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US20090053236A1 - USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR - Google Patents

USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR Download PDF

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Publication number
US20090053236A1
US20090053236A1 US12/092,539 US9253906A US2009053236A1 US 20090053236 A1 US20090053236 A1 US 20090053236A1 US 9253906 A US9253906 A US 9253906A US 2009053236 A1 US2009053236 A1 US 2009053236A1
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quinolinecarboxamide
chloro
methoxy
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Yuji Yamamoto
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Eisai R&D Management Co Ltd
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Eisai R&D Management Co Ltd
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Assigned to EISAI R&D MANAGEMENT CO., LTD. reassignment EISAI R&D MANAGEMENT CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YAMAMOTO, YUJI
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition and a kit comprising a combination of a compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof (hereinafter, also referred to as a “compound of the invention”) and a substance having a c-kit kinase-inhibiting activity (hereinafter, also referred to as a “c-kit inhibitor”), to a method for treating cancer comprising administering an effective amount of the pharmaceutical composition to a patient, to use of the compound of the invention for producing the pharmaceutical composition, and to the compound of the invention used for the pharmaceutical composition.
  • a compound represented by Formula (I) a pharmacologically acceptable salt thereof or a solvate thereof
  • c-kit inhibitor substance having a c-kit kinase-inhibiting activity
  • chemotherapeutic agents for cancer examples include alkylating agents such as cyclophosphamide, antimetabolites such as methotrexate and fluorouracil, antibiotics such as adriamycin, mitomycin and bleomycin, plant-derived taxol, vincristine and etoposide and metal complexes such as cisplatin. None of them, however, provides sufficient antitumor effect, and thus development of a novel antitumor drug has been strongly desired.
  • alkylating agents such as cyclophosphamide
  • antimetabolites such as methotrexate and fluorouracil
  • antibiotics such as adriamycin, mitomycin and bleomycin
  • plant-derived taxol vincristine and etoposide
  • metal complexes such as cisplatin. None of them, however, provides sufficient antitumor effect, and thus development of a novel antitumor drug has been strongly desired.
  • imatinib 4-(4-methylpiperazine-1-ylmethyl)-N-[4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl]benzenamide
  • imatinib 4-(4-methylpiperazine-1-ylmethyl)-N-[4-methyl-3-[4-(3-pyridyl)pyrimidine-2-ylamino]phenyl]benzenamide
  • the present invention was achieved regarding the circumstances described above.
  • the problem to be solved by the invention is to find a pharmaceutical composition having an excellent antitumor effect and a method for treating cancer.
  • the present invention relates to:
  • a pharmaceutical composition comprising a combination of a compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof and a substance having a c-kit kinase-inhibiting activity.
  • a kit comprising: (a) at least one selected from the group consisting of a package, an instruction and an attached document describing combined use of a compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof and a substance having a c-kit kinase-inhibiting activity; and (b) a pharmaceutical composition comprising a compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof.
  • a kit comprising a set of a formulation containing a compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof, and a formulation containing a substance having a c-kit kinase-inhibiting activity.
  • a pharmaceutical composition comprising a compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof which is administered to a patient with a substance having a c-kit kinase-inhibiting activity.
  • a method for treating cancer comprising administering an effective amount of a compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof and an effective amount of a substance having a c-kit kinase-inhibiting activity to a patient.
  • R 1 represents group represented by Formula —V 1 —V 2 —V 3 (wherein, V 1 represents C 1-6 alkylene group that may have a substituent; V 2 represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6 represents a hydrogen atom, C 1-6 alkyl group that may have a substituent or C 3-8 cycloalkyl group that may have a substituent); V 3 represents a hydrogen atom, C 1-6 alkyl group that may have a substituent, C 2-6 alkenyl group that may have a substituent, C 2-6 alkynyl group that may have a substituent, C 3-8 cycl
  • R 7 and R 8 each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6 alkyl group that may have a substituent, C 3-8 cycloalkyl group that may have a substituent, C 1-6 alkoxy group that may have a substituent, C 1-6 alkylthio group that may have a substituent, formyl group, C 2-7 acyl group that may have a substituent, C 2-7 alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2 (wherein, V d1 and V d2 each independently represent a hydrogen atom or C 1-6 alkyl group that may have a substituent); W 1 and W 2 each independently represent a carbon atom or a nitrogen atom that may have a substituent); R 3 and R 4 each independently represent a hydrogen atom, C 1-6 alkyl group that may have a substituent, C 2-6 alkeny
  • the present invention preferably relates to the followings.
  • a pharmaceutical composition comprising a combination of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof and imatinib.
  • a kit comprising: (a) at least one selected from the group consisting of a package, an instruction and an attached document describing combined use of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof and imatinib; and (b) a pharmaceutical composition comprising 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof.
  • a kit comprising a set of a formulation containing 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof and a formulation containing imatinib.
  • a pharmaceutical composition comprising 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof which is administered to a patient together with imatinib.
