (4-2) (Where X 1b , X 2b and X 3b are the same or different and are CH or a nitrogen atom; R 4b is a group represented by [1] or [2], or a salt thereof, which is a group represented by an optionally substituted aryl group or an optionally substituted ar C 1-6 alkyl group) Contains solid cancer treatment.
  • R 2 is represented by the general formula (5-1) or (5-2) (Where R 4c is an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group; R 5c is a hydrogen atom, an optionally substituted aryl group or an optionally substituted C 3-8 cycloalkenyl group. )
  • the treatment agent of solid cancer containing the compound or its salt as described in any one of [1] to [3] which is group represented by these.
  • G 1 is a nitrogen atom
  • R 2 is a group represented by the general formula (5-1) (Where R 4c is an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group; R 5c is a hydrogen atom, an optionally substituted aryl group or an optionally substituted heterocyclic group.
  • a therapeutic agent for solid cancer comprising the compound or salt thereof according to any one of [1] to [4], which is a group represented by:
  • Solid cancer is lung cancer, breast cancer, stomach cancer, liver cancer, colon cancer, tongue cancer, esophageal cancer, bladder cancer, thyroid cancer, pancreatic cancer, kidney cancer, prostate cancer,
  • the compound according to any one of [1] to [5] or a compound thereof, which is at least one selected from uterine cancer, ovarian cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma Treatment for solid cancer containing salt.
  • a treatment for solid cancer comprising the compound or salt thereof according to [6], wherein the solid cancer is at least one selected from lung cancer, colon cancer, and pancreatic cancer.
  • a pharmaceutical composition comprising the treatment agent according to any one of [1] to [7].
  • a method for treating solid cancer comprising a step of administering the treatment agent according to any one of [1] to [7] to a subject.
  • the present invention is useful for treatment such as prevention or treatment of solid cancer.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 3-6 alkyl group means a linear or branched C 3-6 alkyl group such as propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups. To do.
  • the C 1-6 alkyl group is a linear or branched C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups.
  • C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • C 3-8 cycloalkenyl group means a C 3-8 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohexanedienyl groups.
  • Cycloalkyl C 1-6 alkyl group cyclopropylmethyl, 2- (cyclopropyl) ethyl, cyclobutylmethyl, 2- (cyclobutyl) ethyl, C 3-8, such as cyclopentylmethyl and cyclohexylmethyl groups Means a cycloalkyl C 1-6 alkyl group.
  • An aryl group means a phenyl group, a bicyclic condensed hydrocarbon ring group, or a tricyclic condensed hydrocarbon ring group.
  • An ar C 1-6 alkyl group means a methoxy, ethoxy, propoxy or isopropoxy group.
  • Acyl group means formyl group, succinyl group, glutaryl group, maleoyl group, phthaloyl group, C 2-12 alkanoyl group, aroyl group, heterocyclic carbonyl group or ( ⁇ -substituted) aminoacetyl group.
  • the C 2-12 alkanoyl group means a linear or branched C2-12 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
  • An aroyl group means a benzoyl or naphthoyl group.
  • the heterocyclic carbonyl group means nicotinoyl, thenoyl, pyrrolidinocarbonyl or furoyl group.
  • the ( ⁇ -substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Tyrosine, tryptophan, proline and hydroxyproline, etc.) means the N-terminus derived from ( ⁇ -substituted) aminoacetyl groups which may be protected.
  • amino acid glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Tyrosine, try
  • the bicyclic condensed hydrocarbon ring group means a bicyclic condensed hydrocarbon ring in which a part such as pentalenyl, indanyl, indenyl and naphthyl groups may be hydrogenated.
  • the tricyclic fused hydrocarbon ring group means a tricyclic fused hydrocarbon ring in which a part such as biphenylenyl, acenaphthenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl and anthracenyl groups may be hydrogenated.
  • the heterocyclic group means a monocyclic heterocyclic group, a bicyclic heterocyclic group or a tricyclic heterocyclic group.
  • the monocyclic heterocyclic group is a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, a monocyclic nitrogen-containing / oxygen heterocyclic group, or a monocyclic heterocyclic group. This means a nitrogen-containing / sulfur heterocyclic group.
  • the monocyclic oxygen-containing heterocyclic group means a tetrahydrofuranyl, furanyl, tetrahydropyranyl, dihydropyranyl or pyranyl group.
  • the monocyclic sulfur-containing heterocyclic group means a thienyl group.
  • the monocyclic nitrogen-containing / oxygen heterocyclic group is a monocyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring, such as oxazolyl, isoxazolyl, oxadiazolyl and morpholinyl groups.
  • the monocyclic nitrogen-containing / sulfur heterocyclic group is a hetero atom forming the ring such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomorpholinyl and 1,1-dioxidethiomorpholinyl groups.
  • Bicyclic heterocyclic groups are bicyclic nitrogen-containing heterocyclic groups, bicyclic oxygen-containing heterocyclic groups, bicyclic sulfur-containing heterocyclic groups, bicyclic nitrogen-containing and oxygen heterocyclic groups. Alternatively, it means a bicyclic nitrogen-containing / sulfur heterocyclic group.
  • Bicyclic nitrogen-containing heterocyclic groups are indolinyl, indolyl, isoindolinyl, isoindolyl, pyrrolopyridinyl, indazolyl, benzimidazolyl, benzotriazolyl, tetrahydroquinolinyl, dihydroquinolinyl, quinolinyl, tetrahydroquinolinyl, tetrahydroisoxyl.
  • Bicycles containing only nitrogen atoms as heterogeneous atoms forming the ring such as nolinyl, isoquinolinyl, dihydroquinazolinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl and quinuclidinyl groups
  • the nitrogen-containing heterocyclic group of the formula is meant.
  • Bicyclic oxygen-containing heterocyclic groups include 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromanyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl And a bicyclic oxygen-containing heterocyclic group containing only an oxygen atom as a hetero atom forming the ring, such as a 1,4-benzodioxanyl group.
  • the bicyclic sulfur-containing heterocyclic group means a bicyclic sulfur-containing heterocyclic group containing only a sulfur atom as a hetero atom forming the ring, such as 2,3-dihydrobenzothienyl and benzothienyl groups. .
  • Bicyclic nitrogen-containing / oxygen heterocyclic groups include dihydrobenzoxazolyl, benzoxazolyl, benzisoxazolyl, benzoxdiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxynopyridyl and It means a bicyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring, such as a dihydropyridoxazinyl group.
  • Bicyclic nitrogen-containing / sulfur heterocyclic groups include dihydrobenzothiazolyl, benzothiazolyl, benzisothiazolyl and benzothiadiazolyl groups containing nitrogen and sulfur atoms as heterogeneous atoms forming the ring. This means a cyclic nitrogen-containing / sulfur heterocyclic group.
  • Heterocyclic C 1-6 alkyl group means azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidylmethyl, piperidylethyl, pyridylmethyl, pyridylethyl, imidazolylmethyl, imidazolylethyl, pipepe Monocyclic nitrogen-containing heterocyclic C 1-6 alkyl groups such as razinylmethyl and piperazinylethyl groups; monocyclic oxygen-containing heterocyclic C 1-6 alkyl groups such as tetrahydrofuranylmethyl and tetrahydropyranylmethyl; thienyl Monocyclic sulfur-containing heterocyclic C 1-6 alkyl group such as methyl group; oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, isoxazolylethyl, morpholinylmethyl and morpholiny
  • Examples of the salt of the compound of the general formula (1) include a salt in a basic group such as a commonly known amino group or an acidic group such as a phenolic hydroxyl group or a carboxyl group.
  • salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid Can be mentioned.
  • mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
  • formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
  • Salts with organic carboxylic acids such
  • Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
  • alkali metals such as sodium and potassium
  • alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethy
  • the “treatment” of the present invention includes prevention or treatment.
  • Prevention includes inhibition of onset, reduction of risk of onset, delay of onset.
  • Treatment includes amelioration of the disease or condition of interest or suppression (maintenance or delay) of progression.
  • the subject of treatment includes human or non-human animals in need of such treatment.
  • the “agent” of the present invention can be a composition in which formulation adjuvants such as excipients, carriers and diluents used in the formulation are appropriately mixed in addition to the active ingredient compound or a salt thereof.
  • the “agent” may contain other active ingredients and can be used together with a medicine containing other active ingredients.
  • G 1 is CH or a nitrogen atom.
  • R 1 is a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-8 cycloalkyl group, a chlorine atom or an optionally substituted C 3-8 cycloalkyl group It is preferably a chlorine atom or an optionally substituted cyclopropyl group, more preferably a chlorine atom or a cyclopropyl group.
  • substituent for the C 1-6 alkyl group and the C 3-8 cycloalkyl group represented by R 1 include at least one group selected from the substituent group ⁇ .
  • R 2 is an optionally substituted bicyclic fused hydrocarbon ring group or an optionally substituted bicyclic heterocyclic group.
  • substituent of the bicyclic condensed hydrocarbon ring group and the bicyclic heterocyclic group represented by R 2 include at least one group selected from the substituent group ⁇ .
  • G 1 is a nitrogen atom;
  • R 1 is CH and R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group
  • R 2 is a group represented by the general formula (2-1) or (2-2) is there.
  • X 1 , X 2 and X 3 are the same or different and are CR 3 or a nitrogen atom;
  • R 3 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group;
  • R 4 is an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, An optionally substituted aryl group, an optionally substituted ar C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group.
  • Examples of the substituent for the C 1-6 alkyl group represented by R 3 include at least one group selected from substituent group ⁇ .
  • R 4 C 3-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl C 1-6 alkyl group, aryl group, al C 1-6 alkyl group, acyl group, heterocyclic group and heterocycle
  • Examples of the substituent of the ring C 1-6 alkyl group include at least one group selected from substituent group ⁇ .
  • R 2 is preferably a group represented by the general formula (3-1) or (3-2).
  • X 1a , X 2a and X 3a are the same or different and are CR 5 or a nitrogen atom;
  • X 4 is CH or a nitrogen atom;
  • R 4a is an optionally substituted C 1-6 An alkyl group, an optionally substituted aryl group or an optionally substituted ar C 1-6 alkyl group;
  • R 5 is a hydrogen atom, a halogen atom, an optionally substituted C 3-8 cycloalkenyl group, a substituted An aryl group which may be substituted or a heterocyclic group which may be substituted.
  • G 1 is CH and R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group
  • R 2 is represented by the general formula (4-1) or (4-2) It is preferably a group.
  • X 1b , X 2b and X 3b are the same or different and are CH or a nitrogen atom;
  • R 4b is an optionally substituted aryl group or an optionally substituted al C 1-6 alkyl group. It is a group represented.
  • the C 1-6 alkyl group for R 4a is preferably a C 1-4 alkyl group, and more preferably a methyl group.
  • the aryl group for R 4a is preferably a phenyl group.
  • the al C 1-6 alkyl group for R 4a is preferably a phenylmethyl group.
  • Examples of the substituent for the C 1-6 alkyl group, aryl group, and al C 1-6 alkyl group of R 4a include at least one group selected from substituent group ⁇ .
  • the halogen atom for R 5 is preferably a fluorine atom.
  • the C 3-8 cycloalkenyl group for R 5 is preferably a C 3-6 cycloalkyl group, and more preferably a cyclohexenyl group.
  • the aryl group for R 5 is preferably a phenyl group. Examples of the substituent of the C 3-8 cycloalkenyl group, aryl group and heterocyclic group of R 5 include at least one group selected from substituent group ⁇ .
  • the aryl group for R 4b is preferably a phenyl group.
  • the ar C 1-6 alkyl group for R 4b is preferably a phenylmethyl group.
