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WO2019235572A1 - Agent de traitement et composition médicinale contre le cancer solide - Google Patents

Agent de traitement et composition médicinale contre le cancer solide 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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group
optionally substituted
cancer
alkyl group
represented
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Japanese (ja)
Inventor
北澤　諭
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Fujifilm Corp
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Fujifilm Corp
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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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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention aborde le problème de la fourniture d'un agent de traitement et d'une composition médicinale pour la prévention ou le traitement efficaces d'un cancer solide. La présente invention concerne un agent de traitement contre le cancer solide contenant un composé représenté par la formule générale (1) ou un sel de celui-ci.
PCT/JP2019/022540 2018-06-06 2019-06-06 Agent de traitement et composition médicinale contre le cancer solide Ceased WO2019235572A1 (fr)

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JP2018-108730 2018-06-06
JP2018108730 2018-06-06

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WO2019235572A1 true WO2019235572A1 (fr) 2019-12-12

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001302667A (ja) * 2000-04-28 2001-10-31 Bayer Ag イミダゾピリミジン誘導体およびトリアゾロピリミジン誘導体
JP2002540103A (ja) * 1999-03-19 2002-11-26 パーカー ヒューズ インスティテュート キナゾリン類およびそれらの治療上における使用方法
WO2009021696A1 (fr) * 2007-08-10 2009-02-19 Almirall, S.A. Dérivés d'acide azabiphénylaminobenzoïque comme inhibiteurs de la dhodh
JP2010504298A (ja) * 2006-09-21 2010-02-12 エフ．ホフマン−ラ ロシュ アーゲー オキシンドール誘導体
JP2010520268A (ja) * 2007-03-05 2010-06-10 バイオリポックス・アーベー 炎症の治療に有用な新しいメチレンビスフェニル化合物
WO2014069510A1 (fr) * 2012-10-31 2014-05-08 富山化学工業株式会社 Nouveau dérivé d'amine ou sel correspondant

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002540103A (ja) * 1999-03-19 2002-11-26 パーカー ヒューズ インスティテュート キナゾリン類およびそれらの治療上における使用方法
JP2001302667A (ja) * 2000-04-28 2001-10-31 Bayer Ag イミダゾピリミジン誘導体およびトリアゾロピリミジン誘導体
JP2010504298A (ja) * 2006-09-21 2010-02-12 エフ．ホフマン−ラ ロシュ アーゲー オキシンドール誘導体
JP2010520268A (ja) * 2007-03-05 2010-06-10 バイオリポックス・アーベー 炎症の治療に有用な新しいメチレンビスフェニル化合物
WO2009021696A1 (fr) * 2007-08-10 2009-02-19 Almirall, S.A. Dérivés d'acide azabiphénylaminobenzoïque comme inhibiteurs de la dhodh
WO2014069510A1 (fr) * 2012-10-31 2014-05-08 富山化学工業株式会社 Nouveau dérivé d'amine ou sel correspondant

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