  • a method for treating cancer comprising administering an effective amount of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, a pharmacologically acceptable salt thereof or a solvate thereof and an effective amount of imatinib to a patient.
  • a pharmaceutical composition comprising a combination of a compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof and a c-kit inhibitor is provided, which can be used for treating cancer.
  • FIG. 1 shows the combined effect of a VEGF receptor kinase inhibitor and a c-kit inhibitor in a human cancer cell line subcutaneous xenograft model.
  • Compound A refers to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and
  • Compound B refers to imatinib.
  • FIG. 2 shows the combined effect of a VEGF receptor kinase inhibitor and a c-kit inhibitor in a human cancer cell line subcutaneous xenograft model.
  • Compound A refers to 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and Compound B refers to imatinib.
  • a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a halogen atom include a fluorine atom and a chlorine atom.
  • C 1-6 alkyl group refers to linear or branched alkyl group with a carbon number of 1-6, and specific examples include methyl group, ethyl group, 1-propyl group (n-propyl group), 2-propyl group (i-propyl group), 2-methyl-1-propyl group (i-butyl group), 2-methyl-2-propyl group (t-butyl group), 1-butyl group (n-butyl group), 2-butyl group (s-butyl group), 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-1-butyl group, 3-methyl-1-butyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 2,2-dimethyl-1-propyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-1-pentyl group, 3-methyl-1-pentyl group, 4-methyl-1-pentyl group, 2-methyl-2
  • C 1-6 alkyl group examples include methyl group, ethyl group, 1-propyl group, 2-propyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-butyl group and 2-butyl group.
  • C 1-6 alkylene group refers to divalent group derived from the “C 1-6 alkyl group” defined above by removing any one hydrogen atom therefrom, and specific examples include methylene group, 1,2-ethylene group, 1,1-ethylene group, 1,3-propylene group, tetramethylene group, pentamethylene group and hexamethylene group.
  • C 2-6 alkenyl group refers to linear or branched alkenyl group having one double bond and a carbon number of 2-6, and specific examples include ethenyl group (vinyl group), 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, pentenyl group and hexenyl group.
  • C 2-6 alkynyl group refers to linear or branched alkynyl group having one triple bond and a carbon number of 2-6, and specific examples include ethinyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group and hexynyl group.
  • C 3-8 cycloalkyl group refers to monocyclic or bicyclic saturated aliphatic hydrocarbon group with a carbon number of 3-8, and specific examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, bicyclo[2.1.0]pentyl group, bicyclo[3.1.0]hexyl group, bicyclo[2.1.1]hexyl group, bicyclo[4.1.0]heptyl group, bicyclo[2.2.1]heptyl group (norbornyl group), bicyclo[3.3.0]octyl group, bicyclo[3.2.1]octyl group and bicyclo[2.2.2]octyl group.
  • C 3-8 cycloalkyl group include cyclopropyl group, cyclobutyl group and cyclopentyl group.
  • C 6-10 aryl group refers to aromatic hydrocarbon cyclic group with a carbon number of 6-10, and specific examples include phenyl group, 1-naphthyl group, 2-naphthyl group, indenyl group and azulenyl group.
  • C 6-10 aryl group includes phenyl group.
  • a heteroatom refers to a nitrogen atom, an oxygen atom or a sulfur atom.
  • 5-10-membered heteroaryl group refers to aromatic cyclic group having 5-10 atoms forming the ring and 1-5 heteroatoms included in the atom forming the ring, and specific examples include furyl group, thienyl group, pyrrolyl group, imidazolyl group, triazolyl group, tetrazolyl group, thiazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, isothiazolyl group, furazanyl group, thiadiazolyl group, oxadiazolyl group, pyridyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, triazinyl group, purinyl group, pteridinyl group, quinolyl group, isoquinolyl group, naphthridinyl group, quinoxalinyl group, cinnolinyl group, quina
  • “5-10-membered heteroaryl group” include furyl group, thienyl group, pyrrolyl group, imidazolyl group, thiazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, isothiazolyl group, pyridyl group and pyrimidinyl group.
  • (1) has 3-10 atoms forming the ring
  • (3) may include 1-2 double bonds in the ring
  • (4) may have 1-3 carbonyl group, sulfinyl group or sulfonyl group in the ring;
  • (5) is nonaromatic monocyclic or bicyclic group.
  • the nitrogen atom may have a binding hand.
  • Specific examples include aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, azepanyl group, azocanyl group, piperazinyl group, diazepanyl group, diazocanyl group, diazabicyclo[2.2.1]heptyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxothiomorpholinyl group, oxiranyl group, oxetanyl group, tetrahydrofuryl group, dioxoranyl group, tetrahydropyranyl group, dioxanyl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, oxazolidinyl group and thi
  • “3-10-membered nonaromatic heterocyclic group” include aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, azepanyl group, piperazinyl group, diazepanyl group, morpholinyl group, thiomorpholinyl group, 1,1-dioxothiomorpholinyl group, tetrahydrofuryl group and tetrahydropyranyl group.