  • Examples of the substituent of the aryl group of R 4b and the al C 1-6 alkyl group include at least one group selected from the substituent group ⁇ .
  • R 2 is more preferably a group represented by the general formula (5-1) or (5-2).
  • R 4c is an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group
  • R 5c is a hydrogen atom, an optionally substituted aryl group or an optionally substituted C A 3-8 cycloalkenyl group.
  • the C 1-6 alkyl group for R 4c is preferably a C 1-4 alkyl group, and more preferably a methyl group.
  • the aryl group for R 4c is preferably a phenyl group. Examples of the substituent for the C 1-6 alkyl group and aryl group of R 4c include at least one group selected from substituent group ⁇ .
  • the aryl group for R 5c is preferably a phenyl group.
  • the C 3-8 cycloalkenyl group for R 5c is preferably a C 3-6 cycloalkyl group, and more preferably a cyclohexenyl group.
  • Examples of the substituent of the aryl group of R 5c and the C 3-8 cycloalkenyl group include at least one group selected from substituent group ⁇ .
  • R 2 is more preferably a group represented by the general formula (5-1).
  • R 4c and R 5c in the formula have the same meaning as described above.
  • G 1 is preferably a nitrogen atom.
  • Substituent group ⁇ at least one selected from a halogen atom, a hydroxyl group that may be protected, a carboxyl group that may be protected, an amino group that may be protected, a nitro group, a cyano group, and a substituent group ⁇
  • Substituent group ⁇ halogen atom, optionally protected hydroxyl group, optionally protected carboxyl group, optionally protected amino group, carbamoyl group, C 1-6 alkyl group optionally substituted with halogen atom, halogen An optionally substituted C 1-6 alkoxy group, a C 1-6 alkylamino group, a di (C 1-6 alkyl) amino group, a heterocyclic group, an oxo group;
  • Preferred compounds in the present invention include the following compounds. 2-((1-Benzyl-1H-indazol-5-yl) amino) -5-cyclopropylbenzoate, 2-((1- (cyclohexylmethyl) -1H-indol-5-yl) amino) -5 Cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-phenyl-1H-indol-4-yl) amino) nicotinic acid, 5-cyclopropyl-2-((7- (2-fluorophenyl) -1 -Methyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((1-methyl-7- (4-trifluoromethyl) phenyl) -1H-indol-5-yl) amino ) Nicotinic acid, 2-((7- (3-chlorophenyl) -1-methyl-1H-indol-5-
  • the compounds of the present invention include 2-((1-benzyl-1H-indazol-5-yl) amino) -5-cyclopropylbenzoate, 5-cyclopropyl-2-((1-phenyl-1H-indole- 4-yl) amino) nicotinic acid, 5-cyclopropyl-2-((7- (2-fluorophenyl) -1-methyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2 -((1-methyl-7- (4-trifluoromethyl) phenyl) -1H-indol-5-yl) amino) nicotinic acid, 2-((7- (3-chlorophenyl) -1-methyl-1H- Indol-5-yl) amino) -5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-methyl-7- (4- (trifluoromethoxy) phenyl) -1
  • Examples of the compound of the present invention include 5-cyclopropyl-2-((7- (2-fluorophenyl) -1-methyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2- ( (1-Methyl-7- (4-trifluoromethyl) phenyl) -1H-indol-5-yl) amino) nicotinic acid, 2-((7- (3-chlorophenyl) -1-methyl-1H-indole- 5-yl) amino) -5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-methyl-7- (4- (trifluoromethoxy) phenyl) -1H-indol-5-yl) amino) Nicotinic acid, 5-cyclopropyl-2-((1-phenyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((
  • Preferred salts of the present invention include pharmacologically acceptable salts.
  • the present invention when isomers (for example, optical isomers, geometric isomers, tautomers and the like) exist, the present invention includes those isomers, It includes hydrates, hydrates and crystals of various shapes.
  • Solid cancers include lung cancer, breast cancer, stomach cancer, liver cancer, colon cancer, tongue cancer, esophageal cancer, bladder cancer, thyroid cancer, pancreatic cancer, kidney cancer, prostate cancer, and uterus. Ovarian cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma and the like.
  • the solid cancer of the present invention is preferably at least one selected from lung cancer, colon cancer and pancreatic cancer.
  • the pharmaceutical composition means a composition obtained by appropriately mixing formulation adjuvants such as excipients, carriers and diluents used for formulation in addition to the compound of the present invention or a salt thereof as an active ingredient.
  • formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed.
  • the additive include an excipient, a disintegrant, a binder, a lubricant, a corrigent, a colorant, a flavoring agent, a surfactant, a coating agent, and a plasticizer.
  • excipients include sugar alcohols such as erythritol, mannitol, xylitol, and sorbitol; sugars such as sucrose, powdered sugar, lactose, and glucose; ⁇ -cyclodextrin, ⁇ -cyclodextrin, and sulfobutyl ether ⁇ -cyclodextrin sodium Cyclodextrins such as; celluloses such as crystalline cellulose and microcrystalline cellulose; and starches such as corn starch, potato starch and pregelatinized starch.
  • sugar alcohols such as erythritol, mannitol, xylitol, and sorbitol
  • sugars such as sucrose, powdered sugar, lactose, and glucose
  • ⁇ -cyclodextrin, ⁇ -cyclodextrin, and sulfobutyl ether ⁇ -cyclodextrin sodium Cyclodextrins such as; cellulose
  • Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, and partially pregelatinized starch.
  • Examples of the binder include hydroxypropylcellulose, carmellose sodium and methylcellulose.
  • Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, light anhydrous silicic acid, and sucrose fatty acid ester.
  • Examples of the corrigent include aspartame, saccharin, stevia, thaumatin, and acesulfame potassium.
  • Examples of the colorant include titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, edible red No. 102, edible yellow No. 4, and edible yellow No. 5.
  • Examples of flavoring agents include essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, Powder fragrances such as peach micron, strawberry micron and orange micron; vanillin; and ethyl vanillin.
  • Examples of the surfactant include sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate, and polyoxyethylene hydrogenated castor oil.
  • Examples of the coating agent include hydroxypropyl methylcellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S.
  • examples of the plasticizer include triethyl citrate, macrogol, triacetin, and propylene glycol. These additives may be used alone or in combination of two or more.
  • the blending amount is not particularly limited, and may be blended appropriately so that the effect is sufficiently exhibited according to each purpose.
  • These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, It can be administered orally or parenterally in the form of a patch, ointment or injection.
  • the administration method, the dose, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, 0.01 to 1000 mg / kg may be divided into 1 to several times a day by oral or parenteral administration.
  • Growth inhibition rate (%) (luminescence amount of well added with test compound) / (luminescence amount of well added with DMSO) ⁇ 100
  • Compound Nos. 1 to 20 showed an excellent cell growth inhibitory effect.
  • the compound of the present invention or a salt thereof has an excellent effect of suppressing the growth of solid cancer cells, it is useful for treatment such as prevention or treatment of solid cancer.

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Abstract

The present invention addresses the problem of providing a treatment agent and a medicinal composition for effective solid cancer prevention or treatment. The present invention provides a solid cancer treatment agent containing a compound represented by general formula (1) or a salt thereof.

Description

固形がんの処置剤および医薬組成物Solid cancer treatment agent and pharmaceutical composition
　本発明は、固形がんの予防または治療などの処置剤および医薬組成物に関する。 The present invention relates to a treatment agent and a pharmaceutical composition for preventing or treating solid cancer.
　がんは現代医学における主要な健康問題であり、先進国における主な死亡原因の一つである。がんの中でも、肺がんや大腸がん、膵がんを含む固形がんは、最も一般的に同定されているヒトのがんである。 Cancer is a major health problem in modern medicine and one of the leading causes of death in developed countries. Among cancers, solid cancers including lung cancer, colon cancer and pancreatic cancer are the most commonly identified human cancers.
　固形がんの多くは予後不良で、未だ有効な治療法が確立していない。また、それらのがん細胞は、自律的で制御されない増殖を行うため、増殖が速いという課題が存在しており、固形がんに対する有効な治療方法が求められている。 多 く Many solid cancers have poor prognosis, and effective treatment has not been established yet. In addition, since these cancer cells grow autonomously and uncontrolled, there is a problem of rapid growth, and an effective treatment method for solid cancer is required.
　一方、特許文献１には、優れたケラチノサイトの増殖抑制作用を有し、ケラチノサイトの過剰増殖が関与する疾患の予防または治療などの処置に有用な化合物について開示されているが、固形がんの予防または治療に関する検討はなされていない。 On the other hand, Patent Document 1 discloses a compound that has an excellent keratinocyte growth-inhibiting action and is useful for treatment such as prevention or treatment of a disease involving excessive proliferation of keratinocytes. There are no studies on treatment.
国際公開第２０１４／０６９５１０International Publication No. 2014/066951
　固形がんの予防または治療方法として種々の方法が知られているが、その効果は満足できるものではなく、より有効な固形がんの予防または治療のための処置剤および医薬組成物が望まれている。 Various methods are known as methods for preventing or treating solid cancer, but the effects are not satisfactory, and treatment agents and pharmaceutical compositions for more effective prevention or treatment of solid cancer are desired. ing.
　このような状況下において、本発明者らは、鋭意研究を重ねた結果、一般式（１）で表される化合物またはその塩が上記課題を解決できることを見出し、本発明を完成させた。 Under such circumstances, as a result of intensive studies, the present inventors have found that the compound represented by the general formula (1) or a salt thereof can solve the above-mentioned problems, and completed the present invention.
　本発明は、下記を提供する。
［１］　一般式（１）で表される化合物またはその塩を含む固形がんの処置剤。
Figure JPOXMLDOC01-appb-C000007
 （式中、
Ｇ１は、ＣＨまたは窒素原子であり；
Ｒ１は、ハロゲン原子、置換されてもよいＣ１－６アルキル基または置換されてもよいＣ３－８シクロアルキル基であり；
Ｒ２は、置換されてもよい二環式縮合炭化水素環基または置換されてもよい二環式複素環基である。
ただし、
（１）Ｒ２が置換されてもよい二環式縮合炭化水素環基の場合、Ｇ１は窒素原子であり；
（２）Ｇ１がＣＨであり、Ｒ１が塩素原子または置換されてもよいＣ３－８シクロアルキル基の場合、Ｒ２は一般式（２－１）または（２－２）
Figure JPOXMLDOC01-appb-C000008
 （式中、
Ｘ１、Ｘ２、Ｘ３は、同一または異なって、ＣＲ３または窒素原子であり；
Ｒ３は、水素原子、ハロゲン原子、置換されてもよいＣ１－６アルキル基であり、
Ｒ４は、置換されてもよいＣ３－６アルキル基、置換されてもよいＣ３－８シクロアルキル基、置換されてもよいＣ３－８シクロアルキルＣ１－６アルキル基、置換されてもよいアリール基、置換されてもよいアルＣ１－６アルキル基、置換されてもよいアシル基、置換されてもよい複素環基または置換されてもよい複素環Ｃ１－６アルキル基である。）で表される基である。） The present invention provides the following.
[1] A treatment for solid cancer comprising a compound represented by the general formula (1) or a salt thereof.
Figure JPOXMLDOC01-appb-C000007
 (Where
G 1 is CH or a nitrogen atom;
R 1 is a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-8 cycloalkyl group;
R 2 is an optionally substituted bicyclic fused hydrocarbon ring group or an optionally substituted bicyclic heterocyclic group.