  • C 1-6 alkoxy group refers to group in which an oxygen atom is bound to the terminal of “C 1-6 alkyl group” defined above, and specific examples include methoxy group, ethoxy group, 1-propoxy group (n-propoxy group), 2-propoxy group (i-propoxy group), 2-methyl-1-propoxy group (i-butoxy group), 2-methyl-2-propoxy group (t-butoxy group), 1-butoxy group (n-butoxy group), 2-butoxy group (s-butoxy group), 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methyl-1-butoxy group, 3-methyl-1-butoxy group, 2-methyl-2-butoxy group, 3-methyl-2-butoxy group, 2,2-dimethyl-1-propoxy group, 1-hexyloxy group, 2-hexyloxy group, 3-hexyloxy group, 2-methyl-1-pentyloxy group, 3-methyl-1-pentyloxy group, 4-methyl-1-pentyloxy group, 2-methyl-2-
  • C 1-6 alkoxy group examples include methoxy group, ethoxy group, 1-propoxy group, 2-propoxy group, 2-methyl-1-propoxy group, 2-methyl-2-propoxy group, 1-butoxy group and 2-butoxy group.
  • C 1-6 alkylthio group refers to group in which a sulfur atom is bound to the terminal of “C 1-6 alkyl group” defined above, and specific examples include methylthio group, ethylthio group, 1-propylthio group (n-propylthio group), 2-propylthio group (i-propylthio group), 2-methyl-1-propylthio group (i-butylthio group), 2-methyl-2-propylthio group (t-butylthio group), 1-butylthio group (n-butylthio group), 2-butylthio group (s-butylthio group), 1-pentylthio group, 2-pentylthio group, 3-pentylthio group, 2-methyl-1-butylthio group, 3-methyl-1-butylthio group, 2-methyl-2-butylthio group, 3-methyl-2-butylthio group, 2,2-dimethyl-1-propylthio group,
  • C 1-6 alkylthio group examples include methylthio group, ethylthio group, 1-propylthio group (n-propylthio group), 2-propylthio group (i-propylthio group), 2-methyl-1-propylthio group (i-butylthio group), 2-methyl-2-propylthio group (t-butylthio group), 1-butylthio group (n-butylthio group) and 2-butylthio group (s-butylthio group).
  • C 3-8 cycloalkoxy group refers to group in which an oxygen atom is bound to the terminal of “C 3-8 cycloalkyl group” defined above, and specific examples include cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group, bicyclo[2.1.0]pentyloxy group, bicyclo[3.1.0]hexyloxy group, bicyclo[2.1.1]hexyloxy group, bicyclo[4.1.0]heptyloxy group, bicyclo[2.2.1]heptyloxy group (norbornyloxy group), bicyclo[3.3.0]octyloxy group, bicyclo[3.2.1]octyloxy group and bicyclo[2.2.2]octyloxy group.
  • C 3-8 cycloalkoxy group include cyclopropoxy group, cyclobutoxy group and cyclopentyloxy group.
  • “mono-C 1-6 alkylamino group” refers to group in which a hydrogen atom in amino group is substituted with “C 1-6 alkyl group” defined above, and specific examples include methylamino group, ethylamino group, 1-propylamino group (n-propylamino group), 2-propylamino group (i-propylamino group), 2-methyl-1-propylamino group (i-butylamino group), 2-methyl-2-propylamino group (t-butylamino group), 1-butylamino group (n-butylamino group), 2-butylamino group (s-butylamino group), 1-pentylamino group, 2-pentylamino group, 3-pentylamino group, 2-methyl-1-butylamino group, 3-methyl-1-butylamino group, 2-methyl-2-butylamino group, 3-methyl-2-butylamino group, 2,2-dimethyl-1-propy
  • di-C 1-6 alkylamino group refers to group in which two hydrogen atoms in amino group are substituted with identical or different “C 1-6 alkyl group” defined above, and specific examples include N,N-dimethylamino group, N,N-diethylamino group, N,N-di-n-propylamino group, N,N-di-i-propylamino group, N,N-di-n-butylamino group, N,N-di-i-butylamino group, N,N-di-s-butylamino group, N,N-di-t-butylamino group, N-ethyl-N-methylamino group, N-n-propyl-N-methylamino group, N-i-propyl-N-methylamino group, N-n-butyl-N-methylamino group, N-i-butyl-N-methylamino group, N-i-butyl
  • C 2-7 acyl group refers to carbonyl group bound with “C 1-6 alkyl group” defined above, and specific examples include acetyl group, propionyl group, isopropionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group and pivaloyl group.
  • C 2-7 alkoxycarbonyl group refers to carbonyl group bound with “C 1-6 alkoxy group” defined above, and specific examples include methoxycarbonyl group, ethoxycarbonyl group, 1-propyloxycarbonyl group, 2-propyloxycarbonyl group and 2-methyl-2-propoxy group.