However,
(1) When R 2 is an optionally substituted bicyclic fused hydrocarbon ring group, G 1 is a nitrogen atom;
(2) When G 1 is CH and R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group, R 2 is represented by the general formula (2-1) or (2-2)
Figure JPOXMLDOC01-appb-C000008
 (Where
X 1 , X 2 and X 3 are the same or different and are CR 3 or a nitrogen atom;
R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group,
R 4 is an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, An optionally substituted aryl group, an optionally substituted ar C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group. . ). )
［２］　Ｒ１が、塩素原子または置換されてもよいＣ３－８シクロアルキル基である、［１］に記載の化合物またはその塩を含む、固形がんの処置剤。
［３］　Ｒ２が、一般式（３－１）または（３－２）
Figure JPOXMLDOC01-appb-C000009
 （式中、
Ｘ１ａ、Ｘ２ａ、Ｘ３ａは、同一または異なって、ＣＲ５または窒素原子であり；
Ｘ４は、ＣＨまたは窒素原子であり；
Ｒ４ａは、置換されてもよいＣ１－６アルキル基、置換されてもよいアリール基または置換されてもよいアルＣ１－６アルキル基であり；
Ｒ５は、水素原子、ハロゲン原子、置換されてもよいＣ３－８シクロアルケニル基、置換されてもよいアリール基または置換されてもよい複素環式基である。）
で表される基であるか、
あるいは、Ｇ１がＣＨであり、Ｒ１が塩素原子または置換されてもよいＣ３－８シクロアルキル基の場合、Ｒ２は一般式（４－１）または（４－２）
Figure JPOXMLDOC01-appb-C000010
 （式中、
Ｘ１ｂ、Ｘ２ｂ、Ｘ３ｂは、同一または異なって、ＣＨまたは窒素原子であり；
Ｒ４ｂは、置換されてもよいアリール基、置換されてもよいアルＣ１－６アルキル基である）で表される基である、［１］または［２］に記載の化合物またはその塩を含む固形がんの処置剤。 [2] A therapeutic agent for solid cancer, comprising the compound or a salt thereof according to [1], wherein R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group.
[3] R 2 is represented by the general formula (3-1) or (3-2)
Figure JPOXMLDOC01-appb-C000009
 (Where
X 1a , X 2a , and X 3a are the same or different and are CR 5 or a nitrogen atom;
X 4 is CH or a nitrogen atom;
R 4a is an optionally substituted C 1-6 alkyl group optionally, an optionally substituted aryl group or an optionally substituted aralkyl C 1-6 alkyl group;
R 5 is a hydrogen atom, a halogen atom, an optionally substituted C 3-8 cycloalkenyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group. )
Or a group represented by
Alternatively, when G 1 is CH and R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group, R 2 is represented by the general formula (4-1) or (4-2)
Figure JPOXMLDOC01-appb-C000010
 (Where
X 1b , X 2b and X 3b are the same or different and are CH or a nitrogen atom;
R 4b is a group represented by [1] or [2], or a salt thereof, which is a group represented by an optionally substituted aryl group or an optionally substituted ar C 1-6 alkyl group) Contains solid cancer treatment.
［４］　Ｒ２が、一般式（５－１）または（５－２）
Figure JPOXMLDOC01-appb-C000011
 （式中、
Ｒ４ｃは、置換されてもよいＣ１－６アルキル基または置換されてもよいアリール基であり；
Ｒ５ｃは、水素原子、置換されてもよいアリール基または置換されてもよいＣ３－８シクロアルケニル基である。）
で表される基である、［１］から［３］のいずれか一つに記載の化合物またはその塩を含む固形がんの処置剤。
［５］　Ｇ１が、窒素原子であり、Ｒ２が、一般式（５－１）
Figure JPOXMLDOC01-appb-C000012
 （式中、
Ｒ４ｃは、置換されてもよいＣ１－６アルキル基または置換されてもよいアリール基であり；
Ｒ５ｃは、水素原子、置換されてもよいアリール基または置換されてもよい複素環式基である。）で表される基である、［１］から［４］のいずれか一つに記載の化合物またはその塩を含む固形がんの処置剤。 [4] R 2 is represented by the general formula (5-1) or (5-2)
Figure JPOXMLDOC01-appb-C000011
 (Where
R 4c is an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group;
R 5c is a hydrogen atom, an optionally substituted aryl group or an optionally substituted C 3-8 cycloalkenyl group. )
The treatment agent of solid cancer containing the compound or its salt as described in any one of [1] to [3] which is group represented by these.
[5] G 1 is a nitrogen atom, and R 2 is a group represented by the general formula (5-1)
Figure JPOXMLDOC01-appb-C000012
 (Where
R 4c is an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group;
R 5c is a hydrogen atom, an optionally substituted aryl group or an optionally substituted heterocyclic group. A therapeutic agent for solid cancer comprising the compound or salt thereof according to any one of [1] to [4], which is a group represented by:
［６］　固形がんが、肺がん、乳がん、胃がん、肝がん、大腸がん、舌がん、食道がん、膀胱がん、甲状腺がん、膵がん、腎臓がん、前立腺がん、子宮がん、卵巣がん、骨肉腫、軟骨肉腫、横紋筋肉種、平滑筋肉腫から選択される少なくとも１つである、［１］から［５］のいずれか一つに記載の化合物またはその塩を含む固形がんの処置剤。
［７］　固形がんが、肺がん、大腸がん、膵がんから選択される少なくとも１つである、［６］に記載の化合物またはその塩を含む固形がんの処置剤。
［８］　［１］～［７］のいずれか一つに記載の処置剤を含む医薬組成物。
［９］　［１］～［７］のいずれか一つに記載の処置剤を対象に投与する工程を含む、固形がんの処置方法。
［１０］　固形がんの処置において使用するための、［１］～［７］のいずれか一つに記載の処置剤。
［１１］　固形がんの処置において使用するための、上記一般式（１）で表される化合物またはその塩。
［１２］　固形がんの処置剤の製造のための、上記一般式（１）で表される化合物またはその塩の使用。 [6] Solid cancer is lung cancer, breast cancer, stomach cancer, liver cancer, colon cancer, tongue cancer, esophageal cancer, bladder cancer, thyroid cancer, pancreatic cancer, kidney cancer, prostate cancer, The compound according to any one of [1] to [5] or a compound thereof, which is at least one selected from uterine cancer, ovarian cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma Treatment for solid cancer containing salt.
[7] A treatment for solid cancer comprising the compound or salt thereof according to [6], wherein the solid cancer is at least one selected from lung cancer, colon cancer, and pancreatic cancer.
[8] A pharmaceutical composition comprising the treatment agent according to any one of [1] to [7].
[9] A method for treating solid cancer, comprising a step of administering the treatment agent according to any one of [1] to [7] to a subject.
[10] The treatment agent according to any one of [1] to [7] for use in the treatment of solid cancer.
[11] A compound represented by the above general formula (1) or a salt thereof for use in the treatment of solid cancer.
[12] Use of the compound represented by the above general formula (1) or a salt thereof for the manufacture of a therapeutic agent for solid cancer.
　本発明は、固形がんの予防または治療などの処置に有用である。 The present invention is useful for treatment such as prevention or treatment of solid cancer.
　以下、本発明について詳述する。 Hereinafter, the present invention will be described in detail.
　本発明において、特に断らない限り、各用語は以下の意味を有する。
　ハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。
　Ｃ３－６アルキル基とは、プロピル、イソプロピル、ブチル、ｓｅｃ－ブチル、イソブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチルおよびヘキシル基などの直鎖状または分枝鎖状のＣ３－６アルキル基を意味する。
　Ｃ１－６アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ－ブチル、イソブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチルおよびヘキシル基などの直鎖状または分岐鎖錠のＣ１－６アルキル基を意味する。
　Ｃ２－６アルケニル基、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、１，３－ブタジエニル、ペンテニルおよびヘキセニル基などの直鎖状または分枝鎖状のＣ２－６アルケニル基を意味する。
　Ｃ３－８シクロアルキル基とは、シクロプロピル、シクロブチル、シクロペンチルおよびシクロヘキシル基などのＣ３－８シクロアルキル基を意味する。
　Ｃ３－８シクロアルケニル基とは、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニルおよびシクロヘキサンジエニル基などのＣ３－８シクロアルケニル基を意味する。
　Ｃ３－８シクロアルキルＣ１－６アルキル基とは、シクロプロピルメチル、２－（シクロプロピル）エチル、シクロブチルメチル、２－（シクロブチル）エチル、シクロペンチルメチルおよびシクロヘキシルメチル基などのＣ３－８シクロアルキルＣ１－６アルキル基を意味する。 In the present invention, each term has the following meaning unless otherwise specified.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
C 3-6 alkyl group means a linear or branched C 3-6 alkyl group such as propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups. To do.
The C 1-6 alkyl group is a linear or branched C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups. Means a group.
Means a C 2-6 alkenyl group, straight chain or branched C 2-6 alkenyl group such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups .
C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
C 3-8 cycloalkenyl group means a C 3-8 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohexanedienyl groups.
C 3-8 Cycloalkyl C 1-6 alkyl group, cyclopropylmethyl, 2- (cyclopropyl) ethyl, cyclobutylmethyl, 2- (cyclobutyl) ethyl, C 3-8, such as cyclopentylmethyl and cyclohexylmethyl groups Means a cycloalkyl C 1-6 alkyl group.
　アリール基とは、フェニル基、二環式縮合炭化水素環基または三環式縮合炭化水素環基を意味する。
　アルＣ１－６アルキル基とは、メトキシ、エトキシ、プロポキシまたはイソプロポキシ基を意味する。
　アシル基とは、ホルミル基、スクシニル基、グルタリル基、マレオイル基、フタロイル基、Ｃ２－１２アルカノイル基、アロイル基、複素環カルボニル基または（α－置換）アミノアセチル基を意味する。 An aryl group means a phenyl group, a bicyclic condensed hydrocarbon ring group, or a tricyclic condensed hydrocarbon ring group.
An ar C 1-6 alkyl group means a methoxy, ethoxy, propoxy or isopropoxy group.
Acyl group means formyl group, succinyl group, glutaryl group, maleoyl group, phthaloyl group, C 2-12 alkanoyl group, aroyl group, heterocyclic carbonyl group or (α-substituted) aminoacetyl group.
　Ｃ２－１２アルカノイル基とは、アセチル、プロピオニル、バレリル、イソバレリルおよびピバロイル基などの直鎖状または分枝鎖状のＣ２－１２アルカノイル基を意味する。
　アロイル基とは、ベンゾイルまたはナフトイル基を意味する。
　複素環カルボニル基とは、ニコチノイル、テノイル、ピロリジノカルボニルまたはフロイル基を意味する。
　（α－置換）アミノアセチル基とは、アミノ酸（グリシン、アラニン、バリン、ロイシン、イソロイシン、セリン、トレオニン、システイン、メチオニン、アスパラギン酸、グルタミン酸、アスパラギン、グルタミン、アルギニン、リジン、ヒスチジン、ヒドロキシリジン、フェニルアラニン、チロシン、トリプトファン、プロリンおよびヒドロキシプロリンなどのアミノ酸が挙げられる。）から誘導されるＮ末端が保護されてもよい（α－置換）アミノアセチル基を意味する。 The C 2-12 alkanoyl group means a linear or branched C2-12 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
An aroyl group means a benzoyl or naphthoyl group.
The heterocyclic carbonyl group means nicotinoyl, thenoyl, pyrrolidinocarbonyl or furoyl group.
The (α-substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Tyrosine, tryptophan, proline and hydroxyproline, etc.) means the N-terminus derived from (α-substituted) aminoacetyl groups which may be protected.