  • “that may have a substituent” means “that may have one or more substituents in any combination at substitutable positions”, and specific examples include a halogen atom, hydroxyl group, thiol group, nitro group, cyano group, formyl group, carboxyl group, amino group, silyl group, methanesulfonyl group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, C 6-10 aryl group, 5-10-membered heteroaryl group, 3-10-membered nonaromatic heterocyclic group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-8 cycloalkoxy group, mono-C 1-6 alkylamino group, di-C 16 alkylamino group, C 2-7 acyl group and C 2-7 alkoxycarbonyl group.
  • C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, C 6-10 aryl group, 5-10-membered heteroaryl group, 3-10-membered nonaromatic heterocyclic group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-8 cycloalkoxy group, mono-C 1-6 alkylamino group, di-C 1-6 alkylamino group, C 2-7 acyl group and C 2-7 alkoxycarbonyl group may each independently have 1-3 groups selected from the group consisting from the following substituent groups.
  • R 1 represents group represented by Formula —V 1 —V 2 —V 3 (wherein, V 1 represents C 1-6 alkylene group that may have a substituent; V 2 represents a single bond, an oxygen atom, a sulfur atom, carbonyl group, sulfinyl group, sulfonyl group, group represented by Formula —CONR 6 —, group represented by Formula —SO 2 NR 6 —, group represented by Formula —NR 6 SO 2 —, group represented by Formula —NR 6 CO— or group represented by Formula —NR 6 — (wherein, R 6 represents a hydrogen atom, C 1-6 alkyl group that may have a substituent or C 3-8 cycloalkyl group that may have a substituent); V 3 represents a hydrogen atom, C 1-6 alkyl group that may have a substituent, C 2-6 alkenyl group that may have a substituent, C 2-6 alkynyl group that may have a substituent, C 3-8 cycloalky
  • R 1 includes C 1-6 alkyl group.
  • R 1 may have a substituent selected from 3-10-membered nonaromatic heterocyclic group which may have C 1-6 alkyl group, hydroxyl group, C 1-6 alkoxy group, amino group, mono-C 1-6 alkylamino group and di-C 1-6 alkylamino group.
  • R 1 More preferable examples of R 1 include methyl group and group represented by any one of Formulae
  • R a3 represents methyl group
  • R a1 represents a hydrogen atom or hydroxyl group
  • R a2 represents methoxy group, ethoxy group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group, dimethylamino group or diethylamino group).
  • R 1 include methyl group and 2-methoxyethyl group.
  • R 2 represents cyano group, C 1-6 alkoxy group that may have a substituent, carboxyl group, C 2-7 alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV a11 V a12 (wherein, V a11 represents a hydrogen atom, C 1-6 alkyl group that may have a substituent, C 2-6 alkenyl group that may have a substituent, C 2-6 alkynyl group that may have a substituent, C 3-8 cycloalkyl group that may have a substituent, C 6-10 aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered nonaromatic heterocyclic group that may have a substituent; V a12 represents a hydrogen atom, C 1-6 alkyl group that may have a substituent, C 2-6 alkenyl group that may have a substituent, C 2-6 alkynyl group that may have a substitu
  • R 2 include cyano group or group represented by Formula —CONV a11 V a12 (wherein, V a11 and V a12 have the same meaning as defined above).
  • R 2 include cyano group or group represented by Formula —CONHV a16 (wherein, V a16 represents a hydrogen atom, C 1-6 alkyl group, C 3-8 cycloalkyl group, C 1-6 alkoxy group or C 3-8 cycloalkoxy group, where V a16 may have a substituent selected from a halogen atom, cyano group, hydroxyl group and C 1-6 alkoxy group).
  • R 2 includes group represented by Formula —CONHV a17 (wherein, V a17 represents a hydrogen atom, C 1-6 alkyl group or C 1-6 alkoxy group).
  • R 2 include group represented by Formula —CONHV a18 (wherein, V a18 represents a hydrogen atom, methyl group or methoxy group).
  • Y 1 represents group represented by Formula
  • R 7 and R 8 each independently represent a hydrogen atom, a halogen atom, cyano group, nitro group, amino group, C 1-6 alkyl group that may have a substituent, C 3-8 cycloalkyl group that may have a substituent, C 1-6 alkoxy group that may have a substituent, C 1-6 alkylthio group that may have a substituent, formyl group, C 2-7 acyl group that may have a substituent, C 2-7 alkoxycarbonyl group that may have a substituent or group represented by Formula —CONV d1 V d2 (wherein, V d1 and V d2 each independently represent a hydrogen atom or C 1-6 alkyl group that may have a substituent); and W 1 and W 2 each independently represent a carbon atom or a nitrogen atom that may have a substituent).