　二環式縮合炭化水素環基とは、ペンタレニル、インダニル、インデニルおよびナフチル基などの一部分が水素化されてもよい２環の縮合炭化水素環を意味する。
　三環式縮合炭化水素環基とは、ビフェニレニル、アセナフテニル、アセナフチレニル、フルオレニル、フェナレニル、フェナントレニルおよびアントラセニル基などの一部分が水素化されてもよい３環の縮合炭化水素環を意味する。 The bicyclic condensed hydrocarbon ring group means a bicyclic condensed hydrocarbon ring in which a part such as pentalenyl, indanyl, indenyl and naphthyl groups may be hydrogenated.
The tricyclic fused hydrocarbon ring group means a tricyclic fused hydrocarbon ring in which a part such as biphenylenyl, acenaphthenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl and anthracenyl groups may be hydrogenated.
　複素環基とは、単環の複素環基、二環式複素環基または三環式複素環基を意味する。
　単環の複素環基とは、単環の含窒素複素環基、単環の含酸素複素環基、単環の含硫黄複素環基、単環の含窒素・酸素複素環基または単環の含窒素・硫黄複素環基を意味する。
　単環の含酸素複素環基とは、テトラヒドロフラニル、フラニル、テトラヒドロピラニル、ジヒドロピラニルまたはピラニル基を意味する。
　単環の含硫黄複素環基とは、チエニル基を意味する。
　単環の含窒素・酸素複素環基とは、オキサゾリル、イソオキサゾリル、オキサジアゾリルおよびモルホリニル基などの該環を形成する異項原子として窒素原子および酸素原子のみを含む単環の含窒素・酸素複素環基を意味する。
　単環の含窒素・硫黄複素環基とは、チアゾリル、イソチアゾリル、チアジアゾリル、チオモルホリニル、１－オキシドチオモルホリニルおよび１，１－ジオキシドチオモルホリニル基などの該環を形成する異項原子として窒素原子および硫黄原子のみを含む単環の含窒素・硫黄複素環基を意味する。 The heterocyclic group means a monocyclic heterocyclic group, a bicyclic heterocyclic group or a tricyclic heterocyclic group.
The monocyclic heterocyclic group is a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, a monocyclic nitrogen-containing / oxygen heterocyclic group, or a monocyclic heterocyclic group. This means a nitrogen-containing / sulfur heterocyclic group.
The monocyclic oxygen-containing heterocyclic group means a tetrahydrofuranyl, furanyl, tetrahydropyranyl, dihydropyranyl or pyranyl group.
The monocyclic sulfur-containing heterocyclic group means a thienyl group.
The monocyclic nitrogen-containing / oxygen heterocyclic group is a monocyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring, such as oxazolyl, isoxazolyl, oxadiazolyl and morpholinyl groups. Means.
The monocyclic nitrogen-containing / sulfur heterocyclic group is a hetero atom forming the ring such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomorpholinyl and 1,1-dioxidethiomorpholinyl groups. Means a monocyclic nitrogen-containing / sulfur heterocyclic group containing only nitrogen and sulfur atoms.
　二環式複素環基とは、二環式の含窒素複素環基、二環式の含酸素複素環基、二環式の含硫黄複素環基、二環式の含窒素・酸素複素環基または二環式の含窒素・硫黄複素環基を意味する。 Bicyclic heterocyclic groups are bicyclic nitrogen-containing heterocyclic groups, bicyclic oxygen-containing heterocyclic groups, bicyclic sulfur-containing heterocyclic groups, bicyclic nitrogen-containing and oxygen heterocyclic groups. Alternatively, it means a bicyclic nitrogen-containing / sulfur heterocyclic group.
　二環式含窒素複素環基とは、インドリニル、インドリル、イソインドリニル、イソインドリル、ピロロピリジニル、インダゾリル、ベンゾイミダゾリル、ベンゾトリアゾリル、テトラヒドロキノリニル、ジヒドロキノリニル、キノリニル、テトラヒドロキノリニル、テトラヒドロイソキノリニル、イソキノリニル、ジヒドロキナゾリニル、シンノリニル、フタラジニル、キナゾリニル、ジヒドロキノキサリニル、キノキサリニル、ナフチリジニル、プリニル、プテリジニルおよびキヌクリジニル基などの該環を形成する異項原子として窒素原子のみを含む二環式の含窒素複素環基を意味する。
　二環式含酸素複素環基とは、２，３－ジヒドロベンゾフラニル、ベンゾフラニル、イソベンゾフラニル、クロマニル、クロメニル、イソクロマニル、１，３－ベンゾジオキソリル、１，３－ベンゾジオキサニルおよび１，４－ベンゾジオキサニル基などの該環を形成する異項原子として酸素原子のみを含む二環式の含酸素複素環基を意味する。
　二環式含硫黄複素環基とは、２，３－ジヒドロベンゾチエニルおよびベンゾチエニル基などの該環を形成する異項原子として硫黄原子のみを含む二環式の含硫黄複素環基を意味する。
　二環式含窒素・酸素複素環基とは、ジヒドロベンゾオキサゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾオキサジアゾリル、ベンゾモルホリニル、ジヒドロピラノピリジル、ジヒドロジオキシノピリジルおよびジヒドロピリドオキサジニル基などの該環を形成する異項原子として窒素原子および酸素原子のみを含む二環式の含窒素・酸素複素環基を意味する。
　二環式含窒素・硫黄複素環基とは、ジヒドロベンゾチアゾリル、ベンゾチアゾリル、ベンゾイソチアゾリルおよびベンゾチアジアゾリル基などの該環を形成する異項原子として窒素原子および硫黄原子を含む二環式の含窒素・硫黄複素環基を意味する。 Bicyclic nitrogen-containing heterocyclic groups are indolinyl, indolyl, isoindolinyl, isoindolyl, pyrrolopyridinyl, indazolyl, benzimidazolyl, benzotriazolyl, tetrahydroquinolinyl, dihydroquinolinyl, quinolinyl, tetrahydroquinolinyl, tetrahydroisoxyl. Bicycles containing only nitrogen atoms as heterogeneous atoms forming the ring, such as nolinyl, isoquinolinyl, dihydroquinazolinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl and quinuclidinyl groups The nitrogen-containing heterocyclic group of the formula is meant.
Bicyclic oxygen-containing heterocyclic groups include 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromanyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl And a bicyclic oxygen-containing heterocyclic group containing only an oxygen atom as a hetero atom forming the ring, such as a 1,4-benzodioxanyl group.
The bicyclic sulfur-containing heterocyclic group means a bicyclic sulfur-containing heterocyclic group containing only a sulfur atom as a hetero atom forming the ring, such as 2,3-dihydrobenzothienyl and benzothienyl groups. .
Bicyclic nitrogen-containing / oxygen heterocyclic groups include dihydrobenzoxazolyl, benzoxazolyl, benzisoxazolyl, benzoxdiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxynopyridyl and It means a bicyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring, such as a dihydropyridoxazinyl group.
Bicyclic nitrogen-containing / sulfur heterocyclic groups include dihydrobenzothiazolyl, benzothiazolyl, benzisothiazolyl and benzothiadiazolyl groups containing nitrogen and sulfur atoms as heterogeneous atoms forming the ring. This means a cyclic nitrogen-containing / sulfur heterocyclic group.
　複素環Ｃ１－６アルキル基とは、アゼチジニルメチル、アゼチジニルエチル、ピロリジニルメチル、ピロリジニルエチル、ピペリジルメチル、ピペリジルエチル、ピリジルメチル、ピリジルエチル、イミダゾリルメチル、イミダゾリルエチル、ピペラジニルメチルおよびピペラジニルエチル基などの単環の含窒素複素環Ｃ１－６アルキル基；テトラヒドロフラニルメチル、テトラヒドロピラニルメチルなどの単環の含酸素複素環Ｃ１－６アルキル基；チエニルメチル基などの単環の含硫黄複素環Ｃ１－６アルキル基；オキサゾリルメチル、オキサゾリルエチル、イソオキサゾリルメチル、イソオキサゾリルエチル、モルホリニルメチルおよびモルホリニルエチル基などの単環の含窒素・酸素複素環Ｃ１－６アルキル基；チアゾリルメチル、チアゾリルエチル、イソチアゾリルメチルおよびイソチアゾリルエチル基などの単環の含窒素・硫黄複素環Ｃ１－６アルキル基；インドリルメチル、インドリルエチル、ベンズイミダゾリルメチル、ベンズイミダゾリルエチル、キノリルメチルおよびキノリルエチル基などの二環式含窒素複素環Ｃ１－６アルキル基；ベンゾフラニルメチル、イソベンゾフラニルメチルおよびクロマニルメチル基などの二環式の含酸素複素環Ｃ１－６アルキル基；ベンゾチエニルメチル基などの二環式含硫黄複素環Ｃ１－６アルキル基；ベンゾオキサゾリルメチルおよびベンゾイソオキサゾリルメチル基などの二環式の含窒素・酸素複素環Ｃ１－６アルキル基；ベンゾチアゾリルメチルおよびベンゾイソチアゾリルメチル基などの二環式含窒素・硫黄複素環Ｃ１－６アルキル基；カルバゾリルメチル基などの三環式含窒素複素環Ｃ１－６アルキル基；キサンテニルメチル基などの三環式含酸素複素環Ｃ１－６アルキル基ならびにチアントレニルメチル基などの三環式含硫黄複素環Ｃ１－６アルキル基を意味する。 Heterocyclic C 1-6 alkyl group means azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidylmethyl, piperidylethyl, pyridylmethyl, pyridylethyl, imidazolylmethyl, imidazolylethyl, pipepe Monocyclic nitrogen-containing heterocyclic C 1-6 alkyl groups such as razinylmethyl and piperazinylethyl groups; monocyclic oxygen-containing heterocyclic C 1-6 alkyl groups such as tetrahydrofuranylmethyl and tetrahydropyranylmethyl; thienyl Monocyclic sulfur-containing heterocyclic C 1-6 alkyl group such as methyl group; oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, isoxazolylethyl, morpholinylmethyl and morpholinylethyl groups nitrogen-containing, oxygen heterocycle C 1-6 alkyl group of one ring, such as; thiazolylmethyl Chiazoriruechiru, benzisothiazolyl methyl and iso-thiazolyl ethyl monocyclic nitrogen-containing sulfur heterocycles C 1-6 alkyl group such group; indolylmethyl, indolylethyl ethyl, benzimidazolyl methyl, benzimidazolyl ethyl, quinolylmethyl and quinolylethyl group Bicyclic nitrogen-containing heterocyclic C 1-6 alkyl group such as; bicyclic oxygen-containing heterocyclic C 1-6 alkyl group such as benzofuranylmethyl, isobenzofuranylmethyl and chromanylmethyl groups; benzothienyl A bicyclic sulfur-containing heterocyclic C 1-6 alkyl group such as a methyl group; a bicyclic nitrogen-containing / oxygen heterocyclic C 1-6 alkyl group such as a benzoxazolylmethyl and benzoisoxazolylmethyl group; Bicyclic nitrogen-containing and sulfur complex such as benzothiazolylmethyl and benzoisothiazolylmethyl groups C1-6 alkyl; tricyclic oxygen-containing heterocyclic C 1-6 alkyl group and a thianthrenyl such key Sante methylpropenylmethyl group; carbazolylphenyl tricyclic nitrogen-containing heterocyclic C 1-6 alkyl group such as methyl group It means a tricyclic sulfur-containing heterocyclic C 1-6 alkyl group such as a methyl group.
　一般式（１）の化合物の塩としては、通常知られているアミノ基などの塩基性基またはフェノール性ヒドロキシル基もしくはカルボキシル基などの酸性基における塩を挙げることができる。 Examples of the salt of the compound of the general formula (1) include a salt in a basic group such as a commonly known amino group or an acidic group such as a phenolic hydroxyl group or a carboxyl group.