  • a preferable example of Y 1 includes group represented by Formula
  • R 71 represents a hydrogen atom or a halogen atom
  • R 3 and R 4 each independently represent a hydrogen atom, C 1-6 alkyl group that may have a substituent, C 2-6 alkenyl group that may have a substituent, C 2-6 alkynyl group that may have a substituent, C 3-8 cycloalkyl group that may have a substituent, C 2-7 acyl group that may have a substituent or C 2-7 alkoxycarbonyl group that may have a substituent.
  • R 3 and R 4 includes a hydrogen atom.
  • R 5 represents a hydrogen atom, C 1-6 alkyl group that may have a substituent, C 2-6 alkenyl group that may have a substituent, C 2-6 alkynyl group that may have a substituent, C 3-8 cycloalkyl group that may have a substituent, C 6-10 aryl group that may have a substituent, 5-10-membered heteroaryl group that may have a substituent or 3-10-membered nonaromatic heterocyclic group that may have a substituent.
  • R 5 include a hydrogen atom, C 1-6 alkyl group, C 3-8 cycloalkyl group and C 6-10 aryl group (where R 5 may have a substituent selected from a halogen atom and methanesulfonyl group).
  • R 5 More preferable examples of R 5 include methyl group, ethyl group or cyclopropyl group.
  • More preferable examples of the compound represented by Formula (I) further include:
  • a still more preferable example of the compound represented by Formula (I) further includes 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (see Formula (II)).
  • the most preferable example of the compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof includes methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.
  • the compound represented by Formula (I) can be produced by a known method, for example, by methods described in International publication No. 02/32872 pamphlet (WO02/32872) and International publication No. 2005/063713 pamphlet (WO2005/063713).
  • examples of the c-kit inhibitor include:
  • Imatinib, SU5416, SU6668, SU11248, KRN633, PTK787/ZK222584, KRN951, AZD2171, AG013736, BAY 43-9006, AEE-788, PD180970, PD173955, MLN518 and BMS-354825 can be produced by a known method, for example, by methods described in the respective documents.
  • imatinib is available by purchasing GlivecTM from Novartis Pharma K.K.
  • the compound represented by Formula (I) and/or the c-kit inhibitor may form a pharmacologically acceptable salt with acid or base.
  • the compound represented by Formula (I) and/or the c-kit inhibitor of the invention also comprises such pharmacologically acceptable salts.
  • salts formed with acid include inorganic acid salts such as hydrochloride, hydrobromate, sulfate and phosphate, and organic acid salts such as formic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, tartaric acid, stearic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid.
  • salts formed with base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, organic base salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N,N′-dibenzyl ethylenediamine, arginine and lysine and ammonium salt.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • organic base salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N,N′-dibenzyl ethylenediamine, arginine and lysine and ammonium salt.
  • the compound represented by Formula (I) and/or the c-kit inhibitor also comprises, if any, solvates and enantiomers thereof.
  • solvates include hydrates and nonhydrates, preferably hydrates.
  • solvents include water, alcohols (for example, methanol, ethanol, n-propanol) and dimethylformamide.
  • the compound represented by Formula (I) may be crystalline or amorphous. If a crystalline polymorph is present, it may be a single product of any one of the crystal forms or a mixture of such forms.
  • the compound of the invention and/or the c-kit inhibitor also comprises compounds that generate the compound represented by Formula (I) and/or the c-kit inhibitor by undergoing metabolism such as oxidation, reduction and hydrolysis in vivo.
  • an example of the c-kit inhibitor includes an anti-c-kit kinase antibody.
  • an anti-c-kit kinase antibody is an antibody that has affinity with c-kit kinase or a partial fragment thereof.
  • an anti-c-kit kinase antibody is a neutralizing antibody that recognizes and binds with c-kit kinase to inhibit the vascular endothelial cell growth activity of c-kit kinase.
  • an anti-c-kit kinase antibody is, for example, a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a single-chain antibody (scFV) (Huston et al. (1988) Proc. Natl. Acad. Sci.
  • an anti-c-kit kinase antibody may be modified with polyethyleneglycol (PEG) or the like.
  • PEG polyethyleneglycol
  • an anti-c-kit kinase antibody may be produced as a fusion protein with ⁇ -galactosidase, MBP (maltose binding protein), GST (glutathione S-transferase), GFP (green fluorescence protein) or the like, which can be detected in an ELISA method or the like without using a secondary antibody.
  • An anti-c-kit kinase antibody may be modified by being labeled with biotin or the like such that the antibody can be collected using avidin, streptavidin or the like.
  • An anti-c-kit kinase antibody may be produced according to a conventional method using c-kit kinase or a partial fragment thereof (hereinafter, also referred to as a “polypeptide fragment of c-kit kinase”), or a cell expressing c-kit kinase or a partial fragment thereof as a sensitized antigen (“Current Protocols in Molecular Biology” (John Wiley & Sons (1987) Section 11.4-11.13)).
  • a polypeptide fragment of c-kit kinase may be a fusion protein with an Fc region, GST, MBP, GFP, AP (alkaline phosphatase) or the like.
  • a polyclonal antibody and a monoclonal antibody may be prepared according to a method known by those skilled in the art (Antibodies: A Laboratory Manual, E. Harlow and D. Lane, ed., Cold Spring Harbor Laboratory (Cold Spring Harbor, N.Y., 1988)).
  • a polyclonal antibody may be obtained, for example, by administering an antigen to a mammal such as a mouse, a rabbit or a rat, collecting blood from this mammal, and separating and purifying an antibody from the collected blood. Immune sensitization methods are known by those skilled in the art, and may be carried out, for example, by administering an antigen once or more. Furthermore, an antigen (a polypeptide fragment of c-kit kinase) may be used by dissolving it in an appropriate buffer such as a buffer containing a complete Freund's adjuvant or a generally used adjuvant such as aluminum hydroxide, although no adjuvant may be used depending on the administration route or conditions.
  • an antigen a polypeptide fragment of c-kit kinase
  • an antigen may be used by dissolving it in an appropriate buffer such as a buffer containing a complete Freund's adjuvant or a generally used adjuvant such as aluminum hydroxide, although no adjuvant may be used depending
  • Blood is taken from the mammal 1-2 months after the last immune sensitization, and separated and purified according to a conventional method such as centrifugation, precipitation using ammonium sulfate or polyethyleneglycol and various chromatographies, thereby obtaining a polyclonal antibody as a polyclonal antiserum.
  • An example of a method for producing a monoclonal antibody includes a hybridoma technique.
  • the hybridoma technique first sensitizes a mammal in the same manner as in the production of the polyclonal antibody.
  • partial blood collection is carried out appropriate days after the sensitization to determine the antibody titer by a known method such as ELISA method.
  • spleen is removed from the sensitized animal to obtain B cells.
  • the B cells are fused with myeloma cells by a common method to produce antibody-producing hybridomas.
  • the myeloma cells used are not particularly limited and known cells may be used.
  • the method for fusing the cells may be any method selected from methods known in the art such as Sendai virus technique, polyethyleneglycol technique and protoplast technique.
  • the obtained hybridomas are cultured for an appropriate period of time in an HAT medium (a medium containing hypoxanthine, aminopterin and thymidine) by a common method for hybridoma selection. Then, the antibody-producing hybridoma of interest may be screened and cloned.
  • HAT medium a medium containing hypoxanthine, aminopterin and thymidine
  • a known antibody detecting method such as ELISA method or radioimmunoassay method may be used as the screening method, and a method known in the art such as limiting dilution technique, FACS method or the like may be used as the cloning method.
  • the obtained hybridoma may be cultured in an appropriate culture solution, or may be intraperitoneally administered, for example, to a mouse that is compatible with the hybridoma.
  • the desired monoclonal antibody can be isolated and purified from the resulting culture solution or ascites by salt-out, ion-exchange chromatography, gel filtration, affinity chromatography or the like.
  • the present invention relates to a pharmaceutical composition, a kit, a method for treating cancer or the like characterized by combining a compound of the invention and a c-kit inhibitor.
  • the c-kit inhibitor is not particularly limited as long as it has an activity of inhibiting c-kit kinase.
  • the c-kit inhibitor include a c-kit kinase inhibitor and an anti-c-kit kinase antibody.
  • c-kit inhibitors include imatinib, SU5416, SU6668, SU11248, KRN633, PTK787/ZK222584, KRN951, AZD2171, AG013736, BAY 43-9006, AEE-788, PD180970, PD173955, MLN518 and BMS-354825, and more preferable example includes imatinib.
  • the phrase “in combination” refers to a combination for combined use of the compound, and includes both a form for concomitantly using separate substances upon administration and a form as a mixture.
  • the dosage form of the formulation included in the kit of the invention is not particularly limited as long as it contains the compound of the invention and/or the c-kit inhibitor.
  • the pharmaceutical composition and/or the kit of the invention is useful as a pharmaceutical composition and/or a kit for treating cancer.
  • the pharmaceutical composition and/or the kit of the invention may be used as a drug for treating cancer.
  • a drug for treating cancer comprises an antitumor drug, a drug for improving prognosis of cancer, a drug for preventing cancer recurrence, a drug for suppressing cancer metastasis and the like.
  • the effect of cancer treatment may be confirmed by observation of a x-ray picture, CT or the like, by histopathological diagnosis of biopsy, or from a tumor marker value.
  • the pharmaceutical composition and/or the kit of the invention may be administered to a mammal (e.g., human, rat, rabbit, sheep, pig, bovine, cat, dog, monkey, etc.).
  • a mammal e.g., human, rat, rabbit, sheep, pig, bovine, cat, dog, monkey, etc.