　塩基性基における塩としては、たとえば、塩酸、臭化水素酸、硝酸および硫酸などの鉱酸との塩；ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩；ならびにメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩が挙げられる。 Examples of salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid Can be mentioned.
　酸性基における塩としては、たとえば、ナトリウムおよびカリウムなどのアルカリ金属との塩；カルシウムおよびマグネシウムなどのアルカリ土類金属との塩；アンモニウム塩；ならびにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、Ｎ－ベンジル－β－フェネチルアミン、１－エフェナミンおよびＮ，Ｎ’－ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などが挙げられる。 Salts in acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
　本発明の「処置」とは、予防または治療を含む。予防は、発症の阻害、発症リスクの低減、発症の遅延を含む。治療は、対象となる疾患または状態の改善または進行の抑制（維持または遅延）を含む。処置の対象は、その処置の必要のあるヒトまたは非ヒト動物を含む。 The “treatment” of the present invention includes prevention or treatment. Prevention includes inhibition of onset, reduction of risk of onset, delay of onset. Treatment includes amelioration of the disease or condition of interest or suppression (maintenance or delay) of progression. The subject of treatment includes human or non-human animals in need of such treatment.
　本発明の「剤」は、有効成分である化合物またはその塩以外に、製剤化に使用される賦形剤、担体および希釈剤などの製剤補助剤を適宜混合した組成物とすることができる。「剤」は、他の有効成分を含んでいてもよく、また他の有効成分を含む医薬と共に用いることができる。 The “agent” of the present invention can be a composition in which formulation adjuvants such as excipients, carriers and diluents used in the formulation are appropriately mixed in addition to the active ingredient compound or a salt thereof. The “agent” may contain other active ingredients and can be used together with a medicine containing other active ingredients.
　本発明の化合物において、以下の化合物が好ましい。 Among the compounds of the present invention, the following compounds are preferred.
　Ｇ１は、ＣＨまたは窒素原子である。 G 1 is CH or a nitrogen atom.
　Ｒ１は、ハロゲン原子、置換されてもよいＣ１－６アルキル基または置換されてもよいＣ３－８シクロアルキル基であり、塩素原子または置換されてもよいＣ３－８シクロアルキル基であることが好ましく、塩素原子または置換されてもよいシクロプロピル基であることがより好ましく、塩素原子またはシクロプロピル基であることがさらに好ましい。
　Ｒ１のＣ１－６アルキル基、Ｃ３－８シクロアルキル基の置換基としては、置換基群αから選択される少なくとも１種の基が挙げられる。 R 1 is a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-8 cycloalkyl group, a chlorine atom or an optionally substituted C 3-8 cycloalkyl group It is preferably a chlorine atom or an optionally substituted cyclopropyl group, more preferably a chlorine atom or a cyclopropyl group.
Examples of the substituent for the C 1-6 alkyl group and the C 3-8 cycloalkyl group represented by R 1 include at least one group selected from the substituent group α.
　Ｒ２は、置換されてもよい二環式縮合炭化水素環基または置換されてもよい二環式複素環基である。Ｒ２の二環式縮合炭化水素環基および二環式複素環基の置換基としては、置換基群αから選択される少なくとも１種の基が挙げられる。
　ただし、Ｒ２が置換されてもよい二環式縮合炭化水素環基の場合、Ｇ１は窒素原子であり；
　Ｇ１がＣＨであり、Ｒ１が塩素原子または置換されてもよいＣ３－８シクロアルキル基の場合、Ｒ２は一般式（２－１）または（２－２）で表される基である。 R 2 is an optionally substituted bicyclic fused hydrocarbon ring group or an optionally substituted bicyclic heterocyclic group. Examples of the substituent of the bicyclic condensed hydrocarbon ring group and the bicyclic heterocyclic group represented by R 2 include at least one group selected from the substituent group α.
Provided that when R 2 is an optionally substituted bicyclic fused hydrocarbon ring group, G 1 is a nitrogen atom;
When G 1 is CH and R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group, R 2 is a group represented by the general formula (2-1) or (2-2) is there.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　式中、Ｘ１、Ｘ２、Ｘ３は、同一または異なって、ＣＲ３または窒素原子であり；Ｒ３は、水素原子、ハロゲン原子、置換されてもよいＣ１－６アルキル基であり、Ｒ４は、置換されてもよいＣ３－６アルキル基、置換されてもよいＣ３－８シクロアルキル基、置換されてもよいＣ３－８シクロアルキルＣ１－６アルキル基、置換されてもよいアリール基、置換されてもよいアルＣ１－６アルキル基、置換されてもよいアシル基、置換されてもよい複素環基または置換されてもよい複素環Ｃ１－６アルキル基である。
　Ｒ３のＣ１－６アルキル基の置換基としては、置換基群αから選択される少なくとも１種の基が挙げられる。
　Ｒ４のＣ３－６アルキル基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルＣ１－６アルキル基、アリール基、アルＣ１－６アルキル基、アシル基、複素環基および複素環Ｃ１－６アルキル基の置換基としては、置換基群αから選択される少なくとも１種の基が挙げられる。 In the formula, X 1 , X 2 and X 3 are the same or different and are CR 3 or a nitrogen atom; R 3 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group; R 4 is an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, An optionally substituted aryl group, an optionally substituted ar C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group. .
Examples of the substituent for the C 1-6 alkyl group represented by R 3 include at least one group selected from substituent group α.
R 4 C 3-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl C 1-6 alkyl group, aryl group, al C 1-6 alkyl group, acyl group, heterocyclic group and heterocycle Examples of the substituent of the ring C 1-6 alkyl group include at least one group selected from substituent group α.
　Ｒ２は、一般式（３－１）または（３－２）で表される基であることが好ましい。 R 2 is preferably a group represented by the general formula (3-1) or (3-2).
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　式中、Ｘ１ａ、Ｘ２ａ、Ｘ３ａは、同一または異なって、ＣＲ５または窒素原子であり；Ｘ４は、ＣＨまたは窒素原子であり；Ｒ４ａは、置換されてもよいＣ１－６アルキル基、置換されてもよいアリール基または置換されてもよいアルＣ１－６アルキル基であり；Ｒ５は、水素原子、ハロゲン原子、置換されてもよいＣ３－８シクロアルケニル基、置換されてもよいアリール基または置換されてもよい複素環式基である。
　あるいは、Ｇ１がＣＨであり、Ｒ１が塩素原子または置換されてもよいＣ３－８シクロアルキル基の場合、Ｒ２は一般式（４－１）または（４－２）で表される基であることが好ましい。 In the formula, X 1a , X 2a and X 3a are the same or different and are CR 5 or a nitrogen atom; X 4 is CH or a nitrogen atom; R 4a is an optionally substituted C 1-6 An alkyl group, an optionally substituted aryl group or an optionally substituted ar C 1-6 alkyl group; R 5 is a hydrogen atom, a halogen atom, an optionally substituted C 3-8 cycloalkenyl group, a substituted An aryl group which may be substituted or a heterocyclic group which may be substituted.
Alternatively, when G 1 is CH and R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group, R 2 is represented by the general formula (4-1) or (4-2) It is preferably a group.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　式中、Ｘ１ｂ、Ｘ２ｂ、Ｘ３ｂは、同一または異なって、ＣＨまたは窒素原子であり；Ｒ４ｂは、置換されてもよいアリール基、置換されてもよいアルＣ１－６アルキル基で表される基である。 In the formula, X 1b , X 2b and X 3b are the same or different and are CH or a nitrogen atom; R 4b is an optionally substituted aryl group or an optionally substituted al C 1-6 alkyl group. It is a group represented.
　Ｒ４ａのＣ１－６アルキル基としては、Ｃ１－４アルキル基が好ましく、メチル基がより好ましい。
　Ｒ４ａのアリール基としては、フェニル基が好ましい。
　Ｒ４ａのアルＣ１－６アルキル基としては、フェニルメチル基であることが好ましい。
　Ｒ４ａのＣ１－６アルキル基、アリール基およびアルＣ１－６アルキル基の置換基としては、置換基群αから選択される少なくとも１種の基が挙げられる。 The C 1-6 alkyl group for R 4a is preferably a C 1-4 alkyl group, and more preferably a methyl group.
The aryl group for R 4a is preferably a phenyl group.
The al C 1-6 alkyl group for R 4a is preferably a phenylmethyl group.
Examples of the substituent for the C 1-6 alkyl group, aryl group, and al C 1-6 alkyl group of R 4a include at least one group selected from substituent group α.
　Ｒ５のハロゲン原子としては、フッ素原子であることが好ましい。
　Ｒ５のＣ３－８シクロアルケニル基としては、Ｃ３－６シクロアルキル基であることが好ましく、シクロへキセニル基であることがより好ましい。
　Ｒ５のアリール基としては、フェニル基が好ましい。
　Ｒ５のＣ３－８シクロアルケニル基、アリール基および複素環式基の置換基としては、置換基群αから選択される少なくとも１種の基が挙げられる。 The halogen atom for R 5 is preferably a fluorine atom.
The C 3-8 cycloalkenyl group for R 5 is preferably a C 3-6 cycloalkyl group, and more preferably a cyclohexenyl group.
The aryl group for R 5 is preferably a phenyl group.
Examples of the substituent of the C 3-8 cycloalkenyl group, aryl group and heterocyclic group of R 5 include at least one group selected from substituent group α.
　Ｒ４ｂのアリール基としては、フェニル基が好ましい。
　Ｒ４ｂのアルＣ１－６アルキル基としては、フェニルメチル基であることが好ましい。
　Ｒ４ｂのアリール基およびアルＣ１－６アルキル基の置換基としては、置換基群αから選択される少なくとも１種の基が挙げられる。 The aryl group for R 4b is preferably a phenyl group.
The ar C 1-6 alkyl group for R 4b is preferably a phenylmethyl group.
Examples of the substituent of the aryl group of R 4b and the al C 1-6 alkyl group include at least one group selected from the substituent group α.
　Ｒ２は、一般式（５－１）または（５－２）で表される基であることがより好ましい。 R 2 is more preferably a group represented by the general formula (5-1) or (5-2).
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　式中、Ｒ４ｃは、置換されてもよいＣ１－６アルキル基または置換されてもよいアリール基であり；Ｒ５ｃは、水素原子、置換されてもよいアリール基または置換されてもよいＣ３－８シクロアルケニル基である。 In the formula, R 4c is an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group; R 5c is a hydrogen atom, an optionally substituted aryl group or an optionally substituted C A 3-8 cycloalkenyl group.
　Ｒ４ｃのＣ１－６アルキル基としては、Ｃ１－４アルキル基が好ましく、メチル基がより好ましい。
　Ｒ４ｃのアリール基としては、フェニル基であることが好ましい。
　Ｒ４ｃのＣ１－６アルキル基およびアリール基の置換基としては、置換基群αから選択される少なくとも１種の基が挙げられる。 The C 1-6 alkyl group for R 4c is preferably a C 1-4 alkyl group, and more preferably a methyl group.
The aryl group for R 4c is preferably a phenyl group.
Examples of the substituent for the C 1-6 alkyl group and aryl group of R 4c include at least one group selected from substituent group α.
　Ｒ５ｃのアリール基としては、フェニル基であることが好ましい。
　Ｒ５ｃのＣ３－８シクロアルケニル基としては、Ｃ３－６シクロアルキル基であることが好ましく、シクロへキセニル基であることがより好ましい。
　Ｒ５ｃのアリール基およびＣ３－８シクロアルケニル基の置換基としては、置換基群αから選択される少なくとも１種の基が挙げられる。 The aryl group for R 5c is preferably a phenyl group.
The C 3-8 cycloalkenyl group for R 5c is preferably a C 3-6 cycloalkyl group, and more preferably a cyclohexenyl group.
Examples of the substituent of the aryl group of R 5c and the C 3-8 cycloalkenyl group include at least one group selected from substituent group α.
　Ｒ２は、一般式（５－１）で表される基であることがさらに好ましい。 R 2 is more preferably a group represented by the general formula (5-1).
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　式中のＲ４ｃおよびＲ５ｃは、上記と同じ意味である。
　ただし、このときＧ１は窒素原子であることが好ましい。 R 4c and R 5c in the formula have the same meaning as described above.
At this time, however, G 1 is preferably a nitrogen atom.
　置換基群α：ハロゲン原子、保護されてもよいヒドロキシル基、保護されてもよいカルボキシル基、保護されてもよいアミノ基、ニトロ基、シアノ基、置換基群βより選択される少なくとも１種の基で置換されてもよいカルバモイル基、置換基群βより選択される少なくとも１種の基で置換されてもよいＣ１－６アルキル基、置換基群βより選択される少なくとも１種の基で置換されてもよいＣ２－６アルケニル基、置換基群βより選択される少なくとも１種の基で置換されてもよいＣ３－８シクロアルキル基、置換基群βより選択される少なくとも１種の基で置換されてもよいＣ１－６アルコキシ基、置換基群βより選択される少なくとも１種の基で置換されてもよいアシル基、置換基群βより選択される少なくとも１種の基で置換されてもよいアルコキシカルボニル基、置換基群βより選択される少なくとも１種の基で置換されてもよいＣ１－６アルキルアミノ基、置換基群βより選択される少なくとも１種の基で置換されてもよいジ（Ｃ１－６アルキル）アミノ基、置換基群βより選択される少なくとも１種の基で置換されてもよいＣ１－６アルキルチオ基、置換基群βより選択される少なくとも１種の基で置換されてもよいＣ１－６アルキルスルホニル基、置換基群βより選択される少なくとも１種の基で置換されてもよいアリール基、置換基群βより選択される少なくとも１種の基で置換されてもよい複素環基、オキソ基。 Substituent group α: at least one selected from a halogen atom, a hydroxyl group that may be protected, a carboxyl group that may be protected, an amino group that may be protected, a nitro group, a cyano group, and a substituent group β A carbamoyl group which may be substituted with a group, a C 1-6 alkyl group which may be substituted with at least one group selected from substituent group β, and at least one group selected from substituent group β C 2-6 alkenyl group which may be substituted, C 3-8 cycloalkyl group which may be substituted with at least one group selected from substituent group β, at least one selected from substituent group β A C 1-6 alkoxy group that may be substituted with the above group, an acyl group that may be substituted with at least one group selected from substituent group β, and at least one group selected from substituent group β Is replaced with There alkoxycarbonyl group, at least one optionally substituted C 1-6 alkylamino group with a group selected from Substituent group beta, optionally substituted with at least one group selected from Substituent group beta A good di (C 1-6 alkyl) amino group, a C 1-6 alkylthio group optionally substituted with at least one group selected from substituent group β, and at least one selected from substituent group β A C 1-6 alkylsulfonyl group which may be substituted with a group, an aryl group which may be substituted with at least one group selected from substituent group β, and at least one group selected from substituent group β A heterocyclic group which may be substituted with an oxo group;
　置換基群β：ハロゲン原子、保護されてもよい水酸基、保護されてもよいカルボキシル基、保護されてもよいアミノ基、カルバモイル基、ハロゲン原子で置換されてもよいＣ１－６アルキル基、ハロゲン原子で置換されてもよいＣ１－６アルコキシ基、Ｃ１－６アルキルアミノ基、ジ（Ｃ１－６アルキル）アミノ基、複素環基、オキソ基。 Substituent group β: halogen atom, optionally protected hydroxyl group, optionally protected carboxyl group, optionally protected amino group, carbamoyl group, C 1-6 alkyl group optionally substituted with halogen atom, halogen An optionally substituted C 1-6 alkoxy group, a C 1-6 alkylamino group, a di (C 1-6 alkyl) amino group, a heterocyclic group, an oxo group;
　本発明中の好ましい化合物としては、以下の化合物を挙げることができる。
　２－（（１－ベンジル－１Ｈ－インダゾール－５－イル）アミノ）－５－シクロプロピルベンゾアート、２－（（１－（シクロヘキシルメチル）－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、５－シクロプロピル－２－（（１－フェニル－１Ｈ－インドール－４－イル)アミノ)ニコチン酸、５－シクロプロピル－２－（（７－（２－フルオロフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－メチル－７－（４－トリフルオロメチル）フェニル）－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、２－（（７－（３－クロロフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、５－シクロプロピル－２－（（１－メチル－７－（４－（トリフルオロメトキシ）フェニル）－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－フェニル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（５－フェニルナフタレン－１－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（５－フェニルナフタレン－２－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－メチル－７－フェニル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－（３－フルオロフェニル）－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、２－（（１－ベンジル－６－フルオロ－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、２－（（１－ベンジル－４，６－ジフルオロ－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、５－シクロプロピル－２－（（７－（３，６－ジヒドロ－２Ｈ－ピラン－４－イル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－フェニルイソキノリン－６－イル）アミノ）ニコチン酸、２－（（７－（４－シアノフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、２－（（７－（４－クロロフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、５－シクロプロピル－２－（（２－オキソ－１－フェニル－１，２－ジヒドロキノリン－５－イル）アミノ）安息香酸、２－（（7－シクロヘキス－１－エン－１－イル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸。 Preferred compounds in the present invention include the following compounds.
2-((1-Benzyl-1H-indazol-5-yl) amino) -5-cyclopropylbenzoate, 2-((1- (cyclohexylmethyl) -1H-indol-5-yl) amino) -5 Cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-phenyl-1H-indol-4-yl) amino) nicotinic acid, 5-cyclopropyl-2-((7- (2-fluorophenyl) -1 -Methyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((1-methyl-7- (4-trifluoromethyl) phenyl) -1H-indol-5-yl) amino ) Nicotinic acid, 2-((7- (3-chlorophenyl) -1-methyl-1H-indol-5-yl) amino) -5-cyclopropylnicotinic acid, 5-cyclopro 2-((1-Methyl-7- (4- (trifluoromethoxy) phenyl) -1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((1-phenyl-1H -Indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((5-phenylnaphthalen-1-yl) amino) nicotinic acid, 5-cyclopropyl-2-((5-phenylnaphthalene-2 -Yl) amino) nicotinic acid, 5-cyclopropyl-2-((1-methyl-7-phenyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((1- ( 3-fluorophenyl) -1H-indol-5-yl) amino) nicotinic acid, 2-((1-benzyl-6-fluoro-1H-indol-5-yl) amino) -5-cyclop Lopirnicotinic acid, 2-((1-benzyl-4,6-difluoro-1H-indol-5-yl) amino) -5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((7- (3,6 -Dihydro-2H-pyran-4-yl) -1-methyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((1-phenylisoquinolin-6-yl) amino) nicotine Acid, 2-((7- (4-cyanophenyl) -1-methyl-1H-indol-5-yl) amino) -5-cyclopropylnicotinic acid, 2-((7- (4-chlorophenyl) -1 -Methyl-1H-indol-5-yl) amino) -5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((2-oxo-1-phenyl-1,2-dihydroquinoline-5 ) Amino) benzoic acid, 2 - ((7-cyclohex-1-en-1-yl) -1-methyl -1H- indol-5-yl) amino) -5-cyclopropyl-nicotinic acid.
　本発明の化合物としては、２－（（１－ベンジル－１Ｈ－インダゾール－５－イル）アミノ）－５－シクロプロピルベンゾアート、５－シクロプロピル－２－（（１－フェニル－１Ｈ－インドール－４－イル)アミノ)ニコチン酸、５－シクロプロピル－２－（（７－（２－フルオロフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－メチル－７－（４－トリフルオロメチル）フェニル）－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、２－（（７－（３－クロロフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、５－シクロプロピル－２－（（１－メチル－７－（４－（トリフルオロメトキシ）フェニル）－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－フェニル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（５－フェニルナフタレン－１－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（５－フェニルナフタレン－２－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－メチル－７－フェニル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－（３－フルオロフェニル）－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、２－（（１－ベンジル－６－フルオロ－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、２－（（１－ベンジル－４，６－ジフルオロ－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、５－シクロプロピル－２－（（７－（３，６－ジヒドロ－２Ｈ－ピラン－４－イル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－フェニルイソキノリン－６－イル）アミノ）ニコチン酸、２－（（７－（４－シアノフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、２－（（７－（４－クロロフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、５－シクロプロピル－２－（（２－オキソ－１－フェニル－１，２－ジヒドロキノリン－５－イル）アミノ）安息香酸および２－（（7－シクロヘキス－１－エン－１－イル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸から選択される少なくとも１種の化合物またはその塩であることがより好ましい。 The compounds of the present invention include 2-((1-benzyl-1H-indazol-5-yl) amino) -5-cyclopropylbenzoate, 5-cyclopropyl-2-((1-phenyl-1H-indole- 4-yl) amino) nicotinic acid, 5-cyclopropyl-2-((7- (2-fluorophenyl) -1-methyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2 -((1-methyl-7- (4-trifluoromethyl) phenyl) -1H-indol-5-yl) amino) nicotinic acid, 2-((7- (3-chlorophenyl) -1-methyl-1H- Indol-5-yl) amino) -5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-methyl-7- (4- (trifluoromethoxy) phenyl) -1H-i Dol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((1-phenyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((5-phenylnaphthalene) -1-yl) amino) nicotinic acid, 5-cyclopropyl-2-((5-phenylnaphthalen-2-yl) amino) nicotinic acid, 5-cyclopropyl-2-((1-methyl-7-phenyl-) 1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((1- (3-fluorophenyl) -1H-indol-5-yl) amino) nicotinic acid, 2-((1- Benzyl-6-fluoro-1H-indol-5-yl) amino) -5-cyclopropylnicotinic acid, 2-((1-benzyl-4,6-difluoro-1H-indole-5) -Yl) amino) -5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((7- (3,6-dihydro-2H-pyran-4-yl) -1-methyl-1H-indole-5 Yl) amino) nicotinic acid, 5-cyclopropyl-2-((1-phenylisoquinolin-6-yl) amino) nicotinic acid, 2-((7- (4-cyanophenyl) -1-methyl-1H-indole -5-yl) amino) -5-cyclopropylnicotinic acid, 2-((7- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) amino) -5-cyclopropylnicotinic acid, 5 -Cyclopropyl-2-((2-oxo-1-phenyl-1,2-dihydroquinolin-5-yl) amino) benzoic acid and 2-((7-cyclohex-1-en-1-yl)- 1-Me More preferred is at least one compound selected from til-1H-indol-5-yl) amino) -5-cyclopropylnicotinic acid or a salt thereof.