  • the types of cancer treated by the drug are not particularly limited and may include, for example, brain cancer, head&neck cancer, esophagus cancer, tongue cancer, lung cancer, breast cancer, pancreatic cancer, stomach cancer, small intestine cancer, duodenum cancer, colorectal cancer (colon cancer, rectal cancer), bladder cancer, kidney cancer, liver cancer, prostate cancer, uterus cancer, ovary cancer, thyroid gland cancer, gallbladder cancer, pharynx cancer, sarcoma (e.g., osteosarcoma, chondrosarcoma, Kaposi's sarcoma, myosarcoma, angiosarcoma, fibrosarcoma, etc.), leukemia (e.g., chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphatic leukemia (CLL) and acute lymphatic leukemia (ALL), lymphoma, multiple myeloma (MM), etc.) and melanoma.
  • the pharmaceutical composition and/or the kit of the invention may be used through oral or parental administration.
  • the given dose of the compound of the invention differs depending on the degree of the symptom, age, sex, weight and sensitivity difference of the patient, administration mode, administration period, administration interval, nature, prescription and the type of the pharmaceutical formulation, and the type of the active element.
  • the dose of the compound is 0.1-1000 mg/day, preferably 0.5-100 mg/day, more preferably 1-30 mg/day for an adult (weight 60 kg), which may be administered once to three times a day.
  • the given dose of the c-kit inhibitor is usually, but without limitation, 10-6000 mg/day, preferably 50-4000 mg/day, more preferably 50-2000 mg/day for an adult, which may be administered once to three times a day.
  • the given dose of the c-kit kinase inhibitor is usually, but without limitation, 10-6000 mg/day, preferably 50-4000 mg/day, more preferably 50-2000 mg/day for an adult, which may be administered once to three times a day.
  • the given dose of an anti-c-kit kinase antibody is usually, but without limitation, 1-6000 mg/day, preferably 10-2000 mg/day, more preferably 10-1000 mg/day for an adult, which may be administered once a day or a week.
  • the amount of the compound of the invention used is not particularly limited and may differ according to the individual combination with the c-kit inhibitor, for example, it may be about 0.01-100 times (weight ratio) the amount of the c-kit inhibitor. More preferably, it is about 0.1-10 times (weight ratio) the amount of the c-kit inhibitor.
  • the pharmaceutical composition of the invention may be made into various forms, for example, into solid oral formulations, injectable solution or the like.
  • each of the compound and the c-kit inhibitor contained in the kit of the invention may individually be made into solid oral formulations, injectable solution or the like.
  • an excipient In order to prepare a solid oral formulation, an excipient, and if necessary, a binder, disintegrant, lubricant, colorant, a flavoring agent and the like are added to the principal agent, and then made into a tablet, a coated tablet, granule, fine granule, dispersant, a capsule or the like according to a conventional method.
  • lactose, cornstarch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide or the like may be used as the excipient; for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl cellulose or the like may be used as the binder; for example, magnesium stearate, talc, silica or the like may be used as the lubricant; those that are allowed to be added to drugs may be used as the colorant; and for example, cocoa powder, menthol, aromatic acid, peppermint oil, camphor, cinnamon powder or the like may be used as the flavoring agent.
  • these tablets and granule may be coated appropriately with sugar coating, gelatin coating or else.
  • the principal agent may be added with a pH adjuster, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonicity agent, a preservative or the like, and may be made into an intravenously, subcutaneously or intramuscularly injectable solution according to a conventional method. If necessary, the solution may be made into a lyophilized form by a conventional technique.
  • suspending agent examples include methyl cellulose, Polysorbate 80, hydroxyethyl cellulose, gum arabic, powdered tragacanth, carboxy methyl cellulose sodium and polyoxyethylene sorbitan monolaurate.
  • solubilizing agent examples include polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotine acid amide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.
  • examples of the stabilizer include sodium sulfite and sodium metasulfite; examples of the preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
  • a formulation containing the compound of the invention and a formulation containing the c-kit inhibitor may be mixed together or may be separately accommodated and packed together.
  • the order of the formulations above is not particularly limited and they may be administered simultaneously or one may be administered after the other.
  • the pharmaceutical composition and/or the kit of the invention may also contain a package, an instruction, an attached document or the like.
  • the package, the instruction, the attached document or the like may include description of a combination employed for using substances, and description of usage and dosage in the case of administering separate substances in combination or in the case of administering them in a form of a mixture.
  • the usage and dosage may be described referring to the related description above.
  • the kit of the invention may also comprise: (a) at least one selected from the group consisting of a package, an instruction and an attached document describing combined use of the compound of the invention and the c-kit inhibitor; and (b) a pharmaceutical composition containing the compound of the invention.
  • the kit is useful for treating cancer.
  • the pharmaceutical composition containing the compound of the invention is useful for treating cancer.
  • the package, the instruction, the attached document or the like may include the description of combined use of the compound, and description of usage and dosage in the case of administering separate substances in combination upon administration or in the case of administering them in the form of a mixture. The usage and dosage may be described referring to the description of pharmaceutical composition and kit above.