　本発明の化合物としては、５－シクロプロピル－２－（（７－（２－フルオロフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－メチル－７－（４－トリフルオロメチル）フェニル）－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、２－（（７－（３－クロロフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、５－シクロプロピル－２－（（１－メチル－７－（４－（トリフルオロメトキシ）フェニル）－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－フェニル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（５－フェニルナフタレン－２－イル）アミノ）ニコチン酸、５－シクロプロピル－２－（（１－メチル－７－フェニル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、２－（（１－ベンジル－４，６－ジフルオロ－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸、５－シクロプロピル－２－（（７－（３，６－ジヒドロ－２Ｈ－ピラン－４－イル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）ニコチン酸、２－（（７－（４－クロロフェニル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸および２－（（7－シクロヘキス－１－エン－１－イル）－１－メチル－１Ｈ－インドール－５－イル）アミノ）－５－シクロプロピルニコチン酸から選択される少なくとも１種の化合物またはその塩であることがさらに好ましい。 Examples of the compound of the present invention include 5-cyclopropyl-2-((7- (2-fluorophenyl) -1-methyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2- ( (1-Methyl-7- (4-trifluoromethyl) phenyl) -1H-indol-5-yl) amino) nicotinic acid, 2-((7- (3-chlorophenyl) -1-methyl-1H-indole- 5-yl) amino) -5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-methyl-7- (4- (trifluoromethoxy) phenyl) -1H-indol-5-yl) amino) Nicotinic acid, 5-cyclopropyl-2-((1-phenyl-1H-indol-5-yl) amino) nicotinic acid, 5-cyclopropyl-2-((5-phenylnaphthalene- -Yl) amino) nicotinic acid, 5-cyclopropyl-2-((1-methyl-7-phenyl-1H-indol-5-yl) amino) nicotinic acid, 2-((1-benzyl-4,6- Difluoro-1H-indol-5-yl) amino) -5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((7- (3,6-dihydro-2H-pyran-4-yl) -1-methyl -1H-indol-5-yl) amino) nicotinic acid, 2-((7- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) amino) -5-cyclopropylnicotinic acid and 2- ((7-cyclohex-1-en-1-yl) -1-methyl-1H-indol-5-yl) amino) at least one compound selected from 5-cyclopropylnicotinic acid or More preferably a salt.
　本発明の好ましい塩としては、薬理学的に許容される塩を挙げることができる。
　一般式（１）で表わされる化合物において、異性体（たとえば、光学異性体、幾何異性体および互変異性体など）が存在する場合、本発明は、それらの異性体を包含し、また、溶媒和物、水和物および種々の形状の結晶を包含するものである。 Preferred salts of the present invention include pharmacologically acceptable salts.
In the compound represented by the general formula (1), when isomers (for example, optical isomers, geometric isomers, tautomers and the like) exist, the present invention includes those isomers, It includes hydrates, hydrates and crystals of various shapes.
　固形がんとしては、肺がん、乳がん、胃がん、肝がん、大腸がん、舌がん、食道がん、膀胱がん、甲状腺がん、膵がん、腎臓がん、前立腺がん、子宮がん、卵巣がん、骨肉腫、軟骨肉腫、横紋筋肉種、平滑筋肉腫などを挙げることができる。
　本発明の固形がんとしては、肺がん、大腸がん、膵がんから選択される少なくとも１つであることが好ましい。 Solid cancers include lung cancer, breast cancer, stomach cancer, liver cancer, colon cancer, tongue cancer, esophageal cancer, bladder cancer, thyroid cancer, pancreatic cancer, kidney cancer, prostate cancer, and uterus. Ovarian cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma and the like.
The solid cancer of the present invention is preferably at least one selected from lung cancer, colon cancer and pancreatic cancer.
　次に本発明化合物の製造方法について説明する。
　本発明化合物は、国際公開第２０１４／０６９５１０に記載の製造方法にしたがって製造することができるが、これに限定されない。 Next, the manufacturing method of this invention compound is demonstrated.
Although this invention compound can be manufactured in accordance with the manufacturing method of international publication 2014/066951, it is not limited to this.
　医薬組成物とは、有効成分である本発明の化合物またはその塩以外に、製剤化に使用される賦形剤、担体および希釈剤などの製剤補助剤を適宜混合した組成物を意味する。 The pharmaceutical composition means a composition obtained by appropriately mixing formulation adjuvants such as excipients, carriers and diluents used for formulation in addition to the compound of the present invention or a salt thereof as an active ingredient.
　本発明を医薬組成物として用いる場合、通常、製剤化に使用される賦形剤、担体および希釈剤などの製剤補助剤を適宜混合してもよい。
　添加剤としては、たとえば、賦形剤、崩壊剤、結合剤、滑沢剤、矯味剤、着色剤、着香剤、界面活性剤、コーティング剤および可塑剤などが挙げられる。
　賦形剤としては、たとえば、エリスリトール、マンニトール、キシリトールおよびソルビトールなどの糖アルコール類；白糖、粉糖、乳糖およびブドウ糖などの糖類；α－シクロデキストリン、β－シクロデキストリンおよびスルホブチルエーテルβ－シクロデキストリンナトリウムなどのシクロデキストリン類；結晶セルロースおよび微結晶セルロースなどのセルロース類；ならびにトウモロコシデンプン、バレイショデンプンおよびアルファー化デンプンなどのでんぷん類が挙げられる。
　崩壊剤としては、たとえば、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、クロスポピドン、低置換度ヒドロキシプロピルセルロースおよび部分α化デンプンなどが挙げられる。
　結合剤としては、たとえば、ヒドロキシプロピルセルロース、カルメロースナトリウムおよびメチルセルロースなどが挙げられる。
　滑沢剤としては、たとえば、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、含水二酸化ケイ素、軽質無水ケイ酸およびショ糖脂肪酸エステルなどが挙げられる。
　矯味剤としては、たとえば、アスパルテーム、サッカリン、ステビア、ソーマチンおよびアセスルファムカリウムなどが挙げられる。
　着色剤としては、たとえば、二酸化チタン、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、食用赤色102号、食用黄色４号および食用黄色５号などが挙げられる。
　着香剤としては、たとえば、オレンジ油、レモン油、ハッカ油およびパインオイルなどの精油；オレンジエッセンスおよびペパーミントエッセンスなどのエッセンス；チェリーフレーバー、バニラフレーバーおよびフルーツフレーバーなどのフレーバー；アップルミクロン、バナナミクロン、ピーチミクロン、ストロベリーミクロンおよびオレンジミクロンなどの粉末香料；バニリン；ならびにエチルバニリンが挙げられる。
　界面活性剤としては、たとえば、ラウリル硫酸ナトリウム、スルホコハク酸ジオクチルナトリウム、ポリソルベートおよびポリオキシエチレン硬化ヒマシ油などが挙げられる。
　コーティング剤としては、たとえば、ヒドロキシプロピルメチルセルロース、アミノアルキルメタクリレートコポリマーＥ、アミノアルキルメタクリレートコポリマーＲＳ、エチルセルロース、酢酸フタル酸セルロース、ヒドロキシプロピルメチルセルロースフタレート、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＬＤおよびメタクリル酸コポリマーＳなどが挙げられる。
　可塑剤としては、たとえば、クエン酸トリエチル、マクロゴール、トリアセチンおよびプロピレングリコールなどが挙げられる。
　これらの添加物は、いずれか一種または二種以上を組み合わせて用いてもよい。 When the present invention is used as a pharmaceutical composition, formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed.
Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a corrigent, a colorant, a flavoring agent, a surfactant, a coating agent, and a plasticizer.
Examples of excipients include sugar alcohols such as erythritol, mannitol, xylitol, and sorbitol; sugars such as sucrose, powdered sugar, lactose, and glucose; α-cyclodextrin, β-cyclodextrin, and sulfobutyl ether β-cyclodextrin sodium Cyclodextrins such as; celluloses such as crystalline cellulose and microcrystalline cellulose; and starches such as corn starch, potato starch and pregelatinized starch.
Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, and partially pregelatinized starch.
Examples of the binder include hydroxypropylcellulose, carmellose sodium and methylcellulose.
Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, light anhydrous silicic acid, and sucrose fatty acid ester.
Examples of the corrigent include aspartame, saccharin, stevia, thaumatin, and acesulfame potassium.
Examples of the colorant include titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, edible red No. 102, edible yellow No. 4, and edible yellow No. 5.
Examples of flavoring agents include essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, Powder fragrances such as peach micron, strawberry micron and orange micron; vanillin; and ethyl vanillin.
Examples of the surfactant include sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate, and polyoxyethylene hydrogenated castor oil.
Examples of the coating agent include hydroxypropyl methylcellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S. Is mentioned.
Examples of the plasticizer include triethyl citrate, macrogol, triacetin, and propylene glycol.
These additives may be used alone or in combination of two or more.
　配合量は、特に限定されず、それぞれの目的に応じ、その効果が充分に発現されるよう適宜配合すればよい。
　これらは、常法にしたがって、錠剤、カプセル剤、散剤、シロップ剤、課粒剤、丸剤、懸濁剤、乳剤、液剤、紛体製剤、坐剤、点眼剤、点鼻剤、点耳剤、貼付剤、軟膏剤または注射剤などの形態で、経口または非経口で投与することができる。また、投与方法、投与量および投与回数は、患者の年齢、体重および症状に応じて適宜選択することができる。
　通常、成人に対しては、経口または非経口投与により、１日、0.01～1000ｍｇ／ｋｇを１回から数回に分割して投与すればよい。 The blending amount is not particularly limited, and may be blended appropriately so that the effect is sufficiently exhibited according to each purpose.
These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, It can be administered orally or parenterally in the form of a patch, ointment or injection. In addition, the administration method, the dose, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient.
In general, for adults, 0.01 to 1000 mg / kg may be divided into 1 to several times a day by oral or parenteral administration.
　本発明を、実施例を挙げて説明するが、本発明はこれらに限定されるものではない。 The present invention will be described with reference to examples, but the present invention is not limited thereto.
［化合物番号１～２０の製造］
　国際公開第２０１４／０６９５１０に記載の製造方法にしたがって、表１～表３に記載される化合物を製造した。 [Production of Compound Nos. 1 to 20]
According to the production method described in International Publication No. 2014/066951, the compounds listed in Tables 1 to 3 were produced.
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
［細胞増殖試験］
　ヒト非細胞性上皮肺がん由来細胞株H460（住商ファーマインターナショナル株式会社）、ヒト大腸がん由来細胞株HCT15（American Type Culture Collection (ATCC)社）、ヒト膵臓がん由来細胞株MIA-Paca2（国立研究開発法人　医薬基盤・健康・栄養研究所　JCRB細胞バンク）を用いて、細胞増殖試験を行った。細胞の培養液はRPMI1640 (Thermo Fisher Scientific社, 11875-093)に10% Fetal Bovine Serum (Thermo Fisher Scientific社, 10427-028)を加えたものを使用した。H460、HCT15及びMIA-Paca2細胞を3000 cells/100 μL/wellで、96wellプレート(Corning, 3903)に播種した。一晩培養後、所定の濃度の化合物を添加し、4日後に細胞増殖をCell Titer-Glo（登録商標）Luminescent Cell Viability Assay (Promega, G7572)で測定した。各試験化合物濃度における増殖阻害率を下式にて算出した。 [Cell proliferation test]
Human non-cellular epithelial lung cancer-derived cell line H460 (Sumitomo Pharma International Co., Ltd.), human colon cancer-derived cell line HCT15 (American Type Culture Collection (ATCC)), human pancreatic cancer-derived cell line MIA-Paca2 (national research) A cell proliferation test was conducted using the JCRB Cell Bank. The cell culture medium was RPMI1640 (Thermo Fisher Scientific, 11875-093) plus 10% Fetal Bovine Serum (Thermo Fisher Scientific, 10427-028). H460, HCT15 and MIA-Paca2 cells were seeded in a 96-well plate (Corning, 3903) at 3000 cells / 100 μL / well. After overnight culture, a predetermined concentration of the compound was added, and after 4 days, cell proliferation was measured by Cell Titer-Glo (registered trademark) Luminescent Cell Viability Assay (Promega, G7572). The growth inhibition rate at each test compound concentration was calculated by the following formula.
　各化合物濃度における増殖阻害率を求め、XLfitを用いて50% 増殖阻害濃度［GI50（μmol/L）］を算出した。
　増殖阻害率（％）＝（試験化合物添加ウェル発光量）÷（ＤＭＳＯ添加ウェル発光量）×１００ The growth inhibition rate at each compound concentration was determined, and a 50% growth inhibitory concentration [GI50 (μmol / L)] was calculated using XLfit.
Growth inhibition rate (%) = (luminescence amount of well added with test compound) / (luminescence amount of well added with DMSO) × 100
　結果を表４～表６に示す。
　なお、表中の略語は、以下の意味を有する。また、表中の数値は上述の増殖阻害濃度を表し、単位はμmol/Lである。
　Ａ：３種の細胞におけるGI50値がすべて0.1μmol/L未満であった化合物
　Ｂ：１種以上の細胞においてGI50値が0.1μmol/L以上1.0μmol/L未満であり、
　　　且つ、すべての細胞種においてGI50値が1.0μmol/L未満であった化合物
　Ｃ：いずれか１種の細胞においてGI50値が1.0μmol/L以上であった化合物 The results are shown in Tables 4-6.
In addition, the abbreviation in a table | surface has the following meaning. Moreover, the numerical value in a table | surface represents the above-mentioned growth inhibitory concentration, and a unit is micromol / L.
A: Compounds in which GI50 values in all three types of cells were all less than 0.1 μmol / L B: GI50 values in one or more types of cells were 0.1 to 0.1 μmol / L,
A compound having a GI50 value of less than 1.0 μmol / L in all cell types C: A compound having a GI50 value of 1.0 μmol / L or more in any one cell type
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
　化合物番号１～２０は、優れた細胞増殖抑制効果を示した。 Compound Nos. 1 to 20 showed an excellent cell growth inhibitory effect.
　本発明の化合物またはその塩は、優れた固形がん細胞の増殖抑制効果を有することから、固形がんの予防または治療などの処置に有用である。
  Since the compound of the present invention or a salt thereof has an excellent effect of suppressing the growth of solid cancer cells, it is useful for treatment such as prevention or treatment of solid cancer.

Claims (8)

  1. 一般式（１）で表される化合物またはその塩を含む固形がんの処置剤。
    Figure JPOXMLDOC01-appb-C000001
     （式中、
    Ｇ１は、ＣＨまたは窒素原子であり；
    Ｒ１は、ハロゲン原子、置換されてもよいＣ１－６アルキル基または置換されてもよいＣ３－８シクロアルキル基であり；
    Ｒ２は、置換されてもよい二環式縮合炭化水素環基または置換されてもよい二環式複素環基である。
    ただし、
    （１）Ｒ２が置換されてもよい二環式縮合炭化水素環基の場合、Ｇ１は窒素原子であり；
    （２）Ｇ１がＣＨであり、Ｒ１が塩素原子または置換されてもよいＣ３－８シクロアルキル基の場合、Ｒ２は一般式（２－１）または（２－２）
    Figure JPOXMLDOC01-appb-C000002
     （式中、
    Ｘ１、Ｘ２、Ｘ３は、同一または異なって、ＣＲ３または窒素原子であり；
    Ｒ３は、水素原子、ハロゲン原子、置換されてもよいＣ１－６アルキル基であり、
    Ｒ４は、置換されてもよいＣ３－６アルキル基、置換されてもよいＣ３－８シクロアルキル基、置換されてもよいＣ３－８シクロアルキルＣ１－６アルキル基、置換されてもよいアリール基、置換されてもよいアルＣ１－６アルキル基、置換されてもよいアシル基、置換されてもよい複素環基または置換されてもよい複素環Ｃ１－６アルキル基である。）で表される基である。）     The treatment agent of solid cancer containing the compound or its salt represented by General formula (1).
    Figure JPOXMLDOC01-appb-C000001
     (Where
    G 1 is CH or a nitrogen atom;
    R 1 is a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-8 cycloalkyl group;
    R 2 is an optionally substituted bicyclic fused hydrocarbon ring group or an optionally substituted bicyclic heterocyclic group.
    However,
    (1) When R 2 is an optionally substituted bicyclic fused hydrocarbon ring group, G 1 is a nitrogen atom;
    (2) When G 1 is CH and R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group, R 2 is represented by the general formula (2-1) or (2-2)
    Figure JPOXMLDOC01-appb-C000002
     (Where
    X 1 , X 2 and X 3 are the same or different and are CR 3 or a nitrogen atom;
    R 3 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group,
    R 4 is an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, An optionally substituted aryl group, an optionally substituted ar C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group. . ). )
  2. Ｒ１が、塩素原子または置換されてもよいＣ３－８シクロアルキル基である、請求項１に記載の化合物またはその塩を含む、固形がんの処置剤。 The therapeutic agent of solid cancer containing the compound or its salt of Claim 1 whose R < 1 > is a chlorine atom or the C3-8 cycloalkyl group which may be substituted.
  3. Ｒ２が、一般式（３－１）または（３－２）
    Figure JPOXMLDOC01-appb-C000003
     （式中、
    Ｘ１ａ、Ｘ２ａ、Ｘ３ａは、同一または異なって、ＣＲ５または窒素原子であり；
    Ｘ４は、ＣＨまたは窒素原子であり；
    Ｒ４ａは、置換されてもよいＣ１－６アルキル基、置換されてもよいアリール基または置換されてもよいアルＣ１－６アルキル基であり；
    Ｒ５は、水素原子、ハロゲン原子、置換されてもよいＣ３－８シクロアルケニル基、置換されてもよいアリール基または置換されてもよい複素環式基である。）
    で表される基であるか、
    あるいは、Ｇ１がＣＨであり、Ｒ１が塩素原子または置換されてもよいＣ３－８シクロアルキル基の場合、Ｒ２は一般式（４－１）または（４－２）
    Figure JPOXMLDOC01-appb-C000004
     （式中、
    Ｘ１ｂ、Ｘ２ｂ、Ｘ３ｂは、同一または異なって、ＣＨまたは窒素原子であり；
    Ｒ４ｂは、置換されてもよいアリール基、置換されてもよいアルＣ１－６アルキル基である）で表される基である、請求項１または２に記載の化合物またはその塩を含む固形がんの処置剤。     R 2 is represented by the general formula (3-1) or (3-2)
    Figure JPOXMLDOC01-appb-C000003
     (Where
    X 1a , X 2a , and X 3a are the same or different and are CR 5 or a nitrogen atom;
    X 4 is CH or a nitrogen atom;
    R 4a is an optionally substituted C 1-6 alkyl group optionally, an optionally substituted aryl group or an optionally substituted aralkyl C 1-6 alkyl group;
    R 5 is a hydrogen atom, a halogen atom, an optionally substituted C 3-8 cycloalkenyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group. )
    Or a group represented by
    Alternatively, when G 1 is CH and R 1 is a chlorine atom or an optionally substituted C 3-8 cycloalkyl group, R 2 is represented by the general formula (4-1) or (4-2)
    Figure JPOXMLDOC01-appb-C000004
     (Where
    X 1b , X 2b and X 3b are the same or different and are CH or a nitrogen atom;
    R 4b is an aryl group which may be substituted, or a group represented by an optionally substituted ar C 1-6 alkyl group), or a solid containing the compound or a salt thereof according to claim 1 or 2 Cancer treatment.
  4. Ｒ２が、一般式（５－１）または（５－２）
    Figure JPOXMLDOC01-appb-C000005
     （式中、
    Ｒ４ｃは、置換されてもよいＣ１－６アルキル基または置換されてもよいアリール基であり；
    Ｒ５ｃは、水素原子、置換されてもよいアリール基または置換されてもよいＣ３－８シクロアルケニル基である。）
    で表される基である、請求項１から３のいずれか一項に記載の化合物またはその塩を含む固形がんの処置剤。     R 2 is represented by the general formula (5-1) or (5-2)
    Figure JPOXMLDOC01-appb-C000005
     (Where
    R 4c is an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group;
    R 5c is a hydrogen atom, an optionally substituted aryl group or an optionally substituted C 3-8 cycloalkenyl group. )
    The treatment agent of solid cancer containing the compound or its salt as described in any one of Claim 1 to 3 which is group represented by these.
  5. Ｇ１が、窒素原子であり、Ｒ２が、一般式（５－１）
    Figure JPOXMLDOC01-appb-C000006
     （式中、
    Ｒ４ｃは、置換されてもよいＣ１－６アルキル基または置換されてもよいアリール基であり；
    Ｒ５ｃは、水素原子、置換されてもよいアリール基または置換されてもよい複素環式基である。）で表される基である、請求項１から４のいずれか一項に記載の化合物またはその塩を含む固形がんの処置剤。     G 1 is a nitrogen atom, and R 2 is a group represented by the general formula (5-1)
    Figure JPOXMLDOC01-appb-C000006
     (Where
    R 4c is an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group;
    R 5c is a hydrogen atom, an optionally substituted aryl group or an optionally substituted heterocyclic group. The treatment agent of solid cancer containing the compound or its salt as described in any one of Claim 1 to 4 which is group represented by this.
  6. 固形がんが、肺がん、乳がん、胃がん、肝がん、大腸がん、舌がん、食道がん、膀胱がん、甲状腺がん、膵がん、腎臓がん、前立腺がん、子宮がん、卵巣がん、骨肉腫、軟骨肉腫、横紋筋肉種、平滑筋肉腫から選択される少なくとも１つである、請求項１から５のいずれか一項に記載の化合物またはその塩を含む固形がんの処置剤。 Solid cancer is lung cancer, breast cancer, stomach cancer, liver cancer, colon cancer, tongue cancer, esophageal cancer, bladder cancer, thyroid cancer, pancreatic cancer, kidney cancer, prostate cancer, uterine cancer A solid containing the compound or a salt thereof according to any one of claims 1 to 5, which is at least one selected from ovarian cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, and leiomyosarcoma. Treatment agent.
  7. 固形がんが、肺がん、大腸がん、膵がんから選択される少なくとも１つである、請求項６に記載の化合物またはその塩を含む固形がんの処置剤。 The treatment agent of solid cancer containing the compound or its salt of Claim 6 whose solid cancer is at least 1 selected from lung cancer, colon cancer, and pancreatic cancer.
  8. 請求項１～７のいずれか一項に記載の処置剤を含む医薬組成物。 A pharmaceutical composition comprising the treatment agent according to any one of claims 1 to 7.
PCT/JP2019/022540 2018-06-06 2019-06-06 Solid cancer treatment agent and medicinal composition WO2019235572A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001302667A (en) * 2000-04-28 2001-10-31 Bayer Ag Imidazopyrimidine derivative and triazolopyrimidine derivative
JP2002540103A (en) * 1999-03-19 2002-11-26 パーカー ヒューズ インスティテュート Quinazolines and their therapeutic use
WO2009021696A1 (en) * 2007-08-10 2009-02-19 Almirall, S.A. Azabiphenylaminobenzoic acid derivatives as dhodh inhibitors
JP2010504298A (en) * 2006-09-21 2010-02-12 エフ．ホフマン−ラ ロシュ アーゲー Oxindole derivatives
JP2010520268A (en) * 2007-03-05 2010-06-10 バイオリポックス・アーベー New methylenebisphenyl compounds useful for the treatment of inflammation
WO2014069510A1 (en) * 2012-10-31 2014-05-08 富山化学工業株式会社 Novel amine derivative or salt thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002540103A (en) * 1999-03-19 2002-11-26 パーカー ヒューズ インスティテュート Quinazolines and their therapeutic use
JP2001302667A (en) * 2000-04-28 2001-10-31 Bayer Ag Imidazopyrimidine derivative and triazolopyrimidine derivative
JP2010504298A (en) * 2006-09-21 2010-02-12 エフ．ホフマン−ラ ロシュ アーゲー Oxindole derivatives
JP2010520268A (en) * 2007-03-05 2010-06-10 バイオリポックス・アーベー New methylenebisphenyl compounds useful for the treatment of inflammation
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