  • the present invention also comprises use of a compound of the invention for producing a pharmaceutical composition in combination with a c-kit inhibitor.
  • the pharmaceutical composition is useful for treating cancer.
  • the present invention also comprises a method for preventing or treating cancer comprising simultaneously or separately administering a compound of the invention and a c-kit inhibitor to a patient.
  • a method for preventing or treating cancer comprising simultaneously or separately administering a compound of the invention and a c-kit inhibitor to a patient.
  • the route and the method for administering the compound of the invention and the c-kit inhibitor are not particularly limited and reference may be made to the description of the pharmaceutical composition of the invention above.
  • the present invention also comprises a pharmaceutical composition containing the compound of the invention which is simultaneously or separately administered with a c-kit inhibitor to a patient.
  • a pharmaceutical composition containing the compound of the invention which is simultaneously or separately administered with a c-kit inhibitor to a patient.
  • the route and the method for administering the compound of the invention and the c-kit inhibitor are not particularly limited and reference may be made to the description of the pharmaceutical composition of the invention above.
  • Human gastrointestinal stromal tumor cell line GIST882 (supplied by The Brigham and Women's Hospital, Inc.) was cultured in RPMI1640 (containing 10% FBS) in a 5% carbon dioxide incubator to about 80% confluence. Following cultivation, each cell was collected by trypsin-EDTA treatment according to a general method. Using a phosphate buffer containing 50% matrigel, 5 ⁇ 10 7 cells/mL suspension was prepared, and 0.2 mL each of the resulting cell suspension was subcutaneously transplanted into the flank of a nude mouse.
  • 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide 10 mg/kg or 30 mg/kg, once a day, for two weeks
  • imatinib 160 mg/kg, twice a day, for two weeks
  • 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide(methanesulfonate) was prepared based on the description of International publication No. 02/32872 pamphlet (WO02/32872).
  • imatinib was purchased from Novartis Pharma K.K. The major and minor axes of tumors were measured with Digimatic caliper (Mitsutoyo), and tumor volumes and relative tumor volumes were calculated according to the following formulae.
  • Tumor Volume (TV) Major axis of tumor (mm) ⁇ (Minor axis of tumor) 2 (mm 2 )/2
  • Relative Tumor Volume (RTV) Tumor volume on measurement day/Tumor volume on the first administration day
  • Table 1 shows antitumor effects obtained with 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (indicated as Compound A in Table 1) alone, imatinib alone and combined use of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and imatinib in human cancer cell line subcutaneous xenograft models. The first day of administration was considered Day 1.
  • Table 2 shows antitumor effects obtained with 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (indicated as Compound A in Table 2) alone, imatinib alone and combined use of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and imatinib in human cancer cell line subcutaneous xenograft models. The first day of administration was considered Day 1.
  • crystal (C) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter, also referred to as “crystal (C)”, which was produced according to the method described in Example 7 of WO2005/063713) and 192 g of light anhydrous silicic acid (antigelling agent sold under the trade name of AEROSILTM200, Nippon Aerosil) were mixed with 20 L Super Mixer, and then 1236 g of D-mannitol (excipient, Towa-Kasei), 720 g of crystalline cellulose (excipient sold under the trade name of Avicel PH101, Asahi Kasei) and 72 g of hydroxypropylcellulose (binder sold under the trade name of HPC-L.
  • crystal (C) which was produced according to the method described in Example 7 of WO2005/063713
  • the tablets were coated with a tablet coating machine using aqueous 10% Opadry yellow (OPADRY 03F42069 YELLOW, Colorcon Japan) solution as a coating solution, thereby obtaining coated tablets with a total mass of 105 mg per tablet.
  • aqueous 10% Opadry yellow OPDRY 03F42069 YELLOW, Colorcon Japan
  • This granulated body was dried in a rack dryer (60° C.), and then size-regulated using PowerMILL to obtain granules. Together with the granules, 120 g of croscarmellose sodium (disintegrant sold under the trade name of Ac-Di-Sol, FMC International Inc.) and 36 g of sodium stearyl fumarate (lubricant, JRS Pharma LP) were placed in a 20 L tumbler mixer and mixed together, and molded with a tablet machine to obtain tablets with a total mass of 400 mg per tablet.
  • croscarmellose sodium disintegrant sold under the trade name of Ac-Di-Sol, FMC International Inc.
  • lubricant lubricant
  • the tablets were coated with a tablet coating machine using aqueous 10% Opadry yellow (OPADRY 03F42069 YELLOW, Colorcon Japan) solution as a coating solution, thereby obtaining coated tablets with a total mass of 411 mg per tablet.
  • aqueous 10% Opadry yellow OPDRY 03F42069 YELLOW, Colorcon Japan
  • a pharmaceutical composition and/or kit comprising a combination of a compound represented by Formula (I), a pharmacologically acceptable salt thereof or a solvate thereof and a c-kit inhibitor, which can be used for treating cancer.

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